From racemic precursors to fully stereocontrolled products: One-pot synthesis of chiral α-amino lactones and lactams

Article abstract of DOI:10.1039/c6ob00953k

Substituted racemic lactols or cyclic hemiaminals were directly used as nucleophiles in enamine-based asymmetric amination reactions to access enantioenriched α-amino lactones or lactams via a one-pot sequence. The desired products, which are very important building blocks in organic synthesis but difficult to be prepared in the optically enriched form, could be afforded with two stereogenic centers in high yields with excellent enantioselectivities. Moreover, starting from the racemic precursors and catalyzed by the enantiomeric pair of the catalyst, all possible stereoisomeric products were discretely provided only after simple column chromatography. Additionally, this protocol provides facile access to several novel bicyclic carbamates, and such drug-like heterocyclic compounds should be potentially useful in medicinal chemistry.

Full text of DOI:10.1039/c6ob00953k

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DOI: 10.1039/C6OB00953K
Journal Name
ARTICLE
From Racemic Precursors to Fully Stereocontrolled Products: One-
Pot Synthesis of Chiral α-Amino Lactones and Lactams
Received 00th January 20xx,
Accepted 00th January 20xx
Zhi-Hao You, Ying-Han Chen, and Yan-Kai Liu*
DOI: 10.1039/x0xx00000x
Substituted racemic lactols or cyclic hemiaminals were directly used as nucleophiles in enamine-based asymmetric
amination reaction to access enantioenriched α-amino lactones or lactams via one-pot sequence. The desired products,
which are very important building blocks in organic synthesis but difficult to be prepared optically enriched, could be
afforded with two stereogenic centers in high yields with excellent enantioselectivities. Moreover, starting from the
racemic precursors and catalyzed by the enantiomeric pair of the catalyst, all possible stereoisomeric products were
discretely provided only after simple column chromatography. Additionally, this protocol provides facile access to several
novel bicyclic carbamates, and such drug-like heterocyclic compounds should be potentially useful in medicinal chemistry.
www.rsc.org/
8
related drawbacks, including low efficiency, costly transition
9
10
Introduction
metal catalysis, or scope restrictions. Accordingly, the
development of new, flexible, and expedient protocols for the
preparation of these valuable heterocycles is of significant
importance.
Currently, the design and synthesis of polyfunctionalized
heterocyclic synthons which contain multiple stereogenic
centers have become an active topic of research. Along this
line, there was a challenging issue in the field of asymmetric
synthesis, establishing practical and efficient access to useful
chiral heterocyclic building blocks. Particularly, it is highly
desirable from a synthetic point of view that, when starting
from racemic materials, diastereo- and enantiomerically pure
compounds are finally obtained only after simple work up,
such as column chromatography, which makes the overall
As part of our continuous research efforts toward the
chemistry of lactols and cyclic hemiaminals,
interested in exploring a rapid access, which could meet the
1
1,12
we have been
1
process more atom-efficient and attractive.
Chiral α-amino lactones or lactams, especially containing a
stereogenic center adjacent to the O or N atom in the ring, are
the structural feature of numerous biologically active natural
2,3
products and pharmaceuticals (Scheme 1, upper structures).
Moreover, functionalized chiral α-amino γ-lactones are also
the crucial precursors for the preparation of α-amino acids
with a hydroxyl group in γ position which are an important
4
class of naturally occurring products. In spite of their
promising biological activities, the stereocontrolled synthesis
of chiral α-amino lactones or lactams with multiple stereogenic
centers has remained a challenging issue. Indeed, among the
documented examples, stepwise process is generally involved
in the formation of all chiral centers on the ring system of
lactones or lactams, and relies mainly on the application of
5
6
enzymatic resolution, chiral auxiliaries, or chiral starting
7
materials. In addition, most cases still suffered from several
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of
Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People’s
Republic of China.
Email: liuyankai@ouc.edu.cn
Electronic Supplementary Information (ESI) available: all spectroscopic data and
procedures for novel compounds.. See DOI: 10.1039/x0xx00000x
Scheme 1. Selected biologically active compounds and our projected novel synthetic
strategy.
