Access to Anti or Syn 2-Amino-1,3-diol Scaffolds from a Common Decarboxylative Aldol Adduct

Article abstract of DOI:10.1021/acs.joc.8b00901

A straightforward synthetic pathway allowing the access to anti or syn 2-amino-1,3-diol scaffolds is presented. The strategy relies on a diastereoselective organocatalyzed decarboxylative aldol reaction of a N-Boc-hemimalonate that is easily formed from commercial N-Boc-diethyl malonate. Although this method has been optimized previously with the N-Bz-hemimalonate analogue, this key step was reinvestigated with the N-Boc derivative to improve the required reaction time, the yield, and the diastereoselectivity. The new conditions enhance this transformation, and quantitative yields and anti/syn ratios up to 96:4 can be obtained. The anti aldol product was easily isolated in pure form and then taken forward as the key precursor in the preparation of both a set of ten N-/O-alkylated anti 2-amino-1,3-diol derivatives and the syn congeners.

Full text of DOI:10.1021/acs.joc.8b00901

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Article
Access to anti or syn 2-amino-1,3-diol scaffolds
from a common decarboxylative aldol adduct
Pauline Chaumont, Jerome Baudoux, Jacques Maddaluno, Jacques Rouden, and Anne Harrison-Marchand
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00901 • Publication Date (Web): 28 Jun 2018
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The Journal of Organic Chemistry
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Access to anti or syn 2-amino-1,3-diol scaffolds from a common de-
carboxylative aldol adduct
Pauline Chaumont,† Jérome Baudoux,‡ Jacques Maddaluno,† Jacques Rouden,‡* and Anne Harrison-
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Marchand†*
†
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, Laboratoire COBRA (UMR 6014 & FR 3038), 76000 Rouen, France.
‡
Normandie Univ, ENSICAEN, UNICAEN, CNRS, Laboratoire LCMT (UMR 6507 & FR 3038), 14000 Caen, France.
ABSTRACT: A straightforward synthetic pathway allowing the access to anti or syn 2-amino-1,3-diol scaffolds is presented. The
strategy relies on a diastereoselective organocatalyzed decarboxylative aldol reaction of a N-Boc-hemimalonate that is easily
formed from commercial N-Boc-diethyl malonate. Although this method has been optimized previously with the N-Bz-
hemimalonate analogue, this key step was reinvestigated with the N-Boc derivative to improve the required reaction time, the yield
and the diastereoselectivity. The new conditions enhance this transformation, and quantitative yields and anti/syn ratios up to 96 : 4
can be obtained. The anti aldol product was easily isolated in pure form, then taken forward as the key precursor in the preparation
of both a set of ten N-/O-alkylated anti 2-amino-1,3-diol derivatives and the syn congeners.
INTRODUCTION
often require more steps than a convergent synthesis. The
second approach involves the creation of the bond between the
two stereogenic centers from molecular fragments bearing
functional precursors of the required alcohol and amino groups
(Scheme 1, right). In this context, the methodology with the
highest potential involves the nucleophilic addition of a gly-
cine anion equivalent to an aldehydes.4 Thus, in a single step
one can control the stereochemistry of the stereocenters and
build an advanced scaffold containing the target 2-amino-1,3-
diol motif from readily available and inexpensive precursors.5
The main parameters that still require improvement are the
diastereoselectivity (by simplifying or avoiding tedious purifi-
cation steps), the nature of some reagents (solvent and base),
and the operating conditions and cost.
The 2-amino-1,3-diol scaffold (Figure 1) is important in or-
ganic synthesis, and it is found in the structure of many bio-
logically active products (for example sphingosine, sphin-
ganine and chloramphenicol)1 as well as in chiral inductors for
various enantioselective reactions.2 Considering its most popu-
lar fragment, which has two vicinal stereogenic centers (and a
primary alcohol), the anti and syn stereoisomers are found in
an almost equivalent frequency over the multitude of applica-
tions, which is why methods for accessing both configurations
individually need to be studied equally.
Scheme 1. General retrosynthetic strategies for the synthesis
of 2-amino-1,3-diol moieties.
In this paper, we present a simple synthetic method that fol-
lows the second strategy, and the method provides either anti
or syn 2-amino-1,3-diol-substituted derivatives. The approach
takes advantage of a methodology recently developed in a
laboratory of our consortium, i.e., a diastereoselective organo-
catalyzed decarboxylative aldol reaction.6,7 Indeed, in a pio-
neering work from 2013, Rouden’s group reported a stereose-
lective synthesis of anti or syn β-hydroxy-α-aminoacids (3,
Scheme 2) under mild conditions from various aromatic alde-
hydes and N-Bz-hemimalonate 1. The reaction mechanism
followed an original aldol/decarboxylation sequence via char-
acterized intermediate 4 (Scheme 2) and this reaction provided
almost exclusively the anti stereoisomer of aldol adduct 2
(anti/syn ≥ 90:10).6
Figure 1. Targets incorporating the 2-amino-1,3-diol scaffold.
Overall, two main synthetic strategies are used to prepare
these scaffolds. One consists of adding the required functional
groups (i.e., alcohol and amino groups) with the correct stere-
ochemistry to a predefined carbon backbone (Scheme 1, left).3
This strategy encompasses numerous methodologies to append
a vicinal aminoalcohol moiety with a good control of the rela-
tive or absolute stereochemistry. However, its main limitation
is the lack of flexibility inherent to linear syntheses, and which
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Scheme 2. Synthesis of anti or syn β-hydroxy-α-aminoacids 3
Table 1. Optimization of the diastereoselective decarboxyla-
tive aldol reaction of 6.
via a decarboxylative aldol reaction of N-Bz-hemimalonate 1.6
1
2
3
4
5
6
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Entry Solvent T (°C)
t (h)
5 days
5 days
48
yield (%)a anti/synb
1
2
3
4
5
6
THF
none
none
none
none
none
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10
30
40
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60
59
79
75:25
90:10
92:8
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91:9
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96:4
Carrying out the reduction of the residual carbonyl group,
either from 2 (CO2Et) or 3 (CO2H) is an elegant subsequent
step for efficiently and stereoselectively accessing anti 2-
amino-1,3-diol compounds. Otherwise, the syn analogues
should be accessible by means of the stereoinversion of one of
the carbon atoms of the anti aldol product. We report here the
results obtained following this plan.
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79:21
1
aYield determined by H NMR with 1,3,5-trimethoxybenzene as an inter-
nal standard. bNMR ratio measured on the crude product.
We first examined the influence of the solvent by removing
THF and performing the reaction neat at 10 °C. Interestingly,
after 5 days (entry 2), both the yield and the diastereoselectivi-
ty were improved (79% and 90:10, respectively). We decided
to focus on the effect of increasing the temperature from 30 °C
to 60 °C (entries 3 to 6) in the absence of solvent and when
limiting the reaction time to 48 h. Pleasingly, the completion
of the reaction and formation of the desired product could be
observed with a very good 96:4 anti/syn diastereoselectivity at
50°C. Working at a higher temperature (60 °C, entry 7) did not
improve the reaction outcome. The optimal reaction conditions
defined with 6, i.e., no solvent, 48 h, and 50 °C, were thus
used to assess the scope of this new procedure on a set of
twelve aldehydes (7b to 7m, Scheme 4, Table 2).
RESULTS AND DISCUSSION
To easily vary the N-substitution of the final 2-amino-1,3-diol
derivatives (NH2, NHMe and NHBn), we selected N-Boc-
hemimalonate (6, Scheme 3) as the starting material instead of
N-Bz 1. Indeed, a Boc protecting group is more flexible than a
benzamido appendage for accessing a wider variety of deriva-
tives from a common substrate.
Thus, 6 was isolated in 79% yield following a monosaponifi-
cation of commercially available N-Boc-malonate 5 with KOH
(Scheme 3). The decarboxylative aldol reaction was then
carried out on 6 in the presence of benzaldehyde 7a first with
the conditions originally used with 1 (Table 1, entry 1).6 After
5 days of reaction, expected adduct 8a was obtained in a satis-
factory yield (59%) but with a disappointing diastereoselectiv-
ity (anti/syn 75:25). To improve the diastereoselectivity when
using 6, the conditions of this key step had to be re-examined
(Table 1).
Scheme 4. Scope of the decarboxylative aldol reaction of 6
and X-ray structure of anti-8c.
Scheme 3. Diastereoselective decarboxylative aldol reaction
from N-Boc-hemimalonate 6.
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Table 2. Scope of the diastereoselective decarboxylative aldol the basis of the electron-donating effects as well as steric
reaction of 6.
1
considerations. Placing the electron-donating group further
away (7d/8d and 7e/8e, entries 4 and 5) may lead to an im-
provement in the yield (a gain of approximately 10% yield is
observed involving para-tolualdehyde instead of its ortho
congener, entry 4 versus entry 2), but a slight decrease in the
diastereoselectivity, with an average of a 87:13 anti/syn ratio,
is observed regardless of the substituent. Working with α-
naphthaldehyde (7f, entry 6) provided comparable results.
Excellent yields are obtained with electron-withdrawing sub-
stituents as seen with NO2, F and CF3 (entries 7 to 11), and the
products were generated with an average anti/syn ratio of
87:13 regardless of the position of the substituent (ortho, meta
or para). Expanding the scope to non-benzaldehyde substrates
such as thiophene-2-carbaldehyde 7l and butyraldehyde 7m
(entries 12 and 13) confirmed the feasibility of the reaction as
satisfactory yields and anti/syn ratios were obtained. Note that
the anti and syn stereoisomers of all compounds 8 of this
series were easily separated by column chromatography, and
the anti stereoselectivity could be confirmed thanks to crystal-
lographic data obtained from a single-crystal of 8c (Scheme
4).
