Prediction and determination of the stereochemistry of the 1,3,5-trimethyl-substituted alkyl chain in verucopeptin, a microbial metabolite

Article abstract of DOI:10.1021/jo500906v

For the prediction of the relative stereochemistry of 1,3-dimethyl substitution in alkyl chains, a simple approach based on ¹H NMR data was recently proposed; Δδ values of methylene protons located between methyl-substituted methine carbons can

Full text of DOI:10.1021/jo500906v

Article
pubs.acs.org/joc
Prediction and Determination of the Stereochemistry of the
1,3,5-Trimethyl-Substituted Alkyl Chain in Verucopeptin,
a Microbial Metabolite
Aya Yoshimura, Shinji Kishimoto, Shinichi Nishimura, Saori Otsuka, Yuki Sakai, Akira Hattori,
and Hideaki Kakeya*
Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School
of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: For the prediction of the relative stereochemistry
of 1,3-dimethyl substitution in alkyl chains, a simple approach
1
based on H NMR data was recently proposed; Δδ values of
methylene protons located between methyl-substituted methine
carbons can be diagnostic for predicting it. Here we applied this
empirical “geminal proton rule” to verucopeptin, a lipopeptide
from Streptomyces sp. To determine the absolute stereochemistry
of the 1,3,5-trimethyl-substituted alkyl chain in verucopeptin,
we converted the corresponding alkyl chain to a carboxylic
acid by oxidative cleavage. The geminal proton rule clearly
predicted the relative stereochemistry as 31S*,33S*,35R*.
This prediction was definitely confirmed by synthesizing four
possible diastereomers and comparing their NMR spectra.
Furthermore, we reinvestigated the geminal proton rule using reported compounds and our synthesized compounds. Our result
strongly suggests that the rule was solid, at least for predicting the stereochemistry of 2,4-dimethylated and 2,4,6-trimethylated
fatty acids.
candidate diastereomers, which can be compared with those of
a molecule in question.
INTRODUCTION
■
Natural products occupy a wide chemical space and exhibit
unique and sometimes medically important biological activ-
ities.1,2 However, their complex chemical structures often
hamper structure determination. For example, determination of
the stereochemistry of acyclic structures is a challenging task in
spite of the advancement of spectroscopic and chemical
methodologies.
One of the challenging structures often found in natural
products is the 1,3-dimethyl-substituted system. We can
elucidate its stereochemistry by adopting JBCA, whereas
measurement and/or calculation of NMR chemical shift values
can predict it. However, even these excellent methods are not
always applicable and alternative analytical means are required.
Recently, a simple and highly sensitive method only analyzing
Several NMR techniques have been developed for determi-
nation of the stereochemistry in acyclic compounds.3 J-based
configurational analysis (JBCA), developed by Murata and co-
workers, allows the assignment of anti or gauche relationships
of two adjacent stereogenic centers.4,5 This method exploits
1
1
the H NMR data has been proposed: H NMR chemical
shifts of the methylene protons located between two methyl-
bearing methine carbons in acyclic 1,3-dimethyl systems can be
diagnostic (Figure 1).9−11 In 2003, Ishibashi and co-workers
noticed this phenomenon when they synthesized diastereomers
of the partial structure of TT-1/rasfonin.9 In 2010 and 2012,
Breit and co-workers generalized this as an empirical rule by
investigating more than 80 compounds.10,11
1
1H−1H and H−13C coupling constants. By integrating the
J information and NOESY correlations, we can determine
relative stereochemistries of contiguous or 1,3-skipped stereo-
genic centers. The universal NMR database (UDB) is another
powerful means constructed by Kishi and co-workers.6−8
1
In the proposed empirical rule, when the difference of H
This database includes H and 13C NMR chemical shifts for
1
NMR chemical shifts for the methylene protons HA and HB is
small, the configuration might be anti and vice versa (Figure 1).
This rule (here we call this the “geminal proton rule”) can be
logically explained as described previously.11,12 Basically, the
diastereomers of polyol or related chain structures. We can
compare the NMR data of a compound of interest with the
database to identify the most likely diastereomer. In addition to
database approaches, calculation of NMR chemical shifts is
effective for predicting the stereochemistry.3 Quantum
chemistry methods can calculate NMR chemical shifts for
Received: April 24, 2014
© XXXX American Chemical Society
A
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Figure 1. Conformational preference of 1,3-dimethyl-substituted
structures and assignment of the relative stereochemistry. Δδ values
for the methylene protons (HA and HB) are diagnostic for
distinguishing the syn and anti configurations. However, the differential
values are sometimes largely affected by the species of R and R′.
preferentially populated conformations of an acyclic 1,3-
dimethyl system are determined by the avoidance of syn-
pentane interactions. Therefore, the only two conformers that
are free of syn-pentane interactions are preferred, as shown in
Figure 1. In each conformer, HA and HB in an anti
conformation are homotopic, each being syn to one proton
and syn to one methyl group on the adjacent carbons in the
chain. In contrast, the two protons in a syn conformation are
diastereotopic, owing to a different chemical environment even
when R = R′.9 Next, R and R′ functions can affect the
molecular environment experienced by HA and HB. This may
change the absolute chemical shift values of HA and HB,
whereas the effect against differential values between HA and
HB in the anti configuration remains small, judging from the
literature values for more than 80 compounds.10,11 However,
the range of differential values depends on the functional
groups R and R′.11 In addition, ambiguity can arise when
compounds have bulky or shielding substituents. For a correct
assignment, it is important to define the structure types that are
compatible with the geminal proton rule and the corresponding
differential values.
Figure 2. Δδ values for tumescenamide C (1). Δδ values for
methylene protons at C31 for the intact natural product (a) and
synthesized molecules (b, c) are shown. Δδ values are shown in ppm.
2,4-dimethylheptanoic acid in 1 was determined to be 2S,4S by
chemical degradation and asymmetric synthesis; we synthesized
the phenylglycine methyl ester (PGME) derivative 2a and its
diastereomer 2b (Figure 2b,c) and compared their physico-
chemical properties with those of the PGME derivatives of 2,4-
dimethylheptanoic acid that were obtained by hydrolysis of the
natural product 1. To investigate whether the geminal proton
1
rule can be applicable to compound 1, we reanalyzed the H
NMR chemical shift values of the methylene protons at C31.
The difference of the two geminal protons was large enough
(0.62 ppm), suggesting that the two methyl groups at C30 and
C32 are located in a syn configuration (Figure 2a). This
prediction was consistent with our previous results.13 The Δδ
values for methylene protons at C3 in synthetic 2a,b were 0.56
and 0.12 ppm, respectively, confirming the utility of the geminal
proton rule. In addition, the 1H NMR spectrum of
tumescenamide A, a diastereomer of tumescenamide C, also
showed a large chemical shift difference (0.65 ppm) for the
geminal protons at C31, suggesting the syn configuration of the
two methyl groups.14 This prediction was also consistent with
the reported structure that was deduced by the JBCA method.14
NMR Analysis of Verucopeptin. Verucopeptin (3) is an
antitumor compound originally reported from Actinomadura
verrucosospora Q886-2.15,16 This metabolite is composed of a
cyclic depsipeptide and a polyketide side chain possessing three
branched methyl groups. We reisolated verucopeptin (3) from
the culture broth of Streptomyces sp. KUSC_A08. Because the
stereochemistry had not been determined, we tried to predict the
configuration of the 1,3,5-trimethylated alkyl chain by using the
geminal proton rule. However, heavily overlapping signals due to
the dynamic equilibrium between a cyclic hemiacetal form and a
linear keto form hampered the complete assignment of 1H NMR
signals.16 To overcome this problem, we converted compound 3
to the linear derivative 4 using NaBH4 (Figure 3a).16,17 We
successfully assigned the 1H NMR signals (Table S1, Supporting
Information) and obtained Δδ values for H2-32 and H2-34
(Figure 3a). The Δδ value for H2-34 (0 ppm) implied the anti
relationship of the two methyl groups at C33 and C35. However,
the Δδ value for H2-32 (0.14 ppm) was not significant enough to
predict the stereochemistry. As analyzed previously,11 the Δδ
In the course of our screening for bioactive metabolites from
natural sources, we isolated tumescenamide C and veruco-
peptin, both of which possess a 1,3-dimethyl-substituted system
in acyclic structures. We reported the stereochemistry of
2,4-dimethylheptanoic acid in tumescenamide C by comparing
the NMR spectra of the natural product derived compounds
and synthesized authentic samples.13 In this paper, we first
confirmed the applicability of the geminal proton rule to
tumescenamide C and its degradation products. We then
applied the rule to verucopeptin for predicting the stereo-
chemistry of a 1,3,5-trimethyl-substituted aliphatic chain.
1
Analysis of the H NMR data for the fragment structures of
verucopeptin predicted the 31S*,33S*,35R* stereochemistry,
which was definitely confirmed by synthesizing authentic
compounds. Our results indicate that the geminal proton rule
is a reliable method to determine the relative stereochemistry of
2,4-dimethyl and 2,4,6-trimethyl fatty acids.
RESULTS AND DISCUSSION
■
2,4-Dimethyl Carboxylic Acids in Tumescenamides.
