Studies on catalytic enantioselective total synthesis of caprazamycin B: Construction of the western zone

Article abstract of DOI:10.1021/jo301803h

We describe a simple and convenient synthesis of the western zone of caprazamycin B using two catalytic asymmetric reactions as key elements of our approach. Desymmetrization of 3-methylglutaric anhydride with the (S)-Ni ₂-(Schiff base) complex as a catalyst furnished the chiral hemiester, and a thioamide-aldol reaction with mesitylcopper, (R,R)-Ph-BPE, and 2,2,5,7,8-pentamethylchromanol as a catalyst furnished the β-hydroxy thioamide in good yield and enantioselectivity. On further transformation, the thioamide functionality was converted to the corresponding β-hydroxy ester. Finally, a convergent synthesis of the western zone of caprazamycin B was achieved by connecting the hemiester, the β-hydroxy ester, and the 2,3,4-tri-O-methyl-l-rhamnose fragments.

Full text of DOI:10.1021/jo301803h

Article
pubs.acs.org/joc
Studies on Catalytic Enantioselective Total Synthesis of
Caprazamycin B: Construction of the Western Zone
Purushothaman Gopinath, Takumi Watanabe,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: We describe a simple and convenient synthesis
of the western zone of caprazamycin B using two catalytic
asymmetric reactions as key elements of our approach.
Desymmetrization of 3-methylglutaric anhydride with the
(S)-Ni2-(Schiff base) complex as a catalyst furnished the chiral
hemiester, and a thioamide-aldol reaction with mesitylcopper,
(R,R)-Ph-BPE, and 2,2,5,7,8-pentamethylchromanol as a
catalyst furnished the β-hydroxy thioamide in good yield and enantioselectivity. On further transformation, the thioamide
functionality was converted to the corresponding β-hydroxy ester. Finally, a convergent synthesis of the western zone of
caprazamycin B was achieved by connecting the hemiester, the β-hydroxy ester, and the 2,3,4-tri-O-methyl-L-rhamnose
fragments.
NOESY, and its stereochemistry (including the absolute
structure) was determined by NMR spectroscopy and X-ray
crystallography of some of its degradation products.1d
Caprazamycin B has a 5′-β-O-amino-ribosyl-glycyluridine and
a N-methylated diazepanone moiety as characteristic structural
motifs similar to liposidomycins.2 However, unlike liposidomy-
cins, caprazamycin B has a 2,3,4-tri-O-methyl-L-rhamnose
moiety. Due to their structural similarity with liposidomycins,
caprazamycin B may also possess the same mode of action and
is also expected to be a translocase I inhibitor since MraY
translocase is a common target for 6′-N-alkyl-5′-β-O-amino-
ribosyl-C-glycyluridine class of antibiotics.1e
INTRODUCTION
■
Globally, tuberculosis (TB) is one of the most common
diseases responsible for human mortality, accounting for almost
2.5 million deaths annually. Although a number of drugs are
available for treatment, the bacterium causing the disease
continues to evolve and develop resistance against most
modern day drugs, thereby necessitating the search for new
anti-TB drugs with a different mode of action. Caprazamycin B,
a novel lipo-nucleoside antibiotic (Figure 1),1 was isolated from
Although Matsuda et al. reported the first synthesis of
caprazol (deacylated caprazamycin) and its derivatives,3 the
complete synthesis of caprazamycins remains challenging due
to the complex nature of the molecules and their multiple
stereogenic centers. Therefore, we attempted the first
enantioselective total synthesis of caprazamycin B. Herein we
report a catalytic asymmetric synthesis of the western zone of
caprazamycin B.
Figure 1. Structure of caprazamycin B.
RESULTS AND DISCUSSION
■
the culture broth of the actinomycete strain Streptomyces sp.
MK730-62F2 and shows excellent antimycobacterial activity in
vitro against drug-susceptible and multidrug-resistant Mycobac-
terium tuberculosis (M. tuberculosis) strains. The MIC values of
caprazamycin B were 3.13 μg/mL for M. tuberculosis H37Rv
strains and 6.25−12.5 μg/mL for drug-susceptible M. tuber-
culosis. Moreover, caprazamycin B showed good efficacy in a
murine TB model with no significant toxicity in mice that
received single and repeated dose and also in genotoxicity and
cyctotoxicity tests. Therefore, this molecule is considered as a
promising candidate for an anti-TB drug.1a
Our retrosynthetic strategy for synthesis of the western zone
(Scheme 1) involves two key asymmetric transformations,
namely, the thioamide-aldol reaction4 and desymmetrization of
3-methylglutaric anhydride5 previously developed by our group.
We first attempted to synthesize β-hydroxy carboxylic ester
via a direct catalytic asymmetric aldol reaction of 12-
methyltridecanal 16 with thioamides 2a and 2b using a soft
Lewis acid/hard Brønsted base cooperative catalyst system
comprising of mesitylcopper (Mes-Cu), (R,R)-Ph-BPE and
The planar structure of caprazamycin B was assigned on the
basis of 2D NMR experiments such as HMQC, HMBC, and
Received: August 27, 2012
Published: September 28, 2012
© 2012 American Chemical Society
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Scheme 1. Retrosynthetic Strategy of the Western Zone for the Synthesis of Caprazamycin B
a
Table 1. Optimization of the Thioamide-Aldol Reaction Conditions
b
entry
thioamide (equiv)
catalyst (mol %)
solvent
product
yield (%)
ee (%)
1
2
3
4
5
6
2a (1.2)
2a (1.2)
2a (1.2)
2a (2.0)
2a (2.0)
2a (2.0)
2a (2.0)
2b (4.0)
3
3
5
3
5
5
5
THF
DMF
DMF
DMF
DMF
4a
4a
4a
4a
4a
4a
4a
4b
80
78
84
83
80
85
85
87
93
48
66
65
70
THF/DMF (1:1)
THF/DMF (1:3)
THF/DMF (1:3)
>99
>99 (92)
d
c
7
c
8
5
71(69)
a
b
c
d
The reaction was performed using 0.20 mmol of 1. Yield based on 1H NMR using 1,1,2,2-tetrachloroethane as the standard. Isolated yield. This
reaction was also performed on a 1.0 g scale.
