Development of a chiral DMAP catalyst for the dynamic kinetic resolution of azole hemiaminals

Article abstract of DOI:10.1021/acs.joc.6b02955

A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed using late-stage structural modifications of the tert-leucinol-derived chiral subunit of DMAP species.

Full text of DOI:10.1021/acs.joc.6b02955

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Featured Article
Development of a Chiral DMAP Catalyst for the
Dynamic Kinetic Resolution of Azole Hemiaminals
Artis Kinens, Marcis Sejejs, Adam S. Kamlet, David W. Piotrowski, Edwin Vedejs, and Edgars Suna
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02955 • Publication Date (Web): 06 Jan 2017
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Development of a Chiral DMAP Catalyst for the Dynamic Kinetic Resolution of Azole Hemiaminals
†
†§
‡
‡
†
Artis Kinens, Marcis Sejejs, Adam S. Kamlet, David W. Piotrowski,* Edwin Vedejs and Edgars
†
§
Suna*
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†
§
‡
Latvian Institute of Organic Synthesis, Aizkraukles 21, LVꢀ1006, Riga, Latvia
University of Latvia, Department of Chemistry, Jelgavas 1, LVꢀ1004, Riga, Latvia
Worldwide Medicinal Chemistry, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA
edgars@osi.lv, david.w.piotrowski@pfizer.com
H
Me
N
O
O
N
4 variations
N
+
+
Me
H
R2
OH
Me2N
N
O
O
tBu
R1
N
(
t-BuCO)2O
O
HN
chiral DMAP
MTBE
O
(
4 mol%)
CF3
Me
N
R2
F3C
O
N
2
3 variations
R1
N
up to 97:3 er
N
Abstract: A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed
using lateꢀstage structural modifications of the tertꢀleucinolꢀderived chiral subunit of DMAP species.
Keywords: dimethylamino pyridine, nucleophilic catalysis, dynamic kinetic resolution, hemiaminal,
acylation
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Introduction
Chiral N,Nꢀdimethylaminopyridine (DMAP) catalysts have found wide application in asymmetric
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,2
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4,5
synthesis. Following seminal contributions by Vedejs and Fu, a variety of chiral DMAP
6–15
derivatives have been developed for a range of enantioselective acyl transfer reactions.
The
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development of new chiral DMAP catalysts often has relied on an empirical approach involving the
preparation and testing of a large number of structural analogues. For example, the development of a
catalyst for the enantioselective Steglich rearrangement of oxindoles has required the synthesis of a
16,17
small library of chiral DMAP analogues using the multicomponent Ugi reaction.
A
complementary approach to the de novo synthesis of chiral pyridines is structural modification of
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already established DMAP catalysts to enable new synthetic applications. This strategy requires the
pyridine core to possess a chiral subunit amenable to lateꢀstage modifications, preferably by simple
synthetic transformations. Among a variety of chiral DMAP derivatives, the chiral subunit in
AcOLeDMAP catalyst (S,S)–1a is especially suitable for the lateꢀstage structural variations of the
amide and the ester moieties (Figure 1). The AcOLeDMAP was developed for the enantioselective
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Steglich rearrangement of indolyl acetates and carbonates, and subsequently it was also successfully
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employed in the kinetic resolution of secondary alcohols. However, attempts to use the catalyst
(
S,S)–1a in other asymmetric acyl transfer reactions (vide infra) resulted in poor enantiocontrol.
Herein we report that relatively simple structural modifications of the AcOLeDMAP (S,S)–1a allowed
for remarkable improvement of enantioselectivity in the dynamic kinetic resolution (DKR) of azoleꢀ
derived hemiaminals (Figure 1).
O
O
Me
N
(i-PrCO) O
2
Me
N
iPr
N
NH Me
N
H
OH
chiral DMAP
O
N
*
Ph
N
N
N
DKR
Ph
N
N
Ph
N
Me N
OAc
2
Ar
HO
N
Ar
N
N
O
NHBz
N
(S,S)-1a, AcOLeDMAP
(S)-2, Connon's catalyst
Ar = 3,5-(CF ) -C H
3 2
6 3
Figure 1. DKR of azoleꢀderived hemiaminals.
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Chiral hemiaminals are frequently encountered structural motifs in natural products and
pharmaceuticals. For example, a chiral Nꢀacyl hemiaminal subunit was shown to contribute to the
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cytotoxic properties of pederin/mycalamide family of natural products.
In addition, tetrazoleꢀ
derived Oꢀacyl hemiaminals (Figure 1) have recently found increasing application as proꢀdrugs of
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tetrazoles.
hemiaminals, the majority of available synthetic methods provide access only to racemic material.
Only recently, a highly stereoselective method for the synthesis of enantiomerically enriched (up to
8:2 er) tetrazoleꢀderived Oꢀacyl hemiaminals has been developed based on the DKR of equilibrating
Notwithstanding the presence of a stereogenic center in most of the aboveꢀmentioned
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3
1
hemiaminals using Connon’s catalyst (S)–2 (Figure 1). Notably, high regioselectivity in favor of 2,5ꢀ
disubstituted tetrazoles was also observed. When AcOLeDMAP (S,S)–1a was employed as a catalyst
instead of the chiral DMAP (S)–2, the hemiaminal ester of 5ꢀphenyl tetrazole was formed with poor
enantioselectivity (57:43 er). Initial attempts to increase the enantioselectivity of the AcOLeDMAPꢀ
catalyzed DKR by optimizing the reaction conditions resulted only in a slight improvement of
enantiocontrol (68:32 er). This was achieved by 5ꢀfold dilution of the reaction mixture (from [0.4M]
to [0.08M] in tetrazole). It had also become apparent that further increase of the enantiocontrol in the
DKR of azoleꢀderived hemiaminals would require optimization of the chiral subunit of the catalyst
(
S,S)–1a.
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Results and Discussion
The chiral subunit of the catalyst (S,S)–1a comprises a 1,2ꢀamino alcohol core, flanked by a tꢀBu
group and a DMAP moiety (Figure 1). The bulky tꢀBu group helps to stabilize the wellꢀdefined
catalyst geometry with an antiꢀrelationship between the DMAP and tꢀBu moieties and OAc and
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NHBz substituents in the gauche conformation. Hence, modifications of the chiral subunit in (S,S)–
3
2
1a were focused on functionalization of the amine and the alcohol moieties. We envisioned that 1,2ꢀ
aminoalcohol (S,S)–8 could serve as a versatile building block for the synthesis of AcOLeDMAP
analogues. The building block (S,S)–8 was synthesized by addition of 3ꢀLiꢀDMAP (from 3ꢀBrꢀ
3
3
4
DMAP ) to azido aldehyde (S)–6, followed by LiAlH reduction of the azide moiety (36% yield in
two steps). Diastereoselectivity of the addition was moderate (3:1 dr, S,S diastereomer major),
however the diastereomeric azides (S,S)–7 and (R,S)–7 could be easily separated by column
chromatography. The (S,S)ꢀconfiguration of the major diastereomer was confirmed by its conversion
19
to the known AcOLeDMAP (S,S)–1. The azidoaldehyde (S)–6 was synthesized from commercially
34
available (S)ꢀtertꢀleucinol using the diazotransfer reagent 4, followed by oxidation of the azido
alcohol (S)–5 with DessꢀMartin periodinane. With the pure nonracemic 1,2ꢀaminoalcohol (S,S)–8 in
hand, a series of AcOLeDMAP analogues (S,S)–1a-c and (S,S)–1f-s were prepared by initial amide
bond formation, followed by Oꢀacylation (Figure 2). OꢀMe substituted chiral DMAP (S,S)–1d was
synthesized from azide (S,S)–7 in a three step sequence involving Oꢀmethylation, reduction with
LiAlH and Nꢀbenzoylation (27% yield over three steps; Figure 2).
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Figure 2. Synthesis of chiral DMAP catalysts (S,S)–1a-s.
All synthesized chiral DMAP derivatives (S,S)–1a-w were tested as catalysts in the reaction
of 5ꢀphenyltetrazole (10a) with acetaldehyde and isobutyric anhydride under the published DKR
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conditions (Figure 3). First, influence of the catalyst Oꢀsubstituent on enantioselectivity in the DKR
was examined. The Oꢀacetyl moiety ((S,S)–1a) proved to be superior in terms of enantiocontrol in the
DKR compared to other substituents, such as the sterically more demanding Oꢀisobutyryl group
((S,S)–1b) and the less hindered Oꢀformyl moiety ((S,S)–1c). Poor enantioselectivity of the DKR
reaction, catalyzed by the OꢀMe substituted DMAP derivative (S,S)–1d suggests that the presence of
an acyl group in the catalyst is important to achieve good enantiocontrol (Figure 3). Next, the
optimization of the Nꢀacyl substituent was performed. Replacement of the NꢀBz group in (S,S)–1a by
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the sterically hindered Nꢀpivaloyl ((S,S)–1e) and Nꢀdiphenylacetyl ((S,S)–1f) moieties resulted in
decreased enantioselectivities (Figure 3). Importantly, 1ꢀnaphthoyl substituted DMAP ((S,S)–1g)
afforded poor enantiocontrol (55:45 er), whereas attachment of a 2ꢀnaphthoyl group to the nitrogen
atom of the chiral subunit ((S,S)–1h) resulted in improved enantioselectivity of the DKR as compared
to the AcOLeDMAP (75:25 er for (S,S)–1h vs. 68:32 er for (S,S)–1a, Figure 3). The latter result
pointed out that a metaꢀ and/or paraꢀsubstitution pattern of the Nꢀaroyl moiety is beneficial for good
enantiocontrol as opposed to orthoꢀsubstitution. To choose between metaꢀ and paraꢀ substitution, the
corresponding Nꢀbiphenylꢀ4ꢀcarbonyl and Nꢀbiphenylꢀ3ꢀcarbonyl moieties were introduced in the
chiral subunit of the DMAP (catalysts (S,S)–1i and (S,S)–1j, respectively). Superior enantiocontrol in
the DKR using chiral DMAP (S,S)–1j (metaꢀsubstitution, 68:32 er) as compared to (S,S)–1i (paraꢀ
substitution, 55:45 er; see Figure 2) prompted us to rely on the metaꢀsubstitution pattern in all the
subsequent catalyst optimization studies. Indeed, replacement of the metaꢀPh substituent on the Nꢀ
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benzoyl moiety ((S,S)–1j) with a metaꢀCF
enantioselectivity (77:23 er, Figure 3). The most selective chiral DMAP catalyst in the series was
prepared by attachment of two CF groups in the metaꢀpositions of the Nꢀbenzoyl moiety (catalyst
S,S)–1m, 84:16 er, Figure 3). Surprisingly, the corresponding 3,5ꢀdiphenyl substituted benzamide
S,S)–1l was less selective (67:33 er). Likewise, 3,5ꢀdiꢀ(tꢀBu)phenylꢀcontaining catalyst (S,S)–1n was
3
group ((S,S)–1k) resulted in a significant increase of
3
(
(
also inferior to (S,S)–1m suggesting that a steric effect likely is not responsible for the high
enantioselectivity of DKR using the DMAP derivative (S,S)–1m. We also hypothesized that the
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increased acidity of the amide NꢀH bond in (S,S)–1m (pK
two electronꢀwithdrawing CF groups as compared to the AcOLeDMAP (S,S)–1a
pK (DMSO)=23.3) could be responsible for improved enantioselectivity of the DKR. To verify this
a
(DMSO)=20.4) due to the presence of the
3
36
(
a
37
hypothesis, a series of more NꢀH acidic chiral DMAP catalysts, such as thiocarboxamide (S,S)–1t
36
(
pK
a 2
(DMSO)=16.9) and 3,5ꢀdiꢀ(NO )ꢀsubstituted catalyst (S,S)–1o were tested (Figure 3).
