Preparation of β2-Homologous Amino Acids Bearing Polar Side Chains via a Collective Synthesis Strategy

Article abstract of DOI:10.1021/acs.joc.9b02562

β-Homologous amino acids (βhAAs) are a valuable class of building blocks for novel analogues of bioactive peptides. Thus, practical methods to synthesize enantiopure βhAAs are desirable. We report the application of a collective synthesis strategy to prepare protected β²-homologous amino acids with polar side chains. In this approach, a core structure is constructed via proline-catalyzed Mannich reaction and subsequently derivatized to furnish more than one protected β²-homologous amino acid with a proteinogenic side chain.

Full text of DOI:10.1021/acs.joc.9b02562

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Preparation of β2‑Homologous Amino Acids Bearing Polar Side
Chains via a Collective Synthesis Strategy
Shi Liu and Samuel H. Gellman*
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ABSTRACT: β-Homologous amino acids (βhAAs) are a valuable
class of building blocks for novel analogues of bioactive peptides.
Thus, practical methods to synthesize enantiopure βhAAs are
desirable. We report the application of a collective synthesis
strategy to prepare protected β2-homologous amino acids with
polar side chains. In this approach, a core structure is constructed
via proline-catalyzed Mannich reaction and subsequently derivat-
ized to furnish more than one protected β2-homologous amino acid
with a proteinogenic side chain.
he β-homologous amino acids (βhAAs) are homologues
of α-amino acids that bear the same side chain but
phase synthesis. In contrast, only a small set of β2hAA building
blocks can be purchased, mostly with hydrocarbon side chains.
For this reason, homologues of bioactive α-peptides containing
β2hAA replacements have received considerably less attention
to date than have homologues containing β3hAA replacements.
Several synthetic strategies have been explored for the
preparation of enantiopure β2-homologous amino acids, but
none of the reported methods offers practical access to β2hAA
building blocks with all of the proteinogenic side chains.7
Seebach reported the first approach to β2hAA, which involved
using the Evans auxiliary to direct the formation of a
stereocenter.8 This method represents an important contribu-
tion, but the Evans auxiliary-based strategy has some
limitations. First, several synthetic steps were required to
access the starting N-acyl amide. Second, the conditions
necessary to remove the chiral auxiliary may result in
epimerization of the stereogenic center. In peptide synthesis,
the use of building blocks with even low levels of stereo-
chemical impurities, particularly at multiple positions in the
sequence, can lead to complex product mixtures.
Our group previously developed an organocatalytic Mannich
reaction-based method to prepare β2hAAs. The initial version
of this strategy employs a chiral organocatalyst, the Jorgensen−
Hayashi pyrrolidine derivative, to promote asymmetric α-
aminomethylation of aldehydes (Figure 2a).9 Following the in
situ reduction of the Mannich product, Fmoc protection, and
purification, the desired stereoisomer of the 1,3-amino alcohol
derivatives is oxidized to the corresponding β2hAA. A modified
version employs proline as the organocatalyst, and the iminium
T
contain one additional methylene unit in the backbone (Figure
1). There are two classes of βhAAs that differ in side-chain
location. In β2hAAs the side chain projects from the carbon
adjacent to carbonyl, while in β3hAAs the side chain projects
from the carbon adjacent to nitrogen. β-Homologues of the
proteinogenic α-amino acids have proven to be valuable
building blocks for preparation of novel peptides with useful
biological activities.1,2 α/β-Peptides that retain the original
side-chain sequence but contain homologous α-to-β replace-
ments at one site or more display lower susceptibility to
proteolysis relative to the α-peptide prototype.3 Moreover,
such α/β-peptides can adopt a helical conformation that is very
similar to the α-helix, despite the “extra” carbon(s) in the
backbone. Perhaps the most intriguing properties discovered
among peptides containing homologous α-to-β replacements
arise from subtle alterations in recognition properties. Different
patterns of α-to-β3 replacement in the Bim BH3 domain, for
example, resulted in diverse binding profiles with partner
proteins Bcl-xL and Mcl-1.4 A 34-residue α-peptide that
potently activates both parathyroid hormone receptors,
PTHR1 and PTHR2, could be converted to an agonist highly
selective for either the PTHR1 or the PTHR2 by two α-to-β
replacements, depending on replacement site and whether β2
or β3 residues were used.5 Single βhAA replacements in
PTHR1 agonist peptides generated homologues with a strong
bias for G protein activation relative to β-arrestin recruitment.6
Analogues of bioactive α-peptides that contain homologous
α-to-β replacements are readily prepared via conventional
solid-phase synthesis methods. This approach, however,
depends on access to the necessary protected β-amino acids.
Nearly all β3hAA derivatives bearing proteinogenic side chains,
and many with nonproteinogenic side chains, are commercially
available with protecting groups suitable for Fmoc-based solid-
Special Issue: Modern Peptide and Protein Chemistry
Received: September 20, 2019
https://dx.doi.org/10.1021/acs.joc.9b02562
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

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Note
Figure 1. Generic structures of homologous β-amino-acid residues. A generic L-α residue is shown for comparison. Proteinogenic L-α residues
have S configuration, but the homologous β2 and β3 residues have varying configurations depending upon side-chain identity. The designations S*
and R* are applied to β2 and β3 residues as shown, based on the absolute configurations of the β2- and β3-hAla enantiomers.
Figure 2. Preparation of homologous β2-amino acids via organocatalytic Mannich reaction. [cat] represents the Jorgensen−Hayashi catalyst (a) or
proline (b).