Scheme 2. Desymmetrization of 3-Methylglutaric Anhydride with Methanol Followed by Esterification with Thioamide-Aldol
Product 4a
2,2,5,7,8-pentamethylchromanol 3 (second generation catalys-
t).4a Chemoselective activation of thioamide by a soft−soft
interaction between the copper and sulfur atoms formed the
corresponding enolate even in the presence of aldehyde 1,
which then underwent aldol reaction to form the corresponding
β-hydroxy thioamide derivative 4.
A conventional aldol reaction using a chiral organocatalyst
cannot be used in this case as the cross aldol reaction with
acetaldehyde and another simple α-methylene aldehyde (12-
methyltridecanal in this case) is seldom reported in the
literature other than for enzyme-catalyzed reactions. Under the
standard reaction conditions with THF as the solvent,
diallylthioamide 2a7 gave 4a in 80% yield and with good
enantioselectivity (Table 1, entry 1), whereas with DMF as the
solvent we obtained 4a in good enantioselectivity and moderate
yield (48% yield, 84% ee, Table 1, entry 2). Hence in the next
step, the equivalents of thioamide and catalyst loading were
increased to improve the chemical yield using DMF as the
solvent (Table 1, entries 3 and 4), but the chemical yield
improved to only 70% and the enantioselectivity changed little.
Finally using a mixture of THF/DMF (1:3) as the solvent with
2 equiv of thioamide and 5 mol % catalyst loading, the reaction
produced an almost quantitative yield of the thioamide-aldol
product 4a with good enantioselectivity (92% isolated yield and
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Scheme 3. Synthesis of β-Hydroxy Benzyl Ester 13
Scheme 4. Esterification of Chiral Hemiester (S)-6 with β-Hydroxy Benzyl Ester 13
87% ee, Table 1, entry 7). On the other hand, with
dimethylthioamide 2b, the thioamide-aldol product 4b was
obtained in modest yield (69%), but with better enantiose-
lectivity (93% ee) under similar reaction conditions with 4
equiv of thioamide (Table 1, entry 8).
In the next step, we attempted the asymmetric desymmet-
rization of 3-methylglutaric anhydride developed by our group
previously.5 Treatment of 3-methylglutaric anhydride 5 with
MeOH at −20 °C for 15 h in the presence of the
homodinuclear (R)-Ni2-(Schiff base) complex8 (5 mol %) as
a catalyst gave the corresponding chiral hemiester (S)-6 in 91%
yield and 94% ee. Reaction of hemiester (S)-6 with thioamide-
aldol product 4a under a variety of esterification conditions
such as SOCl2/pyridine/DMAP, Yamaguchi esterification,
PPh3/NBS, and DCC/DMAP failed to give the expected
ester (Scheme 2).
We next attempted to convert the thioamide functionality to
a thioester (Scheme 3). Treatment of compound 4a and 4b
with TBDPSOTf and 2,6-lutidine led to the corresponding
TBDPS-protected thioamide-aldol adducts 7a and 7b in 92%
and 95% yield, respectively. Then, conditions for a one-pot
conversion of thioamide to thioester using MeI/TFA/H2O7
were applied to compound 7a. However, silanol (TBDPSOH)
was expelled from the molecule, and a mixture of cis- and trans-
isomers of unsaturated thioesters was obtained. Hence, we
decided to convert the thioamide functionality to a carboxylic
ester to avoid the facile β-elimination.
Accordingly, 7a and 7b were subjected to a sequential one-
pot conversion of thioamide to aldehyde 9 using MeOTf to
activate the thioamide functionality by the formation of
methylthioiminium salt 8, which was then directly treated
with LiAlH(OtBu)3 to give aldehyde 9.4b Since 9 was also prone
to β-elimination upon desilylation to give an enal 10, the formyl
group of 9 had to be transformed to an ester functionality
before removal of the TBDPS group. Aldehyde 9 was converted
to carboxylic acid 11 by Pinnick oxidation (NaOCl2/
NaH2PO4/2-methyl-2-butene) in 92% yield, which was
followed by the DCC coupling with BnOH to afford benzyl
ester 12 in 84% yield. Then, compound 12 was exposed to
TBAF to cleave the silyl ether. However, the corresponding
desilylated product was obtained in less than 50% along with
the remaining starting material and other side products.
Prolonged reaction time and addition of excess amount of
TBAF did not show any beneficial effects. Hence, the
deprotection was carried out with 70% HF·pyridine to give
the desired β-hydroxy benzyl ester 13 in 75% yield. With the
two chiral fragments in hand, the coupling of these compounds
and the succeeding introduction of the rhamnose part were
examined in the next stage.
