Synthesis and Configuration of a p-Aminoacetophenonic Acid Isolated from Endophyte of the Mangrove Plant Kandel candel

Article abstract of DOI:10.1002/ejoc.202000837

Two diastereomers of the title compound were synthesized through an enantioselective route, with the stereogenic center at the C-2 derived from a commercially available reagent and the one at the C-4 installed via Evans asymmetric aldol condensation. By comparison of ¹H and ¹³C NMR spectra as well as optical rotation, the configuration of the natural product was as assigned as (-2R,4R). Some interesting issues such as suppression of the undesired yet dominating formation of cyclic ethers associated with deprotection of a TBS protected terminal hydroxyl group and the previously unknown differences in ¹H NMR and IR between the end product separated by normal phase chromatography and that by reverse phase chromatography are also presented.

Full text of DOI:10.1002/ejoc.202000837

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis and Configuration of A p-Aminoacetophenonic Acid
Isolated from Endophyte of the Mangrove Plant Kandel candel
Authors: Xin Xiong, Yikang Wu, and Bo Liu
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Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000837
Link to VoR: https://doi.org/10.1002/ejoc.202000837
01/2020

10.1002/ejoc.202000837
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
Synthesis and Configuration of A p-Aminoacetophenonic Acid Isolated from
Endophyte of the Mangrove Plant Kandel candel
Xin Xiong,[a][b] Yikang Wu,*[b] and Bo Liu*[a]
Keywords: amino acids / enones / natural products /aldols / condensation
.
Two diastereomers of the title compound were synthesized
through an enantioselective route, with the stereogenic center at
the C-2 derived from a commercially available reagent and the one
at the C-4 installed via Evans asymmetric aldol condensation. By
Some interesting issues such as suppression of the undesired yet
dominating formation of cyclic ethers associated with
deprotection of a TBS protected terminal hydroxyl group and
the previously unknown differences in 1H NMR and IR between
the end product separated by normal phase chromatography and
that by reverse phase chromatography are also presented.
1
comparison of H and 13C NMR as well as optical rotations the
configuration of the natural product was as assigned as (2R,4R).
Introduction
Here below we wish to report a synthetic endeavour, which
allowed for establishment of the relative as well as absolute
configuration of the p-aminoacetophenonic acid 1.
In their search for active compounds as leads for drug discovery,
Guo and Grabley investigated secondary metabolites of mangrove
plants and their endophytes. The endeavour led to isolation of three
p-aminoacetophenonic acids (1-3, Figure 1),[1] which had been
suggested to be precursors of levorin[2] and trichomycin[3], the
Results and Discussion
The synthesis of (2R,4R)-1 is shown in Scheme 1. The
commercially available (S)-Roche ester 4 was protected[4] with
TBSCl and reduced[5] with DIBAL-H to afford 5 according to the
literature. Alcohol 5 was then subjected to Swern oxidation to give
aldehyde 6, which was directly used without any purification in the
subsequent Evans[6a,b] aldol condensation with 7 to furnish the
known[6b] aldol 8.
aminoacetophenone heptane antibiotics which have
a wide
spectrum of therapeutic activities. With the aid of modern
spectroscopy the gross structures of these compounds were reliably
assigned. However, the absence of e. g., OH groups at the
stereogenic centers made it extremely difficult to elucidate the
configurations.
Figure 1. The structures for p-aminoacetophenonic acids 1-3.
____________
[a]
X. Xiong, Prof. Dr. B. Liu, School of Materials Science and
Engineering and Key Laboratory of Green Chemical Technology of
College of Heilongjiang Province, and College of Chemical and
Environmental Engineering, Harbin University of Science and
Technology, Harbin 150040, China
[b]
X. Xiong, Prof. Dr. Y. Wu, State Key Laboratory of Bioorganic and
Natural Products Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
E-mail: yikangwu@sioc.ac.cn; http://www.sioc.ac.cn
Scheme 1. Reagents and conditions. a) TBSCl, imidazole, DMF, 100%; b)
DIBAL-H, THF, 81%; c) Swern oxidation; d) nBu2BOTf, 7, Et3N, CH2Cl2,
84% overall from 5; e) MsCl. Et3N, 75%; f) LiBH4, THF-MeOH, 87%; g)
Swern oxidation, 96%; h) LDA, THF, –78 C, 11, i) MsCl, Et3N, 36% over
2 steps from 11.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
Submitted to the European Journal of Organic Chemistry
1
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10.1002/ejoc.202000837
European Journal of Organic Chemistry
The OH group in 8 was mesylated with MsCl to give 9, which
was then treated with LiBH4 to achieve concurrent deoxygenation
at the C-3 and reductive removal of the chiral auxiliary to afford
the known[7] alcohol 10. Conversion of 10 into the corresponding
aldehyde by Swern[8] oxidation (DMSO/(COCl)2/Et3N) followed
by condensation with the carbanion of 11[9] and elimination of the
resulting OH after activation with MsCl furnished enone 12.
conditions. Unfortunately, the reaction led to a mixture,
presumably caused by intermolecular Michael addition of ethylene
glycol and other side reactions. Reduction of the carbonyl group
under the Luche[15] conditions (NaBH4/CeCl3/MeOH) gave the
expected diol smoothly. However, subsequent Dess-Martin[16]
oxidation of the intermediate diol did not result in aldehyde 18.
Instead, cyclic ether 19a and 19b (assigned with the aid of nOe’s
observed in the corresponding NOESY spectra) were obtained as
the only isolable products.
Removal of the terminal TBS protecting group turned out to be
far more complicated than one would possibly expect. Treatment
12 with nBu4NF,[10a] or HF·py[10b] or FeCl3/MeOH[10c] all led to
undesired cyclic ether 13 (Scheme 2) as the predominant product
(obtained as a mixture of two epimers), while the desired terminal
alcohol 14 was obtained only in negligible quantities. Direct
oxidation of 12 under Jones[11] conditions also led to 13, while
treating 12 with IBX[12] failed to result any reaction at all.
RuCl3/NaIO4 oxidation[13] of 13 to afford lactone 15 (which was
expected to undergo elimination/ring-opening on treatment with a
proper base to provide 15) also failed; no discernible reactions
occurred.
As the attempts to avoid the predominating formation of 13
through masking the enone motif appeared unfeasible, we next
turned to the possibility of suppressing the side reaction through
reducing the catalysis for the ring-closing process: the 1,4-addition
of the terminal OH to the enone is expected to be catalysed by
either acid or base. TABF (nBu4NF, often available as
nBu4NF·xH2O) is known to be basic in the presence of H2O (due to
strong tendency to form HF). It thus appears that addition of equal
molar amounts of a proper acid might neutralize the basicity of
TBAF and consequently suppress the intramolecular Michael
addition. Prompted by this thought, we then attempted to use 1:1
TBAF-AcOH[17] (glacial acetic acid) in deprotection of the TBS in
silyl ether 12.
To our delight, addition of equal molar amounts (with respect to
TBAF) of AcOH indeed suppressed formation of 13 (8%)
significantly, while the yield of desired 14 from previously
negligible to 46%. However, the reaction became remarkably slow:
Previously (i.e., in the absence of AcOH), it would take only 1 h
for full consumption of the starting 12. After introduction of AcOH,
45% of the starting 12 was recovered despite the prolonged
reaction time (15 h). Increasing the substrate concentration from
0.1 M to 0.2 M under the otherwise the same conditions raised the
yield of 14 to 55%, together with 8% of 13 and 37% of recovered
12. Satisfactory results were eventually obtained by using 3 mol
equiv (with respect to 12) of 1:1 TBAF-AcOH (instead of 2 mol
equiv as used in above experiments) and a substrate concentration
of 0.2 M. Under such conditions, the starting 12 was practically
fully consumed, giving 81% of 14 and only traces of 13 (Scheme
3).
O
OTBS
a
O
OH
12
BocNH
4
2
14
b,c
BocNH
CO2H
O
d
BocNH
16
O
CO2H
2
4
25
[
]
D
63.5 (c 0.22, MeOH)
25
H2N
Nat. [
]
72.7 (c 0.22, MeOH)
(2R,4R)-1
D
Scheme 2. Reagents and conditions. a) nBu4NF, THF, or aq. HF, THF or
HF·py, THF, or FeCl3, MeOH, 70-90% of 13 along with negligible amounts
of 14; b) RuCl3, NaIO4, CCl4, CH3CN, H2O; c) HO(CH2)2OH, HC(OMe)3,
p-TsOH; d) NaBH4, CeCl3·7H2O, MeOH; e) nBu4NF, THF, rt, 10 h, 66%
over 2 steps from 12; f) Dess-Martin periodinane, CH2Cl2, 35% of a
mixture of 19a and 19b (3:2) over 3 steps from 12.
Scheme 3. Reagents and conditions. a) 1:1 nBu4NF/AcOH, THF, rt, 81%;
b) Dess-Martin periodinane, CH2Cl2; c) NaClO2/2-methyl-but-2-ene/pH 7
phosphate buffer, 80% from 14; d) CF3CO2H, 70%.
The isolated 14 was then oxidized with Dess-Martin periodinane
to give the intermediate aldehyde, which was further treated with
NaClO2/2-methyl-but-2-ene/phosphate buffer (Pinnic[18] oxidation)
to afford carboxylic acid 16. The Boc protecting group in 16 was
then removed with CF3CO2H to afford the end product (2R,4R)-1.
To mask the enone moiety, which promoted the undesired
intramolecular Michael addition to the enone subunit to afford 13,
we also tried to convert the enone carbonyl group into its ethylene
glycol ketal under the HO(CH2)2OH/HC(OMe)3/p-TsOH[14]
Submitted to the European Journal of Organic Chemistry
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10.1002/ejoc.202000837
European Journal of Organic Chemistry
1
The H and 13C NMR of (2R,4R)-1 were generally consistent
Then, somewhat unexpected, removal of the TBS protecting
group in 23 turned out to be even more difficult than that of 12.