Recently, we reported the isolation and structure elucidation
of a cyclic lipodepsipeptide, tumescenamide C (1), from
Streptomyces sp. (Figure 2a).13 The absolute stereochemistry of
B
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Figure 3. Prediction of the stereochemistries of C31, C33, and C35 in verucopeptin (3): (a) preparation of the reduced derivative 4 and Δδ values at
C32 and C34; (b) preparation of PGME derivatives 6a,b; (c) Δδ values for C32 and C34 in 6a; (d) Δδ (δ(S)‑PGME-δ(R)‑PGME) values for 6a,b. Δδ
values are shown in ppm.
Scheme 1. Synthesis of (2S,4S,6R)-2,4,6-Trimethyloctanoic Acid (12) and Its Derivatives
values for the syn configuration and those for the anti
configuration sometimes do not show a clear difference when
the alkenyl group was located just beside the methyl group. In
addition, the cyclic depsipeptide portion could affect the
conformation of the side chain. In fact, the Δδ value was very
large (0.57 ppm) for the methylene protons in bitungolide A in
spite of its anti configuration, probably because the lactone ring
adjacent to the 1,3-methyl structure affects the stability of the
conformer.11 Another example is atpenin A5: a very large Δδ value
(0.40 ppm) was observed for its anti configuration, which can be
due to the presence of a 2,4-dihydroxy 5,6-dimethoxypyridine ring
that may constrain the conformation and/or exert a magnetic
shielding effect.11
As suggested by Breit and co-workers, and as shown above
using tumescenamides, 2,4-dimethyl and 2,4,6-trimethyl
carboxylic acids seem to give clear results by the geminal
proton rule. Hence, we decided to obtain the side chain of
compound 3 as a carboxylic acid. For this purpose, we tested
several oxidation conditions: e.g., OsO4, H2WO4, and RuCl3.
We found that oxidative cleavage using RuCl3 and NaIO4
successfully furnished the carboxylic acid 5. We converted the
carboxylic acid 5 to PGME derivatives 6a,b and analyzed their
C
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Figure 4. Comparison of the 1H NMR spectra for PGME derivatives of 2,4,6-trimethyloctanoic acids. The aliphatic region of the spectra for natural
product derived 6a (natural) and the synthesized diastereomers 13a−16a is shown. Red and blue indicate anti and syn configurations, respectively.
Spectra were measured in CDCl3 (500 MHz).
NMR spectra (Figure 3b). The Δδ values for positions 32 and
34 in 6a were 0.49 and 0 ppm, respectively (Figure 3c),
indicating that the three methyl groups are located in a syn,anti
configuration. The 1H NMR spectrum of 6b gave a same result
(shown in the Supporting Information).
yielded the alcohol 9. After tosylation of the alcohol 9, one-
carbon elongation was achieved with MeMgBr and CuI to
yield the protected alcohol 10. After deprotection of PMB,
a second Evans asymmetric alkylation was conducted to give
oxazolidinone 11 and its diastereomer. These two diastereomers
were separated by C30 reversed-phase HPLC (dr = 48:1).
Purified oxazolidinone 11 was subjected to oxidative hydrolysis
with alkaline hydrogen peroxide to give the carboxylic acid 12.
The carboxylic acid 12 was condensed with (R)- or (S)-PGME
to give 13a,b, respectively. Three other diastereomers and their
PGME derivatives were synthesized in the same manner.
1H NMR Analysis of 2,4,6-Trimethyloctanoic Acid
Derivatives. With all four diastereomers in hand, we first
compared 1H NMR spectra of the PGME derivatives, including
synthesized compounds 13a−16a, and the natural product
derived compound 6a (Figure 4). The synthesized diaster-
eomers exhibited apparently different spectra, especially signals
The result obtained by the geminal proton rule was
consistent with the previous prediction,18 in which Hoffmann
and co-workers calculated 13C NMR chemical shift values for
possible diastereomers and compared them with that of the
degradation product of verucopeptin (3). Although the
difference in the chemical shift values was subtle between
syn,anti and syn,syn isomers, calculated 13C NMR chemical shift
values suggested that the natural product may have the former
configuration. In contrast, the geminal proton rule gave more
clear differences, especially in the case of fatty acid derivatives
(see below). It is noted that we could determine the absolute
stereochemistry of C31 by converting the carboxylic acid 5 to
PGME derivatives (Figure 3d).19 In combination with the
above prediction, verucopeptin (3) was predicted to have an
absolute stereochemistry of 31S,33S,35R.
Synthesis of a 2,4,6-Trimethyl Carboxylic Acid. To
prove our prediction, we planned to synthesize four possible
diastereomers of 2,4,6-trimethyloctanoic acid: 2S,4S,6R,
2S,4S,6S, 2S,4R,6R, and 2S,4R,6S. Our synthetic scheme for
(2S,4S,6R)-2,4,6-trimethyloctanoic acid (12) is shown in
Scheme 1. The synthesis of 12 was started with (R)-Roche
ester 7, and two stereogenic centers were constructed by
stereoselective alkylation reactions using chiral oxazolidinones.19
We first protected the hydroxyl group of Roche’s ester 7 with a
p-methoxybenzyl (PMB) group under acidic conditions,
followed by reduction of the methyl ester to a hydroxyl group
by LAH. The obtained alcohol was converted to a triflate, which
was immediately subjected to diastereoselective alkylation by
(4R)-propionyloxazolidinone19 to give oxazolidinone 8 and its
diastereomer.20 Although these two diastereomers were not
separated by SiO2 column chromatography, oxazolidinone 8 was
successfully purified by C18 reversed-phase HPLC (dr = 10:1).
Reductive cleavage of the chiral auxiliary from oxazolidinone 8
1
for methylene protons at C3 and C5. The H NMR spectrum
of 6a closely resembled that of 13a, confirming the above
prediction; we unambiguously concluded that the stereo-
chemistry of 6a is 31S,33S,35R.
We next calculated Δδ values for the methylene protons at
C3 and C5 in the synthesized compounds 13a−16a and their
diastereomers 13b−16b (Figure 4, compound list S1). The Δδ
values of methylene protons at C3 were 0.47−0.67 ppm, when
two methyl groups at C2 and C4 were located in a syn
configuration. In contrast, the values were 0−0.23 ppm when
the methyl groups were in an anti configuration. The difference
was large enough to distinguish the relative stereochemistry of
the 2,4-dimethyl carboxylic acid. The Δδ values of methylene
protons at C5 were 0.24−0.28 ppm when in a syn configuration,
whereas they were 0 ppm when in an anti configuration. Although
the Δδ values at C5 were smaller than those at C3, the difference
between syn and anti forms was apparent enough to predict the
configuration.
Reinvestigation of the Geminal Proton Rule. The
trends for Δδ values depending on functional groups adjacent
to the stereogenic centers were analyzed by Breit and
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co-workers previously.11 We summarized the Δδ values of
methylene geminal protons in 86 compounds, including our
isolated or synthesized compounds in addition to those already
analyzed by Breit and co-workers (Figure 5, bottom). The Δδ
group in another tumescenamide congener, tumescenamide B
(17),8 whose configuration has not been determined (Figure 6).
The Δδ values for CH2-31 and -33 were 0.75 and 0.34,
respectively, suggesting the syn,syn configuration.
CONCLUSION
■
We have reinvestigated the utility of an empirical NMR
approach, the geminal proton rule, for determination of the
configuration of 1,3-dimethylated systems. Our data indicated
that the emerging rule is highly reliable when predicting the
stereochemistry of 2,4-dimethyl or 2,4,6-trimethyl fatty acids. In
fact, the stereochemistry of the 1,3,5-trimethylated system in
verucopeptin (3) was successfully predicted after conversion of
the system to a 2,4,6-trimethyl fatty acids. In addition, we could
deduce the relative stereochemistry of the acyl chain in
tumescenamide B (17) from the reported NMR data. So far,
many natural products with methyl branched fatty acids have
been reported. There remain many compounds with unknown
stereochemistries: e.g., dactylfungins21 and totopotensamides.22
The geminal proton rule would be helpful for elucidating the
stereochemistry of such compounds.
Figure 5. Tendencies for Δδ values. Values for syn configurations are
plotted in blue and anti in red. Δδ values for HA and HB (31
compounds, top), Δδ value for HC and HD (17 compounds, middle),
and Δδ values for any methylene protons located between methyl-
bearing methane carbons (86 compunds, bottom) are plotted. Arrows
indicate exceptionally large values for atpenin B and atpenin A5, as
mentioned in the text. The compound list is included in the
Supporting Information.
EXPERIMENTAL SECTION
■
General Considerations. All reagents and solvents were used as
received from commercial suppliers and were used without further
purification. IR spectra were measured using an FTIR spectrometer
equipped with a ZnSe ATR plate. Optical rotations were determined
using the sodium D line (589 nm). NMR spectra were measured on a
500 MHz instrument. 1H and 13C chemical shifts are shown relative to
the solvent: δH 7.26 and δC 77.0 for CDCl3. Chemical shifts (δ) are
shown in parts per million (ppm), and coupling constants (J) are in
hertz (Hz). The following abbreviations are used to describe multiplicities:
s, singlet; d, doublet; dd, doublet of doublets; m, multiplet. Mass spectral
data were collected with FAB MS or ESI IT-TOF MS. Flash column
chromatography was performed over Silica Flash F60 (SiliCycle) using an
elution system as described for each experiment.
values for anti configurations were plotted between 0 and 0.4
ppm, whereas those for syn configurations ranged from 0.1 to
0.8 ppm, indicating that the correct stereochemistries cannot be
predicted when the Δδ values are from 0.1 to 0.4 ppm. In
contrast, such ambiguity was not observed for carboxylic acids.