With these optimized conditions in hand, we turned our atten-
tion to our main objective; stereoselectively preparing anti and
syn 2-amino-1,3-diol species. Compound anti-8a was chosen
as model the compound to serve as a common precursor of
both diastereomers (Scheme 3). Regarding the anti amino-
diols series, carrying out the reduction of the ethyl ester group
of anti-8a to generate the 1,3-diol appendage was the most
obvious and direct method. Thus, anti-8a was reacted with
excess LiBH4, which quantitatively led to N-Boc-1,3-diol anti-
9a (Scheme 5).
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Entry Aldehyde Product : yield (%)a
anti/synb
96:4
1
2
7a
7b
7c
7d
7e
7f
8a : 100 (96)
8b : 55 (46)
8c : 73 (70)
8d : 65 (55)
8e : 56 (49)
8f : 54 (39)
8g : 100 (87)
8h : 98 (86)
8i : 97 (70)
8j : 94 (76)
8k : 95 (66)
8l : 100 (73)
8m : 50 (38)
91:9
3
95:5
4
86:14
89:11
85:15
88:12
87:13
88:12
83:17
86:14
87:13
76:24
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7g
7hc
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7j
7k
7l
7m
aYield determined by 1H NMR with 1,3,5-trimethoxybenzene as the
internal standard. Between parentheses: isolated yield of the anti isomer.
bNMR ratio measured on the crude product. cDiluted in 0.3 mL of THF.
Aldehydes with an ortho electron-donating substituent (me-
thyl: 7b, entry 2 and methoxy: 7c, entry 3) provided the ex-
pected aldol products (8b and 8c) with excellent diastereose-
lectivities (≥ 91:9). The moderate yields can be explained on
Scheme 5. Synthesis of 2-amino-1,3-diols anti derivatives 9 to 13.
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At this point, we can draw our first conclusion: N-Boc-
compounds 13-NH2, 13-NHMe and 13-NHBn were synthe-
sized from 5 in six or seven synthetic steps in 27%, 14% and
33% overall yields, respectively.
protected 2-amino-1,3-diol anti-9a can be synthesized in only
3 steps from inexpensive commercially available reagents
under very mild conditions in 72% overall yield. To apply this
chemistry, functional group manipulations were conducted on
anti-9a, which led to four sets of anti compounds, namely, 2-
amino-1,3-diol 10, 2-amino-1,3-diethers 11 and 2-amino-1,3-
etheralcohols 12 and 13. All transformations and yields are
summarized in Scheme 5.
The second aim of this work was to also access syn 2-amino-
1,3-diol derivatives, thus we investigated the stereoinversion
of one of the stereogenic carbon atom of anti-8a. The strategy
involved anchimeric assistance from the N-Boc protecting
group (Scheme 6).8
9
Scheme 6. Synthesis of syn-9a from anti-8a
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2-Amino-1,3-diol compound 10-NH2 could be prepared from
anti-9a by quantitatively removing the Boc group using tri-
fluoroacetic acid (TFA). Thus, anti-10-NH2 was isolated as the
trifluoroacetate ammonium salt in four synthetic steps from N-
Boc-malonate 5 in 66% overall yield.
Reaching the diethereal analogues 11-NH2 and 11-NHMe
required two synthetic steps from anti-9a: a dibenzylation of
both hydroxy groups with NaH and BnBr (14) followed by
either a Boc deprotection with TFA to form 11-NH2 (66%
yield from 9a) or a reduction of the Boc in the presence of
lithium aluminum hydride (LAH) to obtain 11-NHMe (48%
yield from 9a). N-Benzyl congener 11-NHBn was accessible
through a tribenzylation of anti-9a, i.e., both OH groups plus
the NHBoc (15), followed by the addition of TFA to remove
the Boc group (67% yield from 9a). The three anti 2-amino-
1,3-diethers 11-NH2, 11-NHMe and 11-NHBn were thus
isolated in five synthetic steps from 5 in 50%, 36% and 53%
overall yields, respectively.
Reacting anti-8a with thionyl chloride in Et2O at 0 °C for five
hours enabled the complete stereochemical inversion of C3 by
forming oxazolidinone 23 in 81% yield. To avoid epimeriza-
tion of 23 during hydrolysis of the oxazolidinone ring in a
strong acidic solution, we used an alternative route developed
by Davies.9 Thus, compound 23 was first converted into N-
Boc oxazolidinone 24 in 84% yield, and then treatment of the
latter by an aqueous LiOH solution led to N-Boc β-
hydroxyacid 25 in 65% yield. Reduction of the acidic group of
25 with NaBH4 allowed the isolation of syn-9a in 50% yield.
In summary, syn-9a, the putative precursor of the syn conge-
ners of compounds 10 to 13 in Scheme 4, is easily accessible
from anti-8a in four synthetic steps.
The regioselective monobenzylation reactions of either the
primary or the secondary alcohol (compounds anti-12 and
anti-13, respectively) were more tedious. The regiospecific
benzylation of the primary alcohol of anti-9a was cleanly
achieved via a cyclic dialkoxytin intermediate (Bu2SnO,
i-Pr2NEt, TBAB and BnBr, 16), affording 12-NH2 in 52%
yield from 9a after amino deprotection with TFA. Compound
12-NHMe was synthesized in 64% yield from 9a using the
same monobenzylation strategy followed by an LAH reduc-
tion of the Boc group. Preparing 12-NHBn (25% yield from
9a) required an additional protection of the secondary OH by a
TBDMS group (17), enabling the N-benzylation of the NHBoc
moiety (18) and a global deprotection with TFA (removal of
TBDMS and Boc groups). Thus, aminoalcohols 12-NH2 and
12-NHMe were isolated in five synthetic steps from 5 in 40%
and 50% overall yields, respectively, and seven steps were
necessary to generate 12-NHBn in 20% overall yield.
CONCLUSION
In conclusion, we report in this paper a rapid and flexible
strategy diastereoselectively leading to either the anti or syn
2-amino-1,3-diol scaffolds. The strategy is based on a dia-
stereoselective organocatalyzed10 decarboxylative aldol reac-
tion from inexpensive commercially available N-Boc-
aminomalonate. The main intermediate, the N-Boc protected
2-amino-1,3-diol, was synthesized in only 3 steps in a 72%
overall yield from commercially available inexpensive rea-
gents. Moreover, the reaction conditions for the key reaction,
i.e., the decarboxylative aldol reaction, are very mild and
simple (no strong base, no low or high temperature, no sol-
vent, and operationally simple reaction, work up and purifica-
tion). This very short preparation of 2-amino-1,3-diol is argu-
ably one of the most efficient methods described to date in the
literature. As an application, subsequent chemical transfor-
mations of the anti aldol adduct allowed the isolation of ten
anti 2-amino-1,3-diol derivatives in two to five steps in good
yields. An appropriate stereoinversion on the same anti aldol
adduct via neighboring group participation was also cleanly
achieved, which allowed the synthesis of syn congeners. As
part of our continuing interest in the use of main group metal
nucleophiles in enantioselective addition reactions,11 we plan
An initial regioselective protection of the primary OH was
achieved with a trityl group (19) in the synthesis of com-
pounds 13. Benzylation reactions were next carried out with
either one equivalent or excess BnBr to afford the OBn
(monobenzylated 20) or the OBn-N(Bn)Boc (dibenzylated 22)
synthetic intermediates, respectively. A double cleavage of the
trityl and Boc groups with a large excess of TFA converted the
monobenzylated intermediate into 13-NH2 in 34% yield from
9a, while 13-NHMe was obtained after the selective removal
of the trityl moiety in the presence of only three equivalents of
TFA (21) followed by the LAH reduction of the Boc group to
a methyl substituent. Compound 13-NHMe was thus isolated
in 18% yield from 9a. Compound 13-NHBn was produced in
42% yield from 9a by reacting the trityl dibenzylated species
mentioned earlier (22) with a large excess of TFA. All three
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to develop an enantioselective version of the strategy depicted General procedure for the decarboxylative aldolisation. After
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in this work and then use the obtained compounds as chiral
ligands for organometallics such as organolithium, magnesium
or zinc.11a Beyond this project, we believe that our methodolo-
gy for the synthesis of the priviledged scaffold, i.e., 2-amino-
1,3-diol, combines all the properties (rapid, mild, operationally
simple, selective and inexpensive) that make a process very
attractive to the organic and medicinal chemistry communities.
mixing the N-Boc-hemimalonate 6 with triethylamine and
aldehyde 7, the reaction mixture was stirred for 48 hours at 50
°C. The reaction mixture was then concentrated and the resi-
due was purified by flash chromatography on silica gel (pen-
tane/ethyl acetate 90:10) to afford compound 8 anti.
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-phenylprop
anoate anti-8a. Triethylamine (17 µL, 0.122 mmol) then ben-
zaldehyde 7a (50 µL, 0.488 mmol) were added to 6 (30 mg,
0.122 mmol) according to the general procedure above. After
purification, compound anti-8a was isolated with the 96%
yield (36 mg, 0.117 mmol) as a white solid. The characteriza-
tion data of anti-8a are identical to those reported in the litera-
ture.13 1H (CDCl3, 300 MHz) δ 7.36-7.28 (m, 5H), 5.28 (d, J =
6.4 Hz, 1H), 5.20 (m, 1H), 4.70 (m, 1H), 4.15 (q, J = 7.1 Hz,
2H), 3.95 (d, J = 5.8 Hz, 1H), 1.43 (s, 9H), 1.19 (t, J = 7.1 Hz,
3H); 13C (CDCl3, 75 MHz) δ 169.9, 156.6, 139.4, 128.4 (2C),
128.1, 126.2 (2C), 80.8, 75.3, 61.9, 59.9, 28.4 (3C), 14.1.