Under the conditions optimized for conversion of 12 into 14,
alcohol 24 was obtained in only 32% yield, along with as much as
50% of undesired ring-closure products 25a and 25b (assigned
with the aid of their NOESY spectra).
with those reported in the literature (except that for the C-13,
where the error was slightly larger than 0.5 ppm). And its optical
rotation was measured to be []D25 –63.5 (c = 0.22, MeOH), rather
close to that for the natural product ([]D –72.7 (c = 0.22,
MeOH)).
25
For comparison, we also synthesized (2R,4S)-1 as shown in
Scheme 4, starting with Swern oxidation of alcohol 5 as described
above to afford the intermediate aldehyde. Subsequent Evans
condensation was realized using ent-7 instead of 7. The resulting
aldol was then mesylated and reduced with LiBH4 to give alcohol
22. Another Swern oxidation followed by condensation with 11
afforded enone 23 as planned.
Compared with generation of 13 from 14, formation of 25 is
apparently much more facile, presumably because of a more stable
cyclic transition state (where both methyl groups could adopt an
equatorial orientation). To suppress the chain folding, we decided
to attempt the desilylation at low temperatures. We began with –20
C, but failed to observe any reactions despite prolonged reaction
time (15 h). At 0 C, traces of 24 and 25 could be detected by TLC,
but only after 30 h’s reaction. As further extension of the reaction
time was impractical, to run the desilylation at a higher substrate
concentration seemed to be the only choice available remained.
Gratifyingly, with the concentration of 23 raised from 0.2 M to 1.0
M, the deprotection at 0 C went to completion within 23 h,
affording the desired 26 in 58% yield (along with 45% of 25). The
isolated alcohol 26 was then subjected to Dess-Martin oxidation,
Pinnick oxidation and removal of Boc group as described above for
the (2R,4R)-1 without any unexpected events and finally furnished
the desired (2R,4S)-1.
O
O
OH
OH OTBS
c
a,b
O
N
OTBS
20
5
Bn
O
O
O
O
OMs
OH
OTBS
d
O
N
O
N
OTBS
21
Bn
22
Bn
ent-7
O
OTBS
23
e
The 1H NMR of (2R,4S)-1 was apparent different from what
were reported for natural 1: The H-4 and H-2 of (2R,4S)-1 were
well resolved, appearing as a distinct heptet at  2.48 and a clear-
cut sextet at  2.42, respectively, rather than two unresolved
multiplets as described in the literature. Similarly, the two protons
at C-3 also were two well resolved double-triplets (not two
unresolved multiplets as stated in the literature), respectively.
Minor discrepancies were also found in 13C NMR (cf. the
Supporting Information). Finally, the optical rotation of (2R,4S)-1
O
OTBS
H
f,g
BocNH
22'
h
O
OH
O
i,j
BocNH
24
BocNH
11
O
BocNH
12
9
13
2
4
1
CO2H
25
was found to be ([]D –8.7 (c = 0.22, MeOH)), which was
O
5
25
3
definitely incompatible with that for natural 1 ([]D –72.7 (c =
26
BocNH
11
10
7
0.22, MeOH)). Therefore, the (2R,4S) configuration could be
excluded with high certainty, leaving (2R,4R) as the only possible
configuration for natural 1.
R
8
6
O
k
(
(
H )
H
25a R = -H
)
25b R = -H
O
CO2H
2
4
25
[
]
D
8.7 (c 0.22, MeOH)
H2N
25
(2 ,4 )-1
(cf. Nat. [
]
72.7 (c 0.22, MeOH))
R
S
D
O
6
O
Ar
H
2
4
H
25b
nOe observed
CH3
8
nOe observed
H
H
2
O
Ar
6
4
(no nOe between H-6 and H-4)
5
8
O
H
2
25a
(no nOe between H-6 and H-8)
O
H
Figure 2. The  2.54-2.33 ppm region of the 1H NMR for (2R,4R)-1
obtained by normal phase chromatography (trace (A)) and that by reverse
phase chromatography (trace (B)) recorded in CD3OD under comparable
conditions. Note that the H-4 and H-2 are closer to each other (at  2.471
and 2.425 ppm, respectively) in trace (A) compared with those (at  2.480
and  2.413 ppm, respectively) in trace (B).
5
3
CH3
H
25b
Ar
6
nOe observed
O
Scheme 4. Reagents and conditions. a) Swern oxidation; b) nBu2BOTf, ent-
7, Et3N, CH2Cl2, 88% over 2 steps from 6; c) MsCl. Et3N, 74%; d) LiBH4,
THF-MeOH, 76%; e) Swern oxidation, 92%; f) LDA, THF, –78 C, 11, g)
MsCl, Et3N, 52% over 2 steps from 11; h) 1:1 nBu4NF/AcOH, THF, 58%
of 24 along with 44% of 25 (1:1 mixture of 25a and 25b); i) Dess-Martin
oxidation, 97%; j) Pinnic oxidation, 82% from the intermediate aldehyde or
80% over 2 steps from 24; k) CF3CO2H, 65%.
Somewhat unusual of compound 1 and thus worth of mentioning
is that the NMR, IR and optical rotation of the sample were slightly
yet definitely different before and after an additional reverse phase
1
chromatography. For example, the H-4 and H-2 in the H NMR
recorded on a sample of (2R,4R)-1 separated by normal phase
chromatography (eluting with 1:1 PE/EtOAc; PE = petroleum ether)
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10.1002/ejoc.202000837
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is shown in Figure 2 (bottom trace). This sample was then
subjected to a reverse phase chromatography on C-18 (eluting with
1:1 H2O/MeOH, as reported for natural 1). The H-4 and H-2 in the
1H NMR taken after the reverse phase chromatography (top trace,
Figure 1) apparently moved away from each other, not so much but
definitely unmistakable. And after this reverse phase
chromatography, another normal phase chromatography of the
another normal phase chromatography), what can be different was
the conformation/the hydrogen-bonding related solution structure.
1
same sample made the spacing between the H-4 and H-2 in H
NMR narrowed again, back to the original status (closer to each
other, as in the bottom trace, Figure 1).[19] Discernible changes
were also found in 13C NMR and optical rotation after the reverse
phase chromatography (cf. the Supporting Information).
To understand the rather confusing differences between the
NMR of the sample obtained by normal phase chromatography and
that by reverse phase chromatography, all potentially possible
factors that might affect the spectra were considered, such as
sample concentrations, contamination by traces of silica gel or C-
18 silica gel and residual H2O (which was used as co-eluent in the
reverse phase chromatography). However, the NMR of a given
(2R,4R)-1 sample taken at different sample concentrations turned
out just the same. Filtration of the sample solutions through
commercially available polymer membrane filter to remove any
silica gel or C-18 silica gel leaked from the chromatography
column before rotary evaporation had no influence on the
1
appearance of the H NMR. Finally, addition of H2O (sequentially
0.25 mg, 0.5, 1, and finally 3 mg, well-shaken after each addition)
to the NMR sample solution (in CD3OD) of (2R,4R)-1 (obtained by
normal phase chromatography) did not show any discernible
effects; both the spacing between the H-4 and H-2 in the 1H NMR
and the profiles of the two signals remained unchanged in all
experiments.
Figure 3. The IR of (2R,4R)-1 before (top) and after (bottom) reverse phase
chromatography, with the difference framed (the red dashed line boxes).
For similar changes in IR of (2R,4S)-1, cf. the Supporting Information.
Since 1 is amino acid, the potential possibility of different
extents of protonation of the NH2 by the carboxylic OH as the
cause for the above mentioned NMR differences once was also
considered. In such case, the samples obtained under different
chromatographic conditions are expected to undergo re-equilibrium
in CD3OD to give the same protonation status (because the
influence of the chromatographic solvents no longer exists); the
extent of protonation of the NH2 by the carboxylic OH was decided
only by the acidity of the solution. However, addition of traces of
HCl (3 L of a 0.05 M solution in CD3OD) to the NMR solution of
Under the given circumstances, the most plausible explanation
appears to be that shown in Figure 4: When the sample was
recovered after a normal phase chromatography (from a solution in
1:1 PE/EtOAc, both are non-protic solvents), there were no
competing intermolecular hydrogen-bond donnors from the solvent
molecules. Given the ketone carbonyl group (with an electron-
donating NH2 at the para position of the phenyl ring) being the
most hydrogen-bond accetor in the molecule and the favorable
location of the CO2H, formation of the cyclic conformer through
the intramolecular hydrogen bonding appeared to be the only
possibility (Figure 4, the structure on the left).
1
(2R,4S)-1 did not lead to any discernible changes in H NMR.
Supporting arguments also came from the structure of 1; the amino
group in this case is an aromatic one, which is normally not as
basic as aliphatic NH2. Therefore, it does not seem very likely for
the NH2 to be protonated by the carboxylic acid, especially when a
strongly electron-withdrawing ketone carbonyl group is present on
the phenyl ring at a position para to the NH2.
A critical clue to the cause of the above mentioned NMR
differences between the sample obtained by normal phase
chromatography and that by reverse phase chromatography was
later found by IR: The spectrum of the former showed a huge
background lump in the 3600-2200 cm–1 region (characteristic of
hydrogen-bonded carboxylic OH, Figure 3, top). However, in the
IR taken on the sample after a subsequent reverse phase
chromatography, the lump essentially disappeared (Figure 2,
bottom); unmistakably showing that the carboxylic OH was no
longer hydrogen-bonded. In other words, the samples isolated
under different chromatographic conditions were indeed different.