Disappointingly, both DMAP derivatives (S,S)–1t and (S,S)–1o afforded inferior enantioselectivities
35
in the DKR as compared to (S,S)–1m. Likewise, benzene sulfonamide (S,S)–1u (pK
a
(DMSO)=16.1)
38
and the corresponding 3,5ꢀdiꢀ(CF
3
)ꢀsubstituted analogue (S,S)–1v were nonꢀselective (52:48 er and
50:50 er, respectively). Possibly, the NꢀH acidity of chiral DMAP derivative (S,S)–1m
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(pK
a
(DMSO)=20.4) is optimal for the high enantiocontrol in the DKR and deviations from the
optimal pK value result in drop of enantioselectivity. Consequently, we looked for other Nꢀbenzoyl
a
a
substituents with NꢀH pK values similar to those of the amide (S,S)–1m. A literature survey of
experimentally determined acidity values in DMSO helped to estimate that equilibrium acidity of 3,5ꢀ
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dihalobenzoic acid amides should differ by only ca. 1 pK (DMSO) unit from that of 3,5ꢀdiꢀ(CF )ꢀ
a
3
3
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benzoic acid amides. Hence a series of 3,5ꢀdihalobenzoyl substituted DMAP derivatives (S,S)–1p-s
was synthesized and tested in the DKR reaction (Figure 3). Gratifyingly, 3,5ꢀdibromoꢀbenzoyl DMAP
derivative (S,S)–1p turned out to be the second most selective catalyst (80:20 er) among all tested
chiral DMAP derivatives. Inferior enantiocontrol was observed using 3,5ꢀdichloroꢀ and 3,5ꢀdiiodoꢀ
substituted catalysts ((S,S)–1r and (S,S)–1s, respectively), and 3,5ꢀdifluorobenzoylꢀDMAP (S,S)–1q
was the least selective catalyst in the series (59:41 er). Evidently, the observed enantioselectivity
40,41
trends in the DKR cannot be explained only by the NꢀH acidity values.
Finally, thiourea (S,S)–
42
1
w, possessing two relatively acidic NꢀH bonds, was also found to be less selective (66:34 er) than
the best DMAP derivative (S,S)–1m.
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O
(i-PrCO) O
(S,S)-1a-w
O
2
Me
Me
N
N
NH Me
N
H
OH
(4 mol%)
O
N
N
*
Ph
N
N
N
Et N, Et O
Ph
3
2
N
N
Ph
N
1
0a
11a
12a
R1
Me N
O
0
1
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2
O
O
O
Me
Me
Me
H
HN
O
N
Me
Ph
a, 68:32 er
b, 59:41 er
c, 64:36 er d, 51:49 er
(S,S)-1a-d
O
Me N
OAc
2
O
O
O
HN
S,S)-1e-w
Ph
Ph
N
R
(
e, 52:48 er
f, 54:46 er
g, 55:45 er
h, 75:25 er
O
O
O
l: R=Ph, 67:33 er
m: R=CF , 84:16 er
n: R=t-Bu, 67:33 er
o: R=NO , 62:38 er
3
2
R
R
R
p: R=Br, 80:20 er
Ph
q: R=F,
r: R=Cl, 72:28 er
s: R=I,
73:27 er
59:41 er
i, 55:45 er
j: R=Ph, 68:32 er
k: R=CF , 77:23 er
3
S
O
S
S
O
HN
CF3
R
R
CF3
w, 66:34 er
t, 66:34 er
u: R=H, 52:48 er
v: R=CF , 50:50 er
3
Figure 3. Chiral DMAP catalysts (S,S)ꢀ1a-w.
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With the chiral DMAP derivative (S,S)–1m as the most selective catalyst in hand,
optimization of the DKR conditions was addressed (Table 1). Incomplete conversion of the starting
tetrazole 10 was observed in relatively polar solvents such as THF, EtOAc, CH
Furthermore, enantioselectivity of the DKR in these solvents was lower than that in Et
vs. 1, Table 1). In contrast, enantioselectivity of the DKR in nonꢀpolar toluene was equal to that in
Et O (entry 6 vs. 1), and in MeOtBu the enantiocontrol of DKR was even higher (entry 7).
Importantly, the DKR in MeOtBu does not require addition of an external base such as NEt
2
Cl
2
and MeCN.
2
O (entries 2ꢀ5
10
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2
3
(entry
). Apparently, the stoichiometric base in the DKR reaction is an isobutyrate counter anion of the
Nꢀacylpyridinium ion pair that is generated in the reaction of isobutyric anhydride with the chiral
4
3a
8
43b
36
a
DMAP catalyst (S,S)–1m. In fact, tetrazole (pK (DMSO)=8.2) is more acidic than the isobutyric
44
acid (pK
a
(DMSO)=12.6 for acetic acid), so tetrazole deprotonation by the isobutyrate counter anion
a
should be thermodynamically favored. Furthermore, isobutyric acid is less acidic (pK (MeCN)=23.5)
45
than the conjugated acid of the DMAP (pK
a
(MeCN)=18.0). This also implies that isobutyrate
counter anion is the strongest base in the DKR and that most of the chiral DMAP catalyst (S,S)–1m
apparently is not protonated under the DKR conditions. Indeed, addition of AcOH (1.1 equiv) to the
reaction mixture neither influenced the rate nor the enantioselectivity of the DKR (entry 9). Finally,
o
changing the solvent to a 1:1 mixture of MeOtBu and cyclohexane and performing the DKR at 0 C
allowed for an increase of enantioselectivity up to 97:3 er (entry 10).
At this point, a brief optimization of the best chiral DMAP catalyst (S,S)–1m structure was
attempted. Accordingly, the CF
by the sterically more demanding and more electron withdrawing pentafluorothio groups. The
pentafluorothio substituent has recently been successfully employed as an alternative to the CF group
3
groups in the 3,3’ꢀpositions of the Nꢀbenzoyl moiety were replaced
4
6
3
4
7,48
in the design of chiral Brønsted acids.
The 3,5ꢀbis(pentafluorothio)phenyl substituted chiral
DMAP derivative (S,S)–1x turned out to be equally selective as the catalyst (S,S)–1m (entry 11),
whereas the corresponding monoꢀSF analogue (S,S)–1y afforded inferior enantioselectivity in the
5
DKR (entry 12). Hence, chiral DMAP derivative (S,S)–1m and the reaction conditions from entry 10
(Table 1) were employed to examine the scope of the DKR.
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1
2
2
2
2
2
2
2
2
2
2
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4
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5
5
5
5
5
6
Table 1. Optimization of the DKR conditions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
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9
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1
2
3
4
5
6
7
8
9
0
a
entry variation from the “standard” conditions
conv. (%)
>99%
86%
58%
64%
er
1
2
3
4
5
6
7
8
9
1
None
THF instead of Et O
2
84:16
63:37
66:34
68:32
55:45
83:17
90:10
94:6
EtOAc instead of Et
CH Cl instead of Et
MeCN instead of Et
Toluene instead of Et
MeOtBu instead of Et
without Et N, MeOtBu instead of Et
AcOH instead of Et N; MeOtBu instead of Et
without Et
of Et O, 0 C
2
O
2
2
2
O
2
O
62%
2
O
>99%
>99%
>99%
>99%
2
O
3
2
O
3
2
O
94:6
97:3
0
3
oN, 1:1 MeOtBu:cyclohexane instead >99%
2
11
catalyst (S,S)ꢀ1x, conditions from entry 10
>99%
>99%
97:3
88:12
1
2
catalyst (S,S)ꢀ1y, conditions from entry 10
a
1
Conversion determined by HꢀNMR spectroscopy.
The threeꢀcomponent reaction between acetaldehyde, isobutyric anhydride and 5ꢀ
phenyltetrazole (10a) as well as 5ꢀaryltetrazoles possessing a paraꢀsubstituted phenyl moiety (10bꢀd)
afforded Oꢀacyl hemiaminals as the sole 2,5ꢀregioisomers (entries 1ꢀ4, Table 2). Importantly, there
was no evidence of formation of any regioisomeric 1,5ꢀadducts for these substrates. In contrast, the
presence of orthoꢀsubstituents on the phenyl moiety of the 5ꢀaryltetrazoles (10f,g) resulted in the
formation of 1,5ꢀadducts as minor products along with the major 2,5ꢀregioisomers (entries 6,7).
Likewise, traces of the 1,5ꢀadduct were observed for 2ꢀpyridyl substituted tetrazole 10e (entry 5).
Possibly, greater steric demand of the orthoꢀsubstitutent twists the aryl moiety out of conjugation with
the tetrazole ring making its 1ꢀposition more accessible. Indeed, increased amounts of the 1,5ꢀadducts
were formed using less sterically demanding 5ꢀiPr and 5ꢀMe substituted tetrazoles 10h,i (entries 8,9).