Figure 3. Collective synthesis of both enantiomers of a protected β2-hSer building block.
precursor bears a chiral appendage (Figure 2b).10 The main
purpose of the chiral auxiliary is to facilitate purification of 1,3-
amino alcohol derivatives generated by the Mannich−
reduction sequence, via separation of diastereomers rather
than enantiomers. The configuration of the new stereogenic
center formed in the Mannich reaction is largely controlled by
the organocatalyst (proline, in this case), but small effects on
the diastereomer ratio were attributed to a matched/
mismatched relationship between organocatalyst and auxiliary.
The β2hAA syntheses reported here are based on the latter
approach.
meric separation of the reduced Mannich product presents a
technical challenge. Purification by crystallization would be
desirable, but laborious column chromatography is often
required, under conditions specific to each 1,3-amino alcohol.
To minimize the number of diastereomeric separations
required for access to a set of protected β2hAA building
blocks, we envisioned a collective strategy in which two or
more building blocks would be generated from a common 1,3-
amino alcohol intermediate. The examples described here
provide access to both enantiomers of protected β2-
homoserine (β2-hSer) from one common intermediate and
to both enantiomers of protected β2-hGlu and β2-hGln from
another common intermediate. In general, building blocks for
In the newer version of our method, which makes use of a
chiral precursor to the iminium intermediate, the diastereo-
B
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β2hAA residues with polar side chains are more difficult to
prepare than building blocks for β2hAA residues with
hydrocarbon side chains.
desired β2-hGln building block. An unusual catalytic system (a
combination of Pd/C and Pd(OH)2/C)11 was needed for N-
debenzylation of 12.
The first example of the collective synthesis approach
provides both β2-hSer enantiomers (Figure 3). In this case, the
1,3-amino alcohol derivative generated by the Mannich
reaction−reduction sequence, compound 3, can be seen as a
2-substituted derivative of 1,3-propanediol in which one of the
hydroxyl groups is protected. Carrying this intermediate
forward in the usual way, via intermediate 4, provides Fmoc-
protected (R*)-β2-hSer with a TBS-protected side-chain
hydroxyl (5). On the other hand, the position and identity
of the hydroxyl protecting group can be swapped to generate
intermediate 6, which can be converted to (S*)-β2-hSer with a
trityl-protected side-chain hydroxyl (7). Both the TBS and
trityl groups are suitable for Fmoc-based solid-phase peptide
synthesis.
The second example of collective synthesis provides
enantiopure (R*)-β2-hGlu or (R*)-β2-hGln from the common
core structure 9, which can be generated in stereochemically
pure form by crystallization after the Mannich sequence
(Figure 4). The enantiomer of 9 is available if L-proline and the
enantiomeric iminium precursor are employed in the Mannich
sequence.
For structural and functional mimicry of an α-peptide with
an α-helical bioactive conformation, the (S*)-β2-homologue is
better than the (R*)-β2-homologue. However, when the
bioactive conformation is unknown, we have found that it is
important to evaluate α-to-β replacements involving both the
(S*)-β2-homologue and the (R*)-β2-homologue. The collec-
tive synthetic routes described here provide access to protected
β2-hSer, β2-hGlu, and β2-hGln in each enantiomeric form. Each
of these enantiopure protected β2-homologous amino acids has
been used to construct analogues of the osteoporosis drug
PTH(1-34), and these analogues have been shown to display
distinctive physical and pharmacological properties.5 The
availability of these building blocks should enable the discovery
of new protease-resistant analogues of peptide hormones and
other useful molecules.
EXPERIMENTAL SECTION
■
General Procedures. Unless otherwise stated, all reactions were
performed in oven-dried round-bottom glass flasks. TBS deprotection
reactions were performed in plastic reaction vessels with TBAF. An oil
bath was used for reactions that required heating.
3-(tert-Butyldimethylsiloxy)-propionaldehyde (1). Prepared from
3-(tert-butyldimethylsiloxy)-propanol12 by Cu/TEMPO oxidation.13
To a solution of 3-(tert-butyldimethylsiloxy)-propanol (12.5 g, 65.7
mmol) in 200 mL of of CH3CN were added CuBr (0.47 g, 3.3 mmol),
2,2′-bipyridine (0.52 g, 3.3 mmol), TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy, 0.52 g, 3.3 mmol), and 1-methylimidazole (0.27 g, 3.3
mmol) sequentially. The resulting solution had a dark brown color at
this point. The reaction mixture turned to a green color after being
stirred under air overnight, which indicated reaction completion. To
the reaction solution were added pentane and water. The aqueous
layer was separated and extracted several times with pentane. All the
organic layers were combined, dried over anhydrous sodium sulfate,
and concentrated to afford compound 1 as a colorless oil in good
1
purity (11.2 g, 90% yield). H NMR (500 MHz, CDCl3): δ 9.81 (s,
1H), 3.99 (t, J = 6.0 Hz, 2H), 2.60 (td, J = 6.0, 2.1 Hz, 2H), 0.89 (s,
9H), 0.07 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 202.1, 57.4,
46.6, 25.8, 18.3, −5.4. The spectral data (provided in the Supporting
Information) were consistent with a previous report.14
(R)-2-(tert-Butyldimethylsiloxymethyl)-3-(R)-(N-benzyl-α-
methylbenzylamino)propan-1-ol (3). N,O-Acetal (2) was prepared
by using the reported protocol.9 A suspension of D-proline (0.69 g, 6
mmol) in DMF was stirred at room temperature for several hours and
then cooled to −25 °C. To the above mixture were sequentially added
1 (9.4 g, 50 mmol) and 2 (7.7 g, 30 mmol). The reaction temperature
was maintained around −25 °C, and reaction progress was monitored
by NMR analysis of aliquots from the reaction mixture. Upon the
complete conversion of the limiting reagent, NaBH4 (3.4 g, 90 mmol)
and methanol were added to the solution. The resulting mixture was
stirred for 0.5 h at 0 °C and then slowly transferred to a saturated
aqueous solution of ammonium chloride. The aqueous solution was
extracted several times with Et2O. The organic layers were combined,
dried over anhydrous MgSO4, and concentrated. The residue was
purified by column chromatography (2−5% ethyl acetate in hexane)
Figure 4. Collective synthesis of protected β2-hGlu and β2-hGln
building blocks.
