Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes

Article abstract of DOI:10.1021/acs.joc.6b02568

The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.

Full text of DOI:10.1021/acs.joc.6b02568

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Brief Communication
Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-
Benzoin Reactions Using N-Boc-N-Bn-Protected alpha-Amino Aldehydes
Pouyan Haghshenas, J Wilson Quail, and Michel Gravel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02568 • Publication Date (Web): 22 Nov 2016
Downloaded from http://pubs.acs.org on November 22, 2016
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The Journal of Organic Chemistry
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Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin
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Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes
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Pouyan Haghshenas, J. Wilson Quail and Michel Gravel*
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Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada
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Abstract: The effectiveness of utilizing N-Bn-N-Boc-α-
amino aldehydes in cross-benzoin reactions with
heteroaromatic aldehydes is demonstrated. The reaction is
both chemoselective and syn-selective, making it
complementary to the anti-selective cross-benzoin reaction
of NHBoc-α-amino aldehydes. Good diastereoselectivity is
obtained for a variety of amino aldehydes, including non-hindered ones. A Felkin-Anh model can be used to rationalize the
observed diastereoselectivity.
In recent work we demonstrated that N-Boc-α-amino
aldehydes, with their synergistic balance between
The N-heterocyclic carbene (NHC)-catalyzed cross-
electronic activation and steric hindrance imposed by the
benzoin reaction serves as
a convenient method for
α-substituent, provide
a
route to chemo- and
accessing α-hydroxy ketones.1 Despite renewed interest
directed in this reaction, the variant in which two different
aldehydes are directly coupled via the umpolung of one
partner remains limited in scope. The main reason for this
limitation is the difficulty in controlling the product
diastereoselective cross-benzoin reactions (Scheme 1a).5
Furthermore, facile access to enantioenriched α-amino
aldehydes6 allows formation of enantio-enriched α-
hydroxy-β-amino ketone products. These building blocks
provide a useful entry point to the synthesis of many
natural products and biologically relevant molecules.7
distribution.1g In order for a cross-benzoin reaction to be of
practical synthetic value, chemoselective formation of one
of the four possible benzoin products must be
accomplished. The chemoselectivity problem has generally
been addressed by tuning the electronic and steric
environment of one of the aldehydes. For example, the
NHC-catalyzed cross-benzoin reaction between ortho-
substituted aromatic aldehydes and aliphatic or electron-
poor aromatic aldehydes, has been reported.2 Alternatively,
we have demonstrated that increasing the steric hindrance
on the NHC allows for the chemoselective coupling
between a wide range of aromatic and aliphatic aldehydes.3
Despite these successes, the chemoselective cross-benzoin
reaction between aldehydes remains in its infancy,
particularly when issues of diastereo- and enantioselectivity
are also taken into account.2c, 2e, 3a, 4
Prompted by the synthetic utility of the α-hydroxy-β-
amino ketone products, we became interested in expanding
the scope of this reaction. In this regard, it was intriguing
to examine whether modifications to the protocol could be
used to preferentially obtain the opposite syn diastereomer
(Scheme 1b). The realization of this objective is described
herein.
Scheme 1
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A brief optimization was performed in order to improve
1
the diastereoselectivity of this process (Table 1). Screening
of various solvents showed that the reaction is best
performed in dichloromethane (entries 1-4). Reactions
utilizing a number of known azolium salts showed that
triazolium 2 was the superior choice (entries 4-7). It is
noteworthy that thiazolium 4 also provides efficient access
to the cross-benzoin product, albeit in lower
diastereomeric ratio. Notably, the desired cross-benzoin
products are obtained in high yield using only a slight
excess of the partner heteroaromatic aldehyde (1.5 equiv).
We sought to improve the diastereoselectivity with the
hope of simplifying the purification of the products.
Gratifyingly, we found that by decreasing the reaction time
and temperature an improvement in diastereoselectivity
was accompanied by only a mild decrease in yield (entries
8-9).
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It has been shown that the nature of the protecting
groups can alter the facial selectivity of the attack on α-
amino aldehydes.6a, 8 We hypothesized that modifying the
amino moiety from N-mono-protected (as used in our prior
method) to a doubly protected amino aldehyde might alter
the conformation of this reaction partner in the transition
state and favor the syn diastereomer of the cross-benzoin
product. To this effect, a variety of protecting groups were
examined including N-Tosyl-N-Bn, N-Boc-N-Alkyl, N-Boc-
N-Bn, and N-phtalamide. Of these, it was found that only
Table 1. Optimization of the reaction conditionsa
N-Boc-N-Bn-
and
N-Tosyl-N-Bn-derived-L-alaninal
afforded any significant amount of cross-benzoin product
in a reaction with 2-furaldehyde (Scheme 2). Despite the
competence of the N-Tosyl-N-Bn- derived substrate, we
were reluctant to use this derivative as its use may facilitate
racemization of the α-amino aldehyde under the basic
reaction conditions. In any event, the desired product was
obtained in a modest 2:1 diastereomeric ratio and it
appeared the facial selectivity had been reversed relative to
that observed when using –NHBoc protected substrates.
The major diastereomer was isolated, re-crystallized, and
subjected to X-ray diffraction crystallography. The syn
relationship between the methyl and hydroxyl substituents
was clearly established in this manner (see Supporting
Information).
pre-
catalyst
temp.
(°C)
time NMR yield
(h)
dr
entry
solvent
(%)b
(syn:anti)
1
2
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8
2
2
2
2
3
4
5
2
2
toluene
MeOH
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
70
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70
70
70
70
70
40
40
4
4
4
4
4
4
4
4
1
34
43
63
93
<5
85
30
91
(2 : 1)
(3 : 1)
(4 : 1)
(4 : 1)
N/A
(2 : 1)
(2 : 1)
(5 : 1)
(6 : 1)
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a
Reaction conditions: 1 equiv of N-Boc-N-Bn-amino aldehyde, 1.3
equiv of hetereoaromatic aldehyde, 1 equiv of Hünig’s base, CH2Cl2
b
Scheme 2. Cross-benzoin reaction between amino
aldehyde 1 and 2-furaldehyde
[0.5 M]. Combined yield of both diastereomers of the cross-
1
benzoin product as determined by H NMR spectroscopy (DMSO-
d6 at 80 °C) using dimethylterephthalate as an internal standard.
Having established optimal reaction conditions, we set
out to investigate the scope of this reaction using a variety
of heteroaromatic aldehydes and N-Boc-N-Bn-amino
aldehydes (Table 2).
Unlike our previously reported anti-selective method,
good diastereoselectivities are obtained regardless of the
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steric bulk of the amino aldehyde substituent (6-10). Still,
there appears to be trend toward greater
1
2
a
diastereoselectivity with increasing substituent size.
However, the use of cyclic substrates such as N-Boc-
prolinal results in lower diastereomeric ratio (Table 2, entry
11). The reaction displays good functional group tolerance
as demonstrated by application of a glutamic acid-derived
amino aldehyde (12) and N-Boc-N-Bn-O-BOM-L-serinal
(13). With the exception of 8, all products in Table 2 are
obtained from enantiomerically-enriched amino aldehydes.
Importantly, comparison of HPLC chromatograms of 10 to
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those of
enantiomeric ratio during the course of the reaction (see
Experimental Section). Benzofuran-2-carboxaldehyde
affords moderate yields and diastereomeric ratios under
these reaction conditions (16). survey of reaction
a racemic sample showed no erosion of
a
Reaction conditions: 1 equiv of N-Boc-N-Bn-amino aldehyde, 1.5
A
equiv of hetereoaromatic aldehyde, 1 equiv of Hünig’s base, CH2Cl2
conditions revealed that successful application of highly
reactive hetereoaromatic aldehydes necessitates the use of
lower temperatures and shorter reaction times (14-16).9 The
use of pyrazine-2-carboxaldehyde necessitated even lower
temperatures and shorter reaction times to obtain
acceptable yields of the cross-benzoin products (Table 2,
entry 15). In addition to an increase in yield, the modified
conditions also improve the diastereomeric ratio for these
substrates.10 These observations can be rationalized by
considering the faster rates in both the forward and reverse
direction using these more reactive aldehydes. Lowering
the temperature thus minimizes the thermodynamic
equilibration between the two energetically similar
diastereomers.11
[0.5 M], 40 °C, 1 h. Reported yield is that of the isolated major
c
diastereomer. b3 equiv of hetereoaromatic aldehyde was used.
Modifications to reaction conditions: CH2Cl2 [0.15 M], 0 °C, 30 min.
d Modifications to reaction conditions: CH2Cl2 [0.15 M], -15 °C, 15
min.
Although the yields obtained using 1.5 equivalent of
heteroaromatic aldehyde are generally good, it was found
that they could be increased by using a larger excess (8,
13,14 and 15). Unfortunately, the use of aromatic (entry 17)
or aliphatic (not shown) aldehydes results in poor yields.12
Despite this limitation, we believe this method to be of
particular synthetic value given the continued interest of
heteroaromatic building blocks in medicinal chemistry as
well as the underutilized synthetic potential of the furan
moiety in particular.13
Table 2. Scope of the syn-selective cross-benzoin
reactiona
In our previous work, the presence of a hydrogen bond
was postulated to explain the anti diastereoselectivity in
cross-benzoin reaction using NHBoc amino aldehydes.5 In
the current study, the diastereoselectivity observed when
using N-Bn-N-Boc amino aldehydes can be predicted using
a polar Felkin-Anh transition state model (Figure 1).
Indeed, replacing the -NHBoc moiety with -NBnBoc
prevents formation of an intramolecular hydrogen bond,
effectively acting as a Cram chelate.