Furthermore, the 1,5ꢀhemiaminal 13j was the major product in the DKR of 5ꢀunsubstituted tetrazole
10j (entry 10). These results support the influence of steric effects on the ratio of 2,5ꢀ vs. 1,5ꢀ
regioisomers. Steric effects can also be invoked to explain the completely regioselective formation of
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hemiaminal esters of 2ꢀphenylꢀ and 4ꢀphenyl imidazoles 10k,l, 3ꢀphenyl pyrazole 10m, 3ꢀphenyl
1,2,4ꢀtriazole 10n and theophylline 10q (Figure 4). As anticipated, a mixture of 2,4ꢀ and 1,4ꢀadducts
(9:1 ratio, respectively) was observed for the less sterically biased 4ꢀphenylꢀ2Hꢀ1,2,3ꢀtriazole (10o)
(Figure 4). It should be noted that the 1,5ꢀ and 2,5ꢀsubstituted azole Oꢀacyl hemiaminals could be
easily separated by flash chromatography on silica gel to afford the individual regioisomers.
Table 2. Scope of tetrazoles in the DKR.
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
a
entry
1
R
12:13
for 12
88%, 97:3 er
for 13
ꢀ
100:0
a
b
2
3
4
100:0
100:0
100:0
47%, 95:5 er
72%, 92:8 er
85%, 96:4 er
ꢀ
ꢀ
ꢀ
b
c
b
d
5
6
98:2
97:3
92%, 97:3 er nd
97%, 96:4 er nd
e
f
7
88:12
84%, 96:4 er 8%, 85:15 er
g
8
9
iPr, h
Me, i
H, j
89:11
73:27
41:59
77%, 96:4 er 6%, 87:13 er
65%, 97:3 er 25%, 85:15 er
10
39%, 91:9 er 57%, 58:42 er
a
1
b
Ratio determined by HꢀNMR for crude reaction mixture. in MTBE at rt
Importantly, the 2,5ꢀregioisomers of the tetrazole Oꢀacyl hemiaminals 12aꢀj were formed
with high enantioselectivities (Table 2). In contrast, formation of the regioisomeric 1,5ꢀadducts 13gꢀj
proceeded with inferior enantiocontrol (entries 7ꢀ10, Table 2). A variety of azoleꢀderived hemiaminals
11kꢀo also underwent highly enantioselective DKR to afford the corresponding hemiaminal esters
12kꢀo with high enantiomeric purity (Figure 4). However, a decrease of enantioselectivity was
observed in the DKR of benzimidazole 10p and theophylline 10q (Figure 4). The newly created
stereogenic center in products 12a and 12t (see Table 3 below) was assigned an absolute
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
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3
3
3
4
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4
4
4
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5
5
5
5
5
5
5
5
6
configuration of R based on the comparison of chiral stationary phase HPLC data with that of the
31
enantiomeric (S)–12a,t, obtained using Connon’s catalyst. Furthermore, the R absolute configuration
was also determined for the crystalline hemiaminal (R)–12x (see Table 4 below) by Xꢀray
crystallographic analysis (see Supporting Information). Hence, the R absolute configuration was
assigned for all hemiaminals 12a-j by analogy with (R)–12a,t and (R)–12x.
Figure 4. Scope of azoles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
in MTBE at rt. Accompanied by the corresponding 1,4ꢀdisubstituted triazole 13o, 8%, 4:1 er.
The acylation reagent in the DKR could be varied from isobutyric anhydride to other aliphatic
carboxylic anhydrides such as propionic and phenyl acetic anhydrides. However, pivalic anhydride is
poorly reactive as the acylating agent under standard DKR conditions (<5% yield after 4 h). This
allowed for a mixed anhydride to be generated in situ from the corresponding carboxylic acid and
2
Piv O (Table 3). The new conditions avoid preparation of the carboxylic anhydrides from the
corresponding acids prior the DKR and, hence, improve the versatility of the modular threeꢀ
component reaction between azole, aldehyde and carboxylic acid. Importantly, enantioselectivity of
the DKR with preꢀformed isobutyric anhydride and with the in situ generated mixed anhydride using
pivalic acid was almost identical (entry 1, Table 2 and entry 1, Table 3). Propionic acid yielded
hemiaminal ester (R)–12r with high enantioselectivity (entry 2, Table 3), however decreased levels of
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enantiocontrol were observed using other carboxylic acids such as cyclopentane carboxylic acid
(entry 3), phenyl acetic acid (entry 4), NꢀBoc glycine (entry 5) and NꢀBoc sarcosine (entry 6).
a
Table 3. DKR with the in situ generated mixed anhydrides.
O
(
t-BuCO) O
(S,S)-1m
2
Me
N
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
33
34
35
36
37
38
39
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60
O
O
(4 mol%)
N
10a
+
+
RCO2H
Me
H
MTBE, rt
N
N
(R)-12a,r-v
entry RCO
1
2
H
product
(R)–12a
er
yield, %
95:5 84
2
3
(R)–12r
(R)–12s
95:5 87
90:10 84
4
5
(R)–12t
83:17 95
(R)–12u
(R)–12v
78:22 73
85:15 79
6
a
Reactions were conducted at 0.08 M tetrazole 10a (1.0 equiv), acetaldehyde (1.1 equiv), carboxylic acid (1.3
equiv) and Piv O (1.3 equiv)
2
A purification method to access individual enantiomers was required and we envisioned that
the enantiomeric purity of the enantioenriched hemiaminal esters could be increased by
crystallization. The purification by crystallization turned out to be a challenging approach because of
the poor crystallinity of the hemiaminals (R)–12. After much experimentation it was found that the
crystalline products can be obtained using nitrophenyl tetrazole 10c in the DKR (Table 4).
Gratifyingly, a single recrystallization of the crude solid hemiaminal esters (R)–12w-z resulted in
considerable improvement of the enantiomeric ratio (up to 99:1; see Table 4). Notably, the major
enantiomers of hemiaminals (R)–12x-z turned out to be more soluble than the minor enantiomers
(
entries 2ꢀ4, Table 4). Hence, the recrystallization afforded almost racemic crystalline material, while
enantiomerically pure products (R)–12x-z were recovered from the filtrate. In contrast, the major
enantiomer of (R)–12w was obtained from a solid crop after the recrystallization (Table 4).
Table 4. Recrystallization of hemiaminal esters (R)–12w-z.
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1
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2
2
2
2
2
2
2
2
2
2
3
3
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5
5
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6
O
(
t-BuCO) O
(S,S)-1m
(4 mol%)
Me
N
2
R
N NH
N
N
O
O
N
+
+
RCO H
2
Me
H
N
O N
MTBE, rt
2
N
O N
2
10c
(R)-12w-z
a
b
c
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry RCO
1
H
product er
12w
er (cryst)
yield, %
2
d
90:10 99:1
77
e
2
3
12x
90:10 99:1
40
e
e
12y
12z
87:13 96:4
61
53
4
79:21 97:3
a
b
c
d
Crude product. After single recrystallization. Enantiomerically enriched product. Solid crop after
e
recrystallization. Filtrate after recrystallization
Conclusions
Modular design of the established AcOLeDMAP catalyst (S,S)–1a is wellꢀsuited for the
optimization of its structure for various stereoselective applications. In this work we have
demonstrated that relatively simple modifications of the chiral subunit in the catalyst (S,S)–1a resulted
in the development of a new chiral DMAP analogue (S,S)–1m capable of catalyzing the DKR of
azoleꢀderived hemiaminals with remarkably improved enantiocontrol as compared to the parent (S,S)–
1
a (97:3 er vs. 57:43 er, respectively, for hemiaminal 11a). A wide range of azoles such as tetrazoles,
1
,2,3ꢀ and 1,2,4ꢀtriazoles, imidazoles, pyrazoles, benzimidazole and even theophylline can be
converted into chiral hemiaminal esters with good to excellent enantioselectivities, high
regioselectivity and chemical yields. The chiral DMAPꢀcatalyzed three component DKR reaction
between azole, acetaldehyde and carboxylic acid anhydride does not require addition of external base.
Furthermore, the carboxylic acid anhydride can be conveniently generated in situ from the carboxylic
acid and pivalic anhydride. The latter finding allows for the carboxylic acid to be used directly in the
DKR and, hence, improves versatility of the modular threeꢀcomponent DKR reaction.
With a oneꢀstep method for the preparation of enantiomerically pure hemiaminal esters from
carboxylic acids in hand, synthetic applications of these chiral species was also briefly explored. We
hypothesized that the stereogenic center in the hemiaminal moiety could provide diastereocontrol in
reactions of the corresponding lithium enolates with a suitable electrophile. Indeed, deprotonation of
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o
enantiopure (R)–12w with LiHMDS at ꢀ100 C, followed by the addition of Nꢀ
fluorobenzenesulfonimide (NFSI) and TMSꢀCl afforded the αꢀfluorinated product (R,S)–14 with
excellent 94:6 diastereoselectivity (Figure 5). The relative stereochemistry of the newly created
stereogenic center was assigned as S based on Xꢀray crystallographic analysis of (R,S)–14 (see
Supporting Information). Importantly, the hemiaminal moiety can be readily hydrolyzed to the
carboxylic acid (S)–14 under mild conditions (pH~10) or transformed into ethyl ester (S)–15 (Figure
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
5
). Notably, both transformations proceeded without racemization of the newly created stereogenic
center. The relatively mild cleavage conditions of the hemiaminalꢀbased chiral auxiliary is an
important advantage compared to the widely used alternative auxiliaries such as Evans chiral
49,50
51
oxazolidinones
or Myers pseudoephedrine. Studies to explore the application of the hemiaminal
ester chiral auxiliary in diastereoselective synthesis are currently ongoing in our laboratories.
Figure 5. Application of hemiaminal ester as an easily removable chiral auxiliary for αꢀ
functionalization of carboxylic acids.
Experimental Section
General Information
Unless otherwise noted, all chemicals were used as obtained from commercial sources and all
reactions were performed under argon atmosphere. Analytical thinꢀlayer chromatography (TLC) was
performed on precoated silica gel Fꢀ254 plates. Nuclear magnetic resonance spectra were recorded on
1
13
1
NMR spectrometers at the following frequencies: H, 400 or 300 MHz; C{ H}, 101 or 75 MHz.