EXPERIMENTAL SECTION
9
General details. All reagents were purchased from Acros
Organics, Sigma Aldrich, Alfa Aesar, TCI or Fluka and were
used without further purification. RPE grade solvents were
used as received. Anhydrous solvents were obtained from a
PURESOLV SPS400 apparatus developed by Innovative
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1
Technology Inc. H and 13C NMR spectra were recorded on a
Bruker DRX 300 MHz or a Bruker DRX 400 MHz spectrome-
ter. Samples were dissolved in a deuterated solvent that was
deuteriochloroform (CDCl3) with a calibration at 7.26 ppm for
1H spectra and 77.16 ppm for 13C spectra, tetradeuterometha-
nol (CD3OD) with a calibration at 3.31 ppm for 1H spectra and
49.00 ppm for 13C spectra or deuterium oxide (D2O) with a
calibration at 4.79 ppm for 1H spectra. The chemical shifts (δ)
are expressed in ppm and coupling constants are indicated in
Hz. Abbreviations for signal coupling are as follows: s = sin-
glet; d = doublet; dd = doublet of doublets; t = triplet; dt =
doublet of triplets; q = quartet; quin = quintet; m = multiplet;
br = broad signal. Additional 2D NMR experiments (COSY,
HSQC, HMBC) and NOESY experiments were performed to
ensure correct structural determination. Mass spectra were
obtained on a GC/MS Saturn 2000 spectrometer. High-
resolution mass spectra (HRMS) were performed on Q-TOF
Micro WATERS by electrospray ionisation (ESI). Infrared
(IR) spectra were recorded with a Perkin Elmer 16 PC FT-IR
ATR spectrometer. Pre-coated aluminium plates of silica gel
60 F-254 (Merck) were used to perform Thin Layer Chroma-
tography (TLC). Flash chromatography was performed on
silica gel column (Merck silica gel, 40-63 μm) using air pres-
sure.
Ethyl
2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(o-tolyl)
propanoate anti-8b. Triethylamine (34 µL, 0.244 mmol) then
o-tolualdehyde 7b (113 µL, 0.976 mmol) were added to 6 (60
mg, 0.244 mmol) according to the general procedure. After
purification, compound anti-8b (presence of two rotamers)
was isolated with the 46% yield (36 mg, 0.112 mmol) as a
white solid. m.p. 96-98 °C; 1H (CDCl3, 300 MHz) δ 7.39-7.36
(m, 1H), 7.20-7.12 (m, 3H), 5.46-5.44 (m, 1H), 5.30-5.25 (m,
1H), 4.57-4.53 (m, 1H), 4.13-3.96 (m, 2H), 3.25 (br, 1H), 2.37
(s, 3H), 1.44/1.43 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H); 13C (CDCl3,
75 MHz) δ 170.6, 155.6, 137.6, 135.1, 130.6, 127.9, 126.0
(2C), 80.5, 71.8, 61.5, 58.1, 28.4 (3C), 19.2, 13.9; IR (ATR) ν
(cm-1) 3504, 3379, 2979, 2856, 2113, 1699; HRMS (ESI) m/z
calculated for C17H26NO5 [M+H]+ 324.1811, found 324.1813.
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(2-methoxy
phenyl)propanoate anti-8c. Triethylamine (34 µL, 0.244
mmol) then o-anisaldehyde 7c (118 µL, 0.976 mmol) were
added to 6 (60 mg, 0.244 mmol) according to the general
procedure. After purification, compound anti-8c was isolated
with the 70% yield (58 mg, 0.171 mmol) as a yellowish solid.
The characterization data of anti-8c are identical to those
reported in the literature.14 1H (CDCl3, 300 MHz) δ 7.32-7.23
(m, 2H), 6.97-6.92 (m, 1H), 6.87-6.83 (m, 1H), 5.37-5.34 (m,
1H), 5.31-5.22 (m, 1H), 4.69-4.66 (m, 1H), 4.19-4.03 (m, 2H),
4.01-3.97 (m, 1H), 3.81 (s, 3H), 1.37/1.31 (s, 9H), 1.15 (t, J =
7.1 Hz, 3H); 13C (CDCl3, 75 MHz) δ 171.4, 170.8, 156.4,
156.0, 129.0, 127.6, 120.8, 110.3, 80.2, 71.9, 61.4, 58.8, 55.5,
28.4 (3C), 14.1.
Experimental procedures and characterization data.
2-[(Tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropanoic
acid (or N-Boc-hemimalonate) 6. A solution of KOH (2.2 g,
39.2 mmol) in distillated water (8.6 mL) was added dropwise
to a solution of diethyl(boc-amino)malonate 5 (10 mL, 39.2
mmol) in ethanol (87 mL) at 0 °C. The reaction mixture was
allowed to warm to room temperature and stirred for 15 h.
Ethanol was evaporated then the crude was extracted with
diethyl ether (320 mL) to avoid the presence of starting
material or decarboxylation product. A 1 M HCl aqueous
solution was added dropwise until pH = 1, then the mixture
was saturated with NaCl and extracted with ethyl acetate
(315 mL). The organic layers were combined, dried over
MgSO4 and, after filtration, the solvents were removed under
reduced pressure. The N-Boc-hemimalonate 6 was obtained
without further purification with the 79% yield (7.68 g, 31.2
mmol) as a white solid. The characterization data of 6 (pres-
ence of two rotamers) are identical to those reported in the
literature.12 1H (CDCl3, 400 MHz) δ 11.85 (bs, 1H), 7.73/5.64
(d, J = 4.5 Hz, 1H), 4.98/4.76 (d, J = 7.5 Hz, 1H), 4.25 (q, J =
7.1 Hz, 2H), 1.44/1.42 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H); 13C
(CDCl3, 100 MHz) δ 170.0/168.4, 166.7/166.6, 156.8/155.3,
82.8/81.4, 63.0/62.4, 58.8/57.5, 28.2 (3C), 14.2.
Ethyl
2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(p-tolyl)
propanoate anti-8d. Triethylamine (34 µL, 0.244 mmol) then
p-tolualdehyde 7d (115 µL, 0.976 mmol) were added to 6 (60
mg, 0.244 mmol) according to the general procedure. After
purification, compound anti-8d was isolated with the 55%
yield (43 mg, 0.134 mmol) as a white solid (presence of two
1
rotamers). m.p. 91-93 °C; H (CDCl3, 300 MHz) δ 7.17-7.07
(m, 4H), 5.30-5.27 (m, 1H), 5.18-5.13 (m, 1H), 4.68-4.65 (m,
1H), 4.15 (q, J = 7.1 Hz, 2H), 3.98 (bs, 1H), 2.33 (s, 3H),
1.45/1.43 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H); 13C (CDCl3, 75
MHz) δ 170.0, 156.5, 137.8, 136.3, 129.0 (2C), 126.1 (2C),
80.7, 75.1, 61.8, 59.9, 28.4 (3C), 21.2, 14.1; IR (ATR) ν (cm-1)
3476, 3335, 2969, 2932, 1725, 1679, 1519, 1160; HRMS
(ESI) m/z calculated for C17H26NO5 [M+H]+ 324.1811, found
324.1796.
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The Journal of Organic Chemistry
Page 6 of 13
mmol) then p-fluorobenzaldehyde 7i (105 µL, 0.976 mmol)
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(4-methoxy
1
2
3
4
5
6
7
8
phenyl)propanoate anti-8e. Triethylamine (34 µL, 0.244
mmol) then p-anisaldehyde 7e (119 µL, 0.976 mmol) were
added to 6 (60 mg, 0.244 mmol) according to the general
procedure. After purification, compound anti-8e was isolated
with the 49% yield (41 mg, 0.120 mmol) as a white solid
were added to 6 (60 mg, 0.244 mmol) according to the general
procedure. After purification, compound anti-8i was isolated
with the 70% yield (55 mg, 0.171 mmol) as a white solid. The
characterization data of anti-8i are identical to those reported
in the literature.15 1H (CDCl3, 300 MHz) δ 7.27-7.22 (m, 2H),
7.04-6.98 (m, 2H), 5.33-5.31 (m, 1H), 5.16 (m, 1H), 4.66-4.64
(m, 1H), 4.19 (bs, 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.42 (s, 9H),
1.20 (t, J = 7.1 Hz, 3H); 13C (CDCl3, 75 MHz) δ 169.8, 160.9,
156.5, 135.2, 128.0, 127.9, 115.3, 115.0, 80.9, 74.7, 61.9,
59.9, 28.3 (3C), 14.1; 19F (CDCl3, 282 MHz) δ -114.49.
1
(presence of two rotamers). m.p. 109-111 °C; H (CDCl3, 300
MHz) δ 7.29-7.17 (m, 2H), 6.87-6.83 (m, 2H), 5.28-5.26 (m,
1H), 5.16-5.09 (m, 1H), 4.65-4.64 (m, 1H), 4.15 (q, J = 7.1
Hz, 2H), 3.93 (bs, 1H), 3.79 (s, 3H), 1.43/1.35 (s, 9H), 1.21 (t,
J = 7.1 Hz, 3H); 13C (CDCl3, 75 MHz) δ 171.1/170.0, 159.5,
156.5, 131.4, 127.4 (2C), 113.8 (2C), 80.7, 74.8, 61.8, 59.9,
55.4, 28.4 (3C), 14.2; IR (ATR) ν (cm-1) 3567, 3364, 2986,
2928, 1742, 1689, 1510; HRMS (ESI) m/z calculated for
C17H26NO6 [M + H]+ 340.1760, found 340.1753.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-[2-(trifluo-
romethyl)phenyl]propanoate anti-8j Triethylamine (34 µL,
0.244 mmol) then o-(trifluoromethyl)benzaldehyde 7g (129
µL, 0.976 mmol) were added to 6 (60 mg, 0.244 mmol) ac-
cording to the general procedure. After purification, com-
pound anti-8j was isolated with the 76% yield (70 mg, 0.186
mmol) as a colorless oil (presence of two rotamers). 1H
(CDCl3, 300 MHz) δ 7.76-7.74 (m, 1H), 7.65-7.62 (m, 1H),
7.60-7.55 (m, 1H), 7.43-7.38 (m, 1H), 5.38-5.35 (m, 1H), 5.22
(d, J = 8.9 Hz, 1H), 4.62-4.58 (m, 1H), 4.24-4.08 (m, 2H),
3.58 (bs, 1H), 1.42/1.33 (s, 9H), 1.19-1.13 (m, 3H); 13C
(CDCl3, 75 MHz) δ 171.0, 155.2, 138.5, 132.1, 128.8, 128.3,
127.9 (q, JC-F = 30.1 Hz), 125.6, 122.6, 80.4, 70.3, 61.8, 58.9,
30.4/28.2 (3C), 15.3/14.0; 19F (CDCl3, 282 MHz) δ – 57.48
(3F); IR (ATR) ν (cm-1) 3439, 3376, 2981, 2932, 1696, 1502,
1310; HRMS (ESI) m/z calculated for C17H23F3NO5 [M+H]+
378.1528, found 378.1534.