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Scheme 5. Synthesis of 2,3,4-Tri-O-methyl-L-rhamnose 17
Scheme 6. Esterification of 2,3,4-Tri-O-methyl-L-rhamnose 17 Followed by Selective Deprotection of Methyl Ester
Scheme 7. Desymmetrization of 3-Methylglutaric Anhydride 5 with Benzyl Alcohol
Scheme 8. Construction of the Western Zone of Caprazamycin B (22)
Applying the Yamaguchi’s protocol (2,4,6-trichlorobenzoyl
chloride, Et3N, and DMAP) to chiral hemiester (S)-6 and β-
hydroxy benzyl ester 13 afforded the expected ester 14 in 65%
yield. However, selective deprotection of the methyl ester in the
next step using LiI in refluxing AcOEt was unsuccessful, and a
complex mixture containing mono- and dicarboxylic acids along
with the remaining starting material was obtained instead
(Scheme 4).
Then, we decided to switch the order of the coupling
reactions of the three components: coupling of the chiral
hemiester and rhamnose subunits was carried out prior to the
introduction of the β-hydroxy ester moiety. Toward this end,
2,3,4-tri-O-methyl-L-rhamnose 17 was synthesized from mono-
hydrate of L-rhamnose 15 in two steps (Scheme 5).9 The
starting material 15 was treated with MeI and powdered KOH
in DMSO to afford the corresponding 1,2,3,4-tetra-O-methyl-L-
rhamnose 16. Acidic hydrolysis of the glycosyl bond of this
compound gave the corresponding 2,3,4-tri-O-methyl-L-rham-
nose 17.
Acylation of 17 with the carboxylate counterpart (R)-6,
which was obtained using the (S)-Ni2-(Schiff base) complex in
the asymmetric desymmetrization of 3-methylglutaric anhy-
dride, proceeded effectively to give a mixture of 18a and 18b.
However, selective deprotection of methyl ester in the presence
of the glycosyl ester linkage was very difficult (Scheme 6). This
disappointing result led us to take advantage of chiral
monobenzyl ester of 3-methylglutaric acid, which is expected
to be deprotected by hydrogenolysis without affecting the
glycosyl ester moiety.
As shown in Scheme 7, BnOH (10 equiv) was treated with 3-
methylglutaric anhydride 5 at 0 °C for 48 h in the presence of
the homodinuclear (S)-Ni2-(Schiff base)8 complex (5 mol %)
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was then extracted with AcOEt. The combined organic layers were
washed with brine and dried over Na2SO4. The filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (eluent n-hexane/
AcOEt) to give compound 4a (67.6 mg, 92%) as a pale yellow oil.
Enantiomeric excess was determined by chiral HPLC analysis. IR
(neat) ν 3406, 2924, 2853, 1642, 1490, 1409 cm−1; 1H NMR (CDCl3)
δ 5.86−5.66 (m, 2H), 5.23−5.06 (m, 4H), 4.65−4.49 (m, 2H), 4.20−
4.03 (m, 4H), 2.70 (dd, J = 16.0 Hz, 1.2 Hz, 1H), 2.56 (dd, J = 16.0
Hz, 9.6 Hz, 1H), 1.53−1.18 (m, 19H), 1.10−1.05 (m, 1H), 0.79 (d, J
= 6.8 Hz, 6H); 13C NMR (CDCl3) δ 202.9, 130.5, 130.4, 118.6, 117.8,
69.9, 55.6, 52.8, 47.9, 39.0, 36.6, 29.9, 29.6, 29.5, 27.9, 27.3, 25.6, 22.6;
[α]23D +46.8 (c 0.21, CHCl3, 87% ee sample); HRMS (ESI-Orbitrap)
calcd for C22H41NNaOS m/z 390.2801 [M + Na]+, found 390.2802;
HPLC (Daicel CHIRALCEL OD-H, ϕ 0.46 cm × 25 cm, detection
254 nm, n-hexane/iPrOH = 19/1, flow rate = 0.5 mL/min) tR = 9.3
min (minor), tR = 11.0 min (major). [Note: The above procedure was
used for entries 1−6 in Table 1 with the corresponding thioamide
equivalents and solvents shown in the table.]
as a catalyst. As the result, the corresponding chiral hemiester
19 was obtained in 87% yield and 88% ee. The
enantioselectivity is only slightly lower than that observed in
the case of methanolysis.
After successfully synthesizing the three key synthetic
intermediates for synthesis of the western zone, we attempted
to connect these intermediates. First, we performed a
Yamaguchi esterification reaction between chiral glutaric acid
monobenzyl ester 19 and 2,3,4-tri-O-methyl-L-rhamnose 17 in
the presence of 2,4,6-trichlorobenzoyl chloride, Et3N, and
DMAP to give the corresponding diester with an α:β anomeric
ratio of 95:5 (20a and 20b in Scheme 8, respectively). After
purification, the desired α-anomer 20a was obtained in 70%
isolated yield. The structure of 20a was confirmed by NOE
experiments (see Supporting Information). In the next step,
hydrogenolysis of the benzyl ester of 20a was achieved using
10% Pd/C under a hydrogen atmosphere to give the
corresponding carboxylic acid 21 in 98% yield. Finally, we
attempted the esterification reaction of carboxylic acid 21 with
β-hydroxy benzyl ester 13 using the Yamaguchi esterification
conditions to give the corresponding triester 22 in 90% yield as
a single diastereomer (western zone of caprazamycin B)
(Scheme 8).
(S)-3-Hydroxy-N,N,14-trimethylpentadecanethioamide (4b).