Figure 1. Proposed transition state models to
rationalize the observed diastereoselectivity
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cooled to 0 °C using an ice bath. NaBH4 (5 equiv) was
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4
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8
slowly added to the mixture in three portions. The resulting
suspension was warmed to room temperature and stirred
for one hour. The suspension was once again cooled to 0 °C
and quenched with the addition of sat. NH4Cl(aq.) The
reaction mixture was extracted with EtOAc (×3) and the
combined organic layers were dried over MgSO4. The crude
mixture was reduced in vacuo and carried to next step
without further purification.
In summary, we have developed
a complementary
approach for the chemo- and syn-selective cross-benzoin
reaction between α-amino and heteroaromatic aldehydes.
Combined with the accessibility of both R and S α-amino
aldehydes, all stereoisomers for the cross-benzoin products
of these aldehydes are now directly available. Application of
these methods to the total synthesis of natural products is
under way.
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A(II) N-Boc protection:16 To a solution of N-Bn-amino
alcohol (1.0 equiv) in THF [0.3 M] was added triethylamine
(1 equiv) at room temperature. To this solution was added
di–tert–butyl dicarbonate (Boc2O) (1.1 equiv) and stirred at
ambient temperature for 16 hours. The reaction was
quenched with addition of HCl [1 M] and extracted with
Et2O (×3). The combined organic layers were washed with
brine and dried over MgSO4. The crude product was
purified by column chromatography.
EXPERIMENTAL SECTION
General Methods
A(III) oxidation:5 IBX (1.5 equiv) was added to a solution
of N–Boc-N-Bn–amino alcohol (1.0 equiv) in acetonitrile
[0.2 M] and heated to reflux. The reaction was monitored
for complete consumption of starting material (typical
reaction time = 30 minutes). After completion, the contents
were cooled to room temperature, filtered through a pad of
Celite® and washed with EtOAc (×3). The resulting mixture
was concentrated and purified by column chromatography.
NMR spectra were recorded in CDCl3 solution at 500
MHz for 1H and 125 MHz for 13C. The residual solvent
protons (1H, 7.26 ppm) or the solvent carbons (13C, 77.16)
were used as internal standards for chemical shifts. High-
resolution mass spectra (HRMS) were obtained on a double
focusing high-resolution spectrometer. Infrared spectra
were recorded on a Fourier transform interferometer using
a diffuse reflectance cell (DRIFT); only diagnostic and/or
intense peaks are reported. All samples were prepared as a
film on a KBr disk for IR analysis. Melting points were
General procedure (B);
B(I) N-Benzyl protection: Following
a
modified
procedure,17 to a solution of amino ester HCl salt (1 equiv)
in dry MeOH [0.7 M], triethylamine (1 equiv) followed by
freshly distilled benzaldehyde (1.5 equiv) were added at
room temperature. The resulting solution was stirred for 1.5
h before being cooled to 0 °C using an ice bath. NaBH4 (2
equiv) was slowly added to the mixture in three portions.
The resulting suspension was warmed to rt and stirred for
two hours. The volatiles were removed under reduced
pressure and the crude reaction mixture was partitioned
between H2O and EtOAc. The layers were separated and
the aqueous layer was further extracted with EtOAc (×2).
The organic layers were combined, dried over MgSO4, and
volatiles were removed under reduced pressure. The crude
product was purified by column chromatography.
measured on
a
melting point apparatus and are
uncorrected. Anhydrous solvents were dried using a Braun
Solvent Purification System and were stored under nitrogen
over activated 3 Å molecular sieves for at least 48 hours
prior to use. Moisture content was analyzed by a Karl
Fischer Coulometer 20D and at no time exceeded 15 ppm
prior to use. Commercially available aldehydes that are
solids at room temperature were used directly with no
further purification; aldehydes that are liquids at room
temperature were distilled immediately prior to use. All
reactions were carried out under an inert atmosphere of
argon. N-Boc-prolinol, 2-furaldehyde, benzofuran-2-
carboxaldehyde, 2-pyrdine carboxaldehyde, and methyl 4-
formylbenzoate were purchased from commercial sources.
Pyrazine-2-carboxaldehyde was prepared per reported
literature procedure.14
B(II) N-Boc protection:16 To a solution of N-benzyl-
amino ester (1.0 equiv) in THF [0.3 M] was added
triethylamine (1 equiv) at room temperature. To this
solution was added di–tert–butyl dicarbonate (Boc2O) (1.1
equiv) and stirred at ambient temperature for 16 hours. The
reaction was quenched with addition of HCl [1 M] and
extracted with Et2O (×3). The combined organic layers were
washed with brine, dried over MgSO4 and concentrated in
vacuo. The crude product was purified by column
chromatography.
Synthesis of N-Boc-N-Bn-amino aldehydes:
General procedure (A);
A(I) N-Benzyl protection: Following
a
modified
procedure;15 to a solution of the corresponding α-amino
alcohol (1 equiv) in dry MeOH [0.25 M] freshly distilled
benzaldehyde (1 equiv) was added at room temperature.
The resulting solution was stirred for 2 hours before being
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B(III) LiAlH4 reduction:5 To a suspension of LiAlH4 (3
chromatography (9:1 hexanes/EtOAc). Rf = 0.15 (10% EtOAc
in hexanes). This mixture was carried to the next step
without further purification.
1
2
3
4
5
6
7
8
equiv) in THF [0.2 M] was added the crude ester from the
previous step (1 equiv) in dry THF [0.2 M] at 0 °C. After the
reaction was completed (as judged by TLC analysis) an
aqueous solution of Rochelle’s salt [0.5 M] was slowly
added to the mixture at 0 °C. The reaction was vigorously
stirred at room temperature for two hours. The reaction
mixture was diluted in EtOAc and the layers were
separated. The aqueous phase was extracted using EtOAc
(×2) and the combined organic layers were dried over
MgSO4. The resulting mixture was concentrated in vacuo
and purified by column chromatography.
B(III):
tert-butyl
(S)-benzyl(1-hydroxybutan-2-
yl)carbamate (S5) was isolated by column chromatography
(3:1 hexane/EtOAc). as a clear colorless oil (0.550 g, 38%
over 3 steps). Rf =0.17 (25% EtOAc in hexane); [α]D26 = -33 (c
1.1, CHCl3); FTIR (KBr film) νmax (cm–1): 3445, 2972, 2877,
1690, 1496, 1454, 1366, 1251, 1048; 1H NMR (500 MHz, CDCl3)
mixture of rotamers; δ 7.40–7.26 (m, 4H), 7.26–7.22 (m, 1H),
4.76–4.51 (m, 0.3H), 4.51–4.11 (m, 1.7H), 3.87–3.70 (m, 3H),
3.16–2.91 (m, 1H), 1.74–1.59 (m, 1H), 1.50 (br s, 2.8H), 1.42 (br
s, 9H), 0.96–0.78 (m, 3H); 13C{1H}NMR (125 MHz, CDCl3)
Mixture of rotamers (minor rotamer indicated by asterisk):
δ 157.2, 139.3, 128.6, 127.7*, 127.2, 127.2, 80.4, 64.3, 61.6, 50.0,
48.2*, 28.5, 22.6*, 21.8, 11.2; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd. for C16H25NO3Na 302.1727; Found 302.1722.
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B(IV) oxidation:5 IBX (1.5 equiv) was added to a solution
of N–Boc-N-Benzyl amino alcohol (1.0 equiv) in acetonitrile
[0.2 M] and heated to reflux. The reaction was monitored
for complete consumption of starting material (typical
reaction time = 30 minutes). After completion, the contents
were cooled to room temperature, filtered through a pad of
Celite® and washed with EtOAc (×3). The resulting mixture
was concentrated and purified by column chromatography.
B(IV): tert-butyl (S)-benzyl(1-oxobutan-2-yl)carbamate
(S6) was isolated by column chromatography (8:1
hexanes/EtOAc) as a clear colourless oil (0.360 g, 91%). Rf =
27
tert-butyl (S)-benzyl(1-oxopropan-2-yl)carbamate (1)
0.17 (11% EtOAc in hexanes); [α]D = -161 (c 2.0, CHCl3);
FTIR (KBr film) νmax (cm–1): 3369, 2976, 2934, 1695, 1497,
1455, 1367, 1250, 1166, 1049, 897, 742, 701; 1H NMR (500
MHz, CDCl3) mixture of rotamers; δ 9.46 (s, 0.4H), 9.35 (s,
0.6H), 7.40–7.26 (m, 5H), 5.02 (d, J = 15.0 Hz, 0.6H), 4.71 (d,
J = 15.6 Hz, 0.4H), 4.22 (d, J = 15.8 Hz, 0.4H), 4.13 (d, J = 15.0
Hz, 0.6H), 3.75–3.60 (m, 0.4H), 3.35 (dd, J = 7.2, 5.0 Hz,
0.6H), 2.01 (ddq, J = 13.9, 7.3, 7.3 Hz, 1H), 1.85–1.63 (m, 1H),
1.45 (s, 9H), 0.94 (t, J = 7.3 Hz, 3H); 13C{1H}NMR (125 MHz,
CDCl3) Mixture of rotamers (minor rotamer indicated by
asterisk): δ 199.7, 155.7*, 155.3, 138.3*, 137.8, 128.9, 128.8*,
128.5, 127.9*, 127.7, 81.7, 81.2*, 67.4*, 67.3, 52.3, 51.7*, 28.4*,
28.3, 21.6, 20.5*, 11.1, 11.0*; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd. for C16H23NO3Na 300.1570; Found 300.1552.
Prepared according to general procedure A;
A(I): (S)-2-(benzylamino)propan-1-ol (S1) was isolated as
a mixture of product and benzyl alcohol. This mixture was
carried to the next step without further purification.