After TBS protection of the hydroxyl group of 9, the methyl
ester is hydrolyzed under basic conditions. The resulting
carboxylic acid is converted to either the tert-butyl ester (for
β2-hGlu as the ultimate goal) or the N-trityl amide (for β2-
hGln as the ultimate goal). The latter path must accommodate
the low intrinsic nucleophilicity of tritylamine (TrtNH2); we
used HATU for carboxylic acid activation, and we found that
heating to 60 °C was necessary. After N-debenzylation, Fmoc
protection and hydroxyl oxidation, 10 was converted to the
protected β2-hGlu building block, and 12 was converted to the
1
to provide major diastereomer 3 as a colorless oil in 52% yield. H
C
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NMR (400 MHz, CDCl3): δ 7.32−7.24 (m, 10 H), 4.07 (s, 1H), 3.99
(q, J = 6.9 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.59−3.55 (m, 1H),
3.50 (dd, J = 10.0, 5.1 Hz, 1H), 3.44 (d, J = 13.5 Hz, 1H), 3.40 (dd, J
= 10.0, 6.5 Hz, 1H), 3.31 (dd, J = 10.7, 6.9 Hz, 1H), 2.56 (dd, J =
13.0, 4.9 Hz, 1H), 2.45 (dd, J = 13.0, 10.0 Hz, 1H), 2.09−2.02 (m,
1H), 1.36 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.00 (s, 6H). 13C{1H}
NMR (125 MHz, CDCl3): δ 142.5, 139.2, 129.1, 128.4, 128.14,
128.13, 127.2, 127.0, 65.8, 64.2, 56.6, 54.9, 50.0, 40.0, 25.8, 18.2, 19.8,
−5.53, −5.55. HRMS (ESI): [M + H]+ calculated, 414.2823; found,
414.2821.
(S)-2-(Triphenylmethoxymethyl)-3-(R)-(N-benzyl-α-
methylbenzylamino)propan-1-ol (6). To a solution of 3 (1.24 g, 3
mmol) in 30 mL of CH2Cl2 were added trityl chloride (1.1 g, 3.9
mmol), DMAP (37 mg, 0.3 mmol), and triethyl amine (0.63 mL, 4.5
mmol). This mixture was stirred overnight at room temperature. The
solution was then diluted with CH2Cl2 and washed with brine. The
organic layer was separated, dried over anhydrous MgSO4, and
concentrated. The residue was purified by column chromatography
(2.5% ethyl acetate in hexane) to afford the pure tritylation product
1
(1.8 g, 91% yield). H NMR (500 MHz, CDCl3): δ 7.38−7.37 (m,
6H), 7.29−7.19 (m, 19H), 3.85 (q, J = 6.8 Hz, 1H), 3.67−3.65 (m,
2H), 3.46 (m, 2H), 3.15 (dd, J = 9.0, 4.7 Hz, 1H), 2.73 (t, J = 8.4 Hz,
1H), 2.55 (dd, J = 13.2, 6.0 Hz, 1H), 2.19 (dd, J = 13.2, 7.8 Hz, 1H),
2.02 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H), 0.80 (s, 9H), −0.01 (s, 3H),
−0.04 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 144.4, 142.9,
140.6, 128.8, 128.1, 128.0, 127.7, 127.6, 126.7, 126.6, 126.4, 86.2,
62.7, 62.5, 56.9, 54.7, 48.8, 40.9, 25.9, 18.2, 12.9, −5.4, −5.5. HRMS
(ESI): [M + H]+ calculated, 656.3918; found, 656.3918.
To a plastic reaction vessel containing a solution of the above
tritylation product (1.6 g, 2.4 mmol) in 6 mL of THF was added
TBAF (1 M in THF, 4 mL, 4 mmol) dropwise. The mixture was
stirred at room temperature for 6 h. To this solution were added ethyl
acetate and water. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate several times. All organic layers
were combined, dried over anhydrous MgSO4, and concentrated. The
residue was purified by column chromatography (10−20% ethyl
acetate in hexane) to afford compound 6 in 87% yield. 1H NMR (500
MHz, CDCl3): δ 7.36 (d, J = 7.7 Hz, 6H), 7.33−7.17 (m, 19H), 4.79
(s, 1H), 4.00 (q, J = 7.0 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 3.70 (dd,
J = 10.5, 4.0 Hz, 1H), 3.50 (dd, J = 10.5, 7.7 Hz, 1H), 3.10 (d, J =
13.5 Hz, 1H), 2.98 (dd, J = 9.2, 5.0 Hz, 1H), 2.81 (dd, J = 9.2, 6.3 Hz,
1H), 2.59 (dd, J = 14.1, 11.0 Hz, 1H), 2.31 (m, 2H), 1.49 (d, J = 7.0
Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 143.9, 139.8, 138.9,
129.0, 128.6, 128.5, 128.4, 128.1, 127.8, 127.2, 127.1, 127.0, 86.6,
66.7, 64.1, 57.6, 54.7, 52.0, 38.2, 17.1. HRMS (ESI): [M + H]+
calculated, 542.3054; found, 542.3054.