Since the gross structure and the configuration of the sample
cannot be changed (because the sample after the reverse phase
chromatography could return to its original status by subjection to
Figure 4. The (2R,4R)-1 obtained by normal phase chromatography (left)
and reverse phase chromatography (right) may have different types of
hydrogen-bonding and consequently different conformations; cf. also the
text. Note that the carboxylic group of the conformer on the right could also
be hydrogen-bonded to H2O or/and MeOH though not shown here.
Submitted to the European Journal of Organic Chemistry
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10.1002/ejoc.202000837
European Journal of Organic Chemistry
In the case of reverse phase chromatography, compound 1 was
dissolved in a large excess of H2O and MeOH (hydrogen-bond
donors). And probably while compound 1 was still on the C-18
silica gel, it was already in an open-chain conformation similar to
that shown in Figure 4 (the structure on the right), with the ketone
carbonyl (and very likely, also the carboxylic though for clarity not
shown in Figure 4) group hydrogen-bonded to H2O (which could
be more than one in number, though for clarity not depicted) or/and
MeOH. The situation remained unchanged until all solvents were
removed by rotary evaporation and after dissolution in CD3OD to
form the NMR sample solution. When the sample by reverse phase
chromatography was subjected to normal phase chromatography
again, the hydrogen-bonded H2O was absorbed by silica gel and
thus led to formation of the intrmolecularly hydrogen-bonded
“cyclic” conformer again.
as stated below. ESI-MS data were acquired with a Shimadzu LCMS-2010
eV mass spectrometer or a Agilent Technologirs 6120 Quadrupole LC/MS.
ESI-HRMS data were obtained with a Brucker Maxis 4 G TOF MS
spectrometer or a Thermo Scientific Q Exactive HF Orbitrap-FT MS. Dry
THF was obtained by distillation over Na/Ph2CO under argon before use.
Dry CH2Cl2 and Et3N were obtained by distillation over CaH2 under argon
before use. All other solvents and reagents were used as received from
commercial sources. Column chromatography was performed on silica gel
(300-400 mesh) under slightly positive pressure. PE stands for petroleum
ether (b. p. 60-90 ºC).
Conversion of Roche ester to afford alcohol 5. To a solution of (S)-(+)-
Roche ester (3.856 g, 32.7 mmol) in dry DMF (64 mL) stirred at ambient
temperature were added imidazole (4.0 g, 58.8 mmol) and TBSCl (6.9 g,
45.8 mmol). Stirring was continued at the same temperature for 5 h (TLC
showed completion of the reaction). Aq. sat. NaHCO3 (60 mL) was added
to quench the reaction. The mixture was extracted with n-hexane (100 mL
× 2). The combined organic layers were washed with water (30 mL) and
brine (5 mL) and dried over anhydrous Na2SO4. Filtration and careful rotary
evaporation at 0 C under aspirator vacuum left crude oil, which was
purified by column chromatography (50:1 PE/EtOAc) on silica gel to give
the known TBS protected Roche ester as a colorless oil (7.581 g, 32.7
mmol, 100%), which was directly used in the next step. The following data
Although in the NMR sample solution in CD3OD a substantial
portion of the “cyclic” conformer is expected to break up to give
“non-cyclic” one(s) due to competing intermolecular hydrogen-
bonding to the NMR solvent molecule, this process probably may
never go to completion. This is because CO2H was in the same
molecule as the the ketone, it could never go far away from the
ketone group and thus always had more chance to come back to
form hydrogen-bond to the ketone group than any solvent
molecules. As a consequence, at least a small portion of the
intramolecularly hydrogen-bonded“cyclic” conformer may remain
in the NMR sample solution and causes the aforementioned
differences in e. g. 1H NMR.
25
were acquired for this sample: [α]D = +16.8 (c = 1.00, CHCl3) (lit [20] [α]D
20
1
= +19.0 (c = 1.00, CHCl3)) H NMR (400 MHz, CDCl3) δ 3.77 (dd, J =
9.7, 6.9 Hz, 1H), 3.68 (s, 3H), 3.65 (dd, J = 9.7, 6.1 Hz, 1H), 2.65 (dq, J =
6.0, 7.0 Hz, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.87 (s, 9H), 0.04 (d, J = 1.4 Hz,
6H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.63, 65.38, 51.66, 42.66,
25.91, 18.35, 13.60, –5.36 ppm.
Conclusions
To a solution of the above obtained TBS protected Roche ester (7.581 g,
32.7 mmol) in dry THF (100 mL) stirred in an ice-water bath under argon
(balloon) was added (via a syringe) slowly DIBAL-H (1.0 M, in hexanes,
75.21 mL, 75.21 mmol) over ca. 1 h. After completion of the addition,
stirring was continued at ambient temperature for 3 h (TLC showed
completion of the reaction). The reaction mixture was poured into a mixture
of aq. sat potassium sodium tartrate (250 mL) and n-hexane (250 mL). The
mixture was stirred vigorously for 1 h and then extracted with Et2O (100
mL × 3). The combined organic layers were washed with water (30 mL)
and brine (5 mL) and dried over anhydrous Na2SO4. Filtration and careful
rotary evaporation at 0 C under aspirator vacuum left crude oil, which was
purified by column chromatography (10:1 PE/EtOAc) on silica gel to give
Two diastereomers of the title compound, a naturally occurring
amino acid, were synthesized via an enantioselective route.
Through comparison of the physical and spectroscopic data of the
synthetic samples with those reported in the literature, the absolute
configuration of the natural product was assigned to (2R,4R). En
route to the total synthesis of the end products, a practical method
for suppressing the undesired Michael addition of the terminal OH
to form cyclic ether was developed. The relatively facile access to
the synthetic samples also provided a good opportunity to look into
this structurally unpretending compound. Some previously
unnoticed properties/phenomena, such as the differences in the
NMR, IR and optical rotation between the sample isolated by
normal phase chromatography and that by reverse phase
chromatography, were revealed for the first time. On the basis of
the NMR and IR studies, the previously unknown (also rather
confussing) spectroscopic differences between the samples
obtained under different chromatographic conditions were
attributed to the difference in the type of hydrogen-bonding to the
ketone carbonyl group as a consequence of the chromatographic
solvents employed. Although this interpretation may be not
conclusive, the phenomena observed are definite and thus deserve
special attention.
25
alcohol 5 as a colorless oil (5.410 g, 26.5 mmol, 81% overall from 4). [α]D
[4b]
20
= +7.7 (c = 2.38, CH2Cl2) (lit
[α]D = +9.79 (c = 2.38, CH2Cl2)). 1H
NMR (500 MHz,CDCl3) δ 73.74 (ddd, J = 9.8, 4.4, 0.9 Hz, 1H), 3.67-3.58
(m, 2H) 3.55 (dd, J = 9.9, 8.0 Hz, 1H), 2.88 (dd, J = 7.0, 4.0 Hz, 1H), 1.99-
1.90 (m, 1H), 0.90 (s, 9H), 0.84 (d, J = 7.0 Hz, 3H), 0.08 (s, 6H) ppm; 13C
NMR (125 MHz, CDCl3) δ 68.90, 68.46, 37.18, 26.00, 18.32, 13.22, –5.40,
–5.46. ppm.
Swern oxidation of 5 to afford aldehyde 6. A solution of DMSO (3.1 mL,
43.8 mmol) in dry CH2Cl2 (12 mL) was added very slowly to a solution of
(COCl)2 (2.3 mL, 26.3 mmol) in dry CH2Cl2 (100 mL) stirred at –78 C
under argon (balloon). After completion of the addition, the mixture was
stirred at the same temperature for 15 min. A solution of alcohol 5 (4.420 g,
21.9 mmol) in dry CH2Cl2 (30 mL) was introduced dropwise. Stirring was
then continued at the same temperature for another 2 h. Finally, Et3N (9.1
mL, 65.6 mmol) was added very slowly. The mixture was stirred at –78 C
for 5 min. The cooling bath was allowed to warm to 0 C, at which the
mixture was stirred for another hour. Water (30 mL) was added. The
mixture was extracted with CH2Cl2 (100 mL × 3). The combined organic
layers were washed with brine (10 mL) and dried over anhydrous Na2SO4.
Filtration and careful rotary evaporation at 0 C under aspirator vacuum left
crude aldehyde 6[4b] as a yellowish oil (4.200 g, 21.00 mmol, 96%), which
was used directly in the next step.
Experimental Section
General Methods.