To a flame-dried test tube equipped with a magnetic stirring bar and a
3-way glass stopcock were added (R,R)-Ph-BPE/mesitylcopper/
2,2,5,7,8-pentamethylchromanol solution (0.1 M/THF, 100 μL,
0.010 mmol, 5 mol %), dry DMF and THF (3:1) (2 mL),
dimethylthioamide (2b) (82.4 mg, 0.80 mmol), and aldehyde 1
(51.2 μL, 0.2 mmol) under Ar at −60 °C. After 40 h of stirring at that
temperature, 0.1 M AcOH (100 μL), saturated aq NH4Cl, and
bipyridine (3.0 mg) were added to the reaction mixture (for the
dissociation of product from copper complex). The reaction mixture
was then stirred at room temperature for 15 min. The aqueous layer
was then extracted with AcOEt. The combined organic layers were
washed with brine and dried over Na2SO4. The filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (eluent n-hexane/
AcOEt) to give compound 4b (43.5 mg, 69%) as a colorless oil.
Enantiomeric excess was determined by chiral HPLC analysis. IR
CONCLUSION
■
We achieved a convergent synthesis of the western zone of
caprazamycin B in a chiral fashion using a catalytic asymmetric
desymmetrization reaction and a thioamide-aldol reaction as
key steps with good yield and enantioselectivity. Further studies
oriented toward the catalytic enantioselective total synthesis of
caprazamycin B are underway.
1
(neat) ν 3433, 2924, 2853, 1643, 1522 cm−1; H NMR (CDCl3) δ
EXPERIMENTAL SECTION
■
4.26 (d, J = 2.0 Hz, 1H), 4.17−4.15 (m, 1H), 3.50 (s, 3H), 3.31 (s,
3H), 2.72 (dd, J = 16 Hz, 0.8 Hz, 1H), 2.59 (dd, J = 16 Hz, 5.6 Hz,
1H), 1.63−1.26 (m, 19H), 1.15−1.12 (m, 2H), 0.86 (d, J = 6.2 Hz,
6H); 13C NMR (CDCl3) δ 201.6, 69.4, 48.3, 44.3, 41.6, 39.0, 36.5,
All the reactions were performed in oven-dried round-bottom flasks
and test tubes with a Teflon-coated magnetic stirring bar unless
otherwise noted. Air- and moisture-sensitive liquids were transferred
via a gastight syringe and a stainless-steel needle. All workup and
purification procedures were carried out with reagent-grade solvents
under ambient atmosphere. Flash chromatography was performed
using silica gel 60 (230−400 mesh). Infrared (IR) spectra were
recorded on a Fourier transform infrared spectrophotometer. NMR
was recorded on a 400 MHz spectrometer. For 1H NMR (400 MHz),
chemical shifts for proton are reported in parts per million downfield
from tetramethylsilane and are referenced to residual protium in the
NMR solvent (CDCl3, δ 7.26 ppm). For 13C NMR (100 MHz),
chemical shifts were reported in the scale relative to NMR solvent
(CDCl3, δ 77.0 ppm) as an internal reference. NMR data are reported
as follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd:
doublet of doublets, t: triplet, m: multiplet), coupling constant (Hz),
and integration. Optical rotation was measured using a 2 mL cell with
a 1.0 dm path length on a polarimeter. High-resolution mass spectra
(ESI-Orbitrap) were measured on an ESIMS instrument equipped
with an Orbitrap detector. HPLC analysis was conducted on a HPLC
system equipped with chiral-stationary-phase columns (ϕ 0.46 cm ×
25 cm).
29.9, 29.7, 29.64, 29.59, 27.9, 27.4, 26.7, 22.6; [α]23 +81.0 (c 0.43,
D
CHCl3, 93% ee sample); HRMS (ESI-Orbitrap) calcd for
C18H37NNaOS m/z 338.2488 [M + Na]+, found 338.2494; HPLC
(Daicel CHIRALCEL OD-H, ϕ 0.46 cm × 25 cm, detection 254 nm,
n-hexane/iPrOH = 19/1, flow rate = 1.0 mL/min) tR = 8.1 min
(minor), tR = 11.6 min (major).