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(naphtha
len-1-yl)propanoate anti-8f. Triethylamine (34 µL, 0.244
mmol) then 1-naphthaldehyde 7f (133 µL, 0.976 mmol) were
added to 6 (60 mg, 0.244 mmol) according to the general
procedure. After purification, compound anti-8f was isolated
with the 39% yield (34 mg, 0.095 mmol) as a white solid
1
(presence of two rotamers). m.p 151-153 °C; H (CDCl3, 300
MHz) δ 8.17 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.81
(d, J = 8.2 Hz, 1H), 7.64-7.44 (m, 4H), 5.95-5.86 (m, 1H),
5.53-5.51 (m, 1H), 4.82-4.80 (m, 1H), 4.00-3.90 (m, 2H),
3.44-3.43 (m, 1H), 1.46/1.43 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H);
13C (CDCl3, 75 MHz) δ 170.2, 155.8, 135.3, 133.7, 130.6,
129.0, 128.7, 126.6, 125.8, 125.2, 123.9, 122.9, 80.6, 71.7,
61.5, 59.0, 28.4 (3C), 13.8; IR (ATR) ν (cm-1) 3454, 3371,
2973, 2928, 1699, 1516; HRMS (ESI) m/z calculated for
C20H26NO5 [M+H]+ 360.1811; found 360.1810.
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-[3-(trifluo
romethyl)phenyl]propanoate anti-8k. Triethylamine (34 µL,
0.244 mmol) then m-(trifluoromethyl)benzaldehyde 7h (131
µL, 0.976 mmol) were added to 6 (60 mg, 0.244 mmol) ac-
cording to the general procedure. After purification, com-
pound anti-8k was isolated with the 66% yield (61 mg, 0.162
Ethyl
2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(2-nitro
phenyl)propanoate anti-8g Triethylamine (34 µL, 0.244
mmol) then o-nitrobenzaldehyde 7e (148 mg, 0.976 mmol) in
THF (0.3 mL) were added to 6 (60 mg, 0.244 mmol) accord-
ing to the general procedure. After purification, compound
anti-8g was isolated with the 87% yield (75 mg, 0.212 mmol)
1
mmol) as a white solid. m.p. 70-72 °C; H (CDCl3, 300 MHz)
δ 7.54-7.50 (m, 2H), 7.45-7.43 (m, 2H), 5.34-5.32 (m, 1H),
5.30-5.25 (m, 1H), 4.69-4.68 (m, 1H), 4.41 (d, J = 5.3 Hz,
1H), 4.15 (q, J = 7.1 Hz, 2H), 1.43 (s, 9H), 1.19 (t, J = 7.1 Hz,
3H); 13C (CDCl3, 75 MHz) δ 169.3, 156.8, 140.7, 130.7 (q, JC-
F = 32.3 Hz), 129.6, 128.8, 124.9 (q, JC-F = 3.8 Hz), 123.3 (q,
JC-F = 3.9 Hz), 81.2, 75.1, 62.2, 60.0, 28.3 (3C), 14.1; 19F
(CDCl3, 282 MHz) δ – 62.63 (3F); IR (ATR) ν (cm-1) 3518,
3358, 2986, 2941, 1716, 1678, 1519; HRMS (ESI) m/z calcu-
lated for C17H23F3NO5 [M + H]+ 378.1528, found 378.1522.
1
as a yellowish oil (presence of two rotamers). H (CDCl3, 300
MHz) δ 7.96 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H),
7.67-7.62 (m, 1H), 7.49-7.43 (m, 1H), 5.78-5.71 (m, 1H), 5.32
(d, J = 8.2 Hz, 1H), 4.69-4.64 (m, 1H), 4.30-4.10 (m, 3H),
1.4321.37 (s, 9H), 1.28-1.13 (m, 3H); 13C (CDCl3, 75 MHz) δ
170.5, 155.9, 148.2, 135.3, 133.4, 129.5, 128.9, 124.7, 80.8,
70.6, 62.1, 59.2, 30.4/28.3 (3C), 14.0; IR (ATR) ν (cm-1)
3424, 2979, 2954, 1691, 1525, 1344; HRMS (ESI) m/z calcu-
lated for C16H23N2O7 [M+H]+ 355.1505, found 355.1500.
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(thiophen-
2-yl)propanoate anti-8l. Triethylamine (34 µL, 0.244 mmol)
then o-thiophencarboxaldehyde 7l (91 µL, 0.976 mmol) were
added to 6 (60 mg, 0.244 mmol) according to the general
procedure. After purification, compound anti-8l was isolated
with the 73% yield (56 mg, 0.178 mmol) as a pale pink oil.
The characterization data of anti-8l are identical to those re-
ported in the literature.15 1H (CDCl3, 300 MHz) δ 7.25 (dd, J =
1.2 and 5.0 Hz, 1H), 6.96 (dd, J = 3.5 and 5.0 Hz, 1H), 6.91-
6.86 (m, 1H), 5.50-5.44 (m, 1H), 5.40-5.38 (m, 1H), 4.77-4.71
(m, 1H), 4.49-4.45 (bs, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.45 (s,
9H), 1.25 (t, J = 7.1 Hz, 3H); 13C (CDCl3, 75 MHz) δ : 169.3,
157.0, 142.9, 126.7, 125.2, 124.4, 81.1, 72.2, 62.0, 59.8, 28.4
(3C), 14.2.
Ethyl
2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-(4-nitro
phenyl)propanoate anti-8h Triethylamine (34 µL, 0.244
mmol) then p-nitrobenzaldehyde 7f (148 mg, 0.976 mmol) in
THF (0.3 mL) were added to 6 (60 mg, 0.244 mmol) accord-
ing to the general procedure. After purification, compound
anti-8h was isolated with the 86% yield (74 mg, 0.207 mmol)
as a white solid. The characterization data of anti-8h are iden-
tical to those reported in the literature.6 1H (CDCl3, 300 MHz)
δ 8.19-8.17 (m, 2H), 7.47-7.44 (m, 2H), 5.37-5.32 (m, 2H),
4.69-4.68 (m, 1H), 4.48 (d, J = 5.3 Hz, 1H), 4.18 (q, J = 7.1
Hz, 2H), 1.44 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H); 13C (CDCl3, 75
MHz) δ 169.0, 156.8, 147.7, 147.0, 127.2 (2C), 123.5 (2C),
81.4, 74.9, 62.4, 60.1, 28.3 (3C), 14.2.
Ethyl
2-[(tert-butoxycarbonyl)amino]-3-hydroxyhexanoate
Ethyl 2-[(tert-butoxycarbonyl)amino]-3-(4-fluorophenyl)-3-
hydroxypropanoate anti-8i. Triethylamine (34 µL, 0.244
anti-8m. Triethylamine (34 µL, 0.244 mmol) then butyralde-
hyde 7m (88 µL, 0.976 mmol) were added to 6 (60 mg, 0.244
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The Journal of Organic Chemistry
mmol) according to the general procedure. After purification, tion, brine and dried over MgSO4. After filtration, the solvents
1
2
3
4
5
6
7
8
compound anti-8m was isolated with the 38% yield (26 mg,
0.093 mmol) as a colorless oil (presence of two rotamers). The
characterization data of anti-8m are identical to those reported
in the literature.16 1H (CDCl3, 300 MHz) 5.51-5.38 (m, 1H),
4.39-4.31 (m, 1H), 4.34-4.17 (m, 2H), 3.95-3.85 (m, 1H), 2.75
(br, 1H), 1.53-1.36 (13H), 1.28 (t, J = 8.1 Hz, 3H), 0.91 (t, J =
6.8 Hz, 3H); 13C (CDCl3, 75 MHz) 170.8, 156.2, 80.5, 73.0,
61.8, 58.6, 35.5, 30.5/28.4 (3C), 19.1, 14.3, 14.0.
were removed under reduced pressure. The residue was puri-
fied by flash chromatography under silica gel (pentane/ethyl
acetate) to afford the desired N-methyl compound.
1,3-Dihydroxy-1-phenylpropan-2-ammonium 2,2,2-trifluoro-
acetate anti-10-NH2. Compound anti-9a (100 mg, 0.373
mmol) and TFA (1.14 mL, 14.91 mmol) were mixed in DCM
(3.7 mL) for 4 hours following General procedure A. Pure 2-
amino-1,3-diol anti-10-NH2 was isolated in its trifluoroacetic
ammonium salt in a quantitative yield (106 mg, 0.373 mmol)
Tert-butyl
(1,3-dihydroxy-1-phenylpropan-2-yl)carbamate
9
1
anti-9a. LiBH4 (140 mg, 6.41 mmol) was added at 0 °C to a
solution of anti-8a (662 mg, 2.13 mmol) in i-PrOH/THF (1:2)
(13 mL). The reaction mixture was allowed to warm to room
temperature for 2 hours. Water (10 mL) was added and the
mixture was extracted with ethyl acetate (315 mL). The
organic layers were combined then washed with a saturated
aqueous NaHCO3 solution and brine then dried over MgSO4.