Melting points were uncorrected (measured on a hot-stage melting point
apparatus equipped with a microscope). Optical rotations were measured an
Anton Paar MCP5500 polarimeter. IR spectra were measured with a
Nicolet 380 infrared spectrophotometer. NMR spectra were recorded with a
Bruker Avance III 400 NMR spectrometer (operating at 400 MHz for 1H)
1
or a Brucker Avance III HD 500 NMR (operating at 500 MHz for H) or a
Bruker Avance III HD 600 NMR (operating at 600 MHz for 1H) instrument
Submitted to the European Journal of Organic Chemistry
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000837
European Journal of Organic Chemistry
Evans aldol condensation of 6 to afford 8. nBu2BOTf (1.0 M, in CH2Cl2,
17.8 mL, 17.8 mmol) was added to a solution of acyloxazolidinone 7 (3.760
g, 16.2 mmol) in dry CH2Cl2 (80 mL) stirred at –78 C (EtOH-dry ice)
under argon (balloon). Et3N (3.1 mL, 22.6 mmol) was then introduced
slowly. Stirring was continued at the same temperature for 10 min and then
at 0 C for 45 min. The bath temperature was then re-cooled to –78 C. A
solution of the above obtained crude aldehyde 6 (4.200 g, 21.0 mmol) in
dry CH2Cl2 (30 mL) was introduced dropwise. Stirring was continued at –
78 C for 1 h and then at 0 C for 2 h (TLC showed completion of the
reaction). A solution of methanolic H2O2 (30 mL, with the stock solution
prepared from 35 mL of aq. 30% H2O2 and 70 mL of MeOH). The mixture
was stirred at 0 C for 1 h before being washed with water (50 mL) and
extracted with CH2Cl2 (30 mL × 3). The combined organic layers were
washed with brine (10 mL) and dried over anhydrous Na2SO4. Filtration
and rotary evaporation gave a residue, which was purified by column
chromatography (5:1 PE/EtOAc) on silica gel to afford aldol 8[20] as a white
solid (6.240 g, 14.3 mmol, 88% from 7). M. p. 107-109 ℃ [α]D25 = –21.3 (c
= 1.00, CHCl3) 1H NMR (500 MHz,CDCl3) δ 7.36-7.26 (m, 3H), 7.26-7.20
(m, 2H), 4.72-4.67 (m, 1H), 4.24-4.15 (m, 2H), 4.08 (d, J = 2.2 Hz, 1H),
3.96-3.86 (m, 2H), 3.77 (dd, J = 9.9, 4.3 Hz, 1H), 3.65 (dd, J = 10.0, 7.4 Hz,
1H), 3.34 (dd, J = 13.3, 3.3 Hz, 1H), 2.77 (dd, J = 13.4, 9.7 Hz, 1H), 1.86-
1.76 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 0.92-0.88 (m, 12H), 0.08 (s, 3H),
0.07 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 176.22, 153.33, 135.53,
129.57, 129.06, 127.43, 76.02, 68.41, 66.29, 55.85, 40.98, 37.88, 37.52,
26.00, 18.32, 13.18, 9.51, –5.43, –5.45 ppm; FT-IR (film of a concd
solution in CH2Cl2) ν = 3483, 2955, 2929, 2857, 1782, 1698, 1471, 1386,
1239, 1209, 1076, 1014, 984, 776, 750, 702 cm-1; ESI-MS m/z 458.4 ([M +
Na]+); ESI-HRMS calcd for C23H37NO5SiNa ([M + Na]+): 458.2333, found
458.2338.
CHCl3) 1H NMR (500 MHz, CDCl3) δ 3.51-3.42 (m, 2H), 3.42-3.37 (m,
2H), 1.79-1.68 (m, 2H), 1.52 (s, 1H), 1.21 (ddd, J = 13.7, 9.1, 4.7 Hz, 1H),
1.13 (ddd, J = 13.6, 9.1, 4.9 Hz, 1H), 0.91-0.88 (m, 12H),0.86 (d, J = 6.7
Hz, 3H), 0.04 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 69.18, 69.15,
36.99, 33.25, 33.10, 26.11, 18.52, 16.79, 16.61, –5.198, –5.203 ppm; FT-IR
(film of a concd solution in CH2Cl2) ν = 3364, 2956, 2928, 2857, 1472,
1385, 1256, 1097, 1037, 836, 775 cm–1; ESI-MS m/z 269.2 ([M + Na]+);
ESI-HRMS calcd for C13H30O2SiNa ([M
269.1907.
+
Na]+): 269.1919, found
Boc protection of 1-(4-aminophenyl)ethanone to afford 11. Di-t-butyl
carbonate (Boc2O, 24.2 g, 111.0 mmol) and K2CO3 (15.3 g, 111.0 mmol)
were added in turn to
a solution of commercially available 1-(4-
aminophenyl)ethanone (5.003 g, 37.1 mmol) in dry DMF (100 mL) stirred
at ambient temperature. The mixture was then stirred in a 100 C oil bath
for 3 h. The heating bath was then removed. The mixture was poured into
ice-water (100 mL) and extracted with EtOAc (100 mL × 3). The combined
organic layers were washed with brine (10 mL) and dried over anhydrous
Na2SO4. Filtration and rotary evaporation gave a residue, which was
purified by column chromatography (15:1 PE/EtOAc) on silica gel to give
1
11 as a yellowish solid (5.516 g, 23.5 mmol, 63%). M. p. 145-147 ℃. H
NMR (500 MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz,
2H), 6.85 (s, 1H), 2.56 (s, 3H), 1.53 (s, 9H) ppm; 13C NMR (125 MHz,
CDCl3) δ 197.07, 152.31, 143.09, 131.93, 129.96, 117.54, 81.40, 28.40,
26.49 ppm. FT-IR (film of a concd solution in CH2Cl2) ν = 3307, 2979,
1731, 1667, 1604, 1526, 1409, 1315, 1274, 1155, 1051, 959, 763 cm–1; ESI-
MS m/z 258.3 ([M + Na]+); ESI-HRMS calcd for C13H17O3NNa ([M +
Na]+): 258.1101, found 258.1103.
Swern oxidation of 10 and subsequent condensation with 11 to afford
12. A solution of DMSO (1.3 mL, 18.2 mmol) in dry CH2Cl2 (5 mL) was
added very slowly to a solution of (COCl)2 (0.93 mL, 10.9 mmol) in dry
CH2Cl2 (15 mL) stirred at –78 C under argon (balloon). After completion
of the addition, the mixture was stirred at the same temperature for 15 min.
A solution of alcohol 10 (1.794 g, 7.29 mmol) in dry CH2Cl2 (9 mL) was
introduced dropwise. Stirring was then continued at the same temperature
for another 2 h. Finally, Et3N (1.5 mL, 36.5 mmol) was added very slowly.
The mixture was stirred at –78 C for 5 min. The cooling bath was allowed
to warm to 0 C, at which the mixture was stirred for another hour. Aq HCl
(2%, 5 mL) was added. The mixture was extracted with CH2Cl2 (100 mL ×
2). The combined organic layers were washed with aq. sat. NaHCO3 (5 mL),
water (20 mL) and brine (5 mL), and then dried over anhydrous MgSO4.
Filtration and careful rotary evaporation at 10 C under aspirator vacuum
left the corresponding (low boiling) aldehyde 10’ as a yellowish oil (1.700
g, 6.97 mmol, 96% crude), which was used directly in the next step.
Mesylation of 8 to afford 9. To a solution of aldol 8 (6.048 g, 13.9 mmol)
in dry CH2Cl2 (80 mL) stirred in a 0 C bath under argon (balloon) were
added in turn Et3N (10 mL, 69.5 mmol) and MsCl (4.3 mL, 55.6 mmol).
After completion of the addition, the bath was removed. The mixture was
stirred at ambient temperature for 2h (TLC showed completion of the
reaction). Aq. sat. NaHCO3 (20 mL) was added, followed by water (20 mL).
The mixture was extracted with CH2Cl2 (100 mL × 3). The combined
organic layers were washed with brine (10 mL) and dried over anhydrous
Na2SO4. Filtration and rotary evaporation gave a residue, which was
purified by column chromatography (5:1 PE/EtOAc) on silica gel to afford
9 as a colorless oil (5.362 mg, 10.45 mmol, 75%). [α]D25 = –81.8 (c = 1.00,
CHCl3) 1H NMR (500 MHz, CDCl3) δ 7.36-7.26 (m, 3H), 7.26-7.19 (m,
2H), 5.08 (dd, J = 9.5, 2.2 Hz, 1H), 4.65-4.59 (m, 1H), 4.26-4.21 (m, 1H),
4.20-4.10 (m, 2H), 3.69-3.65 (m, 1H), 3.62 (dd, J = 10.0, 5.1 Hz, 1H), 3.28
(dd, J = 13.4, 3.4 Hz, 1H), 3.04 (s, 3H), 2.80 (dd, J = 13.4, 9.8 Hz, 1H),
2.01-1.92 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 0.89
(s, 9H), 0.05 (s, 3H), 0.0.4 (s, 3H) ppm; 13C NMR (125 MHz,CDCl3) δ
173.76, 153.61, 135.49, 129.40, 128.88, 127.24, 82.42, 66.54, 64.04, 56.13,
39.87, 38.49, 37.86, 37.73, 25.79, 18.20, 13.58, 8.56, –5.45, –5.59 ppm;
FT-IR (film of a concd solution in CH2Cl2) ν = 2948, 2927, 2857, 1781,
1702, 1456, 1384, 1361, 1250, 1213, 1177, 912, 837, 778, 703 cm–1; ESI-
MS m/z 536.5 ([M + Na]+); ESI-HRMS calcd for C24H39NO7SSiNa ([M +
Na]+): 536.2109, found 536.2121.
A solution of 11 (1.093 g, 4.65 mmol) in dry THF (14 mL) was added via a
syringe to a solution of LiN(iPr)2 (LDA, 2.0 M, in THF-n-heptane-
ethylbenzene, 5.1 mL, 10.23 mmol) in dry THF (18 mL) stirred at –78 C
under argon (balloon), followed by a solution of the aldehyde 10’ obtained
above (1.700 g, 6.97 mmol, crude and thus inaccurate) in dry THF (15 mL).
The mixture was stirred at –78 C for 4 h (TLC showed completion of the
reaction). Aq. sat. NaHCO3 (30 mL) was added. The mixture, after warmed
to ambient temperature, was extracted with Et2O (100 mL × 2). The
combined organic layers were washed with aq. HCl (1%, 30 mL), aq. sat.