(S)-5-Methoxy-3-methyl-5-oxopentanoic Acid ((S)-6). To an
oven-dried glass test tube equipped with a magnetic stirring bar was
charged 3-methylglutaric anhydride 5 (25.6 mg, 0.20 mmol), (R)-Ni2-
(Schiff base) (6.8 mg, 0.01 mmol, 5 mol %), and CHCl3 (0.4 mL, 0.5
M). The reaction mixture was then cooled to −20 °C, followed by the
addition of MeOH (81 μL, 2.0 mmol, 10 equiv). The reaction mixture
was then stirred for 15 h. CH2Cl2 (2 mL) was added to the reaction
mixture and then extracted with saturated NaHCO3. The aqueous
layer was then washed with CH2Cl2 and acidified to pH = 1.0 using 1
N HCl. The compound was then extracted with ethyl acetate, dried
over Na2SO4, and evaporated under reduced pressure to to give
compound 6 (29.1 mg, 91%, 94% ee) as a colorless oil. Data has
already been reported.5
(S)-N,N-Diallyl-3-((tert-butyldiphenylsilyl)oxy)-14-methyl-
pentadecanethioamide (7a). To a stirred solution of 4a (73.4 mg,
0.20 mmol) in CH2Cl2 (3 mL) were added 2,6-lutidine (46 μL, 0.40
mmol) and TBDPSOTf (93 μL, 0.30 mmol) at 0 °C, and stirring was
continued for another 2 h. Saturated aq NH4Cl was then added, and
the aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine and dried over Na2SO4. The filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (eluent n-hexane/
AcOEt) to give compound 7a (111 mg, 92%) as a colorless oil. IR
(S)-N,N-Diallyl-3-hydroxy-14-methylpentadecanethioamide
(4a). To a flame-dried test tube equipped with a magnetic stirring bar
and a 3-way glass stopcock were added (R,R)-Ph-BPE/mesitylcopper/
2,2,5,7,8-pentamethylchromanol (3) solution (0.1 M/THF, 100 μL,
0.010 mmol, 5 mol %), dry DMF and THF (3:1) (2 mL),
diallylthioamide (2a) (64 μL, 0.40 mmol), and aldehyde 1 (51.2 μL,
0.2 mmol) under Ar at −60 °C. After 40 h of stirring at that
temperature, 0.1 M AcOH (100 μL), saturated aq NH4Cl, and
bipyridine (3.0 mg) were added to the reaction mixture (for the
dissociation of product from copper complex). The reaction mixture
was then stirred at room temperature for 15 min. The aqueous layer
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(neat) ν 2925, 2854, 1643, 1486, 1464, 1427 cm−1; 1H NMR (CDCl3)
δ 7.69−7.67 (m, 4H), 7.44−7.34 (m, 6H), 5.95−5.86 (m, 1H), 5.74−
5.67 (m, 1H), 5.24−5.20 (m, 3H), 5.17 (dd, J = 2.8 Hz, 1.2 Hz, 1H)
4.85 (dd, J = 14.4 Hz, 5.7 Hz, 1H), 4.50 (dd, J = 13.0 Hz, 5.7 Hz, 1H),
4.43−4.31 (m, 2H), 3.91−3.86 (m, 1H), 3.02 (dd, J = 13.5 Hz, 7.8 Hz,
1H), 2.88 (dd, J = 13.5 Hz, 5.3 Hz, 1H), 1.55−1.45 (m, 1H), 1.44−
1.36 (m, 2H), 1.25−1.04 (m, 16H), 1.02−0.94 (m, 11H), 0.86 (d, J =
6.4 Hz, 6H); 13C NMR (CDCl3) δ 203.0, 136.0, 135.8, 134.5, 133.6,
131.5, 131.4, 129.6, 129.5, 127.53, 127.48, 119.1, 117.6, 74.8, 56.2,
53.0, 50.0, 39.0, 36.9, 29.9, 29.7, 29.6, 29.5, 29.4, 29.3, 28.0, 27.4, 27.1,
24.8, 22.7, 19.4; [α]23D +21.5 (c 0.34, CHCl3, 87% ee sample); HRMS
(ESI-Orbitrap) calcd for C38H59NNaOSSi m/z 628.3979 [M + Na]+,
found 628.3979.
(S)-3-((tert-Butyldiphenylsilyl)oxy)-N,N,14-trimethylpentade-
canethioamide (7b). To a stirred solution of 4b (0.20 mmol) in
CH2Cl2 (3 mL) were added 2,6-lutidine (46 μL, 0.40 mmol) and
TBDPSOTf (93 μL, 0.30 mmol) at 0 °C, and stirring was continued
for another 2 h. Saturated aq NH4Cl was then added, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
washed with brine and dried over Na2SO4. The filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (eluent n-hexane/
AcOEt) to give compound 7b (105 mg, 95%) as a colorless oil. IR
(neat) ν 2926, 2854, 1515, 1465, 1427, 1391 cm−1; 1H NMR (CDCl3)
δ 7.70−7.67 (m, 4H), 7.42−7.34 (m, 6H), 4.47−4.41 (m, 1H), 3.43 (s,
3H), 3.22 (s, 3H), 3.13 (dd, J = 13.0 Hz, 8.0 Hz, 1H), 2.90 (dd, J =
13.0 Hz, 5.0 Hz, 1H), 1.55−1.48 (m, 1H), 1.46−1.40 (m, 2H), 1.29−
1.07 (m, 16H), 1.02−0.94 (m, 11H), 0.86 (d, J = 6.4 Hz, 6H); 13C
NMR (CDCl3) δ 201.7, 136.0, 135.8, 134.5, 133.5, 129.7, 129.5, 127.6,
127.5, 76.6, 50.1, 44.7, 42.3, 39.0, 37.2, 29.9, 29.7, 29.6, 29.5, 29.4,
27.9, 27.4, 27.0, 24.8, 22.7, 19.4; [α]23D +37.8 (c 0.06, CHCl3, 93% ee
sample); HRMS (ESI-Orbitrap) calcd for C34H55NNaOSSi m/z
576.3666 [M + Na]+, found 576.3665.
(S)-3-((tert-Butyldiphenylsilyl)oxy)-14-methylpentadecanal
(9). To a stirred solution of 7a (60.6 mg, 0.10 mmol) in ether (1.0
mL) was added MeOTf (22 μL, 0.20 mmol) at 0 °C. [Note:
Compound 7b (55.4 mg, 0.10 mmol) also gave the same aldehyde 9
(79 mg, 80%).] After stirring at room temperature for 4.5 h, the
reaction mixture was cooled to −78 °C. To the mixture was added
LiAlH(OtBu)3 (200 μL, 1.0 M in THF, 0.20 mmol), and the resulting
solution was stirred for 4 h. The reaction was quenched with silica gel
(1.4 g) at −78 °C and diluted with CH2Cl2 (5 mL). The resulting
mixture was then stirred at −30 °C for 15 h and filtered through a
short pad of silica gel with CH2Cl2 as eluent. The filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (eluent n-hexane/AcOEt
= 99/1 → 50/1) to give compound 9 (71.1 mg, 72%) as a colorless oil.