After filtration, the solvents were removed under reduced
pressure and anti-9a was isolated without further purification
in a quantitative yield (569 mg, 2.13 mmol) as a white solid.
The characterization data of anti-9a are identical to those
reported in the literature.17 1H (CDCl3, 300 MHz) δ 7.41-7.28
(m, 5H), 5.38 (bs, 1H), 5.06 (bs, 1H), 3.81 (m, 2H), 3.62 (m,
1H), 3.08 (bs, 1H), 2.47-2.43 (m, 1H), 1.45 (s, 9H); 13C
(CDCl3, 75 MHz) δ 156.2, 141.2, 128.6 (2C), 127.8, 126.0
(2C), 80.1, 76.2, 62.0, 56.5, 28.5 (3C).
as a colorless oil. H (D2O, 300 MHz) δ 7.45-7.38 (m, 5H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6.97 (d, J = 6.3 Hz, 1H), 3.81-3.68 (m, 2H), 3.62-3.57 (m,
1H); 13C (D2O, 75 MHz) δ 162.9 (J2 = 35.5 Hz), 138.0,
C-F
129.1 (2C), 128.9, 126.3 (2C), 116.3 (J1 = 291.7 Hz), 70.4,
C-F
57.9, 57.2; 19F (D2O, 282 MHz) δ – 73.09; IR (ATR) ν (cm-1)
3068, 2901, 2379, 1659, 1453, 1132; HRMS (ESI) m/z calcu-
lated for C9H14NO2 [M+H]+ 168.1025, found 168.1018.
Tert-butyl [1,3-bis(benzyloxy)-1-phenylpropan-2-yl] carba-
mate 14. Compound anti-9a (85 mg, 0.32 mmol), NaH (31
mg, 0.77 mmol) and benzyl bromide (80 µL, 0.70 mmol) were
mixed in DMF (1.6 mL) following General procedure B.
After purification by flash chromatography under silica gel
(pentane/diethyl ether 90:10), compound 14 was isolated with
the 69% yield (96 mg, 0.22 mmol) as a white solid (presence
1
of two rotamers). m.p. 67-69 °C; H (CDCl3, 400 MHz) δ
7.33-7.22 (m, 15H), 4.82 (d, J = 9.5 Hz, 1H), 4.52-4.36 (m,
4H), 4.23 (d, J = 11.7 Hz, 1H [B part of AB system]), 4.08-
3.98 (m, 1H), 3.85 (dd, J = 4.2 and 9.3 Hz, 1H [A’ part of AB’
system]), 3.47 (dd, J = 4.2 and 9.9 Hz, 1H [B’ part of AB’
system]), 1.23/1.15 (s, 9H); 13C (CDCl3, 75 MHz) δ 155.1,
138.9, 138.4 (2C), 128.5 (3C), 128.4 (2C), 127.9 (2C), 127.8
(4C), 127.7 (4C), 80.7, 79.1, 73.3, 71.1, 68.9, 54.8, 28.4 (3C);
IR (ATR) ν (cm-1) 3377, 3091, 3083, 1687, 1519; HRMS
(ESI) m/z calculated for C28H33NO4 [M + H]+ 448.2488, found
448.2479.
Three general procedures used to transform anti-9a to com-
pounds 10-13.
General procedure A: N-Boc deprotection with TFA. Tri-
fluoroacetic acid was added to a solution of N-Boc compound
in DCM at room temperature. The reaction mixture was stirred
for the indicated period. Volatiles were evaporated under
reduced pressure. The crude product was diluted in a mixture
diethyl ether/water (2:1) (3 mL). To this solution was slowly
added solid sodium hydrogen carbonate. The mixture was
stirred until the solid was all disappeared then extracted with
diethyl ether (310 mL). The organic layers were combined,
dried over MgSO4 and filtrated. The solvents were removed
under reduced pressure. The residue was purified by flash
chromatography under silica gel (100% ethyl acetate or cyclo-
hexane/diethyl ether) to afford the desired N-Boc deprotected
compound.
1,3-Bis(benzyloxy)-1-phenylpropan-2-amine
anti-11-NH2.
Compound 14 (285 mg, 0.64 mmol) and TFA (2 mL, 25.6
mmol) were mixed in DCM (6.5 mL) for 4 h following Gen-
eral procedure A. After purification by flash chromatography
under silica gel (pentane/ethyl acetate 30:70), 2-amino-1,3-
diether anti-11-NH2 was isolated with the 96% yield (213 mg,
0.614 mmol) as a yellowish oil. 1H (CDCl3, 300 MHz) δ 7.27-
7.13 (m, 15H), 4.38-4.37 (m, 2H), 4.34 (m, 1H), 4.31 (d, J =
11.5 Hz, 1H [A part of AB system]), 4.14 (d, J = 11.5 Hz, 1H
[B part of AB system]), 3.51-3.50 (m, 2H), 3.21-3.16 (m, 1H),
2.95 (bs, 2H); 13C (CDCl3, 75 MHz) δ 138.5, 138.1 (2C),
128.7 (2C), 128.5 (2C), 128.4 (2C), 128.3, 127.9 (4C), 127.8
(3C), 127.7, 81.8, 73.4, 70.8, 70.7, 55.9; IR (ATR) ν (cm-1)
3460, 3398, 2863, 1682, 1453; HRMS (ESI) m/z calculated for
C23H26NO2 [M + H]+ 348.1964, found 348.1956.
General procedure B: benzylation reactions with NaH and
benzyl bromide. NaH (60% in oil) then benzyl bromide were
added to a solution of N-Boc compound in DMF at 0 °C. The
reaction mixture was allowed to stir for 18 h at 60 °C. Water
was added to the medium and the mixture was extracted with
ethyl acetate (320 mL). The organic layers were combined
and washed with a saturated aqueous NaHCO3 solution, brine
then dried over MgSO4. After filtration, the solvents were
removed under reduced pressure. The crude product was puri-
fied by flash chromatography under silica gel (pentane or
cyclohexane/diethyl ether) to afford the desired mono-, di- or
tri-benzylated compound.
1,3-Bis(benzyloxy)-N-methyl-1-phenylpropan-2-amine
anti-
11-NHMe. Compound 14 (65 mg, 0.15 mmol) and LiAlH4 (17
mg, 0.44 mmol) were mixed in THF (1.6 mL) for 6 h follow-
ing General procedure C. After purification by flash chroma-
tography under silica gel (pentane/ethyl acetate 70:30), 2-
amino-1,3-diether anti-11-NHMe was isolated with the 69%
yield (37 mg, 0.104 mmol) as a yellowish oil. 1H (CDCl3, 400
MHz) δ 7.33-7.20 (m, 15H), 4.48 (d, J = 6.0 Hz, 1H), 4.45 (m,
2H), 4.41 (d, J = 11.7 Hz, 1H [A part of AB system]), 4.22 (d,
J = 11.7 Hz, 1H [B part of AB system]), 3.60 (dd, J = 5.5 and
9.7 Hz, 1H [A’ part of AB’ system]), 3.53 (dd, J = 4.2 and 9.7
Hz, 1H [B’ part of AB’ system]), 2.93-2.89 (m, 1H), 2.24 (s,
General procedure C: N-Boc reduction with LAH. LiAlH4
(LAH) was added to a solution of N-Boc compound in THF at
0 °C. The reaction mixture was allowed to reach the reflux
temperature of THF and stirred for the indicated period. A
Rochelle-salt solution (10%) was added at 0 °C and stirred
for1 h at room temperature. The crude product was extracted
with ethyl acetate (315 mL), then the combined organic
layers were washed with a saturated aqueous NaHCO3 solu-
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Page 8 of 13
3H), 1.96 (bs, 1H); 13C (CDCl3, 100 MHz) δ 139.5, 138.5
4.63 (d, J = 5.6 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H [A part of
1
2
3
4
5
6
7
8
(2C), 128.5 (2C), 128.4 (4C), 127.9, 127.8 (6C), 127.6 (2C),
81.0, 73.3, 70.9, 68.7, 64.5, 34.8; IR (ATR) ν (cm-1) 3389,
2925, 2852, 1737, 1452; HRMS (ESI) m/z calculated for
C24H28NO2 [M + H]+ 362.2120, found 362.2126.
AB system]), 4.39 (d, J = 11.7 Hz, 1H [B part of AB system]),
3.45-3.35 (m, 2H), 3.21-3.16 (m, 1H), 2.30 (bs, 3H); 13C
(CDCl3, 75 MHz) δ 141.4, 137.9, 128.6 (2C), 128.5 (2C),
128.0, 127.9 (2C), 127.8, 126.4 (2C), 75.9, 73.6, 71.9, 56.0; IR
(ATR) ν (cm-1) 3356, 3298, 2916, 2849, 1671; HRMS (ESI)
m/z calculated for C16H20NO2 [M + H]+ 258.1494, found
258.1490.
Tert-butylbenzyl[1,3-bis(benzyloxy)-1-phenylpropan-2-yl]car-
bamate 15. Compound anti-9a (134 mg, 0.50 mmol), NaH (90
mg, 2.25 mmol) and benzyl bromide (0.27 mL, 2.25 mmol)
were mixed in DMF (2.5 mL) following General procedure B.