(R)-2-(tert-Butyldimethylsiloxymethyl)-3-(9-fluorenylmethylcar-
bamate)-propan-1-ol (4). To a solution of 3 (1.3 g, 3 mmol) in 30
mL of ethanol were added 0.32 g of Pd/C (10 wt % loading), 0.21 g
of Pd(OH)2/C (20% wt % loading), and ammonium formate (1.9 g,
30 mmol). The resulting mixture was stirred for 6 h at 60 °C under
nitrogen. After the hydrogenolysis was complete, the reaction mixture
was filtered through Celite, and the Celite was washed several times
with methanol. The methanol solutions were combined and
concentrated. The resulting residue was dissolved in 15 mL of
CH2Cl2 with Fmoc-OSu (1 g, 3 mmol) and DIEA (0.53 mL, 3
mmol). This solution was stirred for 2 h at room temperature. The
solution was diluted with CH2Cl2 and washed with brine. The organic
layer was separated, dried over anhydrous MgSO4, and concentrated.
The residue was purified by column chromatography (25−35% ethyl
1
acetate in hexane) to provide 4 in 83% yield as a colorless oil. H
NMR (300 MHz, CDCl3): δ 7.76 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.4
Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.17 (s,
1H), 4.43 (d, J = 6.8 Hz, 2H), 4.21 (t, J = 6.8 Hz, 1H), 3.70−3.62 (m,
4H), 3.45−3.26 (m, 2H), 2.83 (s, 1H), 1.87 (m, 1H), 0.90 (s, 9H),
0.07 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 157.4, 143.8,
141.3, 127.7, 127.0, 125.0, 120.0, 66.7, 63.9, 61.9, 47.3, 42.9, 39.8,
25.8, 18.2, −5.6. HRMS (ESI): [M + H]+ calculated, 442.2408;
found, 442.2406; [M + Na]+ calculated, 464.2228; found, 464.2228.
(S)-2-(tert-Butyldimethylsiloxymethyl)-3-(9-fluorenylmethylcar-
bamate)-propanoic acid (5). Prepared from 4 via RuCl3/NaIO4
oxidation.15 A round-bottom flask was charged with 6 mL of carbon
tetrachloride, 6 mL of acetonitrile, 9 mL of water, 4 (0.97 g, 2.2
mmol), and NaIO4 (2.1 g, 9.9 mmol). To this mixture was added
RuCl3 (11 mg, 0.055 mmol). The reaction mixture was stirred at
room temperature until TLC analysis revealed the complete
conversion of the starting alcohol. The reaction mixture was then
diluted with ethyl acetate, and the remaining oxidant was quenched by
adding 0.5 N aqueous Na2S2O3. The organic layer was separated, and
the aqueous layer was extracted several times with ethyl acetate. All
organic layers were combined, dried over anhydrous MgSO4, filtered
through Celite, and concentrated. The residue was purified by column
chromatography (25% ethyl acetate in hexane with 1% acetic acid) to
yield 5 as white foam in 67% yield. 1H NMR (400 MHz, DMSO-d6):
δ 12.30 (s, 1H), 7.88 (d, J = 7.3 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H),
7.42−7.35 (m, 3H), 7.31 (td, J = 7.5, 1.2 Hz, 2H), 4.30−4.17 (m,
3H), 3.75−3.68 (m, 2H), 3.23−3.09 (m, 2H), 2.63−2.57 (m, 1H),
0.83 (s, 1H), −0.00 (s, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ
174.1, 156.6, 144.3, 141.2, 128.1, 127.5, 125.6, 120.6, 65.8, 62.3, 48.4,
(R)-2-(Triphenylmethoxymethyl)-3-(9-fluorenylmethylcarba-
mate)-propanoic Acid (7). To a solution of 6 (1.1 g, 2 mmol) in 20
mL of ethanol were added 0.21 g of Pd/C (10 wt % loading), 0.14 g
of Pd(OH)2/C (20% wt % loading), and ammonium formate (1.2 g,
20 mmol). The resulting mixture was stirred for 4 h at 60 °C under
nitrogen. After the hydrogenolysis was complete, the reaction mixture
was filtered through Celite, and the Celite was washed several times
with methanol. The methanol solutions were combined and
concentrated. The resulting residue was dissolved in 20 mL of
CH2Cl2 with Fmoc-OSu (0.68 g, 2 mmol) and DIEA (0.35 mL, 2
mmol). The above solution was stirred for 2 h at room temperature.
The reaction mixture was diluted with CH2Cl2 and washed several
times with brine. The organic layer was separated, dried over
anhydrous MgSO4, and concentrated. The residue was purified by
column chromatography (25−35% ethyl acetate in hexane) to provide
1
the desired product in 77% yield. H NMR (400 MHz, CDCl3): δ
7.76 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 7.4 Hz, 2H), 7.44−7.38 (m,
8H), 7.30 (t, J = 7.4 Hz, 8H), 7.23 (t, J = 7.4 Hz, 3H), 4.62 (t, J = 6.5
Hz, 1H), 4.39 (d, J = 6.7 Hz, 2H), 4.17 (t, J = 6.7 Hz, 1H), 3.56 (m,
1H), 3.48−3.37 (m, 2H), 3.28−3.20 (m, 2H), 3.08 (dd, J = 9.4, 7.2
Hz, 1H), 2.86 (s, 1H), 1.99 (m, 1H). 13C{1H} NMR (125 MHz,
CDCl3): δ 157.5, 143.83, 143.80, 143.7, 141.3, 128.5, 127.9, 127.7,
20
47.2, 26.2, 18.4, −5.02, −5.04. [α]D = −2.6 (c = 4.6, CHCl3).
HRMS (ESI): [M − H]− calculated, 454.2055; found, 454.2060.
D
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127.2, 127.0, 124.9, 120.0, 86.9, 66.6, 62.4, 61.3, 47.3, 42.0, 39.3.