IR (neat) ν 2926, 2855, 1727, 1465, 1427 cm−1; 1H NMR (CDCl3) δ
9.71 (t, J = 2.6 Hz, 1H), 7.68−7.64 (m, 4H), 7.45−7.36 (m, 6H),
4.22−4.16 (m, 1H), 2.49−2.47 (m, 2H), 1.57−1.45 (m, 3H), 1.23−
1.06 (m, 18H), 1.04 (s, 9H), 0.86 (d, J = 6.7 Hz, 6H); 13C NMR
(CDCl3) δ 202.4, 135.9, 135.8, 133.9, 129.8, 129.7, 127.7, 127.6, 69.3,
50.2, 39.0, 37.3, 29.9, 29.7, 29.6, 29.5, 29.4, 29.3, 28.0, 27.4, 26.9, 24.9,
22.7, 19.3; [α]23D +11.5 (c 0.82, CHCl3, 87% ee sample); HRMS (ESI-
Orbitrap) calcd for C32H50NaO2Si m/z 517.3472 [M + Na]+, found
517.3478.
= 6.6 Hz, 6H); 13C NMR (CDCl3) δ 176.6, 135.89, 135.86, 133.7,
133.5, 129.72, 129.70, 127.6, 127.5, 70.3, 41.4, 39.1, 36.7, 29.9, 29.7,
29.6, 29.5, 29.4, 29.3, 28.0, 27.4, 26.9, 24.8, 22.7, 19.3; [α]23D +14.6 (c
0.55, CHCl3, 87% ee sample); HRMS (ESI-Orbitrap) calcd for
C32H50NaO3Si m/z 533.3421 [M + Na]+, found 533.3412.
(S)-Benzyl 3-((tert-Butyldiphenylsilyl)oxy)-14-methylpenta-
decanoate (12). To a stirred solution of carboxylic acid 11 (102
mg, 0.20 mmol) in CH2Cl2 (5 mL) were added BnOH (31 μL, 0.30
mmol), DCC (82.4 mg, 0.40 mmol), and DMAP (2.4 mg, 0.02 mmol)
at 0 °C. Stirring was continued for 2 h at room temperature followed
by filtration of the reaction mixture through a Celite pad. The filtrate
was concentrated under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (eluent n-hexane/
AcOEt = 50/1 → 20/1) to give compound 12 (101 mg, 84%) as a
1
colorless oil. IR (neat) ν 2925, 2854, 1738, 1589 cm−1; H NMR
(CDCl3) δ 7.68−7.64 (m, 4H), 7.42−7.30 (m, 9H), 7.26−7.24 (m,
2H), 5.01 (d, J = 12.4 Hz, 1H), 4.95 (d, J = 12.4 Hz, 1H), 4.22−4.16
(m, 1H), 2.57−2.43 (m, 2H), 1.55−1.39 (m, 3H), 1.24−1.01 (m,
27H), 0.86 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3) δ 171.4, 135.91,
135.87, 135.8, 134.1, 134.0, 129.5, 128.4, 128.2, 128.1, 127.4, 70.4,
66.1, 42.1, 39.1, 37.0, 29.9, 29.7, 29.6, 29.5, 29.4, 29.3, 28.0, 27.4, 26.9,
24.7, 22.7, 19.3; [α]23 +9.5 (c 0.07, CHCl3, 87% ee sample); HRMS
D
(ESI-Orbitrap) calcd for C39H56NaO3Si m/z 623. 3891 [M + Na]+,
found 623.3896.
(S)-Benzyl 3-Hydroxy-14-methylpentadecanoate (13). To a
stirred solution of TBDPS ether 12 (120 mg, 0.20 mmol) in THF (4
mL) at room temperature was added 70% HF·pyridine (2.0 mL)
(reaction was carried out in a plastic container). The reaction mixture
was stirred at room temperature for 24 h, quenched with NaHCO3,
and extracted with AcOEt. The combined organic extracts were
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (eluent n-hexane/AcOEt
= 20/1 → 10/1) to give compound 13 (54.5 mg, 75%) as a white
solid. Mp 35−37 °C; IR (neat) ν 3450, 2925, 2853, 1734, 1465 cm−1;
1H NMR (CDCl3) δ 7.40−7.31 (m, 5H), 5.15 (s, 2H), 4.06−3.99 (m,
1H), 2.85 (d, J = 3.9 Hz, 1H), 2.56 (dd, J = 16.3 Hz, 3.2 Hz, 1H), 2.46
(dd, J = 16.3 Hz, 8.6 Hz, 1H), 1.55−1.12 (m, 21H), 0.86 (d, J = 6.4
Hz, 6H); 13C NMR (CDCl3) δ 172.9, 135,6, 128.6, 128.4, 128.3, 68.0,
66.5, 41.3, 39.0, 36.5, 29.9, 29.7, 29.64, 29.58, 29.54, 29.50, 27.5, 27.4,
25.4, 22.7; [α]23D +14.5 (c 0.08, CHCl3, 87% ee sample); HRMS (ESI-
Orbitrap) calcd for C23H38NaO3 m/z 385.2713 [M + Na]+, found
385.2713.
(3R,4R,5S,6S)-3,4,5-Trimethoxy-6-methyltetrahydro-2H-
pyran-2-ol (17). A solution of 169 (44.0 mg, 0.20 mmol) in conc
HCl/H2O (1:4, 5 mL) was heated at 60 °C for 12 h. The reaction was
then quenched with saturated NaHCO3 and extracted with AcOEt.