A
(II):
tert-butyl
(S)-benzyl(1-hydroxypropan-2-
was isolated by column
yl)carbamate18
(S2)
chromatography (9:1 hexanes: EtOAc) as a clear colourless
oil (9.56 g, 90% over two steps). Rf = 0.21 (25% EtOAc in
1
hexanes); H NMR (500 MHz, CDCl3): δ 7.35–7.26 (m, 4H),
7.26–7.22 (m, 1H), 4.39 (br s, 2H), 4.05–3.90 (m, 1H), 3.73–
2.85 (m, 1H), 2.93 (br s, 1H), 1.43 (s, 9H), 1.14 (br d, J = 4.9
Hz, 3H).
tert-butyl benzyl(1-oxopent-4-en-2-yl)carbamate (S11)
A(III):
tert-butyl
(1) was
(I)-benzyl(1-oxopropan-2-
isolated by column
yl)carbamate18
benzylglycinate (S7):
chromatography (6:1 hexane/Et2O, Rf =0.26 [11% EtOAc in
To a solution of ethyl glycinate.HCl salt (21.5 mmol, 3.0 g)
in dry MeOH (33 mL, [0.7 M], triethylamine (21.49 mmol,
3.0 mL) followed by freshly distilled benzaldehyde (32.2
mmol, 3.3 mL) were added at room temperature. The
resulting solution was stirred for 1.5 hr before cooling to 0
°C using an ice bath. Sodium borohydride (43.0 mmol, 1.63
g) was added slowly to the mixture in three portions. The
resulting suspension was warmed to rt and stirred for
additional 2 hr. The volatiles were removed under reduced
pressure and the crude reaction mixture was partitioned
between H2O (ca. 75 mL) and CH2Cl2 (100 mL). The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (2 × 100 mL). The organic layers were combined,
dried over MgSO4, and volatiles were removed under
reduced pressure. Crude ethyl benzylglycinate (S7) was
carried to next step without further purification.
1
hexane]) as a clear colorless oil (0.455 g, 92%). H NMR
(500 MHz, CDCl3): mixture of rotamers; δ 9.49 (s, 0.4H),
9.43 (s, 0.6 H), 7.38–7.26 (m, 5H), 4.85 (d, J = 15.0 Hz, 0.6H),
3.79–3.68 (m, 0.4H), 3.51–3.40 (m, 0.6H), 1.46 (s, 9H), 1.34–
1.23 (m, 3H).
tert-butyl (S)-benzyl(1-oxobutan-2-yl)carbamate (S6)
Prepared according to general procedure B;
B(I): methyl (S)-2-(benzylamino)butanoate (S3) was
isolated a mixture of product benzyl alcohol. This mixture
was carried to the next step without further purification.
B
(II):
methyl
(S)-2-(benzyl(tert-
butoxycarbonyl)amino)butanoate (S4) and small amounts
of an unknown impurity were isolated by column
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tert-butyl
ethyl
N-benzyl-N-(tert-
analysis) aqueous solution of Rochelle’s salt [0.5 M] (ca. 20
mL) was slowly added to the mixture at 0 °C. The reaction
butoxycarbonyl)glycinate19 (S8):
1
2
was vigorously stirred at room temperature for an
additional 2 hours. The reaction mixture was diluted in
EtOAc (30 mL) and the layers were separated. The aqueous
phase was extracted using EtOAc (2 × 30 mL) and the
combined organic layers were dried over MgSO4. The crude
product was concentrated in vacuo and purified by column
chromatography (4:1 hexanes/EtOAc) ethyl benzyl(1-
hydroxypent-4-en-2-yl)carbamate (S10) was obtained as a
clear colourless oil (0.350, 36% over two steps); Rf = 0.10
(25% EtOAc in hexane. FTIR (KBr film) νmax (cm–1): 3442,
3066, 1683, 1496, 1367, 1167, 1030; 1H NMR (500 MHz,
CDCl3) mixture of rotamers; δ 7.37–7.22 (m, 5H), 5.73 (br s,
1H), 5.16–4.93 (m, 2H), 3.96–3.46 (m, 3H), 3.36 (br s, 0.6H),
2.54–2.20 (m, 2H), 1.86–1.32 (m, 9H); 13C{1H}NMR (125 MHz,
CDCl3) Mixture of rotamers (minor rotamer indicated by
asterisk): δ 156.9, 139.2, 150.3, 135.0, 128.6, 127.7*, 127.2, 117.3,
80.5, 64.2, 63.8*, 60.0, 59.6*, 50.8, 48.9*, 34.5*, 33.4, 28.4;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for C17H25NO3Na
314.1727; Found 314.1737.
3
4
5
6
7
8
9
To a solution of crude S7 (21.5 mmol) in THF (72 mL, [0.3
M]) was added triethylamine (21.5 mmol, 3.0 mL) at room
temperature. To this solution was added di–tert–butyl
dicarbonate (Boc2O) (23.6 mmol, 5.15 g) and the reaction
was stirred at ambient temperature for 16 hours. The
reaction was quenched with addition of HCl [1 M] and
extracted with Et2O (3 × 100 mL). The combined organic
layers were washed with brine and dried over MgSO4. The
crude product was concentrated in vacuo and purified by
column chromatography (7:1 hexanes: EtOAc). The
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
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59
60
corresponding
tert-butyl
ethyl
N-benzyl-N-(tert-
butoxycarbonyl)glycinate19 (S8) was obtained as a clear
1
colourless oil (4.37g, 85% over two steps); H NMR (500
MHz, CDCl3) mixture of rotamers: δ 7.36–7.29 (m, 1H),
7.29–7.19 (m, 4H), 4.55 (s, 1H), 4.51 (s, 1H), 4.16 (q, J = 4.8,
1H), 4.15 (q, J = 7.0, 1H), 3.92 (s, 1H), 1.47 (s, 4.1H), 1.47 (s,
4.9H), 1.24 (t, J = 1.5 Hz, 3H).
Ethyl
2-(benzyl(tert-butoxycarbonyl)amino)pent-4-
enoate (S9)
ethyl benzyl(1-hydroxypent-4-en-2-yl)carbamate (S11)
According to literature precedence,20 to a flame-dried
flask was added diisopropyl amine (1.05 mmol, 0.150 mL)
followed by THF (1.4 mL) under inert atmosphere. This
solution is cooled to 0 °C using an ice bath and n-BuLi [2.5
M] in THF (0.962 mmol, 0.385 mL) was added drop-wise.
The reaction mixture was stirred at this temperature for
additional 15 min. The reaction was cooled to -78 °C and a
solution of S8 (0.837 mmol, 0.200 g) in THF (2.8 mL) was
added drop-wise to this solution. Stirring was continued for
additional 40 minutes and allyl bromide (1.26 mmol, 0.110
mL) was added to the reaction mixture. The reaction was
stirred at -78 °C for additional 3.5 h and then allowed to
warm to 0 °C. The reaction was quenched with the addition
of sat. NH4Claq and extracted with Et2O (3 × 3 mL). The
organic layers were combined, washed with HCl [1 M] (1 × 3
mL), and dried over sodium sulphate. The crude product
was concentrated in vacuo and purified by column
chromatography (9:1 hexanes: Et2O). Ethyl 2-(benzyl(tert-
butoxycarbonyl)amino)pent-4-enoate20 (S9) was isolated
along with small amounts of an unknown impurity. This
mixture was taken to next step without further purification.
1H NMR (500 MHz, CDCl3): mixture of rotamers δ 7.36–7.27
(m, 4H), 7.26–7.20 (m, 1H), 5.80–5.56 (m, 1H), 5.08–5.00 (m,
1H), 5.08–4.95 (m, 2H), 4.68 (d, J = 15.5 HZ, 0.5H), 4.52 (J =
15.8 Hz, 0.5H), 4.44–4.36 (m, 0.5H), 4.35–4.27 (m, 1H), 4.12–
3.94 (m, 2H), 3.90–3.80 (m, 0.5H), 2.71 (dt, J = 14.4, 6.3 Hz,
1H), 2.62–2.41 (m, 1H), 1.47 (s, 5H), 1.39 (s, 4H), 1.19 (t, J = 7.1
Hz, 3H).
IBX (2.30 mmol, 0.642g) was added to a solution of S10
(1.15 mmol, 0.350g) in acetonitrile (5.8 mL, [0.2 M]) and
heated to reflux. The reaction was monitored for complete
consumption of starting material. After 40 minutes, the
contents were cooled to room temperature, filtered
through a pad of Celite® and washed with EtOAc (3 × 5 mL).