†
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requirements of atom economy and provide chiral α-amino chlorochromate (PCC)-mediated oxidation reactViieownArtficinleisOhnleinde
lactones and lactams with excellent enantio- and the desired products 4a and 5aDOI:a1s0.10t3w9/oC6OiBs0o0la95b3leK
diastereoselectivities. In the stereodivergent reaction process diastereoisomers in one-pot sequence (Table 1). According to
1c
(
Scheme 1, lower equation), substituted racemic lactols or the results in Table 1, we could rationalize the structure
cyclic hemiaminals were directly used as nucleophiles in the features of catalysts applied in these reactions, which
asymmetric catalytic amination reaction under enamine-based exhibited significantly different catalytic activity and
1
3,14
activation,
and the subsequent oxidation step afforded the enantioselectivity toward the amination process, as the
desired chiral α-amino lactones or lactams with multiple following: (1) diarylprolinol derivatives normally resulted with
stereogenic centers as a single diastereoisomer only after moderate to good enantiomeric excess (ee) for both of the
1
5
simple column chromatography workup.
diastereomeric products 4a and 5a
.
It should be noted that
the increased steric hindrance of silyl substituents of the
catalyst would benefit to improve the stereoselectivity (Table 1,
entries 1-3). (2) Proline type catalysts, which contained a
carboxylic acid group, are much more efficient and showed
very good catalytic activity and enantioselectivity. However,
it is unclear for us why no reaction occurs when 3f is applied in
the reaction. Moreover, it is worth mentioning that the
unprotected hydroxyl group in cis-4-hydroxy-L-proline played a
crucial role in the catalytic activity, since the reaction
completely shut down when 3g was used as the catalyst (Table
Results and discussion
To prove the viability of the direct enantioselective
amination of lactol, we conducted the reaction of racemic
lactol 1a and di-tert-butyl azodicarboxylate 2a in CH
room temperature in the presence of organocatalyst
1
6
3
CN at
3, and
subsequent pyridine
after the amination step,
a
a
Table 1. Selected Optimization Studies
1
, entries 4-8). (3) Catalysts with dual-activation via stronger H-
1
7
bonding interaction proved to be promising catalysts. Indeed,
prolinetetrazole 3i showed the best result in this asymmetric
18
transformation (Table 1, entries 9-10). Since catalysts 3d and
gave similar results, however, compared with the
3
i
1
9
preparation of 3i
,
and also from the atom-economy
standpoint, L-proline 3d was finally chosen as the optimal
catalyst. Moreover, to our delight, the amount of the catalyst
3
d had almost no effect on the process, decreasing the
amount of catalyst to 10 molꢀ% and 5 mol%, respectively,
caused only a slightly longer reaction time while both the yield
and enantioselectivity remained unchanged (Table 1, entries
1
1-12).
Given the established ability of 3d promoting the
stereoselective conjugate addition of 1a and 2a, various
substituted racemic lactols and azodicarboxylates were
1
2
studied under the optimized conditions, and the results are
summarized in Table 2. Aromatic (Table 2, entries 1−9),
heteroaromatic (Table 2, entry 10), and aliphatic (Table 2,
entries 11−12) substituted racemic lactols were all converted
Yield (%)
5a
ee (%)
4a 5a
Entry
3
Time (h)
4
a
/
/
b
1
2
3
3a
3b
3c
3d
3e
3f
3g
3h
3i
3
2.5
>13
12
>96
-
-
5
5
37/43
38/44
27/23
37/46
28/30
-
65/49
81/66
39/43
95/93
96/92
-
to 4a
excess in moderate to high yields. The reactivity of
azodicarboxylate compounds were also investigated for the
direct α-amination of , and the corresponding products were
-l and 5a-l with high to excellent level of enantiomeric
b
b
2
4
5
6
7
8
1
obtained with slightly lower enantioselectivities while in good
isolated yields (Table 2, entries 13 and 14). Moreover, the
lactol containing a six-membered ring was also well tolerated,
and gave the aminated product 4o and 5o in high yield and
with excellent enantioselectivity (Table 2, entry 15).