Chemical shifts are reported in parts per million (ppm) relative to TMS or with the residual solvent
peak as an internal reference. Infrared (IR) spectra were recorded with KBr pellet, and wavenumbers
−1
were given in cm . High resolution mass spectra (HRMS) were recorded on an TOF MS instrument
using the ESI or the APCI techniques.
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of 1,2-aminoalcohol (S,S)–8
(S)-2-Azido-3,3-dimethylbutan-1-ol ((S)–5). K
CuSO (0.01 g, 0.000063 mmol, 0.01 equiv) were added to a solution of (S)ꢀ2ꢀaminoꢀ3,3ꢀ
dimethylbutanꢀ1ꢀol ((S)-3) (0.74 g, 6.30 mmol, 1 equiv) in MeOH (15 mL). The reaction mixture was
2
3
CO (1.31 g, 9.50 mmol, 1.5 equiv) and anhydrous
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
52
cooled to 0 °C (crushed ice) and solution of 1Hꢀimidazoleꢀ1ꢀsulfonyl azide (4) (1.09 g, 6.30 mmol, 1
equiv) in EtOAc (6.30 mL) was added. The brown suspension was stirred for 60 h under argon
1
atmosphere and reaction progress was monitored by HꢀNMR analysis. Solids were filtered and
filtrate was concentrated under reduced pressure. Brown oily residue was purified by column
chromatography on silica gel (120 g silica gel) using gradient elution from 0% EtOAc in hexanes to
25% EtOAc in hexanes to afford (S)ꢀ5 as a colorless oil (510 mg, 57% yield); analytical TLC on silica
ꢀ1
1
f 3 3
gel, 2:5 EtOAc/hexanes, R =0.45. IR (KBr, cm ) 3350 (OH), 2099 (N ); H NMR (400 MHz, CDCl ,
ppm) δ 3.85 (1H, dd, J=11.3, 2.7 Hz), 3.54 (1H, dd, J=11.3, 9.6 Hz), 3.24 (1H, dd, J=9.6, 2.7 Hz),
13
2
.27ꢀ2.10 (1H, br s), 0.94 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 75.2, 62.7, 34.8, 26.8. GC–
+
+
+
MS m/z (% relative intensity, ion): 143.0 (0.3, M ), 70.1 (19.7, C
2
H
4
N
3
), 57.1 (100.0, tꢀBu ). HRMSꢀ
–
20
APCI (m/z) calcd for C H N O [M–H] 143.1064, found 143.1063. Optical rotation [α] +5.8 (c
6
13
3
D
2 2
0.14, CH Cl ).
(
S)-2-Azido-3,3-dimethylbutanal ((S)–6).DessꢀMartin periodinane (1.42 g, 3.352 mmol, 1.2 equiv)
was added portion wise to a solution of (S)ꢀ2ꢀazidoꢀ3,3ꢀdimethylbutanꢀ1ꢀol ((S)ꢀ5) (400 mg, 2.79
mmol, 1 equiv) in CH Cl (10 mL) at 0 °C. After 10 min the suspension was warmed to room
temperature and stirred for 2 h. The white suspension was diluted with Et O (80 mL) and poured into
solution of Na S O ·5H O (6.93 g, 27.9 mmol, 10 equiv) in saturated NaHCO solution (80 mL). The
2
2
2
2
2
3
2
3
resulting twoꢀphase system was stirred vigorously until organic layer became clear. Layers were
separated and the organic layer was washed with saturated NaHCO solution (3x80 mL) and brine (80
mL). Organic extract was dried over Na SO , filtered and carefully concentrated (rotary evaporator,
3
2
4
°
4
00 mbar) keeping water bath temperature at 20 C to avoid evaporation of product (S)ꢀ6. The crude
1
residue (colorless oil) was used immediately in the next step without purification. H NMR (400
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1
3
MHz, CDCl
3
, ppm) δ 9.69 (1H, d, J=2.0 Hz), 3.61 (1H, d, J=2.0 Hz), 1.07 (9H, s). C NMR (100.6
MHz, CDCl , ppm) δ 198.6, 77.4, 36.0, 26.7. GC–MS m/z (% relative intensity, ion): 141.0 (0.02,
3
+
+
+
20
M ), 84.1 (11.7, M ꢀtꢀBu), 57.1 (100.0, tꢀBu ). Optical rotation [α]
D 2 2
–12.5 (c 0.83, CH Cl ).
(
1S,2S)-2-Azido-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutan-1-ol ((S,S)–7). tꢀBuLi
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
(
1.79 M solution in pentane, 7.9 mL, 14.13 mmol, 2.1 equiv) was added to the anhydrous THF (10
3
3
mL) at –78 °C under argon atmosphere. A solution of 3ꢀbromoꢀN,Nꢀdimethylpyridinꢀ4ꢀamine (17)
1.49 g, 7.40 mmol, 1.1 equiv) in anhydrous THF (10 mL) was added dropwise at a rate to keep
(
temperature below ꢀ75 °C. After stirring for 30 minutes at –78 °C, a solution of crude (S)ꢀ2ꢀazidoꢀ3,3ꢀ
dimethylbutanal ((S)–6) from above (950 mg, 6.73 mmol, 1.0 equiv) in anhydrous THF (4 mL) was
gradually added to the reaction mixture (light orange solution) keeping temperature below ꢀ75 °C. The
light orange solution was stirred at ꢀ78 °C for 30 minutes whereupon it was quenched by water (5 mL)
1
and warmed to room temperature. H NMR of the aliquot from the reaction mixture showed formation
of azidoalcohol 7 as a 3:1 mixture of diastereomers. Volatiles were removed under reduced pressure,
light brown oil residue was dissolved in EtOAc (50 mL), washed with water (30 mL), brine (30 mL)
and dried on Na
2 4
SO . Column chromatography (30 g of RPꢀ18 silica gel) using gradient elution from
0
% MeCN in water containing 0.1% AcOH to 60% MeCN in water containing 0.1% AcOH afforded,
major (S,S)ꢀ7 isomer as a pale yellow amorphous solid (728 mg, 41% yield); analytical TLC on silica
1
gel, 1:9 MeOH/CHCl
3
, R
f
=0.53. H NMR (400 MHz, CDCl
3
, ppm) δ 8.58 (1H, s), 8.44 (1H, d, J=5.5
Hz), 6.89 (1H, d, J=5.5 Hz), 5.42ꢀ4.15 (1H, br s), 5.27 (1H, d, J=2.9 Hz), 3.35 (1H, d, J=2.9 Hz), 2.80
13
(
6H, s, J=6.0 Hz), 1.04 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 159.0, 149.3, 148.7, 131.3,
+
1
14.5, 77.5, 68.9, 44.3, 36.7, 27.5. HRMSꢀESI (m/z) calcd for C13
H
22
N
5
O [M+H] 264.1824, found
20
2
64.1828. Optical rotation [α] –48.1 (c 0.19, CH Cl ).
D
2
2
(
(
(
1S,2S)-2-Amino-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutan-1-ol ((S,S)–8). LiAlH
4
1.0 M solution in THF, 0.23 mL, 0.23 mmol, 1.2 equiv) was added dropwise to a cooled solution
0 °C) of (1S,2S)ꢀ2ꢀazidoꢀ1ꢀ(4ꢀdimethylaminopyridinꢀ3ꢀyl)ꢀ3,3ꢀdimethylꢀbutanꢀ1ꢀol ((S,S)ꢀ7) (50 mg,
0.19 mmol, 1 equiv) in anhydrous THF (3 mL). After stirring for 30 min, the white suspension was
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warmed to room temperature. After 1 h of stirring at room temperature UPLCꢀMS analysis of the
reaction mixture showed full conversion. The reaction mixture was cooled to 0 °C and quenched by
sequential (within intervals of 10 minutes) addition of water (10 µL), 4 M aqueous NaOH solution (20
µL) and more water (30 µL). Ten minutes after addition of final amount of water, the white
suspension was filtered through a Celite pad. The filter cake was washed with EtOAc (30 mL). The
0
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6
7
8
9
0
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8
9
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5
6
7
8
9
0
filtrate was evaporated to dryness yielding 40 mg (88%) of aminoalcohol (S,S)–8 as yellow oil, which
1
was used in subsequent step without purification. H NMR (400 MHz, CDCl
3
, ppm) δ 8.55 (1H, s),
8.35 (1H, d, J=5.5 Hz), 6.88 (1H, d, J=5.5 Hz), 5.01 (1H, d, J=3.7 Hz), 2.80 (6H, s), 2.68 (1H, d,
13
J=3.7 Hz), 0.92 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 158.7, 149.6, 149.3, 133.4, 113.8,
+
66.6, 64.1, 44.3, 34.5, 27.2. HRMSꢀESI (m/z) calcd for C13
H
24
N
3
O [M+H] 238.1925, found
20
238.1919. Optical rotation [α]
D 2 2
+64.9 (c 0.07, CH Cl ).
General procedure A for synthesis of chiral DMAP catalysts (S,S)-1a–c,f–s,x,y (see Figure 2).
An ovenꢀdried flask was cooled under stream of argon and then charged with corresponding acid (1.1
equiv), 1ꢀ[bis(dimethylamino)methylene]ꢀ1Hꢀ1,2,3ꢀtriazolo[4,5ꢀb]pyridiniumꢀ3ꢀoxide
hexafluorophosphate (HATU) (1.2 equiv) and anhydrous CH Cl (0.1 mmol of acid/1 mL of solvent).
2
2
After stirring at room temperature for 15 minutes (1S,2S)ꢀ2ꢀaminoꢀ1ꢀ(4ꢀ(dimethylamino)pyridinꢀ3ꢀ
yl)ꢀ3,3ꢀdimethylbutanꢀ1ꢀol ((S,S)–8) (0.1 M solution in anhydrous CH Cl ; 1 equiv) was added and
2
2
stirring was continued for another 15 minutes. Then the colorless reaction mixture was cooled to 0 °C
and N,Nꢀdiisopropylethylamine (3 equiv) was added. The pale yellow solution was stirred at room
temperature and reaction progress was monitored by UPLCꢀMS analysis. Acetic anhydride (2 equiv)
was added upon complete conversion of (S,S)–8 and stirring at room temperature was continued
(UPLCꢀMS control of the reaction progress). All volatiles were removed under reduced pressure and
pure catalyst was obtained by column chromatography (12 g of RPꢀ18 silica gel) using 40% MeCN in
water containing 0.1% AcOH as a mobile phase.