The combined organic extracts were concentrated under reduced
pressure, and the resulting residue was purified by silica gel column
chromatography (eluent n-hexane/AcOEt = 10/1 → 5/1) to give
compound 17 (30.9 mg, 75%) as a colorless oil. Compound 17 is
already reported.9
(R)-5-(Benzyloxy)-3-methyl-5-oxopentanoic Acid (19). To an
oven-dried glass test tube equipped with a magnetic stirring bar were
charged 3-methylglutaric anhydride 5 (25.6 mg, 0.20 mmol), (S)-Ni2-
(Schiff base) (6.8 mg, 0.01 mmol, 5 mol %) and CHCl3 (0.4 mL. 0.5
M). The reaction mixture was then cooled to 0 °C, followed by the
addition of BnOH (207 μL, 2.0 mmol, 10 equiv). The reaction mixture
was then stirred for 48 h. CH2Cl2 (2 mL) was added to the reaction
mixture and then extracted with saturated NaHCO3. The aqueous
layer collected was then washed with CH2Cl2 and then acidified to pH
= 1.0 using 1 N HCl. The compound was then extracted with AcOEt,
dried over Na2SO4, and evaporated under reduced presuure to to give
compound 19 (41.0 mg, 87%, 88% ee) as a colorless oil. IR (neat) ν
(S)-3-((tert-Butyldiphenylsilyl)oxy)-14-methylpentadecanoic
Acid (11). To a stirred solution of aldehyde 9 (98.8 mg, 0.20 mmol),
NaH2PO4 (72 mg, 0.60 mmol), and 2-methyl-2-butene (170 μL, 1.60
mmol) in THF/tBuOH/H2O (1:3:5) (4.5 mL) was added NaClO2
(54.3 mg, 0.60 mmol) at 0 °C, and stirring was continued for 2 h at
room temperature. The reaction mixture was then quenched with 1 N
HCl and extracted with AcOEt. The combined extracts were washed
with brine and dried over Na2SO4. The filtrate was concentrated under
reduced pressure, and the resulting residue was purified by silica gel
column chromatography (eluent n-hexane/AcOEt = 9/1) to give
compound 11 (94.0 mg, 92%) as a colorless oil. IR (neat) ν 3418,
1
3034, 1734, 1708, 1455 cm−1; H NMR (CDCl3) δ 7.39−7.29 (m,
5H), 5.12 (s, 2H), 2.56−2.41 (m, 2H), 2.38−2.25 (m, 2H), 1.04 (d, J
= 6.4 Hz, 3H); 13C NMR (CDCl3) δ 178.3, 172.1, 135.8, 128.5, 128.2,
66.3, 40.7, 40.4, 27.2, 19.8; [α]23 −3.6 (c 0.43, CHCl3, 88% ee
1
2926, 2855, 1711, 1428 cm−1; H NMR (CDCl3) δ 7.69−7.64 (m,
D
4H), 7.45−7.34 (m, 6H), 4.15−4.09 (m, 1H), 2.59 (d, J = 5.7 Hz,
2H), 1.53−1.43 (m, 3H), 1.25−1.06 (m, 18H), 1.04 (s, 9H), 0.86 (d, J
sample); HRMS (ESI-Orbitrap) calcd for C13H15O4 m/z 235.0965. [M
− H]−, found 235.0972; HPLC (Daicel CHIRALCEL AD-H, ϕ 0.46
9265
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The Journal of Organic Chemistry
Article
cm × 25 cm, detection 220 nm, n-hexane/iPrOH = 19/1, flow rate =
1.0 mL/min) tR = 12.3 min (minor), tR = 14.3 min (major).
(eluent n-hexane/AcOEt = 10/1 → 5/1) to give compound 22 (122
mg, 90%, a single diastereomer) as a colorless oil. IR (neat) ν 2926,
1
(S)-1-Benzyl 5-((2S,3R,4R,5S,6S)-3,4,5-Trimethoxy-6-methyl-
tetrahydro-2H-pyran-2-yl) 3-Methylpentanedioate (20a). To a
solution of 2,3,4-tri-O-methyl-L-rhamnose 17 (47.4 mg, 0.20 mmol), 3-
methylglutaric acid monobenzyl ester 19 (53.5 mg, 0.26 mmol, 88%
ee), and 2,4,6-trichlorobenzoyl chloride (41 μL, 0.26 mmol) in THF
(3 mL) was added Et3N (56 μL, 0.40 mmol) dropwise, and the
solution was stirred for about 2 min followed by the addition of
DMAP (6.1 mg, 0.05 mmol). The reaction mixture was stirred for 5 h
and quenched with water followed by extraction with AcOEt. The
organic phase was then washed with saturated aq NaHCO3, dried over
Na2SO4, and evaporated to give a crude material containing a mixture
of α/β-anomers (α/β = 95/5). The residue was purified by silica gel
column chromatography (eluent n-hexane/AcOEt = 10/1 → 5/1) to
afford compound 20a (61.6 mg, 70%). IR (neat) ν 2934, 2830, 1734,
1736, 1456 cm−1; 1H NMR (CDCl3) δ 7.34−7.30 (m, 5H), 6.15 (d, J
= 1.6 Hz, 1H), 5.10 (s, 2H), 3.64−3.59 (m, 1H), 3.58−3.52 (m, 4H),
3.50 (s, 3H), 3.47 (s, 3H), 3.41 (dd, J = 9.4 Hz, 3.2 Hz, 1H), 3.15 (t, J
= 9.4 Hz, 1H), 2.52−2.38 (m, 3H), 2.33−2.22 (m, 2H), 1.26 (d, J =
6.2 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3) δ 171.9,
170.6, 135.8, 128.6, 128.3, 128.2, 90.8, 81.5, 80.7, 76.2, 70.4, 66.3, 61.1,
59.0, 57.8, 40.6, 27.3, 19.8, 17.8; [α]23D −42.5 (c 0.55, CHCl3); HRMS
(ESI-Orbitrap) C22H32NaO8 m/z 447.1989 [M + Na]+, found
447.1989.