In the case of 1,3-dimethylated systems, the difference was
apparent. We plotted 31 examples in Figure 5 (top). The Δδ
values for CH2-3 were larger than 0.4 ppm when 2,4-dimethyl
groups were in the syn form. In contrast, the values were less
than 0.3 ppm when the configurations were anti, with two
exceptions: atpenin B and atenin A5. These compounds have a
2,4-dihydroxy-5,6-dimethoxypyridine ring, which seems to
contribute to the unexpectedly large Δδ values due to the
conformation constraint and/or magnetic shielding effect. We
also analyzed the Δδ values for CH2-5 from 17 compounds.
The Δδ values for CH2-5 also gave a clear result, although the
values were relatively small (Figure 5, middle). The Δδ values
were more than 0.2 when 4,6-dimethyl groups were in syn
configurations. The values were almost 0 when the configurations
were anti. These data revealed that the geminal proton rule is
reliable in 2,4-dimethyl and 2,4,6-trimethyl fatty acids. By using
this rule, we could predict the relative stereochemistry of the acyl
Isolation of Verucopeptin (3). n-BuOH extracts of the culture
broth of Streptomyces sp. KUSC_A08 (16 L) were extracted with 90%
MeOH three times. The combined extracts were evaporated and
extracted with CHCl3 three times. The CHCl3 extracts were combined
and concentrated in vacuo. The residue was dissolved in CHCl3/
MeOH (50/50) and fractionated on a LH-20 gel filtration column
with CHCl3/MeOH (50/50). Fractions containing verucopeptin were
combined and chromatographed on a silica gel column with CHCl3/
MeOH (45/1 to 20/1). Fractions eluted by CHCl3/MeOH (45/1)
were subjected to ODS HPLC on CAPCELL PAK UG120 (i.d. 20 ×
250 mm) with MeCN/H2O (75/25) to afford verucopeptin (3; 121.61
20
mg) as a colorless amorphous solid: [α]D = = −91.0° (c 0.12,
CHCl3); IR (neat) 3352, 2955, 1644, 1406, 1241, 754 cm−1; 1H NMR
for the major acetal form (CDCl3, 500 MHz) δ 9.11 (N-OH), 7.32 (d,
J = 9.7 Hz), 7.12 (d, J = 5.9 Hz), 6.08 (dd, J = 9.8, 3.1 Hz, 1H), 5.31
(m, 1H), 5.27 (d, J = 15.5 Hz, 1H), 5.16 (m, 1H), 5.04 (d, J = 16.9 Hz,
1H), 4.90 (m, 1H), 4.77 (dd, J = 9.8, 3.1 Hz, 1H), 4.64 (d, J = 16.3 Hz,
1H), 4.11 (m, 1H), 4.09 (m), 3.88 (d, J = 15.5 Hz, 1H), 3.65 (dd, J =
17.2, 6.5 Hz, 1H), 3.55 (d, J = 17.2 Hz, 1H), 3.44 (m), 3.28 (s, 3H),
3.11 (s, 3H/m), 3.04 (m, 1H), 2.91 (s, 3H), 2.65 (m, 1H), 2.51 (m,
1H), 2.17 (m, 1H), 2.03 (m, 1H), 1.87 (m), 1.80 (m), 1.72 (m), 1.65
(s), 1.57 (m), 1.50 (m), 1.46 (m), 1.40 (s, 3H),1.37 (m), 1.26 (m),
1.20 (m), 1.13 (m), 1.06 (d, J = 6.7 Hz), 1.02 (m), 0.97 (d, J = 6.7
Hz), 0.86 (m), 0.84 (m), 0.80 (m), 0.77 (m); 13C NMR for the major
acetal form (CDCl3, 125 MHz) δ 176.2, 172.0, 171.3, 170.8, 170.2,
167.1, 166.8, 137.0, 130.0, 98.4, 80.0, 79.6, 77.6, 75.7, 56.8, 52.5, 51.7,
51.3, 48.4, 46.9, 46.5, 46.1, 45.0, 42.4, 36.7, 34.7, 31.7, 30.4 (2C), 29.6,
27.7, 27.2, 24.1, 23.9, 21.3 (2C), 20.5, 19.4, 19.2, 19.1, 18.3, 11.4;
HRMS (ESI) m/z 918.5169 [M + Na]+ calcd for C43H73N7NaO13,
1
Figure 6. Structure of tumescenamide B (17) with proposed
stereochemistry. The Δδ values for C31 and C33 are shown in ppm.
918.5159. H and 13C NMR chemical shifts were in agreement with
those reported previously.23
E
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Reduction of 3. To a stirred solution of verucopeptin (3; 8.88 mg,
9.92 × 10−3 mmol) in CHCl3/MeOH (1/1, 1.98 mL) was added
NaBH4 (5.62 mg, 0.15 mmol) at room temperature. After 30 min, PBS
buffer was added to the reaction mixture. The organic layer was
washed with PBS buffer (three times) and concentrated in vacuo. The
residue was chromatographed on an ODS column with a stepwise
elution of H2O/MeOH (from 100/0 to 0/100). Fractions eluted with
H2O/MeOH (10/90 and 0/100) were combined and subjected to
ODS HPLC on Cosmosil AR-II-C18 (i.d. 20 × 250 mm) with H2O/
MeCN (40/60) to afford the reduced verucopeptin derivative 4
127.2, 56.1, 52.7, 44.3, 42.5, 38.8, 31.6, 30.4, 27.9, 19.6, 18.9, 18.3,
11.4; HRMS (ESI) m/z 356.2191 [M + Na]+ calcd for C20H31NNaO3,
356.2196.
PGME Derivatives of Synthetic (2S,4S,6R)-Trimethyloctanoic
Acid (13a,b). (R)-4-Benzyl-3-((2S,4S)-5-((4-methoxybenzyl)oxy)-2,4-
dimethylpentanoyl)oxazolidin-2-one (8). To a stirred solution of
methyl (S)-3-hydroxyisobutyrate (2.0 g, 16.90 mmol) in anhydrous
CH2Cl2 (33.90 mL) were added CSA (0.33 g, 1.42 mmol) and PMB
trichloroacetimidate (5.27 mL, 25.40 mmol). After the mixture was
stirred for 12 h at room temperature, the reaction was quenched by
addition of saturated aqueous NaHCO3. The mixture was extracted
with CHCl3, washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue in cooled hexane was filtered through Celite and
concentrated in vacuo. The residue was suspended in n-hexane/EtOAc
(10/1), filtered through a pad of silica, and used in the next reaction.
A solution of the residue (4.0 g) in anhydrous THF (84.50 mL) was
cooled to 0 °C under a nitrogen atmosphere, to which LAH (0.67 g,
17.60 mmol) was added. After the reaction mixture was stirred for
5.5 h at 0 °C, it was quenched with Na2SO4·10H2O and the slurry was
stirred at room temperature. The mixture was filtered through a pad of
silica and washed with CHCl3. After concentration in vacuo, the
residue was chromatographed (SiO2, n-hexane/EtOAc 5/1 to 1/1) to
give fractions that contained the target alcohol.
A stirred solution of the obtained alcohol (0.11 g) in 1.10 mL of
anhydrous CH2Cl2 under a nitrogen atmosphere was cooled to 0 °C,
and 2,6-lutidine (0.11 mL, 0.81 mmol) and Tf2O (0.14 mL,
0.81 mmol) were added. After the mixture was stirred for 1 h at 0 °C,
the reaction was quenched with saturated aqueous NH4Cl. The organic
layer was washed with saturated aqueous NH4Cl, saturated aqueous
NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was chromatographed (SiO2, n-hexane/EtOAc 10/1)
to give fractions containing the triflate compound. The fractions were
combined and concentrated, and the residue was immediately used in the
next reaction.