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(1S,2S)-2-Benzamido-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate ((S,S)–1a).
The title compound was obtained as light yellow amorphous solid (14 mg, 82%) by following general
procedure A from benzoic acid (6 mg, 0.049 mmol, 1.1 equiv), HATU (20.4 mg, 0.054 mmol, 1.2
equiv), 1,2ꢀamino alcohol (S,S)–8 (10.6 mg, 0.045 mmol, 1 equiv), N,Nꢀdiisopropylethylamine (22
10
11
12
13
14
15
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17
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22
23
24
25
26
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29
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
µL, 0.134 mmol, 3 equiv) and acetic anhydride (8.5 µL, 0.09 mmol, 2 equiv). H NMR spectra was
1
9
identical to that from the literature.
(
1S,2S)-2-benzamido-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl isobutyrate ((S,S)–
b). The title compound was obtained as pale yellow amorphous solid (20 mg, 47%) by following
1
general procedure A benzoic acid (14.2 mg, 0.127 mmol, 1.1 equiv), HATU (53 mg, 0.139 mmol, 1.2
equiv), 1,2ꢀamino alcohol (S,S)–8 (27.5 mg, 0.116 mmol,1 equiv), N,Nꢀdiisopropylethylamine (57
1
µL, 0.348 mmol, 3 equiv) and isobutyric anhydride (38 µL, 0.232 mmol, 2 equiv). H NMR (400
MHz, CDCl
3
, ppm) δ 8.14 (1H, s), 7.79 (1H, d, J=7.0 Hz), 7.60 (2H, dd, J=6.7, 1.5 Hz), 7.50ꢀ7.36
(
3H, m), 6.85 (1H, d, J=7.0 Hz), 6.59 (1H, d, J=1.4 Hz), 6.41 (1H, d, J=10.5 Hz), 4.12 (1H, dd,
J=10.5, 1.4 Hz), 3.33 (6H, s), 2.85 (1H, hept, J=7.0 Hz), 1.26 (3H, d, J=7.0 Hz), 1.22 (3H, d, J=7.0
13
Hz), 1.08 (9H, s). C NMR (100.6 MHz, CDCl , ppm) δ 176.8, 168.3, 160, 139.5, 138.8, 133.3,
3
1
32.2, 129.2, 126.8, 124.1, 111.9, 77.2, 69.4, 57.8, 43.5, 35.7, 33.9, 27.6, 19, 18.9. HRMSꢀESI (m/z)
+
20
calcd for C24
CH Cl ).
34 3 3 D
H N O [M+H] 412.2600, found 412.2595. Optical rotation [α] –27.2 (c 0.18,
2
2
(
1S,2S)-2-Benzamido-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl formate ((S,S)–1c).
The title compound was obtained as yellow amorphous solid (17 mg, 39%) by following general
procedure A from benzoic acid (14.2 mg, 0.127 mmol, 1.1 equiv), HATU (53 mg, 0.139 mmol, 1.2
equiv), 1,2ꢀamino alcohol (S,S)–8 (27.5 mg, 0.116 mmol,1 equiv) and N,Nꢀdiisopropylethylamine (57
µL, 0.348 mmol, 3 equiv). Formylation of intermediate alcohol was achieved with mixture of acetic
anhydride (22 µL, 0.232 mmol, 2 equiv) and formic acid (9 µL, 0.232 mmol, 2 equiv) that was stirred
1
at 60 °C for 1h before the use. H NMR (400 MHz, CDCl
3
, ppm) δ 8.22 (1H, s), 8.09 (1H, s), 7.69
(1H, d, J=7.1 Hz), 7.59 (2H, d, J=7.2 Hz), 7.49ꢀ7.32 (3H, m), 6.81 (1H, d, J=7.1 Hz), 6.66 (1H, s),
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5
6
1
3
6.61 (1H, d, J=10.5 Hz), 4.09 (1H, d, J=10.5 Hz), 3.30 (6H, s), 1.08 (9H, s). C NMR (100.6 MHz,
CDCl , ppm) δ 168.5, 160.6, 159.9, 139.1, 138.4, 133.1, 132.2, 129.1, 126.9, 122.7, 111.6, 68.7, 57.8,
3
+
43.4, 35.8, 27.5. HRMSꢀESI (m/z) calcd for C21
H
28
3
N O
3
[M+H] 370.2131, found 370.2122. Optical
20
rotation [α]
D 2 2
–21.6 (c 1.14, CH Cl ).
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3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
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2
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8
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9
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(
1S,2S)-1-(4-(dimethylamino)pyridin-3-yl)-2-(2,2-diphenylacetamido)-3,3-dimethylbutyl acetate
(S,S)–1f). The title compound was obtained as white amorphous solid (18 mg, 30%) by following
(
general procedure A from 2,2ꢀdiphenylacetic acid (30 mg, 0.139 mmol, 1.1 equiv), HATU (59 mg,
.152 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (30 mg, 0.127 mmol, 1 equiv), N,Nꢀ
0
diisopropylethylamine (62 µL, 0.380 mmol, 3 equiv) and acetic anhydride (29 µL, 0.253 mmol, 2
1
equiv). H NMR (400 MHz, CDCl
3
, ppm) δ 8.39 (1H, d, J=5.6 Hz), 8.08 (1H, s), 7.42ꢀ7.33 (2H, m),
7
.33ꢀ7.26 (3H, m), 7.25ꢀ7.20 (1H, m), 7.20ꢀ7.13 (4H, m), 6.92 (1H, d, J=5.6 Hz), 6.37 (1H, d, J=1.4
Hz), 5.92 (1H, d, J=10.6 Hz), 4.86 (1H, s), 4.12 (1H, dd, J=10.6, 1.4 Hz), 2.83 (6H, s), 1.95 (3H, s),
13
0
.91 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 171.3, 169.5, 158.6, 151.1, 149.9, 147.0, 140.0,
1
39.5, 129.4, 129.2, 129.0, 128.8, 127.5, 127.2, 70.0, 58.4, 43.8, 35.3, 27.2, 21.0. HRMSꢀESI (m/z)
+
20
calcd for C H N O [M+H] 474.2757, found 474.2763. Optical rotation [α] –19.3 (c 0.90,
2
9
36
3
3
D
2 2
CH Cl ).
(
1S,2S)-2-(1-Naphthamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate ((S,S)–
g). The title compound was obtained as pale yellow amorphous solid (6 mg, 9%) by following
1
general procedure A from 1ꢀnaphthoic acid (29 mg, 0.169 mmol, 1.1 equiv), HATU (72 mg, 0.185
mmol, 1.2 equiv), 1,2ꢀamino alohol (S,S)–8 (36 mg, 0.154 mmol, 1 equiv), N,Nꢀ
diisopropylethylamine (75 µL, 0.461 mmol, 3 equiv) and acetic anhydride (29 µL, 0.308 mmol, 2
1
equiv). H NMR (400 MHz, CDCl
3
, ppm) δ 8.43 (1H, d, J=5.4 Hz), 8.33 (1H, s), 7.89 (1H, dd, J=7.1,
2.4 Hz), 7.87ꢀ7.78 (2H, m), 7.56ꢀ7.43 (4H, m), 7.00 (1H, d, J=5.4 Hz), 6.62 (1H, d, J=1.4 Hz), 6.26
13
(1H, d, J=10.8 Hz), 4.55 (1H, dd, J=10.8, 1.4 Hz), 2.94 (6H, s), 2.16 (3H, s), 1.14 (9H, s). C NMR
(100.6 MHz, CDCl
3
, ppm) δ 169.8, 169.3, 157.7, 135.0, 133.7, 130.5, 130.1, 128.2, 127.2, 126.6,
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32 3 3
125.6, 125.0, 124.4, 114.7, 70.6, 58.1, 43.9, 35.4, 27.5, 21.4. HRMSꢀESI (m/z) calcd for C26H N O
+
20
[M+H] 434.2444, found 434.2433. Optical rotation [α] –30.5 (c 0.18, CH Cl ).
D
2
2
(1S,2S)-2-(2-Naphthamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate ((S,S)–
1h). The title compound was obtained as light yellow amorphous solid (17 mg, 28%) by following
general procedure A from 2ꢀnaphthoic acid (29 mg, 0.169 mmol, 1.1 equiv), HATU (72 mg, 0.185
mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (36 mg, 0.154 mmol, 1 equiv), N,Nꢀ
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
diisopropylethylamine (75 µL, 0.461 mmol, 3 equiv) and acetic anhydride (29 µL, 0.308 mmol, 2
1
equiv). H NMR (400 MHz, CDCl
3
, ppm) δ 8.32 (1H, d, J=5.5 Hz), 8.28 (1H, s), 8.13 (1H, s), 7.97ꢀ
7.82 (3H, m), 7.65 (1H, dd, J=8.5, 1.8 Hz), 7.60ꢀ7.49 (2H, m), 6.94 (1H, d, J=5.5 Hz), 6.60 (1H, d,
J=1.7 Hz), 6.49 (1H, d, J=10.7 Hz), 4.40 (1H, dd, J=10.7, 1.7 Hz), 2.90 (6H, s), 2.21 (3H, s), 1.10
13
(
9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 169.9, 167.6, 158.5, 150.3, 147.4, 134.8, 132.8, 129.0,
128.8, 128.6, 127.9, 127.7, 127.2, 126.9, 123.5, 114.6, 70.4, 58.8, 44.0, 35.4, 27.4, 21.4. HRMSꢀESI
+
20
(
32 3 3 D
m/z) calcd for C26H N O [M+H] 434.2444, found 434.2438. Optical rotation [α] +58.0 (c 1.12,
2 2
CH Cl ).