(S)-1-Methyl 5-((2S,3R,4R,5S,6S)-3,4,5-Trimethoxy-6-methyl-
tetrahydro-2H-pyran-2-yl) 3-Methylpentanedioate (18a). Same
procedure to synthesize 20a as above was employed using 3-
methylglutaric acid monomethyl ester (R)-6 to give a crude mixture
of α/β-anomers (α/β = 94/6). The residue was purified by silica gel
column chromatography (eluent n-hexane/AcOEt = 10/1 → 5/1) to
afford compound 18a (55.7 mg, 80% yield). Separation of the
diastereomers was not attempted. A colorless oil. IR (neat) ν 2933,
1739, 1587, 1123 cm−1; 1H NMR (CDCl3) δ 6.17 (d, J = 1.8 Hz, 1H),
3.68−3.60 (m, 4H), 3.58−3.56 (m, 4H), 3.53 (s, 3H), 3.51 (s, 3H),
3.47−3.43 (m, 1H), 3.18 (t, J = 9.4 Hz, 1H), 2.52−2.37 (m, 3H),
2.32−2.24 (m, 2H), 1.30 (d, J = 6.2 Hz, 3H), 1.05 (d, J = 5.7 Hz, 3H);
13C NMR (CDCl3) δ 172.6, 170.5, 90.7, 81.4, 80.7, 76.2, 70.4, 61.0,
2854, 1740, 1457, 1384 cm−1; H NMR (CDCl3) δ 7.39−7.30 (m,
5H), 6.17 (d, J = 1.8 Hz, 1H), 5.28−5.21 (m, 1H), 5.11 (s, 2H), 3.68−
3.61 (m, 1H), 3.57−3.56 (m, 4H), 3.53 (s, 3H), 3.50 (s, 3H), 3.45
(dd, J = 9.4 Hz, 3.4 Hz, 1H), 3.17 (t, J = 9.4 Hz, 1H), 2.67−2.56 (m,
2H), 2.45−2.38 (m, 2H), 2.30−2.16 (m, 3H), 1.61−1.46 (m, 3H),
1.30−1.24 (m, 19H), 1.15−1.12 (m, 2H), 1.00 (d, J = 6.4 Hz, 3H),
0.86 (d, J = 6.7 Hz, 6H); 13C NMR (CDCl3) δ171.4, 170.5, 170.2,
135.7, 128.5, 128.34, 128.30, 90.7, 81.5, 80.7, 76.2, 70.7, 70.4, 66.5,
61.0, 59.0, 57.8, 40.7, 40.6, 39.1, 39.0, 34.0, 29.9, 29.7, 29.6, 29.5, 29.4.
29.3, 27.9, 27.4, 27.3, 25.1, 22.6, 19.6, 17.8; [α]23 −25.5 (c 0.94,
D
CHCl3); HRMS (ESI-Orbitrap) C38H62NaO10 m/z 701.4235 [M +
Na]+, found 701.4233.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds, NOE data for
20a, and HPLC data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: twatanabe@bikaken.or.jp; mshibasa@bikaken.or.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.G. is grateful for a Grant-in-Aid for JSPS fellow. T.W. is
grateful for a KAKENHI (C) (23590037) and to The Uehara
Memorial Foundation for financial support. We thank Dr.
Ryuichi Sawa and Ms. Yumiko Kubota for spectral data
collection.
59.0, 57.8, 51.5, 40.6, 40.4, 27.3, 19.8, 17.7 (NMR data for the major
REFERENCES
α-anomer is shown); [α]23 −44.6 (c 0.41, CHCl3); HRMS (ESI-
■
D
Orbitrap) C16H28NaO8 m/z 371.1674 [M + Na]+, found 371.1676.
(S)-3-Methyl-5-oxo-5-(((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-
methyltetrahydro-2H-pyran-2-yl)oxy)pentanoic Acid (21). To a
suspension of 10% Pd/C in AcOEt (4 mL) was added compound 20a
(88.0 mg, 0.20 mmol). The reaction mixture was stirred under H2
atmosphere for 8 h followed by the filtration of the catalyst over Celite
pad with AcOEt. The filtrate was concentrated under reduced pressure
to give compound 21 (65.6 mg, 98%) as a colorless oil in pure form
without column chromatography. IR (neat) ν 3435, 2936, 1735, 1644,
1455, 1386 cm−1; 1H NMR (CDCl3) δ 6.18 (d, J = 2.0 Hz, 1H), 3.66−
3.61 (m, 1H), 3.58−3.56 (m, 4H), 3.53 (s, 3H), 3.51 (s, 3H), 3.46
(dd, J = 9.4 Hz, 3.4 Hz, 1H), 3.19 (t, J = 9.6 Hz, 1H), 2.53−2.42 (m,
3H), 2.35−2.28 (m, 2H), 1.30 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz,
3H); 13C NMR (CDCl3) δ 177.7, 170.5, 90.7, 81.5, 80.6, 76.2, 70.3,
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dx.doi.org/10.1021/jo301803h | J. Org. Chem. 2012, 77, 9260−9267