20
(4.92 mg, 55%) as a colorless amorphous solid: [α]D = −151.7°
1
(c 0.06, CHCl3); IR (neat) 3344, 2958, 2926, 1648 cm−1; H NMR
(CDCl3, 500 MHz) δ 7.08 (NH), 7.04 (NH), 6.12 (dd, J = 3.0, 8.9 Hz,
1H), 5.27 (d, J = 15.2 Hz, 1H), 5.24 (m, 1H), 5.23 (m, 1H), 4.98 (dd,
J = 2.9, 10.0 Hz, 1H), 4.92 (m, 1H), 4.78 (NH), 4.71 (d, J = 17.3 Hz,
1H), 4.15 (m, 1H), 4.13 (m, 1H), 3.88 (d, J = 15.5 Hz, 1H), 3.65 (dd,
J = 4.1, 17.5 Hz, 2H), 3.44 (m, 1H), 3.43 (m, 1H), 3.40 (s, 3H), 3.28
(m, 1H), 3.11 (s, 3H/m, 1H), 2.91 (s, 3H), 2.67 (m, 1H), 2.51 (m,
1H), 2.23 (m, 1H), 1.87 (m, 1H), 1.79 (m, 1H), 1.76 (m, 1H), 1.70
(m, 2H), 1.63 (s, 3H) 1.60 (m, 1H), 1.56 (m, 1H), 1.46 (m, 1H), 1.41
(s, 3H), 1.39 (m, 1H), 1.25 (m, 1H), 1.20 (m, 1H), 1.15 (m, 1H), 1.11
(d, J = 6.8 Hz, 3H), 1.06 (m, 1H), 1.02 (m, 2H), 0.91 (d, J = 6.5 Hz,
3H), 0.88 (s, 3H), 0.85 (m, 3H), 0.80 (m, 3H), 0.79 (m, 3H); 13C
NMR (CDCl3, 125 MHz) δ 174.8, 171.6 171.4, 170.8, 170.7, 168.5,
167.0, 134,1 131.7, 82.3, 80.2, 76.7, 76.1, 57.6, 52.7, 51.7, 51.4, 48.8,
47.2, 46.9, 46.0, 44.8, 42.3, 36.6, 34.7, 31.7, 30.4, 29.7, 29.5, 27.9, 26.9,
26.0, 23.9, 21.4 (2C), 20.1, 19.5, 19.3, 19.0, 18.5, 13.1, 11.4; HRMS
(ESI) m/z 920.5334 [M + Na]+ calcd for C43H75N7NaO13, 920.5315.
PGME Derivatives of the Natural Trimethyloctanoic Acid
(6a,b). To a stirred solution of 3 (4.26 mg, 4.76 × 10−3 mmol)
in MeCN/CCl4/H2O (2/2/3, 0.32 mL) were added RuCl3·xH2O
(6.50 mg, 0.03 mmol) and NaIO4 (41.46 mg, 0.19 mmol). After the
mixture was stirred at room temperature for 12 h, water was added.
The mixture was chromatographed on an ODS column with a stepwise
elution of H2O/MeOH (from 100/0 to 0/100). Fractions eluted with
H2O/MeOH (40/60 to 0/100) were combined and concentrated in
vacuo. The material was split into two portions. One portion of the
material was mixed with HBTU (13.73 mg, 0.04 mmol), HOBt
(6.17 mg, 0.05 mmol), DIEA (11.0 μL, 0.06 mmol), and (R)-PGME·HCl
(7.86 mg, 0.04 mmol) in DMF (0.11 mL), which was stirred at room
temperature. After 9 h, saturated aqueous NH4Cl was added to the
reaction mixture. The organic layer was washed with saturated aqueous
NH4Cl (three times) and concentrated in vacuo. The obtained residue
was chromatographed on an ODS column with a stepwise elution of
H2O/MeOH (from 100/0 to 0/100) and CHCl3/MeOH (1/1).
Fractions eluted with H2O/MeOH (0/100) were subjected to ODS
HPLC on CAPCELL PACK C18 UG120 (i.d. 20 × 250 mm) with
H2O/MeCN (50/50) to afford 6a (0.25 mg, 32%).
A stirred solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone
(99.80 mg, 0.54 mmol) in anhydrous THF (5.40 mL) under a
nitrogen atmosphere was cooled to −78 °C, and 0.34 mL of 1.9 M
NaHMDS was added. After the mixture was stirred for 15 min at
−78 °C, the triflate compound (0.22 g) in 21.60 mL of anhydrous
THF was added dropwise. The reaction mixture was stirred at −78 °C,
warmed to 0 °C, stirred for 5 h, and then quenched with saturated
aqueous NH4Cl. The aqueous layer was extracted with CHCl3, and the
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was chromatographed (SiO2,
n-hexane/EtOAc 5/1) to give a mixture of 8 and its diastereomer. The
mixture was subjected to reversed-phase HPLC (Cosmosil AR-II, i.d.
20 × 250 mm, H2O/MeCN (35/65)) to give 8 (74.90 mg, 40%) as a
colorless oil. The ratio of 8 and its diastereomer was 11:1, as judged
20
from their yield. Compound 8: [α]D = −5.97° (c 1.10, CHCl3); IR
The remaining portion of the carboxylic acid (0.88 mg) was mixed
with HBTU (19.63 mg, 0.05 mmol), HOBt (8.06 mg, 0.06 mmol),
DIEA (16.35 μL, 0.1 mmol), and (S)-PGME·HCl (11.72 mg,
0.06 mmol) in DMF (0.16 mL), which was stirred for 11 h at room
temperature. The reaction mixture was fractionated as described above
to afford 6b (0.25 mg, 32%).
1
(neat) 2932, 2856, 1776, 1206, 701 cm−1; H NMR (CDCl3, 500
MHz) δ 6.86−7.34 (m, 9H), 4.64 (m, 1H), 4.42 (d, J = 4.6 Hz, 2H),
4.15 (dd, J = 8.5 Hz, 1H), 4.08 (dd, J = 3.3, 9.1 Hz, 1H), 3.88 (m, 1H),
3.80 (s, 3H), 3.29 (m, 2H), 3.26 (m, 1H), 2.50 (dd, J = 10.5, 13.4 Hz,
1H), 1.88 (m, 1H), 1.66 (ddd, J = 7.2, 8.2, 14.0 Hz, 1H), 1.51 (ddd,
J = 6.6, 8.7, 14.0 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 177.4, 159.0, 153.0, 135.5,
130.7, 129.34, 129.31, 128.8, 127.2, 113.7, 75.8, 72.7, 65.89, 55.3,
55.2, 38.0, 37.8, 35.3, 31.3, 17.06 (2C); HRMS (ESI) m/z 448.2111
[M + Na]+ calcd for C25H31NNaO5, 448.2094.
Compound 6a: [α]D20 = −84.64° (c 0.02, CHCl3); IR (neat) 3314,
2957, 2922, 2849, 1746, 1648, 1523 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 7.29−7.37 (5H), 6.4 (NH), 5.60 (d, J = 7.2 Hz, 1H), 3.73 (s, 3H), 2.39
(m, 1H), 1.61 (m, 1H), 1.37 (m, 1H), 1.33 (m, 1H), 1.16 (m, 1H), 1.14
(d, J = 6.9 Hz, 3H), 1.13 (m, 1H), 0.98 (m, 2H), 0.81 (d, J = 6.9 Hz,
3H/t, J = 6.9 Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 176.2, 171.9, 128.9, 128.4, 127.2, 56.1, 52.8, 44.3, 42.6, 38.8,
31.5, 30.2, 27.8, 19.4, 18.8, 18.3, 11.3; HRMS (ESI) m/z 356.2196 [M +
Na]+ calcd for C20H31NNaO3, 356.2196.
(2S,4S)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentan-1-ol (9). A
stirred solution of 8 (0.17 g, 0.39 mmol) in anhydrous THF (1.90 mL)
under a nitrogen atmosphere was cooled to 0 °C, and LAH (18.0 mg,
0.48 mmol) was added. After the mixture was stirred for 5 h at 0 °C,
the reaction was quenched with Na2SO4·10H2O and the slurry was
stirred at room temperature. The mixture was filtered through a pad of
silica and washed with EtOAc. After concentration in vacuo, the
residue was chromatographed (SiO2, n-hexane/EtOAc 3/1 to 2/1) to
Compound 6b: [α]D20 = 154.73° (c 0.02, CHCl3); IR (neat) 3293,
1
2960, 2927, 1748, 1647, 1527 cm−1; H NMR (CDCl3, 500 MHz) δ
7.30−7.37 (5H), 6.36 (NH), 5.59 (d, J= 7.3 Hz, 1H), 3.73 (s, 3H),
2.41 (m, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.39 (m, 1H), 1.26 (m,
1H), 1.17 (m, 1H), 1.14 (m, 1H), 1.11 (d, J = 7.1 Hz, 3H), 1.03 (m,
2H), 0.87 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H), 0.79 (d, J = 6.4
Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 175.9, 171.5, 129.0, 128.5,
20
yield 9 (90.77 mg, 93%) as a colorless oil: [α]D = −14.4° (c 0.98,
CHCl3); IR (neat) 3410, 2910, 2851, 1244, 1033, 818 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.24 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.6 Hz,
F
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2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.44 (dd, J = 6.4, 10.5 Hz, 1H), 3.39
(dd, J = 6.4, 10.7 Hz, 1H), 3.26 (dd, J = 6.7, 9.0 Hz, 1H), 3.23 (dd, J =
6.3, 9.0 Hz, 1H), 1.87 (m, 1H), 1.73 (m, 1H), 1.19 (m, 2H), 0.89 (d,
J = 7.1 Hz, 3H), 0.88 (d, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 159.0, 130.6, 129.1, 113.7, 76.2, 72.6, 68.7, 55.2, 37.2, 32.9,
30.5, 16.9, 16.3; HRMS (ESI) m/z 275.1619 [M + Na]+ calcd for
C15H24NaO3, 275.1618.