(
1S,2S)-2-([1,1'-Biphenyl]-4-carboxamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl
acetate ((S,S)–1i). The title compound was obtained as white amorphous solid (24 mg, 39%) by
following general procedure A from [1,1'ꢀbiphenyl]ꢀ4ꢀcarboxylic acid (29 mg, 0.147 mmol, 1.1
equiv), HATU (62 mg, 0.161 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (32 mg, 0.134 mmol, 1
equiv), N,Nꢀdiisopropylethylamine (65 µL, 0.402 mmol, 3 equiv) and acetic anhydride (26 µL, 0.268
1
mmol, 2 equiv). H NMR (400 MHz, CDCl , ppm) δ 8.21 (1H, s), 7.74ꢀ7.66 (2H, m), 7.67ꢀ7.58 (3H,
3
m), 7.57ꢀ7.48 (2H, m), 7.45ꢀ7.36 (2H, m), 7.38ꢀ7.29 (1H, m), 6.63 (1H, d, J=7.2 Hz), 6.58 (1H, d,
J=1.7 Hz), 6.51 (1H, d, J=10.5 Hz), 4.13 (1H, dd, J=10.5, 1.7 Hz), 3.25 (6H, s), 2.27 (3H, s), 1.07
13
(9H, s). C NMR (100.6 MHz, CDCl , ppm) δ 170.5, 167.7, 159.6, 144.5, 139.8, 139.4, 138.2, 131.7,
3
128.9, 127.9, 127.5, 127.2, 123.2, 111.1, 69.2, 57.3, 43.2, 35.5, 27.4. HRMSꢀESI (m/z) calcd for
+
20
28 34 3 3 D 2 2
C H N O [M+H] 460.2600, found 460.2594. Optical rotation [α] +20.5 (c 1.95, CH Cl ).
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(1S,2S)-2-([1,1'-Biphenyl]-3-carboxamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl
acetate ((S,S)–1j). The title compound was obtained as pale yellow oil (15 mg, 24%) by following
general procedure A from [1,1'ꢀbiphenyl]ꢀ3ꢀcarboxylic acid (30 mg, 0.150 mmol, 1.1 equiv), HATU
(63 mg, 0.163 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (32 mg, 0.136 mmol, 1 equiv), N,Nꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
diisopropylethylamine (66 µL, 0.408 mmol, 3 equiv) and acetic anhydride (26 µL, 0.272 mmol, 2
1
equiv). H NMR (300 MHz, CDCl
3
, ppm) δ 8.26 (1H, s), 7.84ꢀ7.76 (2H, m), 7.67 (1H, ddd, J=7.6,
1.5, 1.5 Hz), 7.64ꢀ7.55 (3H, m), 7.53 (1H, d, J=7.6 Hz), 7.50ꢀ7.40 (2H, m), 7.40ꢀ7.32 (1H, m), 6.80
(
1H, d, J=7.1 Hz), 6.62 (1H, d, J=1.6 Hz), 6.48 (1H, d, J=10.5 Hz), 4.18 (1H, dd, J=10.5, 1.6 Hz),
1
3
3
1
4
3
.33 (6H, s), 2.30 (3H, s), 1.11 (9H, s). C NMR (100.6 MHz, CDCl , ppm) δ 170.6, 168.1, 160.0,
42.0, 140.2, 140.1, 138.8, 133.9, 130.9, 129.8, 129.1, 127.9, 127.4, 125.3, 123.9, 111.6, 69.4, 57.5,
+
3.5, 35.7, 27.6, 21.0. HRMSꢀESI (m/z) calcd for C28
H
34
N
3
O
3
[M+H] 460.2600, found 460.2591.
20
Optical rotation [α]
D 2 2
–5.9 (c 1.12, CH Cl ).
(
1S,2S)-1-(4-(Dimethylamino)pyridin-3-yl)-3,3-dimethyl-2-(3-(trifluoromethyl)benzamido) butyl
acetate ((S,S)–1k). The title compound was obtained as light yellow amorphous solid (10 mg, 38%)
by following general procedure A from 3ꢀ(trifluoromethyl)benzoic acid (12 mg, 0.066 mmol, 1.1
equiv), HATU (28 mg, 0.072 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (14 mg, 0.06 mmol, 1
equiv), N,Nꢀdiisopropylethylamine (39 µL, 0.24 mmol, 3 equiv) and acetic anhydride (17 µL, 0.18
1
mmol, 2 equiv). H NMR (400 MHz, CDCl , ppm) δ 8.31 (1H, s), 7.90ꢀ7.78 (3H, m), 7.74ꢀ7.65 (1H,
3
m), 7.63ꢀ7.53 (1H, m), 6.86 (1H, d, J=6.9 Hz), 6.61 (1H, d, J=1.7 Hz), 6.50 (1H, d, J=10.5 Hz), 4.18
1
3
(
1H, dd, J=10.5, 1.7 Hz), 3.32 (6H, s), 2.29 (3H, s), 1.09 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm)
δ 170.5, 166.7, 159.8, 141.3, 140.2, 134.1, 131.3 (q, J = 32.9 Hz), 130.1, 129.6, 128.6, 124.6, 123.8
1
9
(
3
q, J = 271.6 Hz), 111.9 , 69.5, 57.7, 43.6, 35.6, 27.6, 21.0. F NMR (376.5 MHz, CDCl , ppm) δ ꢀ
+
62.9. HRMSꢀESI (m/z) calcd for C23
H
29
N
3
O
3
F
3
[M+H] 452.2161, found 452.216. Optical rotation
2
0
[α] –13.9 (c 0.43, CH Cl ).
D
2
2
(1S,2S)-2-([1,1':3',1''-Terphenyl]-5'-carboxamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-
dimethylbutyl acetate ((S,S)–1l). The title compound was obtained as colorless oil (9 mg, 25%) by
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following general procedure A from [1,1':3',1''ꢀterphenyl]ꢀ5'ꢀcarboxylic acid (15 mg, 0.074 mmol, 1.1
equiv), HATU (31 mg, 0.081 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (16 mg, 0.067 mmol, 1
equiv), N,Nꢀdiisopropylethylamine (33 µL, 0.202 mmol, 3 equiv) and acetic anhydride (13 µL, 0.134
1
mmol, 2 equiv). H NMR (300 MHz, CDCl
3
, ppm) δ 8.28 (1H, s), 7.94 (1H, d, J=6.6 Hz), 7.89 (1H,
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
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53
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55
56
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58
59
60
dd, J=1.6, 1.6 Hz), 7.73 (2H, d, J=1.6 Hz), 7.69ꢀ7.61 (4H, m), 7.52ꢀ7.43 (4H, m), 7.43ꢀ7.32 (2H, m),
.82 (1H, d, J=6.6 Hz), 6.60 (1H, d, J=1.7 Hz), 6.49 (1H, d, J=10.5 Hz), 4.23 (1H, dd, J=10.5, 1.7
6
13
Hz), 3.17 (6H, s), 2.23 (3H, s), 1.09 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 170.0, 167.6,
158.8, 149.3, 142.5, 140.5, 136.1, 129.3, 129.1, 128.0, 127.5, 124.5, 70.3, 58.7, 43.9, 35.4, 27.5, 21.4.
+
20
38 3 3 D
HRMSꢀESI (m/z) calcd for C34H N O [M+H] 536.2913, found 536.2914. Optical rotation [α]
+
2 2
6.8 (c 0.360, CH Cl ).
(
1S,2S)-2-(3,5-Di-tert-butylbenzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl
acetate ((S,S)–1n). The title compound was obtained as pale yellow oil (11 mg, 16%) by following
general procedure A from 3,5ꢀdiꢀtertꢀbutylbenzoic acid (36 mg, 0.153 mmol, 1.1 equiv), HATU (65
mg, 0.139 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)ꢀ8 (33 mg, 0.139 mmol, 1 equiv), N,Nꢀ
diisopropylethylamine (68 µL, 0.416 mmol, 3 equiv) and acetic anhydride (26 µL, 0.277 mmol, 2
1
equiv). H NMR (300 MHz, CDCl
3
, ppm) δ 8.18 (1H, s), 7.95 (1H, d, J=6.8 Hz), 7.60 (1H, dd, J=1.8,
1.8 Hz), 7.37 (2H, d, J=1.8 Hz), 6.92 (1H, d, J=6.8 Hz), 6.59 (1H, d, J=1.8 Hz), 6.30 (1H, d, J=10.5
13
Hz), 4.16 (1H, dd, J=10.5, 1.8 Hz), 3.28 (6H, s), 2.25 (3H, s), 1.34 (18H, s), 1.09 (9H, s). C NMR
(
100.6 MHz, CDCl
3
, ppm) δ 170.3, 169.0, 160.2, 151.9, 133.3, 126.8, 120.7, 112.2, 99.2, 69.4, 57.8,
+
46 3 3
56.0, 43.6, 35.6, 35.1, 31.5, 31.3, 27.6, 27.5. HRMSꢀESI (m/z) calcd for C30H N O [M+H]
2
0
D
4
96.3539, found 496.3533. Optical rotation [α] –16.5 (c 0.17, CH Cl ).
2
2
(
1S,2S)-1-(4-(Dimethylamino)pyridin-3-yl)-2-(3,5-dinitrobenzamido)-3,3-dimethylbutyl acetate
((S,S)–1o). The title compound was obtained as light yellow amorphous solid (17 mg, 43%) by
following general procedure A from 3,5ꢀdinitrobenzoic acid (20 mg, 0.092 mmol, 1.1 equiv), HATU
(38 mg, 0.101 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)ꢀ8 (20 mg, 0.084 mmol, 1 equiv), N,Nꢀ
diisopropylethylamine (42 µL, 0.252 mmol, 3 equiv) and acetic anhydride (20 µL, 0.168 mmol, 2
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
equiv). H NMR (400 MHz, CDCl
3
, ppm) δ 8.94 (1H, dd, J=2.0, 2.0 Hz), 8.59 (2H, d, J=2.0 Hz), 8.15
(1H, s), 7.99 (1H, d, J=7.1 Hz), 6.98 (1H, d, J=7.1 Hz), 6.94 (1H, d, J=10.5 Hz), 6.64 (1H, d, J=1.7
1
3
Hz), 4.15 (1H, dd, J=10.5, 1.7 Hz), 3.40 (6H, s), 2.25 (3H, s), 1.14 (9H, s). C NMR (100.6 MHz,
CDCl
3
, ppm) δ 170.7, 164.6, 160.0, 148.7, 139.7, 138.6, 136.7, 127.5, 123.2, 121.2, 111.6, 69.0, 58.3,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
43.6, 35.8, 27.7, 20.8. HRMSꢀESI (m/z) calcd for C H N O [M+H] 474.1989, found 474.1999.