NaHCO3 (30 mL) and brine (10 mL), and then dried over anhydrous
MgSO4. Filtration and rotary evaporation left the intermediate aldol, which
was directly dissolved in in dry CH2Cl2 (18 mL) and stirred in an ice-water
bath under argon (Balloon). To this solution (stirred) was added Et3N (4.5
mL, 23.3 mmo), followed by MsCl (0.54 mL, 6.98 mmol). Stirring was
continued at ambient temperature for 2 h (TLC showed completion of the
reaction). Water (20 mL) was added to quench the reaction. The mixture
was extracted with CH2Cl2 (100 mL × 2). The combined organic layers
were washed with aq. HCl (1%, 30 mL), aq. sat. NaHCO3 (30 mL) and
brine (10 mL), and then dried over anhydrous MgSO4. Filtration and rotary
evaporation left the intermediate aldol, which was purified by column
LiBH4 reduction of 9 to afford alcohol 10. To a solution of mesylate 9
(727 mg, 1.42 mmol) in dry THF (3 mL) stirred in an ice-water bath were
added LiBH4 (312 mg, 14.2 mmol) and MeOH (0.57 mL, 14.2 mmol). The
mixture was stirred at ambient temperature for ca. 15 h (TLC showed
completion of the reaction). With cooling (ice-water bath) and stirring, the
excess hydride was quenched by careful addition of water (10 mL). The
mixture was extracted with Et2O (50 mL × 2). The combined organic layers
were washed with brine (5 mL) and dried over anhydrous Na2SO4.
Filtration and rotary evaporation gave a residue, which was purified by
column chromatography (15:1 PE/EtOAc) on silica gel to furnish alcohol
25
10 as a colorless oil (304 mg, 1.24 mmol, 87%). [α]D = +17.5 (c = 1.00,
Submitted to the European Journal of Organic Chemistry
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000837
European Journal of Organic Chemistry
chromatography (15:1 PE/EtOAc) on silica gel to give enone 12 as a pale
yellow solid (772 mg, 1.67 mmol, 36% from alcohol 11). Data for enone
1H, H-3), 1.51 (s, 9H, tBu Me), 1.46-1.39 (m, 1H, H-3), 1.14 (d, J = 7.1 Hz,
3H, H-9), 0.82 (d, J = 6.6 Hz, 3H, H-8) ppm; 13C NMR (150 MHz, CDCl3,
assigned with the aid of HSQC) δ 152.73 (quat, Boc carbonyl), 137.80 (C-
13), 132.02 (C-7), 131.93 (quat, C-10), 128.14 (C-6), 127.29, 118.50, 85.41
(C-5), 80.72 (quat, tBu), 72.72 (C-1), 38.29 (C-3), 30.65 (C-4), 28.98 (C-2),
28.48 (tBu Me), 18.36 (C-8), 17.39 (C-9) ppm; FT-IR (film of a concd
solution in CH2Cl2) ν = 3444, 2962, 2924, 2854, 1730, 1527, 1412, 1367,
1258, 1156, 1112, 1054, 725, 618 cm-1; ESI-MS m/z 354.3 ([M + Na]+);
ESI-HRMS calcd for C20H29O3NNa ([M + Na]+): 354.2040, found 354.2048.
Desilylation of 12 to afford alcohol 14. A solution of equal molar nBu4NF
and AcOH (1 M, in THF, 0.47 mL, 0.47 mmol of each) was added to a
solution of 12 (72 mg,0.16 mmol) in THF (0.3 mL) stirred in an ice-water
bath. The mixture was then stirred at ambient temperature (ca. 23 C) for
11 h (TLC showed completion of the reaction). Aq. sat. NaHCO3 (3 mL)
was added. The mixture was extracted with EtOAc (10 mL × 3). The
combined organic layers were washed with brine (2 mL) and then dried
over anhydrous MgSO4. Filtration and rotary evaporation left a crude oil,
which was purified by column chromatography (2:1 PE/EtOAc) on silica
gel to give first traces of the undesired cyclic ether 13 (a mixture of two
epimers, less polar than 14) and then the main product alcohol 14 as a
colorless oil (45 mg, 0.13 mmol, 81%).
25
1
12: M. p. 77-79 ℃ [α]D = –9.6 (c = 0.47, CHCl3). H NMR (500 MHz,
CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.96 (dd, J =
15.4, 7.8 Hz, 1H), 6.83 (dd, J = 15.4, 0.9 Hz, 1H), 6.69 (s, 1H), 3.45 (dd, J
= 9.8, 5.7 Hz, 1H), 3.41 (dd, J = 9.8, 6.1 Hz, 1H), 2.52 (hept, J = 7.1 Hz,
1H), 1.69 (sext, J = 6.5 Hz, 1H), 1.53 (s, 9H), 1.51-1.44 (m, 1H), 1.27-1.18
(m, 1H), 1.09 (d, J = 6.6 Hz, 3H), 0.91-0.88 (m, 12H), 0.04 (d, J = 2.0 Hz,
6H) ppm; 13C NMR (125 MHz, CDCl3) δ 189.65, 155.17, 152.31, 142.67,
132.77, 130.21, 123.63, 117.61, 81.41, 68.29, 39.98, 34.82, 33.52, 28.44,
26.10, 19.65, 18.50, 17.20, –5.20 ppm; FT-IR (film of a concd solution in
CH2Cl2) ν = 3315, 2957, 2928, 2856, 1753, 1661, 1618, 1593, 1411, 1367,
1314, 1231, 1157, 1094, 1054, 837, 775 cm–1; ESI-MS m/z 484.4 ([M +
Na]+); ESI-HRMS calcd for C26H43O4NSiNa ([M + Na]+): 484.2856, found
484.2854.
Luche reduction, desilylation and Dess-Martin oxidation of 12 to afford
19a and 19b. NaBH4 (7.3 mg, 0.19 mmol) and CeCl3·7H2O (43 mg, 0.115
mmol) were added in turn to a solution of 12 (44 mg, 0.095 mmol) in
MeOH (0.5 mL) stirred in an ice-water bath. Stirring was continued at the
same temperature for 2 h (TLC showed completion of the reaction). Water
(3 mL) was added. The mixture was extracted with EtOAc (5 mL × 3). The
combined organic layers were washed with brine (2 mL) and dried over
anhydrous Na2SO4. Filtration and rotary evaporation gave a residue (42 mg,
the intermediate alcohol), which was dissolved in THF (0.5 mL) and stirred
in an ice-water bath. nBu4NF (1.0 M, in THF, 0.23 mL, 0.23 mmol) was
added. Stirring was continued at ambient temperature for 10 h. Aq. sat.
NaHCO3 (1 mL) was added. The mixture was extracted with EtOAc (5 mL
× 3). The combined organic layers were washed with brine (2 mL) and
dried over anhydrous Na2SO4. Filtration and rotary evaporation gave a
residue, which was purified by column chromatography (1:1 PE/EtOAc) on
silica gel to afford the intermediate diol as a colorless oil (21 mg, 0.0602
mmol, 66% over two steps from 12). Part of this diol (15 mg, 0.043 mmol)
was dissolved in dry CH2Cl2 (0.5 mL) and stirred in an ice-water bath.
Dess-Martin periodinane (73 mg, 0.172 mmol) was introduced. Stirring was
then continued at ambient temperature for 30 min (TLC showed completion
of the reaction). Water (5 mL) was added. The mixture was extracted with
CH2Cl2 (5 mL × 3). The combined organic layers were washed with brine
(2 mL) and dried over anhydrous Na2SO4. Filtration and rotary evaporation
gave a residue, which was purified by column chromatography (10:1
PE/EtOAc) on silica gel to give 19a (less polar than 19b, 3 mg, 0.009 mmol,
21% from the desilylation product or 13.9% overall from 12) and 19b
(more polar than 19a, 2 mg, 0.006 mmol, 14% from the desilylation
product or 9.2 % overall from 12) as colorless oil.
25
1
Data for the main product 14: [α]D = –6.9 (c = 0.70, CH2Cl2). H NMR
(500 MHz, CDCl3) δ 7.91 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.96
(dd, J = 15.4, 7.8 Hz, 1H), 6.85 (d, J = 15.4, 1H), 6.77 (s, 1H), 3.54 (dd, J =
10.5, 5.5 Hz, 1H), 3.47 (dd, J = 10.5, 6.3 Hz, 1H), 2.55 (hept, J = 7.1 Hz,
1H), 1.69 (sext, J = 6.6 Hz, 1H), 1.53 (s, 9H), 1.52-1.45 (m, 1H), 1.33-1.24
(m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3) δ 189.55, 154.73, 152.31, 142.76, 132.58, 130.21,
123.74, 117.59, 81.40, 68.18, 39.79, 34.72, 33.45, 28.42, 19.65, 17.01 ppm;
FT-IR (film of a concd solution in CH2Cl2) ν = 3439, 3309, 2964, 2927,
1731, 1660, 1594, 1529, 1367, 1234, 1156, 1054, 747 cm-1; ESI-MS m/z
370.4 ([M + Na]+); ESI-HRMS calcd for C20H29O4NNa ([M + Na]+):
370.1989, found 370.1990.