HRMS (ESI): [M + Na]+ calculated, 592.2458; found, 592.2459.
The Fmoc-protected amino alcohol intermediate was converted to
7 via Jones oxidation. A solution of Fmoc-protected amino alcohol
(0.65 g, 1.1 mmol) in 20 mL of acetone was added dropwise to 2.3
mmol H2Cr2O7 (prepared by mixing Na2Cr2O7·2H2O and H2SO4) in
30 mL of acetone at 0 °C. The reaction mixture was stirred for several
hours until TLC analysis revealed the complete conversion of the
starting alcohol. Excess isopropanol was then added to quench the
remaining oxidant. To this mixture were added ethyl acetate and
water. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate several times. All organic layers were
combined, washed with brine, dried over anhydrous MgSO4, filtered
through Celite, and concentrated. The residue was purified by column
chromatography (35% ethyl acetate in hexane with 1% acetic acid) to
(R)-2-(Carboxyethyl-tert-butyl ester)-3-(R)-(N-benzyl-α-
methylbenzylamino)propan-1-ol (10). Compound 9 was converted
to 10 by the following 4-step sequence.
Step 1 (TBS protection): To a solution of 9 (5.4 g, 15 mmol) in 50
mL of CH2Cl2 were added TBSCl (2.8 g, 18 mmol) and imidazole (2
g, 30 mmol). The mixture was stirred overnight at room temperature.
The mixture was then diluted with CH2Cl2 and washed with brine.
The organic layer was separated, dried over anhydrous MgSO4, and
concentrated. The residue was purified by column chromatography
(5% ethyl acetate in hexane) to afford the TBS protection product as
1
afford 7 as a white solid in 47% yield. H NMR (300 MHz, DMSO-
1
d6): δ 12.46 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.65 (d, J = 7.4 Hz,
2H), 7.41 (t, J = 7.4 Hz, 2H), 7.36−7.21 (m, 17H), 4.24 (d, J = 6.8
Hz, 2H), 4.17 (t, J = 6.8 Hz, 1H), 3.24−3.11 (m, 4H), 2.77−2.69 (m,
1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 173.7, 156.0, 143.83,
143.81, 143.6, 140.7, 128.1, 127.8, 127.6, 127.02, 127.00, 125.1, 120.1,
a colorless oil in 97% yield. H NMR (300 MHz, CDCl3): δ 7.38−
7.15 (m, 10H), 3.90 (q, J = 6.9 Hz, 1H), 3.65 (s, 3H), 3.59 (d, J =
13.8 Hz, 1H), 3.55 (dd, J = 10.0, 3.8 Hz, 1H), 3.41 (d, J = 13.8 Hz,
1H), 3.19 (dd, J = 10.0, 5.1 Hz, 1H), 2.44−2.17 (m, 4H), 1.75−1.60
(m, 3H), 1.38 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), −0.01 (s, 3H), −0.03
(s, 3H). HRMS (ESI): [M + H]+ calculated, 470.3085; found,
470.3083.
20
85.8, 65.4, 62.1, 46.6, 45.8. [α]D = −3.7 (c = 2.5, CHCl3). HRMS
(ESI): [M − H]− calculated, 582.2286; found, 582.2285.
Step 2 (methyl ester deprotection): The TBS protection product
(2.1 g, 4.5 mmol) from step 1 was dissolved in 5 mL of MeOH and 5
mL of THF. To this solution were added 5 mL of water and KOH
(0.75 g, 13.5 mmol). The resulting mixture was stirred at room
temperature for 8 h. The mixture was then diluted with ethyl acetate
and washed with 5% aqueous citric acid. The organic layer was
separated, and the aqueous layer was extracted several times with
ethyl acetate. All organic layers were combined, dried over anhydrous
MgSO4, and concentrated to afford material that was directly used for
the next step.
Step 3 (formation of tert-butyl ester): The crude product from step
2 was dissolved in 20 mL of CH2Cl2. To this solution were added
EDCI (2.6 g, 13.5 mmol), DMAP (1.1 g, 9 mmol), triethylamine (1.2
mL, 9 mmol) and tert-butanol (3.5 g, 45 mmol). This mixture was
stirred at room temperature for 14 h. The mixture was then diluted
with CH2Cl2 and washed sequentially with 5% citric acid and
saturated NaCl solution. The organic layer was separated, dried over
anhydrous MgSO4, and concentrated to afford material that was
directly used for the next step.
Step 4 (TBS deprotection): The crude tert-butyl ester from step 3
was dissolved in 10 mL of THF and transferred to a plastic reaction
vessel. This solution was cooled in an ice-bath, and 9.5 mL of TBAF
solution (1 M in THF) was added. The mixture was stirred for 3 h at
room temperature. To the solution were added ethyl acetate and
water. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate several times. All organic layers were
combined, dried over anhydrous MgSO4, and concentrated. The
residue was purified by column chromatography (25% ethyl acetate in
hexane) to afford 10 as a colorless oil (1.2 g, 67% yield over three
steps). 1H NMR (400 MHz, CDCl3): δ 7.37−7.23 (m, 10H), 4.65 (s,
1H), 4.01 (q, J = 6.9 Hz, 1H), 3.89 (d, J = 13.2 Hz, 1H), 3.55 (m,
1H), 3.37 (d, J = 13.2 Hz, 1H), 3.02 (dd, J = 10.8, 8.3 Hz, 1H), 2.56
(m, 1H), 2.45 (dd, J = 12.8, 10.8 Hz, 1H), 2.18 (t, J = 7.7 Hz, 2H),
1.94−1.84 (m, 1H), 1.42 (s, 9H), 1.36 (d, J = 6.9 Hz, 3H), 1.40−1.30
(m, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 173.0, 142.6, 138.9,
129.4, 128.7, 128.4, 128.3, 127.5, 127.3, 80.5, 67.4, 56.4, 55.1, 54.0,
36.5, 33.4, 28.2, 25.3, 9.6. HRMS (ESI): [M + H]+ calculated,
398.2690; found, 398.2689.