The resulting solution was concentrated and purified by
chromatography. (5:1 hexanes/ Et2O) tert-butyl benzyl(1-
oxopent-4-en-2-yl)carbamate (S11) was obtained as a
clear colourless oil (0.298, 86%); Rf =0.21 (16% Et2O in
hexane. FTIR (KBr film) νmax (cm–1): 2979, 2816, 1738, 1703,
1454, 1422, 1250, 1165; 1H NMR (500 MHz, CDCl3) mixture of
rotamers; δ 9.45 (s, 0.4H), 9.35 (s, 0.6H), 7.39–7.27 (m, 5H),
5.89–5.68 (m, 1H), 5.16–5.06 (m, 1H), 5.05 (d, J = 15.2 Hz,
0.4H), 4.77 (d, J = 15.9 Hz, 0.6H), 4.16 (d, J = 14.7 Hz, 0.4H),
4.07 (d, J = 15.0 Hz, 0.6H), 3.67 (dd, J = 9.2, 5.2 Hz, 0.4H),
3.46 (dd, J = 8.9, 5.2 Hz, 0.6H), 2.81–2.68 (m ,1H), 2.56 (ddd,
J
= 14.0, 7.1, 7.1 Hz 0.4H), 2.44 (ddd, J = 14.0, 7.1, 7.1 Hz,
0.4H), 1.47 (s, 9H); 13C{1H}NMR (125 MHz, CDCl3) Mixture
of rotamers (minor rotamer indicated by asterisk): δ 198.9*,
198.8, 155.6*, 155.0, 138.0*, 137.7, 134.5*, 134.2, 128.9, 128.8*,
128.5, 127.9*, 127.8, 118.3, 118.1*, 81.9, 81.3*, 65.7*, 65.5, 52.3,
52.2*, 32.9, 31.9*, 28.4*, 28.3; HRMS (FD-TOF) m/z: [M]
Calcd. for C17H23NO3 289.1678; Found 396.1683.
tert-butyl
(S)-benzyl(1-oxo-3-phenylpropan-2-
yl)carbamate (S14)
Prepared according to general procedure A;
ethyl benzyl(1-hydroxypent-4-en-2-yl)carbamate (S10)
A(I): (S)-2-(benzylamino)-3-phenylpropan-1-ol (S12) and
benzyl alcohol were obtained as a mixture. This mixture
was carried to the next step without further purification.
To a suspension of LiAlH4 (4.66 mmol, 0.177g) in THF (7
mL) was added the crude (S9) (1.55 mmol) in dry THF (10.5
mL) at 0°C. After the reaction is complete (judged by TLC
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The Journal of Organic Chemistry
A (II): tert-butyl (S)-benzyl(1-hydroxy-3-phenylpropan-2-
B(I): methyl benzylleucinate (S18) and benzyl alcohol
were obtained as a mixture. This mixture was carried to the
next step without further purification.
1
2
3
4
5
6
7
8
yl)carbamate (S13) and small amounts of an unknown
impurity were isolated by column chromatography (3:1
hexanes: acetone). This mixture was carried to next step
B
(II):
methyl
N-benzyl-N-(tert-
1
without further purification. H NMR (600 MHz, CDCl3): δ
butoxycarbonyl)leucinate18 (S19) was isolated by column
chromatography (9:1 hexanes: EtOAc) as a clear colourless
oil (2.17 g, 59% over two steps). Rf = 0.23 (10% EtOAc in
7.34–7.26 (m, 3H), 7.26–7.18 (m, 2H), 4.49–4.29 (m, 1H),
3.86 (d, J = 14.5 Hz, 0.5H), 3.78–3.59 (m, 2.5H), 3.10–2.88 (m,
1H), 1.44 (s, 7.5H), 1.29–1.24 (m, 1.5H).
1
hexanes). H NMR (500 MHz, CDCl3): mixture of rotamers;
9
A(III): tert-butyl (S)-benzyl(1-oxo-3-phenylpropan-2-
δ 7.41–7.26 (m, 3.6H), 7.26–7.20 (m, 1.4H), 4.79–4.65 (m,
0.5H), 4.59 (d. J = 14.9 Hz, 0.5H), 4.52 (d, J = 16.5 Hz, 0.5H),
4.39 (d, J = 14.8 Hz, 0.5H), 4.30 (d, J = 14.9 Hz, 0.5H), 4.22–
4.04 (m, 0.5H), 3.58 (s, 3H), 1.81–1.69 (m, 1H), 1.64–1.57 (m,
1H), 1.48 (s, 5H), 1.43–1.32 (m, 5H).
10
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
37
38
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44
45
46
47
48
49
50
51
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57
58
59
60
yl)carbamate18 (S14)
was isolated by column
chromatography (8:1 hexane/EtOAc, Rf =0.28 [11% EtOAc in
hexane]) as a light yellow oil (0.756 g, 22% over three
1
steps). H NMR (500 MHz, CDCl3): mixture of rotamers; δ
9.46 (s, 0.4H), 9.36 (s, 0.6H), 7.37–7.27 (m, 4H), 7.26–7.22
(m, 2.2H), 7.17 (d, J = 7.3 Hz, 0.8H), 7.14 (d, J = 7.2 Hz, 1H),
7.08 (d, J = 7 Hz, 2H), 4.89 (d, J = 15.0 Hz, 0.6H), 4.40 (d, J =
15.5 Hz, 0.4H), 3.61 (dd, J = 10.1, 4.5 Hz, 0.4H), 3.53 (dd, J =
10.0, 4.3 Hz, 0.6H), 3.33 (t, J = 6.3 Hz, 0.4H), 3.31 (t, J = 4.5
Hz, 0.6H), 3.22 (d, J = 15.6 Hz, 0.4H), 3.12 (dd, J = 13.9, 10.2
Hz, 0.4H), 3.05 (d, J = 15.1 Hz, 0.6H), 2.96 (dd, J = 13.9, 10.0
Hz, 0.6H), 1.51 (s, 5H), 1.50 (s, 4H).
B(III): tert-butyl benzyl(1-hydroxy-4-methylpentan-2-
yl)carbamate18
(S20)
was
isolated
by
column
chromatography (3:1 hexane/EtOAc). as a clear colorless oil
(0.858 g, 93%). Rf =0.20 (25% EtOAc in hexane); 1H NMR
spectrum was identical to S16.
B(IV):
tert-butyl
(S21)
benzyl(4-methyl-1-oxopentan-2-
was isolated by column
yl)carbamate18
chromatography (9:1 hexanes/EtOAc) as a clear colourless
oil (0.455 g, quantitative). Rf = 0.26 (10% EtOAc in
hexanes); 1H NMR spectrum was identical to S17.
tert-butyl
(S)-benzyl(4-methyl-1-oxopentan-2-
yl)carbamate (S17)
Prepared according to general procedure A;
ethyl
(S)-4-(benzyl(tert-butoxycarbonyl)amino)-5-
A(I): (S)-2-(benzylamino)-4-methylpentan-1-ol (S15) and
benzyl alcohol were obtained as a mixture. This mixture
was carried to the next step without further purification.
oxopentanoate (S25)
(S)-2-(benzylamino)-5-ethoxy-5-oxopentanoic acid (S22)21
To a solution of (S)-2-amino-5-ethoxy-5-oxopentanoic
acid (11.4 mmol, 2.00 g) in dry MeOH (23 mL, [0.5 M]),
triethylamine (22.8 mmol, 3.2 mL) followed by freshly
distilled benzaldehyde (17.13 mmol, 1.8 mL) were added at
room temperature. The resulting solution was stirred for 1 h
A(II): tert-butyl (S)-benzyl(1-hydroxy-4-methylpentan-2-
yl)carbamate18
(S16)
was
isolated
by
column
chromatography (6:1 hexanes/acetone) the corresponding
as a clear colourless oil (2.37g, 90% over two steps). Rf = 0.11
(24% acetone in hexanes); 1H NMR (500 MHz, CDCl3):
mixture of rotamers; δ 7.35–7.20 (m, 10H), 4.69–4.47 (m,
0.4H), 4.47–4.35 (m, 0.6H), 4.35–4.18 (m, 1H), 4.12–3.97 (m,
0.4H), 3.96–3.78 (m, 0.6H), 3.69–3.35 (m, 2H), 2.97–2.81 (m,
1H), 1.54–1.32 (m, 11H), 1.30–1.07 (m, 1H), 0.89 (d, J = 6.4 Hz,
3H), 0.83 (d, J = 6.5 Hz, 3H).
before cooled to
0
°C using an ice bath.
Sodium
borohydride (34.3 mmol, 1.30g) was added to the mixture in
three portions. The resulting suspension was warmed to
room temperature and stirred for additional 2 h. The
volatiles were removed under reduced pressure and the
crude reaction mixture was partitioned between H2O (ca.
75 mL) and EtOAc (100 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (2 × 100 mL).
The organic layers were combined, dried over MgSO4, and
volatiles were removed under reduced pressure to afford
the title compound and benzyl alcohol as white crystals.
The crude reaction mixture was carried to the next step
without further purification.
A(III): tert-butyl (S)-benzyl(4-methyl-1-oxopentan-2-
yl)carbamate18
(S17)
was
isolated
by
column
chromatography (9:1 hexane/EtOAc). Rf = 0.26 (10% EtOAc
1
in hexane) as a clear colorless oil (0.451 g, 91%). H NMR
(500 MHz, CDCl3): mixture of rotamers; δ 9.44 (s, 0.4H),
9.34 (s, 0.6H), 7.37–7.27 (m, 5H), 5.01 (d, J = 14.8 Hz, 0.6H),
4.71 (d, J = 15.5 Hz, 0.4H), 4.19 (d, J = 15.5 Hz, 0.4H), 4.10 (d,
J = 15.0 Hz, 0.6H), 3.94–3.85 (m, 0.4H), 4.54 (dd, J = 7.0, 5.0
Hz, 0.6H), 1.90–1.76 (m, 1H), 1.67–1.55 (m, 2H), 1.46 (s, 9H),
0.94–0.88 (m, 3H), 0.86 (d, J = 6.6 Hz, 3H).