Surprisingly, in several selected cases, a drastic increase in the
enantioselectivity was obtained when prolinetetrazole 3i was
applied as the catalyst (Table 2, entries 1, 2, 7, 13 and 14). It
-
-
39/45
37/44
25/32
40/46
38/40
94/91
98/95
88/84
95/93
95/93
9
b
1
1
1
0
1
2
3j
3d
3d
12
16
30
c
d
a
See the Supporting Information for more details. Yields are of the isolated
diastereomerically pure compounds 4a and 5a. The ee values are should be noted that, in all the cases, both
determined by HPLC analysis of isolated compounds 4a and 5a on chiral
4 and 5 were
obtained as a single diastereoisomer, respectively. Finally, the
possibility to easily isolate the two diastereoisomers for all of
b
stationary phases. 20 mol % p-NO
2
PhCOOH was used as the co-catalyst.
c
d
1
0 mol % 3d was used. 5 mol % 3d was used. PCC = pyridine
adducts
synthetic utility of this process.
4 and 5 by column chromatography testifies to the
chlorochromate, Boc = tert-butoxycarbonyl, TMS = trimethylsilyl, TBS = tert-
butyldimethylsilyl, TES = triethylsilyl.
2
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a
Table 2. Substrate Scope
View Article Online
DOI: 10.1039/C6OB00953K
Scheme 3. The synthesis of another two stereoisomers (-)-4a and (-)-5a.
To our delight, the catalyst (-)-3d showed similar good
catalytic activity, and the process proceeded in good reaction
yield and with high enantioselectivity (Scheme 3). Thus,
starting from the racemic precursors and catalyzed by the
enantiomeric pair of the catalyst, we can obtained all possible
stereoisomeric products only after simple column
chromatography.
Additionally, to demonstrate the practicality of the catalytic
system, the sequential amination and oxidation reactions were
enlarged to a gram scale. When racemic lactol 1a and di-tert-
butyl azodicarboxylate 2a were reacted under the optimal
reaction conditions, the reaction proceed smoothly to afford
1
2
Yield (%)
total (4/5)
ee (%)
4/5
Entry
n
1
1
R /R
4/5
76 (34/42)
71 (31/40)
76 (35/41)
70 (32/38)
95/93
1
2
Ph/t-Bu
4a/5a
4b/5b
[b]
98/97
89/89
4-MePh/t-Bu
[b]
94/98
93/91
93/92
95/92
94/91
88/90
3
4
5
6
1
1
1
1
4-MeOPh/t-Bu
4-FPh/t-Bu
4-ClPh/t-Bu
4-BrPh/t-Bu
4c/5c
4d/5d
4e/5e
4f/5f
77 (37/40)
82 (36/46)
82 (37/45)
86 (42/44)
7
7
7 (38/39)
4 (33/41)
7
1
3-NO
2
Ph/t-Bu
4g/5g
[b]
98/97
95/94
94/92
94/92
94/89
96/93
87/84
the substituted lactol
A in 93% yield, followed by the PCC-
8
9
1
1
1
1
1
2-FPh/t-Bu
2-naphthyl/t-Bu
2-thienyl/t-Bu
Bn/t-Bu
4h/5h
4i/5i
4j/5j
4k/5k
4l/5l
79 (37/42)
75 (34/41)
61 (30/31)
57 (29/28)
83 (38/45)
mediated oxidation reaction to provide the desired lactone 4a
and 5a in good yield and excellent enantionselectivity (Scheme
10
11
12
4
).
The most attractive application of this direct amination
reaction is to provide facial access to optically active α-amino
lactones. Deprotection of 5a in the presence of CF COOH
afforded hydrazine as a CF COOH salt, and the reduction of
with H /Raney Ni followed by a N-Boc protection gives the N-
Boc protected α-amino lactone with maintained
Me/t-Bu
83 (39/44)
86 (41/45)
85 (41/44)
81 (41/40)
13
1
Ph/Et
4m/5m
[b]
89/88
90/86
3
7
3
7
1
4
5
1
2
Ph/i-Pr
4n/5n
4o/5o
[b]
94/93
93/95
2
1
Ph/t-Bu
53 (24/29)
8
a
Unless otherwise specified, all reactions were carried out using 1 (0.30 mmol, 1.0 enantioselectivity (Scheme 5, a). Gratifyingly, 4a
, the
o
equiv), 2 (0.36 mmol, 1.2 equiv) in solvent (0.6 mL) with 3d (20 mol %) at 25 C. diastereoisomer of 5a, could also undergo deprotection
After workup, the crude product was oxidized by PCC to afford 4 and 5 after
purified by flash chromatography on silica gel. The total yield is reported, the
values in brackets refer to the yield of isolated diastereomerically pure
compounds 4 and 5, which could be easily separated by column chromatograph
on silica gel. The ee values are determined by HPLC analysis of isolated others were assigned by analogy.