(R)-2-(Carboxyethyl-methyl ester)-3-(R)-(N-benzyl-α-
methylbenzylamino)propan-1-ol (9). A suspension of D-proline
(0.96 g, 8.4 mmol) in 400 mL of DMF was stirred at room
temperature for several hours and then cooled to −25 °C. To this
mixture were sequentially added 816 (9.2 g, 71 mmol) and 2 (10.8 g,
42 mmol). The reaction temperature was maintained around −25 °C,
and reaction progress was monitored by NMR analysis of aliquots
from the reaction mixture. Upon the complete conversion of the
limiting reagent 2, NaBH4 (4.5 g, 0.12 mol) and 100 mL of methanol
were added to the reaction solution. This mixture was stirred for 1 h
at 0 °C and then slowly transferred to a saturated aqueous solution of
ammonium chloride. The aqueous solution was extracted several
times with Et2O. The organic layers were combined, dried over
anhydrous MgSO4, and concentrated. Silica gel column chromatog-
raphy was then used to remove the residual DMF and N-benzyl-α-
methylbenzylamine (side product from retro-Michael reaction of the
Mannich adduct). This chromatography step is important for efficient
crystallization of 9 from hexane/diethyl ether. To induce crystal-
lization, a hexane suspension of the crude product in a round-bottom
flask was heated. To this mixture was added diethyl ether in a
dropwise fashion with shaking until a homogeneous solution had
formed. The resulting solution was placed in a refrigerator to allow
crystallization. Compound 9 was isolated as white, crystalline solid in
45% yield. 1H NMR (400 MHz, CDCl3): δ 7.36−7.23 (m, 10H), 4.56
(s, 1H), 4.00 (q, J = 6.8 Hz, 1H), 3.88 (d, J = 13.1 Hz, 1H), 3.65 (s,
3H), 3.56 (m, 1H), 3.39 (d, J = 13.1 Hz, 1H), 3.02 (dd, J = 10.8, 8.2
Hz, 1H), 2.55 (m, 1H), 2.46 (dd, J = 12.9, 10.8 Hz, 1H), 2.28 (t, J =
7.7 Hz, 2H), 1.87 (m, 1H), 1.45−1.27 (m, 5H). 13C{1H} NMR (125
MHz, CDCl3): δ 174.0, 142.6, 138.8, 129.4, 128.7, 128.4, 128.3,
127.5, 127.3, 67.1, 56.5, 55.2, 53.9, 51.8, 36.5, 31.9, 25.1, 9.7. HRMS
(ESI): [M + H]+ calculated, 356.2220; found, 356.2217.
Crystals from the preparative crystallization were suitable for X-ray
diffraction; and the X-ray diffraction structure of 9 is shown in the
Supporting Information. The crystal structure allowed us to establish
the new asymmetric center as having R configuration, which was
consistent with our previous report that the use of L-proline and the
enantiomeric iminium precursor enabled the preparation of the 1,3-
amino alcohol derivatives with the opposite configuration at the new
asymmetric center.10
E
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Note
( R ) - 2 - ( C a r b o x y e t h y l - t e r t - b u t y l e s t e r ) - 3 - ( 9 -
fluorenylmethylcarbamate)propanoic Acid (11). To a solution of
10 (0.8 g, 2 mmol) in 20 mL of ethanol were added 0.21 g of Pd/C
(10 wt % loading), 0.14 g of Pd(OH)2/C (20% wt % loading) and
ammonium formate (1.2 g, 20 mmol). The mixture was stirred for 6 h
at 60 °C under nitrogen atmosphere. After the hydrogenolysis was
complete, the reaction mixture was filtered through Celite, and the
Celite was washed several times with methanol. The methanol
solutions were combined and concentrated. The resulting residue was
dissolved in 15 mL of CH2Cl2 with Fmoc-OSu (0.68 g, 2 mmol) and
DIEA (0.35 mL, 2 mmol). This solution was stirred for 2 h at room
temperature. The reaction mixture was diluted with CH2Cl2 and
washed several times with brine. The organic layer was separated,
dried over anhydrous MgSO4, and concentrated. The residue was
purified by column chromatography (25−35% ethyl acetate in
hexane) to afford the desired product as a colorless oil in 75%
yield. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 7.4 Hz, 2H), 7.59
(d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (td, J = 7.4, 1.2 Hz,
2H), 5.22 (t, J = 6.5 Hz, 1H), 4.43 (d, J = 6.9 Hz, 2H), 4.22 (t, J = 6.9
Hz, 1H), 3.56−3.50 (m, 2H), 3.44−3.30 (m, 2H), 3.25−3.05 (m,
2H), 2.37−2.24 (m, 2H), 1.63−1.50 (m, 3H), 1.45 (s, 9H). 13C{1H}
NMR (125 MHz, CDCl3): δ 173.5, 157.9, 143.97, 143.95, 141.5,
127.9, 127.2, 125.1, 120.1, 80.8, 67.0, 62.2, 47.4, 41.3, 41.1, 33.1, 28.2,
23.2. The spectral data for this compound were consistent with those
of its enantiomer.10
with ethyl acetate and washed sequentially with 5% aqueous citric acid
and saturated aqueous NaCl. The organic layer was separated, dried
over anhydrous MgSO4, and concentrated to afford material that was
directly used for the next step.