Data for side-product 13 (an inseparable mixture of two epimers): M. p. 95-
97 ℃. [α]D 25 = –8.9 (c = 0.2, CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.96-
7.91 (m, 4H), 7.46-7.41 (m, 4H), 6.67 (s, 2H), 4.03-3.99 (m, 1H), 3.82 (ddd,
J = 11.2, 4.7, 2.2 Hz, 1H), 3.62-3.57 (m, 2H), 3.55 (dd, J = 11.3, 2.8 Hz,
1H), 3.21 (dd, J = 16.0, 7.7 Hz, 1H), 3.15 (dd, J = 15.6, 8.3 Hz, 1H), 3.06-
2.98 (m, 2H), 2.80 (dd, J = 16.0, 5.2 Hz, 1H), 1.94-1.82 (m, 1H), 1.81-1.71
(m, 1H), 1.70-1.64 (m, 1H), 1.62-1.56 (m, 1H), 1.53 (s, 18H), 1.48-1.37 (m,
2H), 1.09 (d, J = 7.1 Hz, 3H), 1.03 (d, J = 7.1 Hz, 3H), 0.86 (d, J = 6.6 Hz,
3H), 0.74 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 197.82,
197.38, 152.28, 152.26, 142.93, 142.79, 132.29, 132.10, 130.05, 129.95,
117.52, 117.46, 81.45, 81.42, 80.60, 76.38, 75.59, 72.83, 42.68, 41.97,
40.12, 38.48, 31.48, 30.60, 28.97, 28.42, 25.16, 18.39, 17.42, 17.38, 12.80
ppm; FT-IR (film of a concd solution in CH2Cl2) ν = 3446, 2959, 2924,
2854, 1733, 1673, 1603, 1529, 1457, 1384, 1261, 1157, 1052, 1023 cm–1;
ESI-MS m/z 370.3 ([M + Na]+); ESI-HRMS calcd for C20H29O4NNa ([M +
Na]+): 370.1989, found 370.1992.
25
Data for 19a (a colorless oil): [α]D = –35.4 (c = 0.20, CHCl3). 1H
NMR (600 MHz, CDCl3) δ 7.33-7.27 (m, 4H, H-11, H-12), 6.50 (dd, J =
16.1, 1.5 Hz, 1H, H-7), 6.45 (s, 1H, NH), 6.08 (dd, J = 16.1, 5.4 Hz, 1H, H-
6), 4.06-4.02 (m, 1H, H-5), 3.96 (ddd, J = 11.3, 4.7, 2.0 Hz, 1H, H-1), 3.07
(t, J = 11.1 Hz, 1H, H-1), 2.00-1.91 (m, 1H, H-2), 1.91-1.84 (m, 1H, H-4),
1.74-1.69 (m, 1H, H-3), 1.51 (s, 9H, tBu Me), 1.45-1.38 (m, 1H, H-3), 1.00
(d, J = 7.0 Hz, 3H, H-8), 0.79 (d, J = 6.6 Hz, 1H, H-9) ppm; 13C NMR (150
MHz, CDCl3, assigned with the aid of HSQC) δ 152.76 (quat, Boc
carbonyl), 137.58 (quat, C-13), 132.31 (C-10), 129.16 (C-7), 128.52 (C-6),
127.09, 118.58, 80.77 (quat, tBu), 80.44 (C-5), 75.40 (C-1), 39.88 (C-3),
33.24 (C-4), 28.48 (tBu Me), 25.16 (C-2), 17.45 (C-9), 13.02 (C-8) ppm;
FT-IR (film of a concd solution in CH2Cl2) ν = 3383, 2965, 2925, 2870,
1710, 1524, 1412, 1310, 1258, 1160, 1112, 1056, 967, 745, 618 cm–1; ESI-
MS m/z 354.4 ([M + Na]+); ESI-HRMS calcd for C20H29O3NNa ([M +
Na]+): 354.2040, found 354.2047.
Conversion of 14 into carboxylic acid 16 via aldehyde 18. Dess-Martin
periodinane (110 mg, 0.26 mmol) was added to a solution of alcohol 14 (45
mg,0.13 mmol) in dry CH2Cl2 (1.7 mL) stirred in an ice-water bath. Stirring
was then continued at ambient temperature for 20 min (TLC showed
completion of the reaction. Et2O (5 mL) was added, followed by aq. sat.
Na2S2O3 (2 mL). The mixture was extracted with Et2O (10 mL × 3). The
combined organic layers were washed with brine (2 mL) and then dried
over anhydrous MgSO4. Filtration and rotary evaporation left crude
aldehyde 18 as a yellowish oil (44 mg, 0.13 mmol, 100%), which was used
directly in the next step.
=25
1
Data for 19b (a colorless oil): [α]D
= +45.5 (c = 0.10, CHCl3). H
NMR (600 MHz, CDCl3) δ 7.34-7.28 (m, 4H), 6.54 (dd, J = 16.0, 0.9 Hz,
1H, H-7), 6.46 (s, 1H, NH), 6.12 (dd, J = 16.0, 7.4 Hz, 1H, H-6), 3.74 (dt, J
= 11.2, 2.0 Hz, 1H, H-1), 3.64 (dd, J = 11.2, 2.8 Hz, 1H, H-1), 3.48-3.45 (m,
1H, H-5), 1.86-1.79 (m, 1H, H-2), 1.79-1.72 (m, 1H, H-4), 1.66-1.61 (m,
A portion of the above obtained aldehyde 18 (19 mg, 0.055 mmol) was
dissolved in tBuOH (3-mL). To this solution (stirred in an ice-water bath)
were added 2-methyl-buta-2-ene (23 μL, 0.275 mmol), a solution of
NaH2PO4 (20 mg, 0.165 mmol) in water (0.4 mL), and a solution of NaClO2
Submitted to the European Journal of Organic Chemistry
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000837
European Journal of Organic Chemistry
(15 mg, 0.165 mmol) in water (0.4 mL). The mixture was then stirred at
ambient temperature for 10 min (TLC showed completion of the reaction).
EtOAc (5 mL) was added, followed by water (1 mL). The mixture was
extracted with EtOAc (10 mL × 3). The combined organic layers were
dried over anhydrous Na2SO4. Filtration and rotary evaporation left crude
oil, which was purified by column chromatography (2:1 PE/EtOAc) on
silica gel to afford acid 16 as a colorless oil (16 mg, 0.044 mmol, 80%
176.92, 152.86, 135.26, 129.56, 129.09, 127.53, 74.83, 67.98, 66.17, 55.29,
41.01, 37.91, 37.38, 26.00, 18.35, 13.63, 11.56, –5.45, –5.49 ppm; FT-IR
(film of a concd solution in CH2Cl2) ν = 3475, 2955, 2929, 2857, 1783,
1697, 1455, 1383, 1209, 1132, 1076, 1020, 972, 837, 777, 702 cm–1; ESI-
MS m/z 236.2 ([M + H]+); ESI-HRMS calcd for C23H38O5NSi ([M + H]+):
436.2514, found 436.2513.
Mesylation of 20 to afford 21. This was performed using the same
procedures described above for the “Mesylation of 8 to afford 9” except
that 8 was replaced by 20. Data for 21 (a white solid, 9.567 g, 18.6 mmol,
chromatography using 5:1:1 n-hexane/EtOAc/CH2Cl2, 74% from 20): M. p.
135-137 ℃. [α]D25 = +63.2 (c = 1.00, CHCl3). 1H NMR (500 MHz, CDCl3)
δ 7.36-7.26 (m, 3H), 7.22-7.18 (m, 2H), 5.02 (dd, J = 7.0, 3.7 Hz, 1H),
4.66-4.60 (m, 1H), 4.28-4.21 (m, 2H), 4.16 (dd, J = 8.9, 2.3 Hz, 1H), 3.64
(dd, J = 10.4, 7.4 Hz, 1H), 3.50 (dd, J = 10.4, 5.7 Hz, 1H), 3.27 (dd, J =
13.4, 3.3 Hz, 1H), 3.07 (s, 3H), 2.80 (dd, J = 13.4, 9.6 Hz, 1H), 2.10-2.00
(m, 1H), 1.32 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H),
0.07 (d, J = 1.3 Hz, 6H). ppm; 13C NMR (125 MHz,CDCl3) δ 173.94,
153.55, 135.47, 129.57, 129.06, 127.47, 84.16, 66.58, 64.74, 56.00, 41.17,
38.73, 38.61, 37.93, 26.00, 18.35, 13.77, 11.15, –5.36, –5.38 ppm; FT-IR
(film of a concd solution in CH2Cl2) ν = 2929, 1778, 1695, 13691, 1359,
1338, 1288, 1213, 1196, 1175, 1132, 1076, 905, 839, 812, 779, 704 cm–1;
ESI-MS m/z 514.2 ([M + H]+); ESI-HRMS calcd for C24H39O7NSSiNa ([M
+ Na]+): 536.2109, found 536.2112.
25
overall from 14). [α]D = –44.2 (c = 0.25, CHCl3). 1H NMR (600 MHz,
CDCl3) δ 7.92 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 6.91 (d, J =
15.4 Hz, 1H), 6.86 (dd, J = 15.3, 8.1 Hz, 1H), 2.57-2.48 (m, 2H), 1.89-1.83
(m, 1H), 1.53 (s, 9H), 1.52-1.46 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H), 1.13 (d,
J = 6.7 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 189.30, 181.62,
152.76, 142.84, 132.49, 130.26, 125.08, 117.68, 81.52, 40.17, 37.48, 35.58,
28.42, 20.30, 17.87 ppm; FT-IR (film of a concd solution in CH2Cl2) ν =
3327, 2925, 2855, 1735, 1708, 1660, 1595, 1528, 1457, 1412, 1368, 1155,
1054, 800 cm–1; ESI-MS m/z 384.4 ([M + Na]+); ESI-HRMS calcd for
C20H27O5NNa ([M + Na]+): 384.1781, found 384.1776.
Removal of the Boc in 16 to afford (2R,4R)-1. CF3CO2H (0.1 mL, 1.35
mmol) was added to a solution of 16 (12 mg, 0.033 mmol) in CH2Cl2 (1
mL) stirred in an ice-water bath. Stirring was then continued at ambient
temperature for 1 h (TLC showed completion of the reaction). The mixture
was diluted with EtOAc (5 mL), neutralized with aq. NaHCO3 (1 M) to pH
5, and extracted with EtOAc (5 mL × 3). The combined organic layers were
dried over anhydrous Na2SO4. Filtration and rotary evaporation left crude
oil, which was purified by column chromatography (1:1 Pe/EtOAc) on
silica gel to furnish (2R,4R)-1 as a yellowish oil (6 mg, 0.023 mmol, 70%).