After purification by flash chromatography under silica gel
(pentane/diethyl ether 95:5), compound 15 was isolated with
the 67% yield (179 mg, 0.335 mmol) as a yellow oil (presence
of two rotamers). 1H (CDCl3, 300 MHz) δ 7.34-7.00 (m, 20H),
4.83-4.58 (m, 1H), 4.46-3.79 (m, 9H), 1.30/1.20 (s, 9H); 13C
(CDCl3, 75 MHz) δ 155.7, 139.7, 139.3, 138.6, 138.4, 128.5,
128.4, 128.3 (2C), 128.2 (2C), 128.0 (4C), 127.7 (5C), 127.6
(2C), 127.4, 127.1, 126.3, 80.8, 80.1, 79.6, 72.9, 71.0, 69.1,
53.5, 28.3 (3C); IR (ATR) ν (cm-1) 3030, 2975, 2868, 1738,
1688; HRMS (ESI) m/z calculated for C35H40NO4 [M + H]+
538.2957, found 538.2953.
3-Benzyloxy-2-methylamino-1-phenylpropan-1-ol
anti-12-
NHMe. Compound 16 (381 mg, 1.096 mmol) and LiAlH4
(125 mg, 3.288 mmol) were mixed in THF (11 mL) for 15 h
following General procedure C. After purification by flash
chromatography under silica gel (pentane/ethyl acetate 30:70),
compound anti-12-NHMe was isolated with the 76% yield
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(227 mg, 0.833 mmol) as a yellowish oil. H (CDCl3, 300
MHz) δ 7.27-7.18 (m, 10H), 4.94 (d, J = 3.9 Hz, 1H), 4.34 (d,
J = 11.7 Hz, 1H [A part of AB system]), 4.29 (d, J = 11.7 Hz,
1H [B part of AB system]), 3.95 (bs, 2H), 3.41 (dd, J = 5.4
and 9.7 Hz, 1H [A’ part of AB’ system]), 3.22 (dd, J = 5.4 and
9.7 Hz, 1H [B’ part of AB’ system]), 2.91-2.86 (m, 1H), 2.48
(s, 3H); 13C (CDCl3, 75 MHz) δ 141.0, 137.7, 128.6 (2C),
128.4 (2C), 128.0, 127.9 (2C), 127.3, 125.8 (2C), 73.6, 71.2,
68.5, 64.4, 33.9; IR (ATR) ν (cm-1) 3367, 3029, 2856, 1736,
1561; HRMS (ESI) m/z calculated for C17H22NO2 [M + H]+
272.1651, found 272.1641.
N-Benzyl-1,3-bis(benzyloxy)-1-phenylpropan-2-amine anti-11-
NHBn. Compound 15 (70 mg, 0.13 mmol) and TFA (0.4 mL,
5.21 mmol) were mixed in DCM (1.5 mL) for 3 h following
General procedure A. After purification by flash chromatog-
raphy under silica gel (cyclohexane/diethyl ether 90:10), 2-
amino-1,3-diether anti-11-NHBn was isolated in a quantita-
Tert-butyl (3-benzyloxy-1-tert-butyldimethylsilyloxy-1-phenyl
propan-2-yl)carbamate 17. Imidazole (48 mg, 0.70 mmol), 4-
dimethylaminopyridine (11 mg, 0.09 mmol) and TBDMSCl
(81 mg, 0.54 mmol) were added to a solution of 16 (100 mg,
0.28 mmol) in DMF (1.4 mL). The reaction mixture was
stirred at room temperature for 18 h. After addition of water
(10 mL), the reaction mixture was extracted with DCM (315
mL). The organic layers were combined, dried over MgSO4
and, after filtration, the solvents were removed under reduced
pressure. The residue was purified by flash chromatography
on silica gel (cyclohexane/diethyl ether 90:10). Compound 17
was isolated with the 80% yield (105 mg, 0.22 mmol) as a
colorless oil (presence of two rotamers). 1H (CDCl3, 300
MHz) δ 7.28-7.15 (m, 10H), 4.87 (d, J = 5.3 Hz, 1H), 4.76 (d,
J = 8.6 Hz, 1H), 4.45-4.34 (m, 2H), 3.91 (m, 1H), 3.69 (dd, J =
5.8 and 10.1 Hz, 1H [A’ part of AB’ system]), 3.37 (dd, J =
4.0 and 10.1 Hz, 1H [B’ part of AB’ system]), 1.30/1.22 (s,
9H), 0.84 (s, 9H), -0.01 (s, 3H), -0.23 (s, 3H); 13C (CDCl3, 75
MHz) δ 155.4, 141.8, 138.2, 128.5 (2C), 128.0 (3C), 127.9
(2C), 127.8, 127.4, 126.8, 79.1, 74.4, 73.1, 68.2, 56.4, 28.4
(3C), 25.9 (3C), 18.3, -4.6, -5.1; IR (ATR) ν (cm-1) 3453,
2929, 2857, 1710, 1495; HRMS (ESI) m/z calculated for
C27H42NO4Si [M + H]+ 472.2883, found 472.2885.
1
tive yield (56 mg, 0.13 mmol) as a yellowish oil. H (CDCl3,
300 MHz) δ 7.37-7.06 (m, 20H), 4.50-4.49 (m, 3H), 4.45 (d, J
= 11.7 Hz, 1H [A part of AB system]), 4.25 (d, J = 11.7 Hz,
1H [B part of AB system]), 3.70-3.53 (m, 4H), 3.08-3.03 (m,
1H), 1.66 (bs, 1H); 13C (CDCl3, 75 MHz) δ 140.7, 139.8,
138.6 (2C), 128.4 (3C), 128.3, 128.2 (4C), 128.0 (2C), 127.9,
127.8 (4C), 127.6 (4C), 126.8, 81.5, 73.2, 70.8, 69.3, 61.4,
51.9; IR (ATR) ν (cm-1) 3379, 3028, 2901, 2858, 1494;
HRMS (ESI) m/z calculated for C30H32NO2 [M + H]+
438.2433, found 438.2431.
Tert-butyl (3-benzyloxy-1-hydroxy-1-phenylpropan-2-yl) car-
bamate 16. DIPEA (1.82 mL, 10.5 mmol) and benzyl bromide
(1.25 mL, 10.5 mmol) were sequentially added in a round-
bottomed flask to a mixture of anti-9a (700 mg, 2.62 mmol),
Bu2SnO (65 mg, 0.26 mmol) and TBAB (253 mg, 0.79 mmol).
The flask was sealed and reach to 70 °C for 24 hours. After
purification by flash chromatography on silica gel (cyclohex-
ane/ethyl acetate 80:20), compound 16 was isolated with the
84% yield (790 mg, 2.20 mmol) as a white solid (presence of
1
two rotamers). m.p. 62-64 °C; H (CDCl3, 300 MHz) δ 7.39-
7.20 (m, 10H), 5.41-5.28 (m, 1H), 4.97-4.89 (m, 1H), 4.46 (d,
J = 11.6 Hz, 1H [A part of AB system]), 4.40 (d, J = 11.6 Hz,
1H [B part of AB system]), 4.03-3.92 (m, 1H), 3.82-3.69 (m,
1H), 3.58-3.45 (m, 2H), 1.43 (s, 9H); 13C (CDCl3, 75 MHz) δ
155.7, 141.4, 137.1, 128.7 (2C), 128.6 (2C), 128.3, 128.1
(2C), 127.9, 127.4, 125.7, 79.7, 75.9, 73.9, 69.7, 54.8, 28.4
(3C); IR (ATR) ν (cm-1) 3424, 3380, 2974, 1753, 1518;
HRMS (ESI) m/z calculated for C21H28NO4 [M + H]+
358.2018, found 358.2013.
Tert-butylbenzyl(3-benzyloxy-1-tert-butyldimethylsilyloxy-1-
phenylpropan-2-yl)carbamate 18. Compound 17 (43 mg, 0.09
mmol), NaH (5 mg, 0.12 mmol) and benzyl bromide (12 µL,
0.10 mmol) were mixed in DMF (0.5 mL) following General
procedure B. After purification by flash chromatography un-
der silica gel (cyclohexane/diethyl ether 97:3), compound 18
was isolated with the 53% yield (27 mg, 0.048 mmol) as a
colorless oil (presence of two rotamers). 1H (CDCl3, 300
MHz) δ 7.32-6.98 (m, 15H), 5.08-4.82 (m, 1H), 4.31-3.82 (m,
7H), 1.26/1.21 (s, 9H), 0.82 (s, 9H), -0.03 (s, 3H), -0.32 (s,
3H); 13C (CDCl3, 75 MHz) δ 155.7/155.5, 142.4, 139.7, 138.4,
128.2 (2C), 128.1, 127.9 (2C), 127.9 (2C), 127.8, 127.7,
127.5, 127.4, 127.2 (2C), 127.1, 126.3, 79.5, 74.2, 73.7, 73.0,
72.9, 69.3, 28.3 (3C), 25.9 (3C), 18.1, -4.5, -5.0; IR (ATR) ν
2-Amino-3-benzyloxy-1-phenylpropan-1-ol
anti-12-NH2.
Compound 16 (302 mg, 0.85 mmol) and TFA (2.62 mL, 34
mmol) were mixed in DCM (8.5 mL) for 4 h following Gen-
eral procedure A. After purification by flash chromatography
under silica gel (pentane/ethyl acetate 30:70), compound anti-
12-NH2 was isolated with the 62% yield (136 mg, 0.53 mmol)
as a colorless oil. 1H (CDCl3, 300 MHz) δ 7.30-7.19 (m, 10H),
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The Journal of Organic Chemistry
(cm-1) 3056, 3031, 2956, 1689, 1495; HRMS (ESI) m/z calcu-
lated for C34H48NO4Si [M + H]+ 562.3353, found 562.3340.
2-Amino-3-benzyloxy-3-phenylpropan-1-ol
anti-13-NH2.