Step 4 (TBS deprotection): The crude trityl amide from step 3 was
dissolved in 10 mL of THF and transferred to a plastic reaction vessel.
This solution was cooled in an ice-bath, and TBAF·3H2O (0.68 g, 2.2
mmol) was added. The reaction mixture was stirred for 3 h at room
temperature. To this solution were added ethyl acetate and water. The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate several times. All organic layers were combined, dried
over anhydrous MgSO4, and concentrated. The residue was purified
by column chromatography (20−25% ethyl acetate in hexane with 1%
triethylamine) to afford 12 as a white solid (41% yield over four
steps). 1H NMR (400 MHz, CDCl3): δ 7.35−7.10 (m, 25H), 6.53 (s,
1H), 3.97 (q, J = 6.9 Hz, 1H), 3.80 (d, J = 13.1 Hz, 1H), 3.51 (dd, J =
10.8, 2.5 Hz, 1H), 3.35 (d, J = 13.1 Hz, 1H), 3.03 (dd, J = 10.8, 7.7
Hz, 1H), 2.47 (dd, J = 13.0 and 3.4 Hz, 1H), 2.40 (dd, J = 13.0, 10.6
Hz, 1H), 2.25−2.15 (m, 2H), 1.82 (m, 1H), 1.50−1.40 (m, 1H), 1.33
(d, J = 6.9 Hz, 3H), 1.30−1.20 (m, 1H). 13C {1H} NMR (125 MHz,
CDCl3): δ 171.6, 144.8, 129.3, 128.8, 128.6, 128.32, 128.30, 128.1,
127.4, 127.3, 127.2, 70.6, 66.8, 56.4, 55.0, 53.7, 36.7, 35.2, 25.4, 9.8.
HRMS (ESI): [M + H]+ calculated, 583.3319; found, 583.3318.
The Fmoc-protected amino alcohol was converted to 11 via
RuCl3/NaIO4 oxidation. A round-bottom flask was charged with 4
mL of carbon tetrachloride, 4 mL of acetonitrile, 6 mL of water, the
Fmoc-protected amino alcohol (0.58 g, 1.35 mmol), and NaIO4 (1.3
g, 6.1 mmol). To the above mixture was added RuCl3 (10 mg, 0.034
mmol). This mixture was stirred at room temperature until TLC
analysis revealed complete conversion of the starting alcohol. The
reaction mixture was then diluted with ethyl acetate, and the
remaining oxidant was quenched by 0.5 N aqueous Na2S2O3. The
organic layer was separated, and the aqueous layer was extracted
several times with ethyl acetate. All organic layers were combined,
dried over anhydrous MgSO4, filtered through Celite, and
concentrated. The residue was purified by column chromatography
(35% ethyl acetate in hexane with 1% acetic acid) to afford 11 as
white solid in 70% yield. 1H NMR (300 MHz, DMSO-d6): δ 12.35 (s,
1H), 7.88 (d, J = 7.4 Hz, 2H), 7.69 (d, J = 7.4 Hz, 2H), 7.49−7.39
(m, 3H), 7.32 (td, J = 7.4, 1.3 Hz, 2H), 4.33−4.18 (m, 3H), 3.21 (m,
1H), 3.07 (m, 1H), 2.44 (m, 1H), 2.30−2.10 (m, 2H), 1.72−1.59 (m,
2H), 1.38 (s, 9H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 174.9,
171.7, 156.1, 143.9, 140.7, 127.6, 127.1, 125.2, 120.1, 79.6, 65.4, 46.7,
(R)-2-(Carboxyethyl-triphenylmethyl amide)-3-(9-
fluorenylmethylcarbamate)propanoic Acid (13). To a solution of
12 (0.23 g, 0.4 mmol) in 5 mL of ethanol were added 85 mg of Pd/C
(10 wt % loading), 56 mg of Pd(OH)2/C (20% wt % loading), and
ammonium formate (0.25 g, 4 mmol). The resulting mixture was
stirred for 7 h at 60 °C under nitrogen. After the hydrogenolysis was
complete, the reaction mixture was filtered through Celite, and the
Celite was washed several times with methanol. The methanol
solutions were combined and concentrated. The residue was dissolved
in 10 mL of CH2Cl2 with Fmoc-OSu (0.14 g, 0.4 mmol) and DIEA
(70 μL, 0.4 mmol). The above solution was stirred for 2 h at room
temperature. The reaction mixture was diluted with CH2Cl2 and
washed with 5% aqueous citric acid and saturated aqueous NaCl. The
organic layer was separated, dried over anhydrous MgSO4, and
concentrated. The residue was purified by column chromatography
(5% MeOH in DCM) to yield the desired Fmoc-protected amino
alcohol in 84% yield. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.4
Hz, 2H), 7.55 (d, J = 7.4, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.35−7.15
(m, 17H), 6.74 (s, 1H), 5.19 (t, J = 6.6 Hz, 1H), 4.32 (d, J = 6.9 Hz,
2H), 4.16 (t, J = 6.9 Hz, 1H), 3.42 (dd, J = 11.8, 3.6 Hz, 1H), 3.32−
3.22 (m, 2H), 2.95−2.85 (m, 1H), 2.50−2.25 (m, 2H), 1.53 (m, 3H),
0.87 (s, 1H). HRMS (ESI): [M + H]+ calculated, 611.2904; found,
611.2902.