compounds 4 and 5 on chiral stationary phases. 3i (20 mol%) was used as the
catalyst.
3
leading to CF COOH salt 9 (Scheme 5, b). The absolute
configuration of the amination product
9 was determined
unambiguously by X-ray crystal structure analysis, and those of
2
0
b
Notably, except the readily formation of α-amino lactones,
2
when catalyzed by BF •Et O instead of CF COOH in CH Cl ,
3
2
3
2
We noticed that, except for the lactols, substituted racemic
cyclic hemiaminals, with both aromatic and aliphatic
substituents, were also successfully applied in this one-pot
reaction and provided α-amino lactams 4p-q and 5p-q with
excellent enantioselectivity (Scheme 2).
Scheme 4. The gram-scale synthesis of 4a and 5a
.
Scheme 2. The synthesis of α-amino lactams.
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DOI: 10.1039/C6OB00953K
Time (h)
ee (%)
2
10
4
15
6
25
8
34
Scheme 7. Control experiment for mechanism studies.
under the optimized conditions. These reactions were then
quenched after 2 h, 4 h, 6 h, and 8 h, respectively, and the
unreacted 1a was isolated and directly oxidized into lactone 6,
Scheme 5. The synthesis of target α-amino lactone derivatives.
the enantiomeric excess of
6 are analyzed by chiral HPLC
lactol 10 underwent Boc-deprotection and transesterification
sequence to give bicyclic carbamate 11, and the subsequent
cleavage of the N-N bond gave a novel bicyclic oxazolidinone
derivative 12 as a single diastereoisomer, which might be
2
1
potentionally used as chiral auxiliary (Scheme 6, a). The
absolute configuration of 11 was determined unambiguously
20
by X-ray crystal structure analysis. Reduction of the aminated
lactol 13 with NaBH gave the corresponding functionalized
4
amino alcohol 14 (Scheme 6, b). All these interesting
backbones might be suitable for further medicinal chemistry
exploration.
Experimentally, racemic lactols were directly used in this
asymmetric C-N bond formation reaction. Thus, to gain more
insight into the reaction mechanism, some control
experiments were performed under the optimized conditions.
Several parallel reactions between 1a and 2a were carried out
Scheme 8. Proposed transition state.
Scheme 6. The synthesis of bicyclic oxazolidinone and amino alcohol.
4
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2
2
analysis. Surprisingly, we found that the enantiomeric excess Chromatographic purification of products was accomplished
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of 6
was increased along with the reaction time until the using force-flow chromatography (FC) oDnOsI:il1i0ca.10g3e9l/C(62O0B000- 945030K
reaction was complete, which showed different reaction mesh). For thin layer chromatography (TLC) analysis
behavior from our previous studies (Scheme 7). We view throughout this work, Merck precoated TLC plates (silica gel 60
this to be a very significant control experiment, suggesting that GF254, 0.25 mm) were used, using UV light as the visualizing
11e
(
R)-1a, as the benzylic stereogenic center showing
R
,
agent and Phosphomolybdic acid as stain developing solutions.
Organic solutions were concentrated under reduced pressure
configuration, worked faster with 2a than its isomer (S)-1a
and thus some of (S)-1a remained unchanged in the reaction on a Büchi rotary evaporator. HPLC analyses on chiral
process, which was then isolated and further oxidized into stationary phase were performed on an Hitachi Chromaste.
lactone
6. All these results showed that there might be a Daicel Chiralpak IA, IB or IC columns with i-PrOH/n-hexane as
kinetic resolution of lactol
amination step.