1
2
3
4
5
6
7
8
Compound 20 (33 mg, 0.055 mmol) and TFA (0.31 mL, 4.016
mmol) were mixed in DCM (1 mL) for 3 h following General
procedure A. After purification by flash chromatography un-
der silica gel (cyclohexane/diethyl ether 90:10), compound
anti-13-NH2 was isolated with the 78% yield (11 mg, 0.043
2-Benzylamino-3-benzyloxy-1-phenylpropan-1-ol
anti-12-
NHBn. Compound 18 (27 mg, 0.048 mmol) and TFA (0.15
mL, 1.92 mmol) were mixed in DCM (0.25 mL) for 4 h fol-
lowing General procedure A. After purification by flash
chromatography under silica gel (cyclohexane/diethyl ether
70:30), compound anti-12-NHBn was isolated with the 70%
1
mmol) as a colorless oil. H (CDCl3, 300 MHz) δ 7.32-7.15
(m, 10H), 4.37 (d, J = 11.5 Hz, 1H [A part of AB system]),
4.20 (d, J = 6.8 Hz, 1H), 4.15 (d, J = 11.5 Hz, 1H [B part of
AB system]), 3.63 (dd, J = 4.6 and 11.0 Hz, 1H [A’ part of
AB’ system]), 3.49 (dd, J = 6.0 and 11.0 Hz, 1H [B’ part of
AB’ system]), 3.02-2.99 (m, 1H), 2.36 (bs, 3H); 13C (CDCl3,
75 MHz) δ 138.9, 138.0, 128.8 (2C), 128.5 (2C), 128.4, 127.9
(3C), 127.6 (2C), 83.7, 70.9, 63.6, 57.4; IR (ATR) ν (cm-1)
3406, 3367, 2918, 2863, 1584; HRMS (ESI) m/z calculated for
C16H20NO2 [M + H]+ 258.1494, found 258.1495.
1
yield (12 mg, 0.034 mmol) as a colorless oil. H (CDCl3, 300
MHz) δ 7.28-7.15 (m, 15H), 4.89 (d, J = 4.2 Hz, 1H), 4.32 (d,
J = 11.7 Hz, 1H [A part of AB system]), 4.26 (d, J = 11.7 Hz,
1H [B part of AB system]), 3.88 (d, J = 13.3 Hz, 1H [A” part
of AB” system]), 3.79 (d, J = 13.3 Hz, 1H [B” part of AB”
system]), 3.38 (dd, J = 7.4 and 9.7 Hz, 1H [A’ part of AB’
system]), 3.18 (dd, J = 4.1 and 9.7 Hz, 1H [B’ part of AB’
system]), 3.05-2.99 (m, 1H), 2.69 (bs, 2H); 13C (CDCl3, 75
MHz) δ 141.0 (2C), 137.9, 128.7 (2C), 128.6 (2C), 128.4 (2C),
128.3 (2C), 127.9, 127.8 (2C), 127.3 (2C), 125.8 (2C), 73.5,
71.8, 69.2, 61.4, 51.3; IR (ATR) ν (cm-1) 3536, 3335, 2862,
1736, 1452; HRMS (ESI) m/z calculated for C23H26NO2 [M +
H]+ 348.1964, found 348.1978.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tert-butyl (1-benzyloxy-3-hydroxy-1-phenylpropan-2-yl) car-
bamate 21. Trifluoroacetic acid (28 µL, 0.364 mmol) was
added to a solution of compound 20 (31 mg, 0.052 mmol) in
DCM (0.26 mL) at room temperature. The reaction mixture
was stirred overnight. After completion of the reaction, the
reaction mixture was quenched by addition of a saturated
sodium hydrogen carbonate solution (10 mL). After extraction
with dichloromethane (310 mL), the combined organic
layers were washed with brine (210 mL), dried over MgSO4
then filtrated. The solvents were removed under reduced pres-
sure. The residue was purified by flash chromatography under
silica gel (cyclohexane/ethyl acetate 85:25) to afford com-
pound 21 with the 70% yield (13 mg, 0.036 mmol) as a white
Tert-butyl (1-hydroxy-1-phenyl-3-trityloxypropan-2-yl) car-
bamate 19. 4-Dimethylaminopyridine (6 mg, 0.05 mmol) then
triethylamine (70 µL, 0.5 mmol) were added at 0 °C to a solu-
tion of anti-9a (134 mg, 0.5 mmol) and trityl chloride (139
mg, 0.5 mmol) in DCM/DMF (3:1) (2 mL). The reaction mix-
ture was allowed to warm to room temperature for 12 h. After
extractions with ethyl acetate (315 mL), the organic layers
were combined, washed with brine, dried over MgSO4 and
filtrated. The solvents were removed under reduced pressure
and the residue was purified by flash chromatography on silica
gel (cyclohexane/ethyl acetate 80:20). Compound 19 was
obtained with the 68% yield (173 mg, 0.34 mmol) as a white
solid (presence of two rotamers). m.p. 153-155 °C; 1H (CDCl3,
300 MHz) δ 7.39-7.13 (m, 20H), 5.23 (d, J = 8.9 Hz, 1H), 4.96
(dd, J = 3.3 and 7.4 Hz, 1H), 4.04-4.02 (m, 1H), 3.73 (d, J =
7.4 Hz, 1H), 3.26 (dd, J = 4.3 and 9.6 Hz, 1H [A’ part of AB’
system]), 3.11-3.08 (m, 1H [B’ part of AB’ system]),
1.46/1.38 (s, 9H); 13C (CDCl3, 75 MHz) δ 156.0, 143.6, 143.3
(3C), 128.6 (6C), 128.3, 128.1 (10C), 127.4 (2C), 126.0, 87.6,
79.9, 76.0, 62.9, 55.3, 28.6 (3C); IR (ATR) ν (cm-1) 3437,
3346, 2960, 1686, 1500; HRMS (ESI) m/z calculated for
C33H35NO4,Na [M + Na]+ 532.2464, found 532.2460.
1
solid (presence of two rotamers). m.p. 65-67 °C; H (CDCl3,
300 MHz) δ 7.41-7.30 (m, 10H), 5.37 (d, J = 7.5 Hz, 1H),
4.78-4.77 (m, 1H), 4.62 (d, J = 11.7 Hz, 1H [A part of AB
system]), 4.30 (d, J = 11.7 Hz, 1H [B part of AB system]),
3.89 (dd, J = 3.3 and 11.5 Hz, 1H [A’ part of AB’ system]),
3.74-3.68 (m, 1H), 3.52 (m, 1H [B’ part of AB’ system]), 2.84
(bs, 1H), 1.43/1.40 (s, 9H); 13C (CDCl3, 75 MHz) δ 155.8,
138.5, 137.7, 128.7 (2C), 128.6 (2C), 128.0 (2C), 127.8 (2C),
126.9 (2C), 83.2, 79.5, 71.8, 61.4, 56.4, 28.4 (3C); IR (ATR) ν
(cm-1) 3346, 3241, 3063, 1670, 1549; HRMS (ESI) m/z calcu-
lated for C21H28NO4 [M + H]+ 358.2018, found 358.2026.
3-Benzyloxy-2-methylamino-3-phenylpropan-1-ol
anti-13-
NHMe. Compound 21 (214 mg, 0.616 mmol) and LiAlH4 (70
mg, 1.85 mmol) were mixed in THF (6 mL) for 15 h following
General procedure C. After purification by flash chromatog-
raphy under silica gel (pentane/ethyl acetate 30:70), compound
anti-13-NHMe was isolated with the 58% yield (97 mg, 0.357
Tert-butyl
(1-benzyloxy-1-phenyl-3-trityloxypropan-2-yl)
carbamate 20. Compound 19 (150 mg, 0.29 mmol), NaH (13
mg, 0.32 mmol) and benzyl bromide (37 µL, 0.31 mmol) were
mixed in DMF (2.9 mL) following General procedure B.
After purification by flash chromatography under silica gel
(pentane/diethyl ether 90:10), compound 20 was isolated with
the 64% yield (112 mg, 0.19 mmol) as a colorless oil (pres-
1
mmol) as a yellowish oil. H (CDCl3, 300 MHz) δ 7.40-7.29
(m, 10H), 4.62 (d, J = 5.7 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H
[A part of AB system]), 4.47 (bs, 2H), 4.28 (d, J = 11.5 Hz,
1H [B part of AB system]), 3.75 (dd, J = 5.1 and 11.5 Hz, 1H
[A’ part of AB’ system]), 3.63 (dd, J = 4.2 and 11.5 Hz, 1H
1
ence of two rotamers). H (CDCl3, 300 MHz) δ 7.41-7.38 (m,
[B’ part of AB’ system]), 2.79-2.74 (m, 1H), 2.33 (s, 3H); 13
C
5H), 7.31-7.19 (m, 20H), 4.80 (d, J = 10.0 Hz, 1H), 4.65 (d, J
= 6.8 Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H [A part of AB sys-
tem]), 4.29 (d, J = 11.6 Hz, 1H [B part of AB system]), 4.11-
4.05 (m, 1H), 3.49 (dd, J = 4.2 and 9.2 Hz, 1H [A’ part of AB’
system]), 3.16 (dd, J = 4.2 and 9.2 Hz, 1H [B’ part of AB’
system]), 1.31/1.26 (s, 9H); 13C (CDCl3, 75 MHz) δ 155.3,
144.1 (3C), 138.8, 138.4, 129.0 (6C), 128.5 (2C), 128.4, 128.0
(10C), 127.9 (2C), 127.8, 127.7, 127.2 (2C), 86.8, 81.4, 79.2,
71.2, 62.3, 55.2, 28.6 (3C); IR (ATR) ν (cm-1) 3386, 3030,
2967, 1702, 1597; HRMS (ESI) m/z calculated for
C40H41NO4,Na [M + Na]+ 622.2933, found 622.2904.
(CDCl3, 75 MHz) δ 138.6, 137.8, 129.0 (2C), 128.6 (2C),
128.4, 128.1 (2C), 128.0, 127.3 (2C), 80.8, 71.3, 65.4, 59.1,
33.5; IR (ATR) ν (cm-1) 3410, 3367, 2863, 1735, 1554;
HRMS (ESI) m/z calculated for C17H22NO2 [M + H]+
272.1651, found 272.1642.