The data for this sample (i.e., separated using normal phase
LiBH4 reduction of 21 to afford alcohol 22. This was performed using the
same procedures described above for the “LiBH4 reduction of 9 to afford
alcohol 10” except that 9 was replaced by 21. Data for 22 (a colorless oil,
263 mg, 1.07 mmol, chromatography using 15:1 PE/EtOAc, 76% from 21):
25
1
20
chromatography): [α]D = –63.5 (c = 0.22, MeOH). H NMR (500 MHz,
CD3OD) δ 7.78 (d, J = 8.8 Hz, 2H), 6.97 (dd, J = 15.3, 0.9 Hz, 1H), 6.73
(dd, J = 15.3, 8.7 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 2.52-2.44 (m, 1H),
2.44-2.37 (m, 1H), 1.78 (ddd, J = 13.7, 9.7, 5.2 Hz, 1H), 1.43 (ddd, J = 14.0,
[α]D25 = –2.5 (c = 1.00, CHCl3) (lit [22] [α]D = –2.0 (c = 1.00, CHCl3)). 1H
NMR (500 MHz, CDCl3) δ 3.50 (dd, J = 10.6, 5.2 Hz, 1H), 3.46-3.39 (m,
2H), 3.37 (dd, J = 9.7, 6.3 Hz, 1H), 1.77-1.66 (m, 2H), 1.60 (s, 1H), 1.44
(dt, J = 13.6, 6.9 Hz, 1H), 0.94 (dd, J = 6.7, 0.7 Hz, 3H), 0.92-0.87 (m,
12H), 0.04 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 68.41, 68.37, 37.43,
33.44, 33.40, 26.10, 18.50, 17.97, 17.85, –5.23 ppm; FT-IR (film of a
concd solution in CH2Cl2) ν = 3444, 2956, 2928, 2857, 1471, 1257, 1196,
1095, 1076, 836, 775 cm–1; ESI-MS m/z 247.2 ([M + H]+); ESI-HRMS
calcd for C13H31O2Si ([M + H]+): 247.2088, found 247.2090.
9.4, 5.0 Hz, 1H), 1.14 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H) ppm; 13
C
NMR (125 MHz, CD3OD) δ 190.60, 180.58, 155.70, 152.87, 132.66,
127.17, 126.28, 114.48, 41.74, 39.16, 36.95, 20.81, 18.60 ppm; FT-IR (film
of a concd solution in CH2Cl2) ν = 3466, 3359, 3232, 2964, 2927, 1707,
1610, 1590, 1558, 1442, 1361, 1286, 1245, 1176, 982, 833, 611 cm–1; ESI-
MS m/z 284.2 ([M + Na]+); ESI-HRMS calcd for C15H19NO3Na ([M +
Na]+): 284.1257, found 284.1261.
Swern oxidation of 22 and subsequent condensation with 11 to afford
23. This was performed using the same procedures described above for the
“Swern oxidation of 10 and subsequent condensation with 11 to afford 12”
except that 10 was replaced by 22. Data for 23 (a yellowish solid, 788 mg,
1.71 mmol, chromatography using 15:1 PE/EtOAc, 52% from 11): M. p.
The above sample obtained using normal phase chromatography was then
subjected to reverse phase chromatography (eluting with 1:1 H2O/MeOH)
on C-18 silica gel and the following set of data for (2R,4R)-1 (isolated
25
25
1
using reverse phase chromatography) were collected: [α]D = –55.9 (c =
64-66 ℃. [α]D = +5.6 (c = 1.00, CHCl3). H NMR (500 MHz, CDCl3) δ
7.90 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.89 (dd, J = 15.4, 7.7 Hz,
1H), 6.76 (s, 1H), 3.41 (dd, J = 9.8, 5.8 Hz, 1H), 3.37 (dd, J = 9.8, 6.2 Hz,
1H), 2.58-2.49 (m, 1H), 1.68-1.59 (m, 1H), 1.58-1.53 (m, 1H), 1.52 (s, 9H),
1.18-1.12 (m, 1H), 1.11 (d, J = 6.7 Hz, 3H), 0.90-0.85 (m, 12H), 0.02 (s,
6H) ppm; 13C NMR (125 MHz, CDCl3) δ 189.56, 154.56, 152.31, 142.68,
132.66, 130.19, 124.03, 117.57, 81.36, 68.54, 40.16, 34.91, 33.60, 28.41,
26.08, 20.80, 18.48, 16.83, –5.22, –5.24 ppm; FT-IR (film of a concd
solution in CH2Cl2) ν = 3314, 2957, 2929, 2857, 1735, 1662, 1593, 1528,
1411, 1314, 1231, 1157, 1093, 1054, 837 cm–1; ESI-MS m/z 462.2 ([M +
H]+); ESI-HRMS calcd for C26H44O4NSi ([M + H]+): 462.3034, found
462.3036.
0.22, MeOH). 1H NMR (500 MHz, CD3OD) δ 7.79 (d, J = 8.8 Hz, 2H),
6.98 (d, J = 15.3 Hz, 1H), 6.75 (dd, J=15.2, 8.7 Hz, 1H), 6.64 (d, J = 8.8 Hz,
2H), 2.54-2.45 (m, 1H), 2.45-2.36 (m, 1H), 1.79 (ddd, J = 13.7, 9.7, 5.2 Hz,
1H), 1.42 (ddd, J = 13.9, 9.3, 5.0 Hz, 1H), 1.14 (d, J = 7.0 Hz, 3H), 1.10 (d,
J = 6.7 Hz, 3H) ppm; 13C NMR (150 MHz, CD3OD) δ 190.60, 181.29,
155.62, 153.01, 132.61, 127.15, 126.15, 114.43, 41.83, 39.57, 36.93, 20.78,
18.69 ppm; FT-IR (film of a concd solution in CH2Cl2) ν = 3466, 3359,
3231, 2965, 2927, 2865, 1706, 1609, 1589, 1558, 1442, 1285, 1244, 1076,
1026, 982, 833 cm–1; ESI-MS m/z 262.2 ([M + H]+); ESI-HRMS calcd for
C15H20O3N ([M + H]+): 262.1438, found 262.1438.
Evans aldol condensation of 6 to afford 20. This was performed using the
same procedures described above for the “Evans aldol condensation of 6 to
afford 8” except that 7 was replaced by ent-7. Data for 20 (a white solid,
11.04 g, 25.4 mmol, chromatography using 5:1 PE/EtOAc, 88% from
Desilylation of 23 to afford alcohol 24. A solution of equal molar nBu4NF
and AcOH (1 M, in THF, 1.96 mL, 1.0 mmol of each) was added to a flask
containing 23 (82 mg,0.178 mmol) stirred at 0 C bath (controlled by a
cooling pump system). The mixture was then stirred at 0 C for 23 h (TLC
showed completion of the reaction). Aq. sat. NaHCO3 (5 mL) was added.
The mixture was extracted with EtOAc (10 mL × 3). The combined organic
layers were washed with brine (2 mL) and then dried over anhydrous
MgSO4. Filtration and rotary evaporation left a crude oil, which was
purified by column chromatography (2:1 PE/EtOAc) on silica gel to give
first the undesired cyclic ether 25 (less polar than 24) as a pair of epimers
25
aldehyde 6): M. p. 70-72 ℃. [α]D = +34.4 (c = 1.00, CHCl3). 1H NMR
(500 MHz,CDCl3) δ 7.36-7.27 (m, 3H), 7.23-7.18 (m, 2H), 4.70-4.64 (m,
1H), 4.23-4.15 (m, 2H), 4.07 (dd, J = 6.7, 4.1 Hz, 1H), 3.97 (quint, J = 6.8
Hz, 1H), 3.75 (dd, J = 9.9, 3.9 Hz, 1H), 3.63 (dd, J = 9.9, 4.3 Hz, 1H), 3.31
(s, 1H), 3.25 (dd, J = 13.4, 3.4 Hz, 1H), 2.77 (dd, J = 13.4, 9.5 Hz, 1H),
1.79-1.71 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.90
(s, 9H), 0.07 (d, J = 1.7 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ
Submitted to the European Journal of Organic Chemistry
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000837
European Journal of Organic Chemistry
(ca. 1:1, could be separated, 27 mg in total, 0.078 mmol, total yield 44%)
and then the main product alcohol 24 as a colorless oil (36 mg, 0.104 mmol,
58%).
Data for (2R,4S)-1 (a colorless oil, 14 mg, 0.054 mmol, normal phase
25
chromatography using 1:1 PE/EtOAc, 65% from 26): [α]D = –8.7 (c =
0.22, MeOH). 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J = 8.8 Hz, 2H, H),
6.97 (dd, J = 15.3, 0.9 Hz, 1H), 6.74 (dd, J = 15.3, 8.4, Hz, 1H), 6.62 (d, J =
8.8 Hz, 2H), 2.48 (hept, J = 7.1 Hz, 1H), 2.42 (sext, J =7.1 Hz, 1H), 1.81
(dt, J = 13.7, 7.8 Hz, 1H), 1.42 (dt, J = 13.6, 6.7 Hz, 1H), 1.14 (d, J = 7.0
Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (125 MHz, CD3OD) δ
190.60, 180.55, 155.66, 153.03, 132.66, 127.18, 125.68, 114.50, 41.36,
38.89, 36.56, 20.49, 17.94 ppm; FT-IR (film of a concd solution in CH2Cl2)
ν = 3467, 3358, 3231, 2968, 2931, 1706, 1589, 1558, 1361, 1286, 1176,
1132, 982, 833 cm–1; ESI-MS m/z 284.4 ([M + Na]+); ESI-HRMS calcd for
C15H19O3NNa ([M + Na]+): 284.1257, found 284.1263.