(S)-2-(benzyl(tert-butoxycarbonyl)amino)-5-ethoxy-5-
oxopentanoic acid22 (S23)
To a solution of crude S22 (3.78 mmol) in (1:1 v/v)
dioxane:H2O (13 mL, [0.3 M]) was added triethylamine (11.4
mmol, 1.6 mL) at room temperature. To this solution was
added di–tert–butyl dicarbonate (Boc2O) (3.79 mmol, 0.826
g) and stirred at ambient temperature for 16 hours. The
tert-butyl
benzyl(4-methyl-1-oxopentan-2-
yl)carbamate (S20)
Prepared according to general procedure B;
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reaction was quenched with addition of HCl [1 M] and
14.9 Hz, 0.6H), 4.77 (d, J = 15.5 Hz, 0.4H), 4.18 (d, J = 15.5
1
2
3
4
5
6
7
8
extracted with EtOAc (3 × 100 mL). The combined organic
layers were washed with brine and dried over MgSO4. The
crude product was concentrated in vacuo and purified by
column chromatography (1:1 hexane/EtOAc). N2-Benzyl-N2-
(tert-butoxycarbonyl)-N-ethyl-L-glutamine and benzyl
alcohol were obtained as a mixture which were carried to
Hz, 0.6H), 4.15–4.08 (m, 2H), 4.06 (d, J = 14.9 Hz, 0.6H),
3.77–3.67 (m, 0.4H), 3.56 (app t, J = 6.3 Hz, 0.6H), 2.45–2.25
(m, 3H), 2.08–1.90 (m, 1H), 1.47 (s, 3H), 1.44 (s, 6H), 1.24, (t,
J = 7.1 Hz, 3H); 13C{1H}NMR (125 MHz, CDCl3) Mixture of
rotamers (minor rotamer indicated by asterisk): δ 199.0,
190.0*, 173.1*, 173.0, 155.5*, 155.1, 138.0*, 137.7, 128.9, 128.6,
128.0*, 127.8, 82.0, 81.4*, 64.8*, 64.5, 60.6, 60.6*, 51.9, 51.8*,
30.5, 28.4*, 28.2, 23.6, 22.6*, 14.3; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd. for C19H27NO5Na 372.1781; Found 372.1795.
1
the next step without further purification. H NMR (500
MHz, CDCl3) mixture of rotamers: δ 7.36–7.26 (m, 5H),
4.70–4.61 (m, 0.4H), 4.61–4.48 (m, 0.6H), 4.35 (d, J = 15.6
Hz, 1H), 4.28–4.14 (m, 0.6H), 4.12–4.01 (m, 1.8H), 4.00–3.88
(m, 0.6H), 2.40–2.15 (m, 3H), 2.15–1.97 (m, 1H), 1.46 (s, 9H),
1.22 (t, J = 7.2Hz, 3H).
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13
14
15
16
17
18
19
20
21
22
23
24
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26
27
28
29
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31
32
33
34
35
36
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38
39
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41
42
43
44
45
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47
48
49
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53
54
55
56
57
58
59
60
tert-butyl
(S)-benzyl(1-((benzyloxy)methoxy)-3-
oxopropan-2-yl)carbamate (S30)
Prepared according to general procedure B;
ethyl
(S)-4-(benzyl(tert-butoxycarbonyl)amino)-5-
hydroxypentanoate (S24)
B(I): methyl benzyl-L-serinate (S26) and benzyl alcohol
were isolated as a mixture. This mixture was carried to the
next step without further purification.
Crude (S23) (1.01 mmol, 0.369 g) was dissolved in THF (5.1
mL, [0.2 M]) and cooled to –10 °C. To this solution was
added 4-methyl morpholine (NMM) (2.03 mmol, 0.22 mL)
followed by ethyl chloroformate (1.52 mmol, 0.14 mL). The
mixture was stirred at this temperature for 1 h, then NaBH4
(3.04 mmol, 0.115g) was added in one portion followed by
addition of MeOH (10.2 mL). The mixture was stirred for an
additional 30 minutes and the crude product was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine and dried over MgSO4. The resulting
solution was concentrated in vacuo and purified by column
chromatography (1:1 hexane/EtOAc) (S24) was obtained as
a clear colourless oil (0.239g, 27% over three steps); Rf =0.18
B
(II): methyl N-benzyl-N-(tert-butoxycarbonyl)-L-
serinate23 (S27) was isolated by column chromatography
(9:1 hexane/ EtOAc) as a clear colourless oil (2.11 g, 53%
1
over two steps). H NMR (500 MHz, CDCl3): mixture of
rotamers; δ 7.37–7.27 (m, 5H), 4.58–4.51 (m, 1.5H), 4.47–4.39
(m, 0.5H), 4.15–4.02 (m, 1.5H), 3.87–3.73 (m, 1H), 3.70 (s,
3H), 3.52–3.43 (m, 0.5H), 3.13–3.04 (m, 0.5H), 2.43–2.34 (m,
0.5H), 1.45 (s, 9H).
methyl
N-benzyl-O-((benzyloxy)methyl)-N-(tert-
butoxycarbonyl)-L-serinate23 (S28)
27
(50% EtOAc in hexane. [α]D = -122 (c 1.1, CHCl3); FTIR
To a solution of S27 (1.90 g, 6.15 mmol) in dry DMF (6.2
mL [1 M]) was added i-Pr2NEt (3.4 mL, 19.7 mmol) at room
temperature under argon. This was followed by the
addition of BOMCl (70% purity w/w) (4.11 g, 18.4 mmol).
After 24 hours, the reaction mixture was diluted in EtOAc
(150 mL) and washed sequentially with sat. NH4Claq (150
mL), distilled water (150 mL), and brine (150 mL). The
organic layer was dried over MgSO4 and concentrated. The
volatiles were removed in vacuo and the reaction mixture
was purified by chromatography (7:1 hexane/ EtOAc) to
afford methyl S28 as light yellow oil (2.00 g, 76%). Rf = 0.17
(13% EtOAc in hexane). 1H NMR (500 MHz, CDCl3):
mixture of rotamers; δ 7.38–7.26 (m, 8.8H), 7.26–7.20 (m,
1.2H), 4.77 (d, J = 15.3 Hz, 0.5H), 4.72–4.66 (m, 1H), 4.66–
4.63 (m, 0.5H), 4.61–4.55 (m, 1.5H), 4.52–4.39 (m, 3H), 4.11–
4.04 (m, 1H), 4.03–3.95 (m, 1H), 3.84 (app t, 9.4 Hz, 0.5H),
3.69 (s, 1.5H), 3.65 (s, 1.5H), 1.44 (s, 4.5H), 1.39 (s, 4.5H).
(KBr film) νmax (cm–1): 3458, 2978, 1735, 1690, 1496, 1392,
1
1366, 1249, 1165; H NMR (500 MHz, CDCl3) mixture of
rotamers; δ 7.36–7.27 (m, 4H), 7.26–7.23 (m, 1H), 4.56–4.39
(m, 1H), 4.39–4.21 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.77–3.50
(m, 3H), 3.23–3.15 (m, 1H), 2.47–2.18 (m, 2H), 2.08–1.83 (m,
2H), 1.44 (br s, 9H), 1.24 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (125
MHz, CDCl3) Mixture of rotamers (minor rotamer
indicated by asterisk): δ 173.3, 156.9, 139.1, 128.7, 127.4, 127.4,
80.8, 64.4, 60.6, 59.4, 59.1, 50.8, 48.4, 31.0, 28.5, 25.6*, 23.6,
14.3; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for
C19H29NO5Na 374.1937; Found 374.1945.
ethyl
(S)-4-(benzyl(tert-butoxycarbonyl)amino)-5-
oxopentanoate (S25): IBX (2.30 mmol, 0.642 g) was added
to a solution of S24 (0.595 mmol, 0.209 g) in acetonitrile (6
mL, [0.1 M]) and heated to reflux. The reaction was
monitored for complete consumption of starting material.
After 1 h, the contents were cooled to room temperature,
filtered through a pad of Celite® and washed with EtOAc (3
× 5 mL). The resulting solution was concentrated and
purified by chromatography (7:1 hexane/ EtOAc). S25 was
obtained as a clear colourless oil (0.179, 86%); Rf =0.16 (13%
B(III): tert-butyl (R)-benzyl(1-((benzyloxy)methoxy)-3-
hydroxypropan-2-yl)carbamate23 (S29) was isolated by
column chromatography (2:1 hexane/EtOAc) as a clear
colorless oil (0.346 g, 74%). Rf =0.22 (33% EtOAc in hexane);
1H NMR (500 MHz, CDCl3) mixture of rotamers; δ 7.39–7.26
(m, 8.2H), 7.26–7.22 (m, 1.8H), 4.74–4.64 (m, 2H), 4.64–4.58
(m, 0.7H), 4.54 (dd, J = 12.1, 2.5Hz, 2.3H), 4.43-4.30 (m,
1H),3.96–3.62 (m, 5H), 3.40 (br s, 1H), 1.54–1.37 (m, 9H).
27
EtOAc in hexane). [α]D = -120 (c 3.2, CHCl3); FTIR (KBr
film) νmax (cm–1): 3389, 2993, 1738, 1703, 1497, 1250, 1163,
1
1030; H NMR (500 MHz, CDCl3) mixture of rotamers; δ
9.38 (s, 0.4H), 9.27 (s, 0.6H), 7.36–7.26 (m, 5H), 5.04 (d, J =
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The Journal of Organic Chemistry
B(IV): tert-butyl (S)-benzyl(1-((benzyloxy)methoxy)-3-
The corresponding N–Boc-N-Bn–amino aldehyde (0.152
oxopropan-2-yl)carbamate23 (S30) was isolated by column
chromatography (5:1 hexanes: acetone) as a clear colourless
mmol, 1.0 equiv) and triazolium salt 1 (0.0304 mmol, 0.2
equiv) were added to an oven–dried test tube with a
Schlenk take–off and fitted with a septum. The vessel was
placed under vacuum and re–filled with argon three times
to ensure inert atmosphere. The hetereoaromatic aldehyde
(0.228 mmol, 1.5 equiv) and CH2Cl2 (1.0 mL, 0.15 M) were
added sequentially. The reaction was cooled to 0 °C and i-
Pr2NEt (0.152 mmol, 1 equiv) was added. After 30 minutes
the reaction mixture was warmed to room temperature and
quenched by addition of 1M HCl (2 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 2 mL) and dried over
Na2SO4. The crude product was purified by column
chromatography followed by preparative thin layer
chromatography to afford the corresponding cross–benzoin
product.