1-((((2S,4R)-2,4-Dimethylhexyl)oxy)methyl)-4-methoxybenzene
(10). To a stirred solution of 9 (0.65 g, 2.59 mmol) in 17.30 mL of
anhydrous CH2Cl2 under a nitrogen atmosphere were added Et3N
(0.90 mL, 6.48 mmol), DMAP (32.0 mg, 0.26 mmol), and TsCl
(0.60 g, 3.17 mmol) at room temperature. After the mixture was
stirred for 12 h, saturated aqueous NH4Cl was added. The organic
layer was dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was chromatographed (SiO2, n-hexane/EtOAc 5/1) to
give fractions containing tosylated compounds.
1H NMR (CDCl3, 500 MHz) δ 7.19−7.35 (5H), 4.68 (m, 1H), 4.17
(m, 2H), 3.94 (m, 1H), 3.29 (dd, J = 3.6, 13.5 Hz, 1H), 2.72 (dd, J =
9.7, 13.3 Hz, 1H), 1.82 (ddd, J = b 6.4, 8.1, 14.1 Hz, 1H), 1.55 (m,
1H), 1.42 (m, 1H), 1.27 (m, 1H), 1.22 (m, 1H), 1.16 (m, 1H/d, J =
6.7 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.10 (m, 2H), 0.89 (d, J = 6.8
Hz, 3H), 0.86 (t, J = 7.5 Hz, 3H), 0.82 (d, J = 12.4 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 177.7, 153.0, 135.4, 129.4, 128.9, 127.3, 65.9,
55.3, 43.9, 42.1, 38.0, 35.2, 31.6, 30.3, 28.2, 19.8, 18.9, 17.8, 11.4;
HRMS (ESI) m/z 368.2197 [M + Na]+ calcd for C21H31NNaO3,
368.2196.
(R)-Methyl-2-phenyl-2-((2S,4S,6R)-2,4,6-trimethyloctamido)-
acetate (13a). To a stirred solution of 11 (24.90 mg, 5.85 ×
10−2 mmol) in THF/H2O (4/1, 0.98 mL) was added LiOH·H2O
(7.36 mg, 0.18 mmol) and 30% aqueous H2O2 (66.30 μL, 0.59 mmol)
at 0 °C. The mixture was stirred for 1 h at 0 °C, warmed to room
temperature, stirred for 2.5 h, and then quenched with saturated
aqueous Na2S2O3. After being acidified with 6 N HCl, the reaction
mixture was extracted with CHCl3. The organic layers were combined
and concentrated in vacuo to give a residue containing 12.
A half-portion of the material above containing 12 (18.20 mg),
HBTU (76.80 mg, 0.20 mmol), HOBt (31.10 mg, 0.20 mmol), DIEA
(33.70 mL, 0.20 mmol), and (R)-PGME·HCl (42.60 mg, 0.21 mmol)
were dissolved in 0.98 mL of anhydrous DMF, and this mixture was
stirred for 10 h at room temperature. The reaction was quenched with
saturated aqueous NH4Cl, dried over anhydrous Na2SO4, and concentrated
A mixture of CuI (0.45 g, 2.34 mmol) and 1 M MeMgBr (23.40 mL,
23.40 mmol) was cooled to −20 °C under a nitrogen atmosphere, and
the tosylated material (0.95 g) in anhydrous THF was added. The
mixture was warmed to 0 °C and stirred for 10 h. The reaction was
quenched with saturated aqueous NH4Cl and filtered through Celite.
The organic layer was washed with saturated aqueous NH4Cl, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
chromatopraphed (SiO2, n-hexane/EtOAc 50/1) to yield 10 (0.53 g,
20
83% over two steps) as a colorless oil: [α]D = −11.75° (c 1.03,
1
CHCl3); IR (neat) 2957, 2911, 1512, 1245, 1096, 819 cm−1; H NMR
in vacuo. The residue was chromatographed (SiO2, n-hexane/EtOAc 3/1)
20
to yield 13a (8.70 mg, 89%) as a colorless amorphous solid: [α]D
=
(CDCl3, 500 MHz) δ 7.31 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H),
4.48 (d, J = 2.6 Hz, 2H), 3.81 (s, 3H), 3.34 (dd, J = 5.7, 8.9 Hz, 1H),
325 (dd, J = 7.4, 9.2 Hz, 1H), 1.91 (m, 1H), 1.48 (m, 1H), 1.37 (m,
1H), 1.23 (m, 1H), 1.22 (m, 1H), 1.15 (m, 1H), 0.97 (d, J = 6.8 z, 3H),
0.93 (t, J = 7.4 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 158.9, 130.8, 128,8, 113.5, 76.3, 72.5, 54.9,
40.6, 31.5, 30.8, 30.3, 18.8, 16.9, 11.3; HRMS (ESI) m/z 273.1821
[M + Na]+ calcd for C16H26NaO2, 273.1825.
(R)-4-Benzyl-3-((2S,4S,6R)-2,4,6-trimethyloctanoyl)oxazolidin-2-
one (11). A stirred solution of 10 (0.24 g, 0.95 mmol) in CH2Cl2/H2O
(15/1, 9.50 mL) was cooled to 0 °C, and DDQ (0.33 g, 1.44 mmol)
was added. After the mixture was stirred for 1 h at 0 °C, the reaction
was quenched with saturated aqueous NaHCO3. The organic layer was
washed with saturated aqueous NaHCO3, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was chromato-
graphed (SiO2, n-hexane/Et2O 4/1) to give a fraction that contained
the target alcohol.
A stirred solution of the obtained material (0.28 g) in anhydrous
CH2Cl2 (4.40 mL) under a nitrogen atmosphere was cooled to 0 °C,
and 2,6-lutidine (0.45 g, 3.27 mmol) and Tf2O (0.55 g, 3.27 mmol)
were added. After the mixture was stirred for 1 h at 0 °C, the reaction
was quenched with saturated aqueous NH4Cl. The organic layer was
washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3,
and brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was chromatographed (SiO2, n-hexane/EtOAc 20/1) to
give a fraction that contained triflated material. The fraction was
concentrated in vacuo, and the residue was immediately used in the
next reaction.
−127.05° (c 0.72, CHCl3); IR (neat) 2959, 2924, 1779, 1697, 1384, 1206,
1
701 cm−1; H NMR (CDCl3, 500 MHz) δ 7.29−7.36 (5H), 6.42 (NH),
5.60 (d, J = 7.5 Hz, 1H), 3.73 (s, 3H), 2.39 (m, 1H), 1.61 (m, 1H), 1.37
(m, 1H), 1.32 (m, 1H), 1.16 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H), 1.12 (m,
1H), 1.07 (m, 1H), 0.97 (m, 2H), 0.81 (d, J = 7.4 Hz, 3H), 0.80 (t, J = 7.4
Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 175.9,
171.5, 136.8, 128.9, 128.4, 127.2, 56.1, 52.7, 44.3, 42.7, 38.8, 31.5, 30.2, 27.9,
19.4, 18.8, 18.3, 11.3; HRMS (ESI) m/z 356.2200 [M + Na]+ calcd for
C20H31NNaO3, 356.2196.
(S)-Methyl-2-phenyl-2-((2S,4S,6R)-2,4,6-trimethyloctamido)-
acetate (13b). A solution of the remaining half-portion of the above
material containing 12 (19.10 mg), HBTU (78.50 mg, 0.21 mmol),
HOBt (33.0 mg, 0.24 mmol), DIEA (35.50 mL, 0.21 mmol), and
(S)-PGME·HCl (44.80 mg, 0.22 mmol) in 1.0 mL of anhydrous DMF
was stirred for 10 h at room temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was chromato-
graphed (SiO2, n-hexane/EtOAc 3/1) to yield 13b (6.0 mg, 61% over
20
two steps) as a colorless oil: [α]D = +113.41° (c 0.50, CHCl3); IR
(neat) 3300, 2960, 2927, 1749, 1647 cm−1; 1H NMR (CDCl3,
500 MHz) δ 7.30−7.37 (5H), 6.36 (NH), 5.59 (d, J = 7.4 Hz, 1H),
3.73 (s, 3H), 2.41 (m, 1H), 1.65 (ddd, J = 6.0, 8.5, 14.0 Hz, 1H), 1.54
(m, 1H), 1.39 (m, 1H), 1.25 (m, 1H), 1.17 (m, 1H), 1.14 (m, 1H),
1.11 (d, J = 6.4 Hz, 3H), 1.03 (m, 2H), 0.87 (d, J = 6.8 Hz, 3H), 0.85
(t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 175.9, 171.5, 136.7, 129.0, 128.7, 127.2, 56.1, 52.7, 44.3, 42.5,
38.2, 31.6, 30.4, 27.9, 19.6, 18.9, 18.3, 11.4; HRMS (ESI) m/z
356.2201 [M + Na]+ calcd for C20H31NNaO3, 356.2196.
A stirred solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone
(0.16 g, 0.71 mmol) in anhydrous THF (7.10 mL) under a nitrogen
atmosphere was cooled to −78 °C, and 0.45 mL of 1.9 M NaHMDS
was added. After the mixture was stirred for 15 min at −78 °C, the
triflated material (0.12 g) in 15.10 mL of anhydrous THF was added
dropwise. The reaction mixture was stirred at −78 °C, warmed to
0 °C, stirred for 5.5 h, and then quenched with saturated aqueous
NH4Cl. The aqueous layer was extracted with CHCl3, and the
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was chromatographed (SiO2,
n-hexane/EtOAc 5/1) to give a mixture of 11 and its diastereomer.