25
Data for 24: [α]D = +22.9 (c = 1.00, CH2Cl2) 1H NMR (500 MHz, CDCl3)
δ 7.91 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 6.91-6.83 (m, 2H), 6.90
(s, 1H), 3.47 (dd, J = 10.5, 5.9 Hz, 1H), 3.43 (dd, J = 10.5, 6.3 Hz, 1H),
2.60-2.51 (m, 1H), 1.69-1.60 (m, 1H), 1.60-1.54 (m, 1H), 1.53 (s, 9H),
1.24-1.17 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 189.56, 154.18, 152.38, 142.86, 132.45,
130.20, 124.23, 117.61, 81.34, 68.49, 40.02, 34.89, 33.72, 28.40, 20.90,
16.53 ppm; FT-IR (film of a concd solution in CH2Cl2) ν = 3439, 3307,
2963, 2927, 1731, 1660, 1594, 1530, 1411, 1367, 1314, 1235, 1151054,
985, 838, 777 cm–1; ESI-MS m/z 348.2 ([M + H]+); ESI-HRMS calcd for
C20H30O4N ([M + H]+): 348.2169, found 348.2171.
The above sample obtained using normal phase chromatography was then
subjected to reverse phase chromatography (eluting with 1:1 H2O/MeOH)
on C-18 silica gel and the following set of data for (2R,4S)-1 (isolated using
Data for side product 25a (recored on a pure analytical sample obtained by
25
25
further chromatoragphy, less polar than 25b): [α]D = +8.5 (c = 1.00,
reverse phase chromatography) were collected: [α]D = –8.6 (c = 0.22,
CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.7 Hz, 2H), 7.43 (d, J
= 8.8 Hz, 2H), 6.75 (s, 1H, NH), 3.77 (ddd, J = 11.2, 4.4, 2.3 Hz, 1H, H-1),
3.54 (ddd, J = 9.8, 8.4, 3.2 Hz, 1H, H-5), 3.11 (dd, J = 15.5, 8.4 Hz, 1H, H-
6), 3.01 (dd, J = 15.5, 3.3 Hz, 1H, H-6), 2.93 (t, J = 11.1 Hz, 1H, H-1),
1.84-1.77 (m, 1H, H-3), 1.77-1.68 (m, 1H, H-2), 1.59-1.53 (m, 1H, H-4),
1.53 (s, 9H, tBu), 0.92-0.83 (m, 1H, H-3), 0.88 (d, J = 6.6 Hz, 3H, H-8),
0.76 (d, J = 6.6 Hz, 3H, H-9) ppm; 13C NMR (125 MHz, CDCl3, assigned
with the aid of HSQC) δ 197.95 (quat, C-7), 152.30 (quat, Boc carbonyl),
142.85, 132.26, 130.04 (quat, C-10), 117.46 (quat, C-13), 81.36 (quat, tBu),
80.12 (C-5), 74.64 (C-1), 42.54 (C-6), 41.77 (C-3), 35.95 (C-4), 31.48 (C-
2), 28.41 (tBu Me), 18.19 (C-8), 17.23 (C-9) ppm; FT-IR (film of a concd
solution in CH2Cl2) ν = 3333, 2955, 1732, 1672, 1603, 1528, 1410, 1318,
1231, 1157, 1096, 1053, 851 cm–1; ESI-MS m/z 348.2 ([M + H]+); ESI-
HRMS calcd for C20H30O4N ([M + H]+): 348.2169, found 348.2169.
MeOH). 1H NMR (500 MHz, CD3OD) 7.78 (d, J=8.8 Hz, 2H), 6.97 (d, J =
15.3 Hz, 1H), 6.77 (dd, J = 15.3, 8.3, Hz, 1H), 6.63 (d, J = 8.8 Hz, 2H),
2.50 (hept, J = 7.1 Hz, 1H), 2.42 (sext, J = 7.1 Hz, 1H), 1.82 (dt, J = 13.5,
7.7 Hz, 1H), 1.40 (dt, J = 13.6, 6.8 Hz, 1H), 1.14 (d, J = 6.9 Hz, 3H), 1.11
(d, J = 6.7 Hz, 3H) ppm; 13C NMR (150 MHz, CD3OD) δ 190.60, 181.86,
155.54, 153.30, 132.55, 127.10, 125.41, 114.39, 41.56, 39.63, 36.46, 20.30,
18.16 ppm; FT-IR (film of a concd solution in CH2Cl2) ν = 3473, 3357,
3231, 2967, 2928, 2870, 1706, 1610, 1589, 1361, 1286, 1176, 1132, 1018,
832 cm–1; ESI-MS m/z 262.2 ([M + H]+); ESI-HRMS calcd for C20H30O4N
([M + H]+): 262.1438, found 262.1439.
Supporting Information Copies of the 1H and 13C NMR spectra, FT-IR
spectra for all new compounds, comparison tables of NMR and optical
rotation data, comparison of 1H NMR (expansions) and IR spectra recored
on samples obtained under different chromatographic conditions.
Data for side product 25b (recorded on a pure analytical sample obtained
by further chromatoragphy, more polar than 25a): [α]D25 = –54.4 (c = 1.00,
CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 8.7 Hz, 2H), 7.45 (d, J
= 8.6 Hz, 2H), 6.82 (s, 1H, NH), 4.46 (dt, J = 9.4, 4.8 Hz, 1H, H-5), 3.54
(ddd, J = 11.6, 4.6, 1.7 Hz, 1H, H-1), 3.29-3.21 (m, 2H, H-6 and H-1), 2.94
(dd, J = 15.1, 4.7 Hz, 1H, H-6), 2.12-2.04 (m, 1H, H-4), 1.79-1.71 (m, 1H,
H-2), 1.71-1.62 (m, 1H, H-3), 1.53 (s, 9H, tBu), 1.07 (dt, J = 13.3, 11.3 Hz,
1H, H-3), 0.88 (d, J = 7.0 Hz, 3H, H-8), 0.85 (d, J = 6.7 Hz, 3H, H-9) ppm;
13C NMR (125 MHz, CDCl3) δ 197.73 (quat, C-7), 152.30 (quat, Boc
carbonyl), 142.97, 131.80, 129.86 (quat, C-10), 117.59 (quat, C-13), 81.37
(quat, tBu), 74.00 (C-5), 67.45 (C-1), 35.83 (C-3), 35.18 (C-6), 33.62 (C-4),
31.13 (C-2), 28.40 (Boc Me), 17.85 (C-8), 17.78 (C-9) ppm; FT-IR (film of
a concd solution in CH2Cl2) ν = 3333, 2955, 1732, 1672, 1590, 1528, 1409,
1367, 1290, 1233, 1156, 1077, 1052 cm–1; ESI-MS m/z 348.3 ([M + H]+);
ESI-HRMS calcd for C20H30O4N ([M + H]+): 348.2169, found 348.2171.
Conversion of 24 into carboxylic acid 26. This was performed using the
same procedures described above for the “Conversion of 14 into carboxylic
acid 16 via aldehyde 18” except that 14 was replaced by 24. Data for 26 (a
colorless oil, 30 mg, 0.083 mmol, chromatography using 2:1 PE/EtOAc,
82% from the intermediate aldehyde 24’ or 80% over two steps from
alcohol 24): [α]D25 = +4.4 (c = 0.10, CHCl3). 1H NMR (500 MHz, CDCl3) δ
7.90 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.92-6.85 (m, 2H), 2.57-
2.45 (m, 2H), 1.94-1.87 (m, 1H), 1.53 (s, 9H), 1.51-1.43 (m, 1H), 1.21 (d, J
= 7.0 Hz, 3H), 1.15 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3)
δ 189.33, 181.98, 152.98, 142.85, 132.42, 130.24, 124.44, 117.69, 81.52,
39.70, 37.43, 35.28, 28.42, 20.04, 17.30 ppm; FT-IR (film of a concd
solution in CH2Cl2) ν = 3438, 3334, 2964, 2919, 1730, 1701, 1655, 1561,
1384, 1150, 1052, 902, 836, 770 cm–1; ESI-MS m/z 384.4 ([M + Na]+); ESI-
HRMS calcd for C20H27O5NNa ([M + Na]+): 384.1781, found 384.1779.
Removal of the Boc in 26 to afford (2R,4S)-1. This was performed using
the same procedures described above for the “Removal of the Boc in 16 to
afford (2R,4R)-1” except that 16 was replaced by 26.
Acknowledgments
This work was supported by the National Natural Science Foundation of
China (21532002, 21672244) and the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20020200).
____________
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European Journal of Organic Chemistry
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Received: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
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Entry for the Table of Contents ((Please choose one layout.))
Layout 2:
Natural Product Synthesis
Xin Xiong, Yikang Wu* and Bo Liu*
…….... Page No. – Page No.
Synthesis and Configuration of A p-
Aminoacetophenonic Acid Isolated from
Endophyte of the Mangrove Plant Kandel
candel
Although as a target of total synthesis
and structural assignment of natural
products a molecule of this size and
complexity might never catch much
attention, there is still something
unusual and very interesting here --- the
NMR, IR and optical rotation were
actually dependent on, to everyons’
surprise, the chromatographic conditions
employed…
Keywords: amino acids / enones /
natural products /aldols / condensation
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10.1002/ejoc.202000837
European Journal of Organic Chemistry
Supporting Information
((Please insert the Supporting Information here))
Submitted to the European Journal of Organic Chemistry
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