1
2
3
4
5
6
7
8
1
oil (0.271 g, 79%). Rf = 0.20 (17% acetone in hexanes); H
NMR (500 MHz, CDCl3) mixture of rotamers; δ 9.44 (s,
0.4H), 9.33 (s, 0.6H), 7.39–7.27 (m, 10H), 5.11 (d, J = 15.0 Hz,
0.6H), 4.88 (d, J = 15.5 Hz, 0.4Hz), 4.74 (app t, J = 6.9 Hz,
0.8H), 4.71 (app t, J = 6.0 Hz, 1.2H), 4.60–4.52 (m, 2H), 4.29
(d, J = 15.6 Hz, 0.4H), 4.22 (d, J = 15 Hz, 0.6H), 4.18–4.09 (m,
1H), 3.98 (app t, 7.8Hz, 0.4H), 3.91–3.79 (m, 1H), 3.69 (app
t, J = 6.9 Hz, 0.6H), 1.46 (s, 4H), 1.43 (s, 5H).
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 (S)-2-formylpyrrolidine-1-carboxylate (N-
Boc-prolinal) (S31)24
IBX (3.74 mmol, 1.05 g) was added to a solution of N–Boc-
prolinol (2.49 mmol, 0.500 g) in acetonitrile (12.5 mL, [0.2
M]) and heated to reflux. The reaction was monitored for
complete consumption of starting material. After 30
minutes the contents were cooled to room temperature,
filtered through a pad of Celite® and washed with EtOAc (3
× 10 mL). The resulting mixture was concentrated and
purified by column chromatography. S31 was isolated by
column chromatography (8:1 hexane/EtOAc, Rf =0.10 [11%
tert-butyl benzyl((2S,3S)-4-(furan-2-yl)-3-hydroxy-4-
oxobutan-2-yl)carbamate (6)
Prepared according to general procedure C; Column
chromatography (5:1 hexane/acetone) followed by PTLC (7:1
toluene: EtOAc) afforded the major product as white solids
(38 mg, 69%). Rf = 0.22 (17% acetone in hexanes); melting
point = 121.1 °C, [α]D26 = -30 (c 1.9, CHCl3); FTIR (KBr film)
νmax (cm–1): 3457, 3123, 2978, 1678, 1466, 1392, 1367, 1166,
1034, 921, 769, 733, 700; 1H NMR (500 MHz, CDCl3) mixture
of rotamers; δ 7.89 (br s, 1H), 7.70 (s, 1H), 7.33–7.27 (m,
2H), 7.24–7.17 (m, 3H), 6.62 (dd, J = 3.7, 1.7 Hz, 1H), 5.09
(app d, J = 3.7 Hz, 1H), 4.73–4.60 (m, 2H), 4.49 (d, J = 16.8
Hz, 1H), 4.05 (d, J = 5.3 Hz, 0.8H), 3.58 (br s, 0.2H), 1.57 (s,
1.5H), 1.38 (s, 7.5H), 0.98 (d, J = 7.2 Hz, 3H); 13C{1H}NMR
(125 MHz, CDCl3) Mixture of rotamers (minor rotamer
indicated by asterisk): δ 187.5, 156.4, 148.2, 147.7*, 140.5,
128.3, 126.8, 126.4, 122.08, 120.0*, 112.8, 80.5, 77.4, 76.7*, 55.4,
54.9*, 48.7, 28.7*, 28.4, 13.5*, 11.5*; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd. for C20H25NO5Na 382.1625; Found 382.1620.
1
EtOAc in hexane]) as clear colourless oil (0.413 g, 83%). H
NMR (500 MHz, CDCl3): mixture of rotamers; δ 9.56 (s,
0.4H), 9.46 (d, J = 2.8 Hz, 0.6H), 4.25–4.14 (m, 0.4H), 410–
3.99 (m, 0.6H), 3.61–3.52 (m, 0.gH), 3.52–3.39 (m, 1.4H),
2.17–2.09 (m, 0.6H), 2.08–2.01 (m, 0.4H), 2.01–1.91 (m, 1H),
1.91–1.82 (m, 2H), 1.48 (s, 3H), 1.43 (s, 6H).
General procedures for the cross-benzoin reaction.
General procedure C
The corresponding N–Boc-N-Bn–amino aldehyde (0.152
mmol, 1.0 equiv) and triazolium salt 1 (0.0304 mmol, 0.2
equiv) were added to an oven–dried test tube with a
Schlenk take–off and fitted with a septum. The vessel was
placed under vacuum and re–filled with argon three times
to ensure inert atmosphere. The hetereoaromatic aldehyde
(0.228 mmol, 1.5 equiv) and CH2Cl2 (0.3 mL, [0.5 M]) were
added sequentially. Lastly i-Pr2NEt (0.152 mmol, 1 equiv)
was added and the septum was then quickly exchanged for
a cold finger. Once inert atmosphere was re–established the
tert-butyl benzyl((2S,3S)-1-(furan-2-yl)-2-hydroxy-1-
oxopentan-3-yl)carbamate (7)
Prepared according to general procedure C; Column
chromatography (7:1 hexane/acetone) followed by PTLC (7:1
toluene: EtOAc) afforded the major product as a clear
colourless oil (39 mg, 69%). Rf = 0.18 (13% acetone in
flask was sealed and heated to 40 °C for
1 hour.
26
hexanes); [α]D = +31 (c 1.3, CHCl3); FTIR (KBr film) νmax
(WARNING: when performed on a larger scale, it is advised
to use a water condenser instead of a cold finger to avoid
the small pressure buildup). The crude reaction mixture
was cooled to room temperature and quenched by addition
of HCl (2 mL, [1 M]). The aqueous layer was extracted with
CH2Cl2 (3 × 2 mL) and dried over Na2SO4. The crude
product was purified by column chromatography followed
by preparative thin layer chromatography to afford the
corresponding cross–benzoin product.
1
(cm–1): 3452, 2934, 1679, 1568, 1496, 1367, 1297, 1250, 1165; H
NMR (500 MHz, CDCl3) mixture of rotamers; δ 7.81 (br s,
1H), 7.67 (s, 1H), 7.39–7.28 (m, 4H), 7.25–7.17 (m, 1H), 6.60
(s, 1H), 5.00 (dd, J = 5.2, 2.2 Hz, 1H), 4.62 (d, J = 15.8 Hz, 1H),
4.43 (d, J = 16.0 Hz, 1H), 4.35 (br s, 1H), 3.49 (br s, 0.2H),
1.84–1.67 (m, 1H), 1.56–1.45 (m, 2H), 1.39 (s, 8H);
13C{1H}NMR (125 MHz, CDCl3) Mixture of rotamers (minor
rotamer indicated by asterisk): δ 187.9, 157.0, 149.9, 147.9,
139.9, 128.3, 127.9*, 127.2, 126.9, 121.8, 120.1*, 112.8, 80.6, 78.2,
62.6, 50.0*, 28.7*, 28.4, 19.3, 11.2, 10.8*; HRMS (ESI-TOF)
General procedure D
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26
m/z: [M+Na]+ Calcd. for C21H27NO5Na 396.1781; Found
hexanes); [α]D = +5.9 (c 1.6, CHCl3); HPLC analysis –
1
2
3
4
396.1789.
Chiralcel IC column, 2% isopropanol in hexanes, 0.1
mL/min. Major: 20.0 min, minor: 33.0 min FTIR (KBr film)
tert-butyl (1-(benzofuran-2-yl)-2-hydroxy-1-oxohex-5-
en-3-yl)(benzyl)carbamate (8)
1
νmax (cm–1): 3452, 2958, 1679, 1496, 1390, 1366, 1165, 991; H
NMR (500 MHz, CDCl3) mixture of rotamers; δ 7.84 (br s,
1H), 7.68 (s, 1H), 7.41–7.26 (m, 4H), 7.24–7.16 (m, 1H), 6.61
(s, 1H), 5.03 (s, 1H), 4.81–4.54 (m, 2H), 4.46 (d, J = 16.0 Hz,
1H), 4.14 (br s, 0.8H), 3.57 (br s, 0.2H), 1.76–1.57 (m, 1H),
1.31–1.22 (m, 1H), 1.52 (s, 2.2H), 1.38 (s, 6.8H), 1.00–0.77 (m,
1H), 0.69–0.41 (m, 6H); 13C{1H}NMR (125 MHz, CDCl3)
Mixture of rotamers (minor rotamer indicated by asterisk):
δ 187.7, 156.9, 149.7, 148.1, 147.7*, 140.2, 128.3, 127.6*, 127.0,
126.8, 121.8, 120.0*, 112.9, 111.1*, 80.5, 78.5, 58.2, 49.2*, 34.9,
28.6*, 28.4, 24.8, 24.2*, 23.14, 21.7, 21.4*; HRMS (ESI-TOF)
m/z: [M+1]+ Calcd. for C23H32NO5 402.2275; Found 402.2271.