The mixture was subjected to reversed-phase HPLC (YMC
Carotenoid, i.d. 20 × 250 mm, H2O/MeCN (35/65)) to yield 11
(50.6 mg, 15% over three steps) as a colorless oil. The ratio of 11 and
its diastereomer was 48:1, as judged from their yield: [α]D20 = −37.88°
(c 2.32, CHCl3); IR (neat) 2959, 2924, 1779, 1697, 1384, 1206, 701 cm−1;
PGME Derivatives of Synthetic (2S,4S,6S)-Trimethyloctanoic
Acid (14a,b). (S)-4-Benzyl-3-((2R,4S)-5-((4-methoxybenzyl)oxy)-2,4-
dimethylpentanoyl)oxazolidin-2-one (S1).
This compound was synthesized in the same manner as that of 8
(1.7 g, 53% over four steps). The ratio of S1 and its diastereomer was
27:1, as judged from their yield: [α]D20 = +21.49° (c 0.73, CHCl3); IR
(neat) 2957, 2931, 2854, 1775, 1694, 1207, 702 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 6.84−7.34 (9H), 4.66 (m, 1H), 4.44 (s, 2H),
4.09−4.18 (m, 2H), 3.96 (m, 1H), 3.77 (s, 3H), 3.28 (dd, J = 3.2, 13.5
Hz, 1H), 3.41 (dd, J = 5.5, 8.7 Hz, 1H), 3.24 (dd, J = 6.7, 9.1 Hz, 1H),
2.67 (dd, J = 10.3, 13.9 Hz, 1H), 1.96 (ddd, J = 6.2, 7.5, 14.0 Hz, 1H),
G
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1.86 (m, 1H), 1.25 (ddd, J = 6.3, 7.5, 13.6 Hz, 1H), 1.20 (d, J = 6.7 Hz,
3H), 1.0 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.1,
158.9, 152.9, 135.3, 130.7, 129.2, 128.9, 128.8, 127.1, 113.6, 75.2, 72.4,
65.8, 55.2, 55.1, 37.9 (2C), 35.1, 31.3, 17.9, 17.6; HRMS (ESI) m/z
448.2119 [M + Na]+ calcd for C25H31NNaO5, 448.2094; colorless oil.
(2R,4S)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentan-1-ol (S2).
175.8, 171.6, 136.8, 128.9, 128.4, 127.2, 56.1, 52.7, 44.9, 41.9, 38.9,
31.3, 28.0, 29.0, 20.2, 19.5, 18.6, 11.2; HRMS (ESI) m/z 356.2199
[M + Na]+ calcd for C20H31NNaO3, 356.2196; colorless oil.
(S)-Methyl 2-Phenyl-2-((2S,4S,6S)-2,4,6-trimethyloctamido)-
acetate (14b).
This compound was synthesized in the same manner as that of 9 (0.8
g, 87%): [α]D20 = +5.73° (c 1.07, CHCl3); IR (neat) 3405, 2910, 2869,
1
1512, 1246, 1035 cm−1; H NMR (CDCl3, 500 MHz) δ 7.23 (d, J =
This compound was synthesized in the same manner as that of 13b
20
8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 4.40 (d, J = 3.4 Hz, 2H), 3.75 (s,
3H), 3.40 (dd, J = 5.3, 10.8 Hz, 1H), 3.31 (dd, J = 5.8, 10.3 Hz, 1H),
3.28 (dd, J = 5.8, 8.9 Hz, 1H), 3.19 (dd, J = 6.4, 9.7 Hz, 1H), 1.83 (m,
1H), 1.66 (m, 1H), 1.45 (m, 1H), 0.93 (d, J = 7.5 Hz, 3H), 0.91 (d, J =
6.9 Hz, 3H), 0.90 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 158.8,
130.4, 128.9, 113.5, 75.4, 72.4, 67.3, 54.9, 37.4, 32.9, 30.7, 17.9, 17.4;
HRMS (ESI) m/z 275.1616 [M + Na]+ calcd for C15H24NaO3,
275.1618; colorless oil.
(9.2 mg, 91% over two steps): [α]D = 114.56° (c 0.92, CHCl3); IR
1
(neat) 3296, 2957, 2927, 1748, 1645, 697 cm−1; H NMR (CDCl3,
500 MHz) δ 7.30−7.37 (5H), 6.36 (NH), 5.59 (d, J = 7.3 Hz, 1H),
3.73 (s, 3H), 2.41 (m, 1H), 1.72 (ddd, J = 4.8, 9.5, 14.1 Hz, 1H), 1.53
(m, 1H), 1.41 (m, 1H), 1.32 (m, 1H), 1.12 (d, J = 6.5 Hz, 3H), 1.17
(m, 1H), 1.05 (m, 1H), 1.04 (m, 1H), 0.92 (m, 1H), 0.89 (d, J = 7.0
Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 175.8, 171.5, 136.7, 129.0, 128.4, 127.2, 56.2,
52.7, 45.0, 41.7, 38.9, 31.5, 29.1, 28.0, 20.3, 19.7, 18.7, 11.2; HRMS
(ESI) m/z 356.2204 [M + Na]+ calcd for C20H31NNaO3, 356.2196;
colorless oil.
1-((((2S,4S)-2,4-Dimethylhexyl)oxy)methyl)-4-methoxybenzene
(S3).
PGME Derivatives of Synthetic (2S,4R,6R)-Trimethyloctanoic
acid (15a,b). (R)-4-Benzyl-3-((2S,4R)-5-((4-methoxybenzyl)oxy)-2,4-
dimethylpentanoyl)oxazolidin-2-one (S5).
This compound was synthesized in the same manner as that of 10 (0.6
g, 75% over two steps): [α]D = +12.06° (c 0.84, CHCl3); IR (neat)
20
2956, 2910, 1511, 1245, 1095, 819 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.30 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 9.5 Hz, 2H), 4.47 (d, J =
7.6 Hz, 2H), 3.82 (s, 3H), 3.37 (dd, J = 7.2, 9.2 Hz, 1H), 3.22 (dd, J =
5.3, 9.1 Hz, 1H), 1.90 (m, 1H), 1.47 (m, 1H), 1.40 (m, 1H), 1.39 (m,
1H), 1.14 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 (m, 1H), 0.92 (d, J =
6.7 Hz, 3H), 0.91 (t, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ 158.9, 130.9, 128.9, 113.6, 75.7, 72.5, 55.0, 41.1, 31.5, 30.8, 29.0,
19.7, 17.9, 11.1; HRMS (ESI) m/z 273.1823 [M + Na]+ calcd for
C16H26NaO2, 273.1825; colorless oil.
This compound was synthesized in the same manner as that of 8 (1.7
g, 33% over four steps). The ratio of S5 and its diastereomer was 10:1,
as judged from their yield: [α]D20 = +7.02° (c 0.71, CHCl3); IR (neat)
2976, 2934, 2857, 1776, 1695, 1206, 1093, 701 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 6.86−7.33 (9H), 4.62 (m, 1H), 4.42 (s, 2H),
4.13 (m, 1H), 4.06 (dd, J = 3.0, 9.1 Hz, 1H), 3.89 (m, 1H), 3.79 (s,
3H), 3.25 (dd, J = 3.2, 13.4 Hz, 1H), 3.30 (m, 2H), 2.51 (dd, J = 10.2,
13.2 Hz, 1H), 1.89 (m, 1H), 1.67 (ddd, J = 7.0, 8.0, 14.6 Hz, 1H), 1.52
(ddd, J = 6.4, 7.5, 13.8 Hz, 1H), 1.16 (d, J = 7.0 Hz, 3H), 0.97 (d, J =
6.8 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.3, 159.0, 152.9,
135.5, 130.7, 129.9 (2C), 113.6, 128.8, 127.1, 75.8, 72.7, 65.8, 55.6
(2C), 37.9, 37.8, 35.2, 31.2, 17.0 (2C); HRMS (ESI) m/z 448.2115
[M + Na]+ calcd for C25H31NNaO5, 448.2094; colorless oil.
(R)-4-Benzyl-3-((2S,4S,6S)-2,4,6-trimethyloctanoyl)oxazolidin-2-
one (S4).
This compound was synthesized in the same manner as that of 11
(41.2 mg, 11% over three steps). The ratio of S4 and its diastereomer
(2S,4R)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentan-1-ol (S6).
20
was 54:1, as judged from their yield: [α]D = −20.58° (c 0.83,
1
CHCl3); IR (neat) 2957, 2913, 1778, 1696, 1383, 1204 cm−1; H
NMR (CDCl3, 500 MHz) δ 7.20−7.35 (5H), 4.69 (m, 1H), 4.16 (m,
2H), 3.97 (m, 1H), 3.30 (dd, J = 3.5, 13.8 Hz, 1H), 2.73 (dd, J = 9.8,
13.3 Hz, 1H), 1.92 (ddd, J = 5.1, 9.0, 13.7 Hz, 1H), 1.71 (d, J = 6.8 Hz,
3H), 1.51 (m, 1H), 1.47 (m, 1H), 1.34 (m, 1H), 1.26 (m, 1H), 1.11
(m, 1H), 1.08 (m, 1H), 0.94 (m, 1H), 0.92 (d, J = 7.1 Hz, 3H), 0.86
(t, J = 7.8 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 177.6, 153.0, 135.3, 129.4, 128.9, 127.3, 65.8, 55.3, 44.5, 41.3,
38.0, 35.1, 31.4, 29.0, 28.3, 20.6, 19.6, 18.2, 11.1; HRMS (ESI) m/z
368.2197 [M + Na]+ calcd for C21H31NNaO3, 368.2196; colorless oil.