20
44.3, 41.9, 32.4, 27.7, 24.3. [α]D = −1.0 (c = 2.7, CHCl3). The
spectral data for 11 were consistent with those of Fmoc-(S*)-β2-
hGlu.10
The above Fmoc-protected amino alcohol was converted to 13 via
Jones oxidation. A solution of Fmoc-protected amino alcohol (0.19 g,
0.3 mmol) in 5 mL of acetone was added dropwise to 0.6 mmol
H2Cr2O7 (prepared by mixing Na2Cr2O7·2H2O and H2SO4) in 3 mL
of acetone at 0 °C. The reaction mixture was stirred for 2 h. Excess
isopropanol was then added to quench the remaining oxidant. To this
mixture were added ethyl acetate and water. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate
several times. All organic layers were combined, washed with brine,
dried over anhydrous MgSO4, filtered through Celite, and
concentrated. The residue was purified by column chromatography
(2−5% MeOH in DCM with 1% acetic acid) to afford 13 as a white
solid in 88% yield. 1H NMR (300 MHz, DMSO-d6): δ 12.27 (s, 1H),
8.59 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.41
(t, J = 7.4 Hz, 2H), 7.34−7.10 (m, 17H), 4.23 (m, 3H), 3.25−3.00
(m, 2H), 2.42 (m, 1H), 2.29 (m, 2H), 1.61 (m, 2H). 13C{1H} NMR
(R)-2-(Carboxyethyl-triphenylmethyl amide)-3-(R)-(N-benzyl-α-
methylbenzylamino)propan-1-ol (12). Prepared from 9 by a 4-step
sequence.
Step 1 (TBS protection): See step 1 in the synthesis of 10.
Step 2 (methyl ester hydrolysis): The TBS protection product
(1.02 g, 2.2 mmol) from step 1 was dissolved in 5 mL of MeOH and 5
mL of THF. To the above solution were added 5 mL of water and
KOH (0.49 g, 8.7 mmol). See step 2 in the synthesis of 10 for the
experimental details.
Step 3 (formation of trityl amide): The crude product from step 2
was dissolved in 10 mL of DMF. To the above solution were added
HATU (1.2 g, 3.2 mmol) and triethylamine (0.62 mL, 4.4 mmol).
The mixture was stirred at room temperature for 40 min. Trityl amine
(0.83 g, 3.2 mmol) was then added to the solution. The reaction
mixture was stirred for 30 h at 60 °C. The solution was then diluted
F
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The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(125 MHz, DMSO-d6): δ 175.2, 171.4, 156.1, 144.9, 143.9, 140.7,
128.5, 127.6, 127.4, 127.1, 126.3, 125.2, 120.1, 69.1, 65.4, 46.7, 44.8,
41.9, 33.5, 25.1. The spectra data were consistent with a previous
(9) Chi, Y. G.; Gellman, S. H. Enantioselective Organocatalytic
Aminomethylation of Aldehydes: A Role for Ionic Interactions and
Efficient Access to beta(2)-amino acids. J. Am. Chem. Soc. 2006, 128,
6804−6805.
report.17 [α]D = 7.6 (c = 0.5, CHCl3). HRMS (ESI): [M − H]−
20
calculated, 623.2552; found, 623.2557.
(10) Chi, Y.; English, E. P.; Pomerantz, W. C.; Horne, W. S.; Joyce,
L. A.; Alexander, L. R.; Fleming, W. S.; Hopkins, E. A.; Gellman, S. H.
Practical Synthesis of Enantiomerically Pure Beta(2)-Amino Acids via
Proline-Catalyzed Diastereoselective Aminomethylation of Aldehydes.
J. Am. Chem. Soc. 2007, 129, 6050−6055.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b02562.
■
sı
(11) Li, Y.; Manickam, G.; Ghoshal, A.; Subramaniam, P. More
Efficient Palladium Catalyst for Hydrogenolysis of Benzyl Groups.
Synth. Commun. 2006, 36, 925−928.
NMR spectra for all new compounds (PDF)
Crystallographic data for compound 9 (CIF)
(12) McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. A
Convenient Procedure for The Monosilylation of Symmetrical 1, n-
Diols. J. Org. Chem. 1986, 51, 3388−3390.
AUTHOR INFORMATION
Corresponding Author
■
(13) Hoover, J. M.; Steves, J. E.; Stahl, S. S. Copper(I)/TEMPO-
Catalyzed Aerobic Oxidation of Primary Alcohols to Aldehydes with
Ambient Air. Nat. Protoc. 2012, 7, 1161−1166.
Samuel H. Gellman − University of Wisconsin
Madison, Madison, Wisconsin; orcid.org/0000-0001-
5617-0058; Email: gellman@chem.wisc.edu
(14) Li, X. J.; Lantrip, D.; Fuchs, P. L. Gamma-Allyl Phosphinoyl
Phenyl Sulfone (GAPPS): A Conjunctive Reagent for the Synthesis of
EE, EZ, and ET 1,3-Dienes. J. Am. Chem. Soc. 2003, 125, 14262−
14263.
Other Author
(15) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. A
Greatly Improved Procedure for Ruthenium Tetraoxide Catalyzed
Oxidation of Organic Compounds. J. Org. Chem. 1981, 46, 3936−
3938.
(16) Cook, C.; Liron, F.; Guinchard, X.; Roulland, E. Study of the
Total Synthesis of (−)-Exiguolide. J. Org. Chem. 2012, 77, 6728−
6742.
(17) Lelais, G.; Campo, M. A.; Kopp, S.; Seebach, D.
Enantioselective Preparation of Beta(2)-Amino Acids with Aspartate,
Glutamate, Asparagine, and Glutamine Side Chains. Helv. Chim. Acta
2004, 87, 1545−1560.
Shi Liu − University of WisconsinMadison, Madison,
Wisconsin; orcid.org/0000-0002-9113-6207
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b02562
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by NIH Grant R01 GM056414.
We thank Dr. Ilia Guzei for assistance with X-ray
crystallography.
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