5
6
7
8
Prepared according to general procedure C;
Column chromatography (4:1 hexane/EtOAc) followed by
PTLC (7:1 toluene/EtOAc) afforded the major product as a
clear colourless oil (1.5 equiv of 2-furaldehyde: 40 mg, 66%;
3 equiv of 2-furaldehyde: 45 mg, 74%). Rf = 0.45 (13% EtOAc
in toluene); FTIR (KBr film) νmax (cm–1): 3444, 2978, 1679,
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
1568, 1465, 1367, 1165, 1033, 914; H NMR (600 MHz, CDCl3)
mixture of rotamers; δ 7.70 (br s, 1H), 7.66 (s, 1H), 7.33–7.26
(m, 3H), 7.26–7.20 (m, 2H), 6.58 (br s, 1H), 5.48 (dddd, J =
16.0, 7.4, 7.4, 7.4 Hz, 0.8H), 5.44–5.33 (m, 0.2H), 4.99 (s,
1H), 4.94 (d, J = 17.0 Hz, 0.7H), 4.90 (d, J = 10.2 Hz, 1 H),
4.87–4.81 (m, 0.3H), 4.61 (d, J = 16.0 Hz, 1.7 H), 4.43 (br s,
1H), 4.35 (d, J = 16.1 Hz, 1H), 3.53 (br s, 0.2H), 2.62–2.50 (m,
0.9H), 2.50–2.39 (m, 0.1H), 2.18 (ddd, J = 14.4, 6.9, 6.9 Hz,
1H), 1.52 (s, 2H), 1.39 (s, 7H); 13C{1H}NMR (125 MHz, CDCl3)
Mixture of rotamers (minor rotamer indicated by asterisk):
δ 187.6, 156.9, 150.1, 147.9, 139.4, 134.5, 128.3, 127.9*, 127.3,
127.0, 121.7, 120.1*, 118.0, 117.7*, 112.7, 80.7, 77.9, 70.0, 50.9,
30.9, 28.6*, 28.39; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd.
for C22H27NO5Na 408.1781; Found 408.1798.
rac-tert-butyl benzyl-(furan-2-yl)-2-hydroxy-5-
methyl-1-oxohexan-3-yl)carbamate (rac-10)
Prepared according to general procedure C;
Column chromatography (5:1 hexane/EtOAc) afforded the
major diastereomer as a clear colourless oil (48 mg, 77%).
Rf = 0.21 (16% EtOAc in hexanes); HPLC analysis – Chiralcel
IC column, 2% isopropanol in hexanes, 0.1 mL/min. Major:
1
20.0 min, minor: 32.9 min; H NMR spectrum was identical
to 10.
tert-butyl benzyl((2S,3S)-4-(furan-2-yl)-3-hydroxy-4-
oxo-1-phenylbutan-2-yl)carbamate (9)
tert-butyl (S)-2-((S)-2-(furan-2-yl)-1-hydroxy-2-
oxoethyl)pyrrolidine-1-carboxylate (11)
Prepared according to general procedure C; Column
chromatography (4:1 hexane/acetone) followed by PTLC
(7:1 toluene: EtOAc) afforded the major product as a light
yellow oil (43 mg, 66%). Rf = 0.25 (20% acetone in
Prepared according to general procedure C; Column
chromatography (3:1 hexane/acetone) followed by (7:1
toluene: EtOAc) afforded the product along with small
amounts of impurities. This mixture was re-crystallized in
hexanes to afford the major diastereomer as white solids
(38 mg, 43%). Rf = 0.28 (25% acetone in hexanes); melting
point = 91.0 °C, [α]D26 = +120 (c 1.9, CHCl3); FTIR (KBr film)
26
hexanes); [α]D = -34 (c 2.2, CHCl3); FTIR (KBr film) νmax
(cm–1): 3446, 3029, 1679, 1569, 1496, 1367, 1249, 1165; 1H NMR
(500 MHz, CDCl3) mixture of rotamers; δ 7.69–7.51 (m, 2H),
7.37–7.26 (m, 0.7H), 7.26–7.09 (m, 6H), 7.09–6.98 (m, 3H),
6.90–6.82 (m, 0.3H), 6.58 (s, 0.2H), 6.52 (s, 0.8H), 5.08–4.91
(m, 1.3H), 4.71–4.43 (m, 0.7H), 4.48 (d, J = 15.4 Hz, 1H),
4.04–3.76 (m, 0.7H), 3.76 –3.60 (m, 0.3 H), 3.28–3.04 (m,
0.8H), 2.99–2.87 (m, 0.2H), 2.79 (dd, J = 14.2, 4.9 Hz, 0.9H),
2.73–2.58 (m, 0.1H), 1.45–1.28 (m, 9H); 13C{1H}NMR (125
MHz, CDCl3) Mixture of rotamers (minor rotamer
indicated by asterisk): δ 187.3, 157.0, 150.2, 147.6, 146.9, 138.9,
138.0, 129.5*, 129.4, 128.6, 128.5*, 128.3, 127.3, 126.9, 126.5,
121.4, 119.8*, 112.8*, 112.6, 80.9, 78.0, 63.3, 52.1*, 32.6, 31.7*,
28.4; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for
C26H29NO5Na 458.1938; Found 458.1927.
1
νmax (cm–1): 3460, 2976, 1683, 1466, 1394, 1168, 1084, 771; H
NMR (500 MHz, CDCl3) mixture of rotamers; δ 7.81 (d, J =
3.4 Hz, 0.7H), 7.70 (s, 0.7H), 7.67 (s, 0.3H), 7.35 (br s, 0.3H),
6.64–6.56 (m, 1H), 5.37 (dd, J = 6.4, 1.7 Hz, 0.7H), 5.20–5.10
(m, 0.3H), 4.30–4.21 (m, 0.7H), 4.21–4.12 (m, 0.3H), 3.82 (d, J
= 6.4 Hz, 0.7H), 3.59–3.55 (m, 0.3H), 3.55–3.50 (m, 0.2H),
3.47–3.32 (m, 1.8H), 2.08–1.96 (m, 1H), 1.82–1.62(m, 3H), 1.48
(s, 9H); 13C{1H}NMR (125 MHz, CDCl3) Mixture of rotamers
(minor rotamer indicated by asterisk): δ 188.4*, 188.2, 155.1,
154.1*, 150.6*, 149.8, 148.11, 147.6*, 122.0, 119.9*, 112.8*, 112.8,
80.2*, 79.7, 74.9*, 74.7, 61.5, 60.4*, 47.3, 47.1*, 28.6, 26.3*,
24.8, 24.8, 23.7; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for
C15H21NO5Na 318.1312; Found 318.1318.
tert-butyl benzyl((2S,3S)-1-(furan-2-yl)-2-hydroxy-5-
methyl-1-oxohexan-3-yl)carbamate (10)
Prepared according to general procedure C; Column
chromatography (5:1 hexane/acetone) followed by PTLC (7:1
toluene: EtOAc) afforded the major product as a clear
colourless oil (49 mg, 77%). Rf = 0.25 (20% acetone in
ethyl (4S,5S)-4-(benzyl(tert-butoxycarbonyl)amino)-
6-(furan-2-yl)-5-hydroxy-6-oxohexanoate (12)
Prepared according to general procedure A; Column
chromatography (4:1 hexanes: acetone) followed by PTLC
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The Journal of Organic Chemistry
(7:3 toluene/ EtOAc) afforded the major product as a light
rotamer indicated by asterisk): δ 199.7*, 199.3, 156.3, 152.3,
1
2
3
4
5
6
7
8
yellow oil (43 mg, 64%). Rf = 0.18 (20% acetone in hexane);
152.0, 148.7, 140.2, 137.7, 137.5, 128.2, 127.8, 127.2, 126.7, 123.4,
123.3, 80.0, 79.0, 78.6, 57.8, 49.5*, 36.5, 28.3, 28.2*, 24.8,
24.2*, 23.2, 21.8, 21.4*; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd. for C24H32N2O4Na 435.2254; Found 435.2267.
[α]D27 = +17 (c 2.2, CHCl3); FTIR (KBr film) νmax (cm–1): 3451,
1
2979, 1733, 1683, 1496, 1392, 1251, 1164; H NMR (500 MHz,
CDCl3) mixture of rotamers; δ 7.71 (br s, 1H), 7.66 (d, J = 1.1
Hz, 1H), 7.40–7.27 (m, 4H), 7.25–7.17 (m, 1H), 6.59 (s, 1H),
5.00 (dd, J = 5.1, 2.2 Hz, 1H), 4.63 (d, J = 16.0 Hz, 1H), 4.43 (d,
J = 15.7 Hz, 1H), 4.34 (br s, 0.7H), 3.97 (q, J = 7 Hz, 2H), 3.59
(br s, 0.2H), 2.14–1.85 (m, 3H), 1.71–1.59 (m, 1H), 1.50 (s, 2H),
1.40 (s, 7H), 1.13 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (125 MHz,
CDCl3) Mixture of rotamers (minor rotamer indicated by
asterisk): δ 187.4, 172.7, 156.8, 149.9, 147.8, 139.5, 128.4,
127.9*, 127.3, 127.0, 121.8, 120.0*, 112.8, 80.9, 77.8, 60.4, 60.0,
50.0*, 31.0, 30.5*, 28.4, 22.5*, 21.7, 14.2; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd. for C24H31NO7Na 468.1993; Found
468.2005.
tert-butyl benzyl((2S,3S)-2-hydroxy-5-methyl-1-oxo-1-
(pyrazin-2-yl)hexan-3-yl)carbamate (15)
9
Prepared according to general procedure D with the
following modifications: in place of 1.5 equiv
heteroaromatic aldehyde, 3 equiv of that reagent was used,
in place of an ice batch, a brine ice bath (ca. -15 °C) was
used. The reaction was quenched at 15 minutes.