(R)-Methyl 2-Phenyl-2-((2S,4S,6S)-2,4,6-trimethyloctamido)-
acetate (14a).
This compound was synthesized in the same manner as that of 9 (0.7
20
g, 77%): [α]D = +15.03° (c 0.92, CHCl3); IR (neat) 3405, 2912,
1
2869, 1512, 1244, 1033, 819 cm−1; H NMR (CDCl3, 500 MHz) δ
7.24 (d, J = 8.3rrr Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.42 (s, 2H), 3.77
(s, 3H), 3.41 (dd, J = 6.5, 10.5 Hz, 1H), 3.36 (dd, J = 6.3, 10.5 Hz,
1H), 3.27 (dd, J = 6.3, 8.8 Hz, 1H), 3.23 (dd, J = 6.9, 9.2 Hz, 1H), 1.87
(m, 1H), 1.71 (m, 1H), 1.18 (m, 2H), 0.89 (d, J = 6.6 Hz, 3H), 0.87
(d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.9, 139.0,
130.5, 113.5, 76.0, 72.5, 68.4, 55.0, 37.0, 32.8, 30.4, 16.8, 16.2; HRMS
(ESI) m/z 275.1616 [M + Na]+ calcd for C15H24NaO3, 275.1618;
colorless oil.
1-((((2R,4R)-2,4-Dimethylhexyl)oxy)methyl)-4-methoxybenzene
(S7).
This compound was synthesized in the same manner as that of 10 (0.6
20
This compound was synthesized in the same manner as that of 13a
g, 96% over two steps): [α]D = +12.09° (c 0.82, CHCl3), IR (neat)
20
2956, 2910, 2850, 1511, 1246, 1096, 820 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.31 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 4.49 (d, J =
2.5 Hz, 2H), 3.81 (s, 3H), 3.35 (dd, J = 5.8, 8.9 Hz, 1H), 3.25 (dd, J =
7.1, 8.9 Hz, 1H), 1.92 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 1.23 (m,
2H), 1.16 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H),
0.91 (d, J = 6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.9, 130.8,
128.9, 113.6, 76.3, 72.4, 55.0, 40.6, 31.5, 30.8, 30.3, 18.8, 16.9, 11.3; IR
(8.08 mg, 86% over two steps): [α]D = −102.90° (c 0.81, CHCl3);
IR (neat) 3293, 2956, 2926, 1746, 1648 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.29−7.36 (5H), 6.42 (NH), 5.60 (d, J = 7.3 Hz, 1H), 3.73 (s,
3H), 2.39 (m, 1H), 1.68 (ddd, J = 4.6, 9.7, 14.0 Hz, 1H), 1.34 (m,
2H), 1.22 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H), 1.10 (m, 1H), 1.02 (m,
1H), 0.95 (m, 1H), 0.85 (m, 1H), 0.83 (d, J = 6.7 Hz, 3H), 0.79 (t, J =
7.5 Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
H
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Article
(neat) 2956, 2910, 2810, 1511, 1245, 1096, 819 cm−1; 1H NMR
(CDCl3, 500 MHz); HRMS (ESI) m/z 273.1823 [M + Na]+ calcd for
C16H26NaO2, 273.1825; colorless oil.
(R)-4-Benzyl-3-((2S,4R,6R)-2,4,6-trimethyloctanoyl)oxazolidin-2-
one (S8).
(neat) 2958, 2931, 2854, 1775, 1695, 1385, 1207, 1092, 819, 702 cm−1;
1H NMR (CDCl3, 500 MHz) δ 6.85−7.35 (9H), 4.67 (m, 1H), 4.45 (s,
2H), 4.11−4.19 (m, 2H), 3.96 (m, 1H), 3.41 (dd, J = 5.8, 9.5 Hz, 1H),
3.29 (dd, J = 3.5, 13.2 Hz, 1H), 3.24 (dd, J = 7.0, 9.3 Hz, 1H), 2.67 (dd, J
= 9.7, 13.2 Hz, 1H), 1.97 (ddd, J = 6.2, 8.2, 14.1 Hz, 1H), 1.86 (m, 1H),
1.25 (ddd, J = 6.4, 7.5, 13.6 Hz, 1H), 1.20 (d, J = 6.8 Hz, 3H), 1.00 (d,
J = 6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 177.2, 158.9, 153.0,
135.3, 130.8, 129.3, 129.0, 128.8, 127.2, 113.6, 75.2, 72.5, 65.8, 55.3, 55.1,
38.0, 37.9, 35.1, 31.3, 18.0, 17.7; HRMS (ESI) m/z 448.2106 [M + Na]+
calcd for C25H31NNaO5, 448.2094; colorless oil.
This compound was synthesized in the same manner as that of 11
(36.3 mg, 16% over 3 steps). The ratio of S8 and its diastereomer was
3:1, as judged from their yield: [α]D20 = −15.79° (c 0.94, CHCl3); IR
(2R,4R)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentan-1-ol
(S10).
1
(neat) 2960, 2916, 1780, 1698, 1383, 1209 cm−1; H NMR (CDCl3,
500 MHz) δ 7.20−7.35 (5H), 4.68 (m, 1H), 4.16 (m, 2H), 3.89 (m,
1H), 3.32 (dd, J = 3.6, 13.9 Hz, 1H), 2.69 (dd, J = 10.1, 13.0 Hz, 1H),
1.63 (m, 1H), 1.59 (m, 1H), 1.41 (m, 1H), 1.35 (m, 1H), 1.29 (m,
1H), 1.16 (m, 1H/d, J = 7.0 Hz, 3H), 1.10 (m, 2H), 0.89 (d, J = 5.8
Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 177.8, 153.0, 135.5, 129.4, 128.9, 127.3, 65.9,
55.4, 44.7, 41.7, 38.1, 35.3, 31.6, 30.2, 27.9, 19.0 (2C), 16.8, 11.4;
HRMS (ESI) m/z 368.2198 [M + Na]+ calcd for C21H31NNaO3,
368.2196; colorless oil.
This compound was synthesized in the same manner as that of 9 (0.8
20
g, 85%): [α]D = −5.22° (c 1.05, CHCl3); IR (neat) 3362, 2911,
1
2869, 1511, 1246, 1033, 822 cm−1; H NMR (CDCl3, 500 MHz) δ
7.23 (d, J = 9.2 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.40 (d, J = 3.5 Hz,
2H), 3.75 (s, 3H), 3.40 (dd, J = 5.3, 10.2 Hz, 1H), 3.31 (dd, J = 6.2,
10.5 Hz, 1H), 3.28 (dd, J = 6.0, 9.1 Hz, 1H), 3.19 (dd, J = 7.1, 9.4 Hz,
1H), 1.83 (m, 1H), 1.66 (m, 1H), 1.45 (m, 1H), 0.93 (d, J = 6.9 Hz,
3H), 0.91 (d, J = 6.4 Hz, 3H), 0.90 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 158.9, 130.4, 128.9, 113.5, 75.4, 72.5, 67.3, 54.9, 37.5, 32.9,
30.7, 17.9, 17.4; HRMS (ESI) m/z 275.1613 [M + Na]+ calcd for
C15H24NaO3, 275.1618; colorless oil.
(R)-Methyl 2-Phenyl-2-((2S,4R,6R)-2,4,6-trimethyloctamido)-
acetate (15a).
1-((((2R,4S)-2,4-Dimethylhexyl)oxy)methyl)-4-methoxybenzene
(S11).
This compound was synthesized in the same manner as that of 10 (0.6
g, 76% over two steps): [α]D20 = −10.43° (c 1.21, CHCl3); IR (neat)
2910, 2851, 1512, 1245, 1095, 819 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.30 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.67 (d, J =
7.6 Hz, 2H), 3.82 (s, 3H), 3.36 (dd, J = 5.5, 9.0 Hz, 1H), 3.21 (dd, J =
7.3, 9.3 Hz, 1H), 1.89 (m, 1H), 1.46 (m, 1H), 1.40 (m, 1H), 1.38 (m,
1H), 1.13 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H), 0.97 (m, 1H), 0.91 (d, J =
6.3 Hz, 3H/t, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.0,
130.9, 128.9, 113.6, 75.7, 72.5, 55.0, 41.1, 31.5, 30.9, 29.0, 19.7, 18.0,
11.1; HRMS (ESI) m/z 273.1821 [M + Na]+ calcd for C16H26NaO2,
273.1825; colorless oil.