22
27
5
7
2
0
Optical rotation [α]
D 2 2
–20.0 (c 0.13, CH Cl ).
(
1S,2S)-2-(3,5-Dibromobenzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate
(S,S)–1p). The title compound was obtained as light yellow oil (15 mg, 24%) by following general
(
procedure A from 3,5ꢀdibromoꢀbenzoic acid (35.5 mg, 0.127 mmol, 1.1 equiv), HATU (53 mg, 0.116
mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)ꢀ8 (25 mg, 0.096 mmol, 1 equiv), N,Nꢀ
diisopropylethylamine (57 µL, 0.35 mmol, 3 equiv) and acetic anhydride (24 µL, 0.23 mmol, 2
1
equiv). H NMR (400 MHz, CDCl
3
, ppm) δ 8.28 (1H, s), 7.95 (1H, d, J=7.0 Hz), 7.72 (1H, dd, J=1.4,
1
.4 Hz), 7.61 (2H, d, J=1.4 Hz), 6.91 (1H, d, J=7.0 Hz), 6.59 (1H, s), 6.53 (1H, d, J=10.4 Hz), 4.11
13
(
1H, d, J=10.4 Hz), 3.34 (6H, s), 2.27 (3H, s), 1.09 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ
1
70.6, 165.7, 160.0, 140.1, 138.8, 137.5, 136.7, 128.9, 123.6, 123.5, 111.6, 69.2, 57.9, 43.5, 35.7,
+
2
28 3 3 2
7.6, 21.0. HRMSꢀESI (m/z) calcd for C22H N O Br [M+H] 540.0497, found 540.049. Optical
20
rotation [α]
D 2 2
–19.9 (c 0.29, CH Cl ).
(
1S,2S)-2-(3,5-Difluorobenzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate
(S,S)–1q). The title compound was obtained as white amorphous solid (45 mg, 47%) by following
(
general procedure A from 3,5ꢀdifluoroꢀbenzoic acid (20 mg, 0.127 mmol, 1.1 equiv), HATU (96 mg,
.25 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (27.5 mg, 0.116 mmol, 1 equiv), N,Nꢀ
0
diisopropylethylamine (104 µL, 0.63 mmol, 3 equiv) and acetic anhydride (40 µL, 0.42 mmol, 2
1
equiv). H NMR (400 MHz, CDCl , ppm) δ 9.83 (1H, dddd, J=8.6, 8.6, 1.9, 1.9 Hz), 8.23 (1H, s),
3
7.92 (1H, d, J=7.0 Hz), 7.11 (2H, dd, J=7.1, 1.9 Hz), 6.90 (1H, d, J=7.0 Hz), 6.59 (1H, d, J=1.2 Hz),
13
6.58 (1H, d, J=10.5 Hz), 4.11 (1H, dd, J=10.5, 1.2 Hz), 3.33 (6H, s), 2.26 (3H, s), 1.08 (9H, s). C
NMR (100.6 MHz, CDCl
3
, ppm) δ 170.8, 166.1, 164.3 (d, J = 12.2 Hz), 161.8 (d, J = 12.2 Hz), 160.0,
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139.7, 138.7, 136.6 , 123.4, 111.6, 110.3 (d, J = 26.0 Hz), 107.3 (dd, J = 26.0, 26.0 Hz), 69.2, 57.8,
19
43.4, 35.7, 27.6, 20.8. F NMR (376.5 MHz, CDCl , ppm) δ ꢀ107.8 (dd, J = 7.0, 7.0 Hz). HRMSꢀESI
3
+
20
(m/z) calcd for C22
1.52, CH Cl ).
28 3 3 2 D
H N O F [M+H] 420.2099, found 420.2114. Optical rotation [α] –35.5 (c
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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58
59
60
(
1S,2S)-2-(3,5-Dichlorobenzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate
(S,S)–1r). The title compound was obtained as pale yellow amorphous solid (23 mg, 47%) by
(
following general procedure A from 3,5ꢀdichloroꢀbenzoic acid (44 mg, 0.23 mmol, 1.1 equiv), HATU
53 mg, 0.116 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8 (25 mg, 0.096 mmol, 1 equiv), N,Nꢀ
(
diisopropylethylamine (57 µL, 0.35 mmol, 3 equiv) and acetic anhydride (24 µL, 0.23 mmol, 2
1
equiv). H NMR (400 MHz, MeOHꢀd
3
, ppm) δ 8.30ꢀ8.04 (2H, m), 7.62 (1H, dd, J=1.9, 1.9 Hz), 7.55
(
(
2H, d, J=1.9 Hz), 7.12 (1H, s), 6.60 (1H, d, J=1.5 Hz), 4.24 (1H, d, J=1.5 Hz), 3.05 (6H, s), 2.23
13
3H, s), 1.10 (9H, s). C NMR (100.6 MHz, MeOHꢀd
3
, ppm) δ 171.7, 168.2, 160.2, 138.9, 136.3,
1
32.1, 127.1, 111.4, 70.9, 60.2, 54.8, 49.9, 43.8, 36.1, 27.9, 21.0. HRMSꢀESI (m/z) calcd for
+
20
C
22 28 3 3 2 D 2 2
H N O Cl [M+H] 452.1508, found 452.1511. Optical rotation [α] +19.8 (c 0.06, CH Cl ).
(
1S,2S)-2-(3,5-Diiodobenzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate
(S,S)–1s). The title compound was obtained as light yellow oil (10 mg, 7%) by following general
(
procedure A from 3,5ꢀdiiodoꢀbenzoic acid (87 mg, 0.23 mmol, 1.1 equiv), HATU (96 mg, 0.25 mmol,
1
.2 equiv), 1,2ꢀamino alcohol (S,S)ꢀ8 (50 mg, 0.21 mmol, 1 equiv), N,Nꢀdiisopropylethylamine (104
1
µL, 0.63 mmol, 3 equiv) and acetic anhydride (40 µL, 0.42 mmol, 2 equiv). H NMR (400 MHz,
MeOHꢀd , ppm) δ 8.29ꢀ8.19 (1H, m), 8.24 (1H, dd, J=1.5, 1.5 Hz), 8.14ꢀ8.05 (1H, m), 7.90 (2H, d,
3
J=1.5 Hz), 7.24ꢀ7.02 (1H, m), 6.59 (1H, d, J=1.5 Hz), 4.25 (1H, d, J=1.5 Hz), 3.01 (6H, s), 2.23 (3H,
1
3
s), 1.09 (9H, s). C NMR (100.6 MHz, MeOHꢀd
139.2, 136.7, 95.3, 71.0, 60.2, 49.9, 43.8, 36.1, 27.9, 21.0. HRMSꢀESI (m/z) calcd for C H N O I
3 2
3
, ppm) δ 171.7, 167.8, 160.7, 149.0, 148.0, 146.0,
22
28
3
+
20
[M+H] 636.022, found 636.0223. Optical rotation [α]
D 2 2
+25.6 (c 0.06, CH Cl ).
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2-(3,5-Bis(pentafluoro-λ -sulfanyl)benzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-
dimethylbutyl acetate ((S,S)–1x). The title compound was obtained as white amorphous solid (300
6
mg, 66%) by following general procedure A from 3,5ꢀbis(pentafluoroꢀλ ꢀsulfanyl)benzoic acid (295
mg, 0.788 mmol, 1.1 equiv), HATU (327 mg, 0.860 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)ꢀ8 (170
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mg, 0.716 mmol, 1 equiv), N,Nꢀdiisopropylethylamine (371 µL, 2.149 mmol, 3 equiv) and acetic
1
anhydride (203 µL, 2.149 mmol, 3 equiv). H NMR (400 MHz, CDCl
3
, ppm) δ 8.35 (1H, d, J=5.5
Hz), 8.24 (1H, dd, J=1.9, 1.9 Hz), 8.17 (1H, s), 8.08 (2H, d, J=1.9 Hz), 6.94 (1H, d, J=5.5 Hz), 6.58
(
1H, d, J=1.7 Hz), 6.32 (1H, d, J=10.6 Hz), 4.34 (1H, dd, J=10.6, 1.7 Hz), 2.88 (6H, s), 2.22 (3H, s),
13
1
.08 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 169.7, 163.8, 158.5, 154.1, 150.7, 147, 136.9,
19
1
28.1, 127.4, 126.7, 114.7, 70.2, 59.6, 43.3, 27.3, 21.3. F NMR (376.5 MHz, CDCl
3
, ppm) δ 80.7 (p,
+
J = 151.0 Hz), 63.0 (d, J = 151.0 Hz). HRMSꢀESI (m/z) calcd for C22
H
28
N
3
O
3
S
2
F
10 [M+H] 636.1412,
20
found 636.1414. Optical rotation [α]
D 2 2
+1.2 (c 0.85, CH Cl ).
6
2
-(3-Bromo-5-(pentafluoro-λ -sulfanyl)benzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-
dimethylbutyl acetate ((S,S)–1y). The title compound was obtained as white amorphous solid (51
6
mg, 31%) by following general procedure A from 3ꢀbromoꢀ5ꢀ(pentafluoroꢀ λ ꢀsulfanyl)benzoic acid
(
(
100 mg, 0.307 mmol, 1.1 equiv), HATU (127 mg, 0.335 mmol, 1.2 equiv), 1,2ꢀamino alcohol (S,S)–8
66 mg, 0.279 mmol, 1 equiv), N,Nꢀdiisopropylethylamine (135 µL, 0.837 mmol, 3 equiv) and acetic
1
anhydride (52 µL, 0.558 mmol, 2 equiv). H NMR (400 MHz, CDCl , ppm) δ 8.33 (1H, d, J=5.4 Hz),
3
8
.21 (1H, s), 7.99 (1H, dd, J=1.8, 1.8 Hz), 7.89 (1H, dd, J=1.8, 1.8 Hz), 7.81 (1H, dd, J=1.8, 1.8 Hz),
.93 (1H, d, J=5.4 Hz), 6.57 (1H, d, J=1.6 Hz), 6.32 (1H, d, J=10.7 Hz), 4.31 (1H, dd, J=10.7, 1.6
6
13
Hz), 2.89 (6H, s), 2.21 (3H, s), 1.07 (9H, s). C NMR (100.6 MHz, CDCl , ppm) δ 169.7, 164.3,
3
1
58.5, 150.2, 146.9, 137.3, 132.5, 131.8, 128.1, 123.7, 122.7, 114.6, 70.2, 59.2, 43.9, 35.3, 27.4, 21.4.