Tert-butylbenzyl(1-benzyloxy-1-phenyl-3-trityloxypropan-2-yl)
carbamate 22. Compound 19 (60 mg, 0.12 mmol), NaH (10
mg, 0.24 mmol) and benzyl bromide (28 µL, 0.24 mmol) were
mixed in DMF (0.6 mL) following General procedure B.
After purification by flash chromatography under silica gel
ACS Paragon Plus Environment

The Journal of Organic Chemistry
(cyclohexane/diethyl ether 97:3), compound 22 was isolated
Page 10 of 13
27.9 (3C), 14.3; IR (ATR) ν (cm-1) 2982, 2936, 1825, 1728,
1
2
3
4
5
6
7
8
with the 67% yield (55 mg, 0.08 mmol) as a colorless oil
(presence of two rotamers). 1H (CDCl3, 300 MHz) δ 7.39-7.38
(m, 4H), 7.32-7.22 (m, 16H), 7.09-6.87 (m, 10H), 4.73-4.71
(m, 1H), 4.42-4.37 (m, 1H), 4.21-3.97 (m, 4H), 3.65-3.62 (m,
2H), 1.29/1.26 (s, 9H); 13C (CDCl3, 75 MHz) δ 156.8, 147.0
(3C), 144.2, 139.2, 138.1, 128.9 (6C), 128.5, 128.2 (2C),
128.1 (9C), 127.8 (6C), 127.5, 127.4 (2C), 126.9 (2C), 82.1,
80.7, 79.7, 71.4, 70.6, 70.0, 29.8, 28.5 (3C); IR (ATR) ν (cm-1)
3060, 3030, 2954, 1696, 1598; HRMS (ESI) m/z calculated for
C47H47NO4,Na [M + Na]+ 712.3403, found 712.3420.
1322, 1153; HRMS (ESI) m/z calculated for C17H25N2O6 [M +
NH4]+ 353.1713, found 353.1707.
2-Tert-butoxycarbonylamino-3-hydroxy-3-phenylpropanoic
acid 25. A 2 M aqueous solution of lithium hydroxide (1,27
mL, 2.53 mmol) was added to a solution of 24 (85 mg, 0.253
mmol) in 1,4-dioxane (6.3 mL). The reaction mixture was
stirred for 30 minutes at room temperature then concentrated
under reduced pressure. The residue was purified by flash
chromatography under silica gel (dichloromethane/methanol
93:7), which led to 25 with the 65% yield (46 mg, 0.165
mmol) as a white solid (presence of two rotamers). The char-
acterization data of 25 are identical to those reported in the
literature.19 1H (CD3OD, 300 MHz) δ 7.41-7.22 (m, 5H), 5.26
(bs, 1H), 4.36 (bs, 1H), 1.32/1.15 (s, 9H); 13C (CD3OD, 75
MHz) δ 176.4, 157.7, 142.8, 129.0 (2C), 128.3, 127.4 (2C),
81.1/80.4, 75.0/74.7, 61.4, 28.6/28.2 (3C).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Benzylamino-3-benzyloxy-3-phenylpropan-1-ol
anti-13-
NHBn. Compound 22 (41 mg, 0.059 mmol) and TFA (0.36
mL, 4.70 mmol) were mixed in DCM (1 mL) for 4 h following
General procedure A. After purification by flash chromatog-
raphy under silica gel (cyclohexane/diethyl ether 60:40), com-
pound anti-13-NHBn was isolated with the 93% yield (19 mg,
0.056 mmol) as a colorless oil. 1H (CDCl3, 300 MHz) δ 7.33-
7.15 (m, 13H), 7.06-7.04 (m, 2H), 4.48 (d, J = 5.9 Hz, 1H),
4.46 (d, J = 11.6 Hz, 1H [A part of AB system]), 4.20 (d, J =
11.6 Hz, 1H [B part of AB system]), 3.66-3.51 (m, 4H), 2.82-
2.77 (m, 1H), 2.53 (bs, 2H); 13C (CDCl3, 75 MHz) δ 139.5,
138.9, 137.9, 128.8 (2C), 128.6 (2C), 128.5 (2C), 128.3, 128.2
(2C), 128.0 (2C), 127.9, 127.3 (3C), 81.0, 71.1, 62.8, 59.9,
51.2; IR (ATR) ν (cm-1) 3445, 3256, 3029, 2869, 1736;
HRMS (ESI) m/z calculated for C23H26NO2 [M + H]+
348.1964, found 348.1961.
Tert-butyl(1,3-dihydroxy-1-phenylpropan-2-yl)carbamate syn-
9a. Sodium borohydride (4 mg, 0.105 mmol) was added to a
solution of 25 (24 mg, 0.089 mmol) in THF (0.44 mL) at 0 °C
for 10 minutes then I2 was added (11 mg, 0.044 mmol). After
20 minutes, the reaction mixture was warm up at room tem-
perature and stirred for 2 hours. After quenching with water (3
mL), the pH was adjusted until reaching pH = 4 with an 1 M
hydrochloride aqueous solution (about 0.2 mL). The suspen-
sion was extracted with ethyl acetate (35 mL) and the com-
bined organic layers were washed with a 2 M aqueous solution
of sodium hydroxide (35 mL) then brine (25 mL). The
organic layer was dried over Na2SO4 and filtrated. The sol-
vents were removed under reduced pressure. The residue was
purified by flash chromatography under silica gel (n-
pentane/ethyl acetate 50:50) to afford syn-9a with the 50%
yield (12 mg, 0.045 mmol) as a colorless oil. The characteriza-
tion data of syn-9a are identical to those reported in the litera-
ture (presence of two rotamers).20 1H (CDCl3, 300 MHz) δ
7.36-7.16 (m, 5H), 5.21 (d, J = 7.4 Hz, 1H), 4.98 (d, J = 3.4
Hz, 1H), 3.81-3.76 (m, 3H), 3.25 (bs, 1H), 2.56 (bs, 1H),
1.35/1.26 (s, 9H); 13C (CDCl3, 75 MHz) δ 156.6, 141.3,
129.2/128.4, 128.6/127.9 (2C), 126.2/125.4 (2C), 80.0, 74.7,
64.2, 57.3, 29.8/28.4 (3C).
Ethyl 2-oxo-5-phenyloxazolidine-4-carboxylate 23. Compound
anti-8a (172 mg, 0.556 mmol) was diluted in dry Et2O (2.8
mL) and cooled to 0 °C. SOCl2 (0.37 mL, 5 mmol) was added
and the solution was stirred for 5 h at this temperature. An
aqueous solution of NaHCO3 was added and the mixture was
extracted with AcOEt (25 mL). The combined organic lay-
ers were dried over MgSO4 and after filtration, the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography under silica gel (pentane/ethyl acetate
80:20), which led to pure oxazolidin-2-one 23 with the 81%
yield (106 mg, 0.45 mmol) as a colorless oil. The characteriza-
tion data of 23 are identical to those reported in the literature.18
1H (CDCl3, 300 MHz) δ 7.44-7.35 (m, 5H), 6.65 (bs, 1H), 5.63
(d, J = 5.1 Hz, 1H), 4.38-4.23 (m, 3H), 1.33 (t, J = 7.1 Hz,
3H); 13C (CDCl3, 75 MHz) δ 169.8, 159.0, 138.2, 129.2, 129.1
(2C), 125.5 (2C), 79.6, 62.6, 61.5, 14.2.
ASSOCIATED CONTENT
Supporting Information
3-Tert-butyl
4-ethyl
2-oxo-5-phenyloxazolidine-3,4-
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
dicarboxylate 24. Triethylamine (92 µL, 0.663 mmol), di-tert-
butyl-dicarbonate (0.35 mL, 1.527 mmol) and DMAP (12 mg,
0.101 mmol) were added to a solution of oxazolidin-2-one 23
(78 mg, 0.332 mmol) in THF (4.2 mL). The reaction mixture
was stirred for 15 hours at room temperature. After completion
of the reaction, the reaction mixture was concentrated under
reduced pressure. The residue was diluted in CHCl3, washed
with a saturated aqueous solution of NaHCO3 (210 mL) and
the organic layer was washed with brine (210 mL) and dried
over MgSO4. After filtration, the solvent was removed under
reduced pressure. The residue was purified by flash chroma-
tography under silica gel (cyclohexane/ethyl acetate 95:5),
which led to pure oxazolidine-3,4-dicarboxylate 24 with the
1H and 13C NMR spectra for new compounds (PDF)
X-ray crystallography data for compound anti-8c
AUTHOR INFORMATION
Corresponding authors
anne.harrison@univ-rouen.fr and jacques.rouden@ensicaen.fr
ACKNOWLEDGMENT
The authors thank the Labex SynOrg (PC, ANR-11-LABX-
0029), the University of Rouen (AHM), the University of
Caen (JB), the CNRS (JM) and the ENSICAEN (JR) for fi-
nancial supports. The Région Normandie is also acknowl-
edged for material support and assistance. The CNRS and the
European Union (FEDER) are also greatly acknowledged for
1
84% yield (93 mg, 0.278 mmol) as a yellow oil. H (CDCl3,
300 MHz) δ 7.46-7.35 (m, 5H), 5.36 (d, J = 4.3 Hz, 1H), 4.61
(d, J = 4.3 Hz, 1H), 4.42-4.26 (m, 2H), 1.49 (s, 9H), 1.34 (t, J
= 7.1 Hz, 3H); 13C (CDCl3, 75 MHz) δ 169.6, 150.9, 148.6,
137.3, 129.5, 129.3 (2C), 125.1 (2C), 84.9, 76.1, 63.9, 62.7,
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participating in funding this work. Amaury Renou is warmly starting materials
thanked for generously giving of his time by synthesizing
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