This compound was synthesized in the same manner as that of 13a
20
(8.0 mg, 82% over two steps): [α]D = −82.39° (c 0.74, CHCl3); IR
1
(neat) 3282, 2959, 2920, 1751, 1634 cm−1; H NMR (CDCl3, 500
MHz) δ 7.29−7.36 (5H), 6.38 (NH), 5.60 (d, J = 7.8 Hz, 1H), 3.73 (s,
3H), 2.38 (m, 1H), 1.50 (m, 1H), 1.46 (m, 1H), 1.35 (m. 1H), 1.27
(m, 1H), 1.23 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H), 1.02 (m, 2H), 0.96
(m, 1H), 0.83 (t, J = 7.7 Hz, 3H), 0.77 (d, J = 6.5 Hz, 3H), 0.70 (d, J =
6.7 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 176.1, 171.6, 136.7,
128.9, 128.4, 128.3, 56.2, 52.8, 44.4, 42.3, 38.8, 31.6, 30.4, 27.8, 19.4,
18.8, 17.8, 11.4; HRMS (ESI) m/z 356.2200 [M + Na]+ calcd for
C20H31NNaO3, 356.2196; colorless amorphous solid.
(R)-4-Benzyl-3-((2S,4R,6S)-2,4,6-trimethyloctanoyl)oxazolidin-2-
one (S12).
(S)-Methyl 2-Phenyl-2-((2S,4R,6R)-2,4,6-trimethyloctamido)-
acetate (15b).
This compound was synthesized in the same manner as that of 11
(39.4 mg, 15% over three steps). The ratio of S12 and its diastereomer
was 4:1, as judged from their yield: [α]D20 = −41.31° (c 0.75, CHCl3);
IR (neat) 2959, 2915, 1779, 1697, 1209 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.20−7.34 (5H), 4.67 (m, 1H), 3.85 (m, 1H), 3.30 (dd, J =
2.8, 13.7 Hz, 1H), 2.70 (dd, J = 10.0, 13.5 Hz, 1H), 1.61 (m, 1H), 1.52
(m, 1H), 1.43 (m, 1H), 1.42 (m, 1H), 1.34 (m, 1H), 1.24 (m, 1H),
1.15 (d, J = 7.0 Hz, 3H), 1.08 (m, 1H), 0.99 (m, 1H), 0.91 (d, J = 6.4
Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 177.8, 152.9, 135.4, 129.4, 128.9, 127.3, 65.9,
55.3, 45.1, 40.6, 38.0, 35.3, 31.5, 29.2, 27.7, 19.7, 19.5, 16.4, 11.2;
HRMS (ESI) m/z 368.2198 [M + Na]+ calcd for C21H31NNaO3,
368.2196; colorless oil.
This compound was synthesized in the same manner as that of 13b
(8.5 mg, 88% over two steps): [α]D20 = +128.66° (c 0.73, CHCl3); IR
1
(neat) 3295, 2959, 2926, 1748, 1647 cm−1; H NMR (CDCl3, 500
MHz) δ 7.23−7.37 (5H), 6.38 (NH), 5.58 (d, J = 6.5 Hz, 1H), 3.73 (s,
3H), 2.38 (m, 1H), 1.54 (m, 1H), 1.53 (m, 1H), 1.40 (m, 1H), 1.31
(m, 1H), 1.27 (m, 1H), 1.14 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H), 1.08
(m, 2H), 0.86 (t, J = 7.4 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H), 0.81 (d, J =
7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 176.1, 171.5, 136.8,
128.9, 128.5, 127.2, 56.2, 52.7, 44.5, 42.4, 38.8, 31.7, 30.4, 27.8, 19.4,
18.9, 17.6, 11.4; HRMS (ESI) m/z 356.2195 [M + Na]+ calcd for
C20H31NNaO3, 356.2196; colorless oil.
(R)-Methyl 2-Phenyl-2-((2S,4R,6S)-2,4,6-trimethyloctamido)-
acetate (16a).
PGME Derivatives of Synthetic (2S,4R,6S)-Trimethyloctanoic
Acid (16a,b). (S)-4-Benzyl-3-((2R,4R)-5-((4-methoxybenzyl)oxy)-2,4-
dimethylpentanoyl)oxazolidin-2-one (S9).
This compound was synthesized in the same manner as that of 8
(1.9 g, 32% over four steps). The ratio of S9 and its diastereomer was
23:1, as judged from their yield: [α]D20 = −21.85° (c 0.93, CHCl3); IR
This compound was synthesized in the same manner as that of 13a
20
(10.7 mg, 87% over two steps): [α]D = −117.43° (c 0.89, CHCl3);
IR (neat) 3275, 2959, 2915, 1752, 1641, 1535 cm−1; 1H NMR
I
dx.doi.org/10.1021/jo500906v | J. Org. Chem. XXXX, XXX, XXX−XXX

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(CDCl3, 500 MHz) δ 7.30−7.37 (5H), 6.40 (NH), 5.60 (d, J = 8.1 Hz,
1H), 3.73 (s, 3H), 2.36 (m, 1H), 1.48 (m, 1H), 1.38 (m, 2H), 1.37 (m,
1H), 1.26 (m, 1H), 1.17 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.97 (m,
1H), 0.90 (m, 1H), 0.80 (m, 3H), 0.79 (m, 3H) 0.78 (m, 3H); 13C
NMR (CDCl3, 125 MHz) δ 176.2, 171.6, 136.7, 129.0, 128.5, 127.3,
56.2, 52.7, 44.9, 41.3, 38.7, 31.4, 29.0, 27.8, 20.1, 19.7, 17.5, 11.2;
HRMS (ESI) m/z 356.2205 [M + Na]+ calcd for C20H31NNaO3,
356.2196; colorless oil.
(12) Stahl, M.; Schopfer, U.; Frenking, G.; Hoffmann, R. W. J. Org.
Chem. 1996, 61, 8083.
(13) Kishimoto, S.; Tsunematsu, Y.; Nishimura, S.; Hayashi, Y.;
Hattori, A.; Kakeya, H. Tetrahedron 2012, 68, 5572.
(14) Motohashi, K.; Toda, T.; Sue, M.; Furihata, K.; Shizuri, Y.;
Matsuo, Y.; Kasai, H.; Shin-Ya, K.; Takagi, M.; Izumikawa, M.;
Horikawa, Y.; Seto, H. J. Antibiot. 2010, 63, 549.
(15) Nishiyama, Y.; Sugawara, K.; Tomita, K.; Yamamoto, H.; Kamei,
H.; Oki, T. J. Antibiot. 1993, 46, 921.
(16) Sugawara, K.; Toda, S.; Moriyama, T.; Konishi, M.; Oki, T. J.
Antibiot. 1993, 46, 928.
(S)-Methyl 2-Phenyl-2-((2S,4R,6S)-2,4,6-trimethyloctamido)-
acetate (16b).
(17) Reduction using NaBH4 gave two diastereomers, compound 4
and its epimer at C24. The ratio of compound 4 and its diastereomer
was 2.5:1.
(18) Stahl, M.; Schopfer, U.; Frenking, G.; Hoffmann, R. W. Mol.
Phys. 1997, 92, 569.
(19) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J.
Am. Chem. Soc. 1990, 112, 5290.
This compound was synthesized in the same manner as that of 13a
(11.3 mg, 92% over two steps): [α]D20 = +104.87° (c 0.94, CHCl3); IR
1
(neat) 3307, 2958, 2928, 1749, 1649, 1524 cm−1; H NMR (CDCl3,
(20) The ratio of compound 8 and its diastereomer was 10.6:1. The
absolute stereochemistry at the β position in these compounds was
confirmed by analyzing PGME derivatives of the hydrolyzed products.
(21) Xaio, J.; Kumazawa, S.; Yoshikawa, N.; Mikawa, T.; Sato, Y. J.
Antibiot. 1993, 46, 48.
(22) Lin, Z.; Flores, M.; Forteza, I.; Henriksen, N. M.; Concepcion,
G. P.; Rosenberg, G.; Haygood, M. G.; Olivera, B. M.; Light, A. R.;
Cheatham, T. E., 3rd; Schmidt, E. W. J. Nat. Prod. 2012, 75, 644.
(23) Tsantrizos, Y. S.; Shen, J. H.; Trimble, L. A. Tetrahedron Lett.
1997, 38, 7033.
500 MHz) δ 7.30−7.37 (5H), 6.39 (NH), 5.57 (d, J = 6.9 Hz, 1H),
3.73 (s, 3H), 2.37 (m, 1H), 1.55 (m, 1H), 1.43 (m, 1H), 1.42 (m, 2H),
1.34 (m, 1H), 1.23 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 1.05 (m, 1H),
0.95 (m, 1H), 0.85 (m, 6H), 0.84 (m, 3H); 13C NMR (CDCl3, 125
MHz) δ 176.1, 171.5, 136.7, 128.9, 128.5, 127.2, 56.2, 52.7, 44.5, 42.1,
38.8, 31.6, 30.4, 27.8, 20.9, 19.4, 17.6, 11.4; HRMS (ESI) m/z
356.2203 [M + Na]+ calcd for C20H31NNaO3, 356.2196; colorless oil.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, a table, and figures giving H and 13C NMR spectra of
1
synthesized materials and natural product derivatives and a list
of analyzed compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for H.K.: scseigyo-hisyo@pharm.kyoto-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by research grants from the
Japan Society for the Promotion of Sciences (JSPS), the
Ministry of Health and Welfare of Japan, and the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
of Japan.
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