19
F NMR (376.5 MHz, CDCl
3
, ppm) δ 81.7 (p, J = 150.8 Hz), 62.9 (d, J = 150.8 Hz). HRMSꢀESI
+
20
(m/z) calcd for C H N O SBrF [M+H] 588.0955, found 588.0952. Optical rotation [α] +64.6 (c
2
2
28
3
3
5
D
2 2
0.40, CH Cl ).
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General procedure B for multi-step synthesis of chiral DMAP catalysts (S,S)–1e,m,u,v (see
Figure 6).
10
11
12
13
14
15
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20
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60
Figure 6. Multistep synthesis of chiral DMAP catalysts (S,S)–1e,m,u,v
Step 1. Acid chloride (1 equiv) was added dropwise to a colorless solution of triethylamine (2.2
2 2 2 2
equiv) and (S)ꢀ2ꢀaminoꢀ3,3ꢀdimethylbutanꢀ1ꢀol ((S)–3) (1 equiv) in CH Cl (1 mL of CH Cl / 0.5
mmol aminoalcohol (S)ꢀ3) at 0 °C (crushed ice). The reaction progress was monitored by UPLCꢀMS
analysis. Upon complete conversion of the starting (S)–3 precipitates were filtered and filter cake was
washed with CH
by column chromatography (120 g silica gel) using gradient elution from 0% EtOAc in hexanes to
00% EtOAc.
Step 2. DessꢀMartin periodinane (1.2 equiv) was added portion wise to a solution of amidoalcohol
S)ꢀ20 (1 equiv) in CH Cl (1 mL CH Cl / 0.3 mmol amidoalcohol (S)ꢀ20) at 0 °C. After 10 min the
2 2
Cl (2 x 10 mL). Filtrate was concentrated and the colorless oily residue was purified
1
(
2
2
2
2
suspension was warmed to room temperature. The reaction progress was monitored by UPLCꢀMS
analysis. Upon complete conversion of the starting (S)–20 the white suspension was diluted with Et
2
O
and poured into Na
resulting twoꢀphase system was stirred vigorously until organic layer became clear. Layers were
separated and the organic layer was washed with saturated NaHCO solution and brine. Organic
extract was dried over Na SO , filtered and concentrated under reduced pressure. The crude residue
2 2 3 2 3
S O ·5H O (0.3 M solution in saturated NaHCO solution, 10 equiv). The
3
2
4
was used immediately in the next step without purification.
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Step 3. The title compound was prepared using modified literature procedure. Thus, an ovenꢀdried
flask was charged with tꢀBuLi (1.6 M solution in pentane, 4.6 equiv) and cooled to –100 °C (liquid
2
nitrogen/Et O) then anhydrous THF was added to obtain 0.6 M tꢀBuLi solution. Then, a solution of 3ꢀ
bromoꢀN,Nꢀdimethylpyridinꢀ4ꢀamine (17) (0.1 M solution in anhydrous THF, 2.3 equiv) was added
by syringe pump to the tꢀBuLi solution maintaining reaction temperature below ꢀ95 °C (addition rate
0
1
2
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0
1
.5 mL/min). The light orange solution was stirred at –100 °C for 1 h whereupon (S)ꢀNꢀ(3,3ꢀdimethylꢀ
ꢀoxobutanꢀ2ꢀyl)ꢀ3,5ꢀbis(trifluoromethyl)benzamide ((S)ꢀ27m) (0.1 M solution in anhydrous THF, 1
1
equiv) was added by syringe pump to the reaction mixture maintaining reaction temperature below –
5 °C (addition rate 1.5 mL/min). The orange solution was stirred at –100 °C for 2 h, quenched with
neat Ac O (8 equiv) and warmed to room temperature. Volatiles were removed under reduced
pressure, the light brown oil was dissolved in CH Cl (30 mL) and washed with aqueous 1M NaOH
solution (40 mL). Aqueous layer was washed with CH Cl (2 x 30 mL), combined organic layers were
dried over Na SO , filtered and concentrated. Purification of the crude product by column
9
2
2
2
2
2
2
4
chromatography (120 g of RPꢀ18 silica gel) using isocratic elution with 25% MeCN in water
containing 0.1% AcOH afforded product as a light yellow amorphous solid.
(
S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)pivalamide ((S)–20e). The title compound was obtained
as white amorphous solid (755 mg, 95%) by following general procedure B, step 1 from (S)ꢀ2ꢀaminoꢀ
3
,3ꢀdimethylbutanꢀ1ꢀol ((S)–3) (463 mg, 3.95 mmol, 1 equiv), pivaloyl chloride (0.53 mL, 4.3 mmol,
1
1
.1 equiv) and triethylamine (1.2 mL, 8.7 mmol, 2.2 equiv). H NMR (300 MHz, CDCl
3
, ppm) δ 5.84
1
(
s, 1H), 3.77ꢀ3.92 (m, 2H), 3.57 (dd, J=10.7, 7.7 Hz, 1H), 1.26 (s, 9H), 0.98 (s, 9H). The H NMR
53
spectra is in full agreement with that reported in the literature.
(
S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)-3,5-bis(trifluoromethyl)benzamide ((S)–20m). The
title compound was obtained as white amorphous solid (4.54 g, 74%) by following general procedure
B, step 1 from triethylamine (5.22 mL, 37.546 mmol, 2.2 equiv), (S)ꢀ2ꢀaminoꢀ3,3ꢀdimethylbutanꢀ1ꢀol
((S)–3) (2.0 g, 17.1 mmol, 1 equiv) and 3,5ꢀbis(trifluoromethyl)benzoyl chloride (3.1 mL, 17.1 mmol,
1
1 equiv). Analytical TLC on silica gel, 2:5 EtOAc/Hexanes, R
f
=0.35. H NMR (400 MHz, CDCl
3
,
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ppm) δ 8.18 (2H, s), 7.97 (1H, s), 6.52 (1H, d, J=9.5 Hz), 4.10 (1H, ddd, J=9.5, 7.2, 3.8 Hz), 3.99ꢀ
13
3.90 (1H, m), 3.80ꢀ3.68 (1H, m), 2.44 (1H, s), 1.04 (9H, s). C NMR (100.6 MHz, CDCl , ppm) δ
3
1
9
165.8, 137.0, 132.3 (q, J = 34.0 Hz), 127.4, 125.2, 123.0 (q, J = 272.8 Hz), 62.5, 60.0, 34.3, 27.2. F
+
NMR (376.5 MHz, CDCl
3
) δ ꢀ63.0. HRMSꢀESI (m/z) calcd for C15
H18NO
2
F
6
[M+H] 358.1242,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
0
found 358.1238. Optical rotation [α] –6.5 (c 0.73, CH Cl ).
D
2
2
(
S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)benzenesulfonamide ((S)–20u). The title compound was
obtained as white amorphous solid (200 mg, 91%) by following general procedure B, step 1 from
triethylamine (0.26 mL, 1.9 mmol, 2.2 equiv), (S)ꢀ2ꢀaminoꢀ3,3ꢀdimethylbutanꢀ1ꢀol ((S)–3) (100 mg,
0
.85 mmol, 1 equiv) and benzenesulfonyl chloride (166 mg, 0.94 mmol, 1.1 equiv). Analytical TLC
1
on silica gel, 2:5 EtOAc/Hexanes, R
f
=0.36. H NMR (300 MHz, CDCl
3
, ppm) δ 7.96ꢀ7.86 (2H, m),
7
1
6
.63ꢀ7.45 (3H, m), 4.88ꢀ4.69 (1H, m), 3.71ꢀ3.53 (2H, m), 3.03 (1H, ddd, J=9.6, 6.0, 4.2 Hz), 2.07ꢀ
13
.95 (1H, m), 0.81 (9H, s). C NMR (100.6 MHz, CDCl
3
, ppm) δ 140.7, 132.9, 129.2, 127.4, 64.2,
+
2.4, 34.2, 27.1. HRMSꢀESI (m/z) calcd for C12
H18NO
3
S [MꢀH] 256.1007, found 256.1018. Optical
20
rotation [α]
D 2 2
–17.6 (c 0.62, CH Cl ).
(
S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)-3,5-bis(trifluoromethyl)benzenesulfonamide ((S)–
0v). The title compound was obtained as white amorphous solid (285 mg, 85%) by following general
2
procedure B, step 1 from triethylamine (0.26 mL, 1.9 mmol, 2.2 equiv), (S)ꢀ2ꢀaminoꢀ3,3ꢀ
dimethylbutanꢀ1ꢀol ((S)–3) (100 mg, 0.85 mmol, 1 equiv) and 3,5ꢀ
bis(trifluoromethyl)benzenesulfonyl chloride (293 mg, 0.94 mmol, 1.1 equiv). Analytical TLC on
1
silica gel, 2:5 EtOAc/Hexanes, R =0.71. H NMR (400 MHz, CDCl , ppm) δ 8.36 (2H, s), 8.04 (1H,
f
3
s), 5.12 (1H, d, J=9.8 Hz), 3.72 (1H, dd, J=11.3, 3.8 Hz), 3.60 (1H, dd, J=11.3, 6.8 Hz), 3.19 (1H,
13
3
ddd, J=9.8, 6.8, 3.8 Hz), 1.86ꢀ1.68 (1H, br s), 0.87 (9H, s). C NMR (100.6 MHz, CDCl , ppm) δ
19
144.2, 132.8 (q, J = 34.5 Hz), 127.7, 126.0, 122.7 (q, J = 273.3 Hz), 64.8, 62.0, 34.3, 27.1. F NMR
+
(376.5 MHz, CDCl
3
, ppm) δ ꢀ63.0. HRMSꢀESI (m/z) calcd for C14
H
16NO
3
F
6
S [MꢀH] 392.0755,
2
0
D
found 392.0771. Optical rotation [α]
2 2
+2.2 (c 0.68, CH Cl ).
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