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
Column chromatography (3:1 hexane/EtOAc) followed by
PTLC (3:1 toluene/acetone) afforded a mixture. The mixture
was washed with cold hexanes and the filtrate was
concentrated in vacuo to afford the major diastereomer as a
light-yellow oil (37 mg, 50%). Rf = 0.24 (25% acetone in
tert-butyl benzyl((2S,3S)-1-((benzyloxy)methoxy)-4-
(furan-2-yl)-3-hydroxy-4-oxobutan-2-yl)carbamate (13)
27
hexane); [α]D = +11 (c 0.9, CHCl3); FTIR (KBr film) νmax
Prepared according to general procedure D with the
following modifications: in place of 1.5 equiv
heteroaromatic aldehyde, 3 equiv of that reagent was used.
1
(cm–1): 3439, 2958, 1690, 1407,1497, 1166, 1052, 1018; H NMR
(500 MHz, CDCl3) mixture of rotamers; δ 9.29 (s, 0.1H), 9.22
(s, 0.9H), 8.86–8.76 (m, 0.9H), 8.74 (s, 0.1H), 8.70 (s, 0.1H),
8.64 (s, 0.9H), 7.41–7.28 (m , 3.1H), 7.25–7.02 (m, 1.9H),
5.47–5.41 (m, 0.1H), 5.38 (dd, J = 9.9, 4.8 Hz, 0.9H), 4.75–
4.34 (m, 3.7H), 3.74 (br s, 0.3H), 1.69–1.60 (m, 1H), 1.42 (s,
3H), 1.33 (s, 6H), 0.71–0.46 (m, 6H); 13C{1H}NMR (125 MHz,
CDCl3) Mixture of rotamers (minor rotamer indicated by
asterisk): δ 200.1*, 199.4, 156.4, 148.6*, 148.3, 146.7, 144.8,
143.3, 139.8, 128.3, 127.7*, 127.3, 126.9, 80.5*, 78.1, 58.1, 50.3*,
36.5, 28.4*, 28.3, 28.2, 24.8, 24.2*, 23.1, 22.7*, 21.9, 21.5*;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd. for C23H31N3O4Na
436.2207; Found 436.2226.
Column chromatography (4:1 hexane/acetone) followed
by PTLC (7:1 toluene/EtOAc) afforded the major product as
a light yellow wax (51 mg, 68%). Rf = 0.24 (20% acetone in
hexane); [α]D27 = +3.1 (c 2.0, CHCl3); FTIR (KBr film) νmax
1
(cm–1): 3442, 2976, 1681, 1497, 1391, 1250, 1165, 1047; H NMR
(500 MHz, CDCl3) mixture of rotamers; δ 7.71 (br s, 1H),
7.65 (d, J = 0.9 Hz, 1H), 7.38–7.27 (m, 5.5H), 7.26–7.16 (m,
4.5H), 6.58 (s, 1H), 5.03 (br s, 1H), 4.72 (m, 2H), 4.52–4.40
(m, 3H), 4.37 (s, 2H), 3.82–3.72 (m, 1H), 3.72–3.63 (m, 0.8H),
3.63–3.54 (m, 0.2 H), 1.54 (s, 2H), 1.39 (s, 7H); 13C{1H}NMR
(125 MHz, CDCl3) Mixture of rotamers (minor rotamer
indicated by asterisk): δ 187.0, 156.6, 150.1, 147.5, 139.6, 137.8,
128.5, 128.4, 128.0, 127.8, 126.9, 126.8, 120.9, 112.6, 94.5, 80.9,
76.4, 69.4, 64.5, 60.1, 50.6*, 28.4; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd. for C28H33NO7Na 518.2149; Found 518.2159.
tert-butyl ((2R,3R)-1-(benzofuran-2-yl)-2-hydroxy-5-
methyl-1-oxohexan-3-yl)(benzyl)carbamate (16)
Prepared according to general procedure D; Column
chromatography (5:1 hexane/Et2O) followed by PTLC (7:1
toluene: EtOAc) afforded the major product as a clear
colourless oil (50 mg, 73%). Rf = 0.18 (25% Et2O in hexanes);
tert-butyl benzyl((2S,3S)-2-hydroxy-5-methyl-1-oxo-1-
(pyridin-2-yl)hexan-3-yl)carbamate (14)
27
[α]D = -30 (c 2.5, CHCl3); FTIR (KBr film) νmax (cm–1):
1
Prepared according to general procedure D:
3455, 2958, 1678, 1550, 1496, 1367, 1165, 1030; H NMR (500
MHz, CDCl3) mixture of rotamers; δ 8.13 (br s, 1H), 7.79 (d,
J = 7.4 Hz, 0.8H), 7.76–7.71 (m, 0.2H), 7.60 (d, J = 8.2 Hz,
1H), 7.55–7.46 (m, 1H), 7.41–7.28 (m, 5H), 7.26–7.19 (m, 1H),
5.16 (s, 1H), 4.72 (d, J = 16.0 Hz, 1H), 6.63 (br s, 0.9H), 4.45
(d, J = 16.0 Hz, 1H), 3.59 (br s, 0.1H), 1.85–1.62 (m, 1H), 1.51
(s, 2H), 1.41 (s, 7H), 1.36–1.24 (s, 1H), 1.10–0.98 (s, 1H), 0.68–
0.48 (m, 6H); 13C{1H}NMR (125 MHz, CDCl3) Mixture of
rotamers (minor rotamer indicated by asterisk): δ 189.9,
157.00, 156.0, 149.7, 139.9, 129.2, 128.37, 127.7*, 127.1, 124.2,
124.2, 123.6*, 117.5, 115.9*, 112.7, 80.7, 79.0, 77.9*, 59.0, 50.1*,
35.07. 28.6*, 28.4, 24.8, 24.1*, 23.14, 21.9, 21.5*; HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd. for C27H33NO5Na 474.2262;
Found 474.2260.
Column chromatography (7:1 hexane/acetone) followed
by PTLC (7:1 toluene: EtOAc) to afford the major product as
a clear colourless oil (1.5 equiv 2-pyridinecarboxaldehyde:
38 mg, 61%; 3 equiv 2-pyridinecarboxaldehyde: 44 mg, 71%).
Rf = 0.17 (17% EtOAc in hexane); [α]D27 = -22 (c 1.2, CHCl3);
FTIR (KBr film) νmax (cm–1): 3470, 2958, 1690, 1584, 1496,
1
1347, 1244, 1166; H NMR (500 MHz, CDCl3) mixture of
rotamers; δ 8.68 (d, J = 3.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H),
7.88 (s, 1H), 7.52 (s, 1H), 7.40–7.26 (m, 3H), 7.26–7.06 (m,
1H), 5.41–5.09 (m, 2H), 4.79–4.49 (m, 2H), 4.49–4.37 (m,
1H), 1.67–1.53 (m, 1H), 1.40–1.32 (m, 4H), 1.29 (s, 6H), 1.19–
0.98 (m, 0.7H), 0.95–0.85 (m, 0.3H), 0.71–0.43 (m, 6H);
13C{1H}NMR (125 MHz, CDCl3) Mixture of rotamers (minor
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The Journal of Organic Chemistry
Page 12 of 13
methyl
4-((2S,3S)-3-(benzyl(tert-
ACKNOWLEDGMENTS
1
2
3
4
5
6
7
8
butoxycarbonyl)amino)-2-hydroxy-5-
methylhexanoyl)benzoate (17)
We thank the Natural Sciences and Engineering Research
Council (NSERC), the Canadian Foundation for Innovation,
and the University of Saskatchewan for financial support.
Prepared according to general procedure C; Column
chromatography (9:1 hexanes/EtOAc) followed by PTLC (4:1
hexane/acetone) afforded the major product as a clear
colourless oil (13 mg, 18%). Rf = 0.20 (10% EtOAc in
hexanes); [α]D27 = -28 (c 1.3, CHCl3); FTIR (KBr film) νmax
9
REFERENCES
(cm–1): 3461, 2957, 1730, 1683, 1496, 1367, 1281, 1164; H NMR
1
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
(500 MHz, CDCl3) mixture of rotamers; δ 8.26–8.12 (m,
3.4H), 8.07–7.96 (m, 0.6H), 7.39–7.27 (m, 4H), 7.24–7.17 (m,
1H), 5.34 (s, 0.7H), 5.29 (s, 0.3H), 7.72 (d, J = 16.1 Hz, 1H),
4.65 (br s, 1H), 4.46 (d, J = 15.8 Hz, 1H), 4.12 (br s, 0.6H),
2.96 (s, 3H), 3.72 (br s, 0.2H), 1.70–1.58 (m, 1H), 1.48 (s, 3H),
1.38 (s, 6H), 1.23–1.12 (m, 1H), 0.83–0.71 (m, 0.7H), 0.69–0.61
(m, 0.3H), 0.57–0.42 (m, 6H); 13C{1H}NMR (125 MHz,
CDCl3) Mixture of rotamers (minor rotamer indicated by
asterisk): δ 200.1, 166.2, 256.8, 140.3, 136.8, 134.8, 130.2, 129.2,
128.8*, 128.3, 127.5*, 126.9, 126.7, 80.5, 78.6, 78.1*, 56.8, 52.7*,
48.9, 39.9, 28.7,*, 28.4, 24.7, 24.0*, 23.1, 21.7, 21.3*; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd. for C27H35NO6Na 492.2357;
Found 492.2351.
(1) For recent reviews on NHC-catalyzed transformations
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the
ACS
Publications
website
at
DOI:
10.1021/acs.joc.xxxxxxx
1H NMR and 13C{1H}NMR spectra of all new
compounds, and HPLC chromatogram for compound
X (PDF).
Crystallographic data for compound X (CIF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: michel.gravel@usask.ca
Notes
The authors declare no competing financial interest.
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1
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