1
in the reaction process of the the eluent were used. HPLC traces were compared to racemic
samples catalyzed by DL-Proline. All catalysts and
Based on these observations, we proposed two transition azodiformates were commercial reagents. All cyclic
states, TS1 and TS2, to rationalize the possible reaction hemiacetals were synthesized from corresponding Weinreb
23
mechanisms of the formation of 4a and 5a (Scheme 8). In amide reduced by LiAlH
4
or corresponding lactone reduced by
both TS1 and TS2, the azodicarboxylate might be directed by DIBAL-H (1.5M solution in toluene).
2
the proton of the carboxylic acid from the conbination of the
substrate–catalyst.
General procedure
A glass vial equipped with a magnetic stirring bar was charged
with cyclic hemiacetal (0.3 mmol), azodicarboxylate (0.36
mol) and 3d (7 mg, 20 mol%) in acetonitrile (0.6 mL) at 25 C.
Until the starting material cyclic hemiacetal was completely
1
2
o
Conclusions
1
In summary, we have developed a novel strategy that
involves the first organocatalyzed directly asymmetric α-
amination of lactols or cyclic hemiaminals, and a subsequent
oxidation reaction providing easy access to optically active α-
amino lactones or lactams. These reactions are operationally
simple and proceed smoothly under mild reaction conditions.
Notably, starting from racemic lactols or cyclic hemiaminals,
catalyzed by the enantiomeric pair of the catalyst, all possible
stereoisomeric products, which are very useful building blocks
for the synthesis of complex molecules but difficult to prepare
optically enriched, were discretely provided only after simple
column chromatography workup. Furthermore, the reactions
could be performed on a gram scale under the optimized
conditions. Additionally, α-aminated products can be easily
transformed into other more useful chiral building blocks.
Further studies based on the reactivity of substituted racemic
lactols or cyclic hemiaminals and its application are in progress.
consumed by TLC monitor, the solvent was removed under
vacuum and the crude product was dissolved in
dichloromethane (3 mL). Then PCC (194 mg, 0.3 mmol) and
Celite (194 mg) were added before stirred at 40 C for 6h. Then
the reaction mixture was filtered, and the filtrate was purified
o
by flash chromatography on silica gel to give products
For the synthesis of compound (-)-4a and (-)-5a, D-Proline was
added instead of the 3d
di-tert-butyl 1-((3R,5S)-2-oxo-5-phenyltetrahydrofuran-3-
4 and 5.
.
yl)hydrazine-1,2-dicarboxylate (4a) was obtained as a white
solid (40 mg) in 34% yield (36 mg; 31% yield by cat. 3i) for two
steps; mp = 115−117 °C; TLC: R
f
= 0.75 (petroleum ether/EtOAc
1
=
4:1 v/v); H NMR (500 MHz, CDCl ) δ 7.30 – 7.41 (m, 5H),
3
6
1
1
.50 (s, 1H), 5.35 (dd, J = 11.0, 5.5 Hz, 1H), 5.15 (d, J = 156.3 Hz,
H), 2.75 - 2.99 (m, 1H), 2.28 - 2.57 (m, 1H), 1.44 (d, J = 17.8 Hz,
1
3
8H) ppm; C NMR (150 MHz, CDCl
3
) δ 173.8, 155.7, 154.4,
1
2
39.4, 129.0, 128.5, 125.0, 82.7, 81.9, 78.5, 56.8, 33.2, 28.3,
+
8.2 ppm; HRMS: [M+Na] calcd. For C20
28
H N
2
O
6
Na 415.1845,
20
Experimental
General methods
found: 415.1849; [α]
D
= +14.77 (c = 0.52 in CHCl ); The
3
enantiomeric excess was determined by HPLC analysis on
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20,
1
13
The H and C NMR spectra were recorded at 500 or 600 MHz
1
9
mL/min], λ = 210 nm, tminor = 6.22 min, tmajor = 7.26 min, ee =
5%. (by cat. 3i: tminor = 6.25 min, tmajor = 7.25 min, ee = 98%)
1
13
for H and at 125 or 150 MHz for C, respectively. The
1
13
chemical shifts (δ) for H and C are given in ppm relative to
residual signals of the solvents (CDCl
7.23 ppm C NMR). Coupling constants are given in Hz. The
di-tert-butyl
1-((3R,5R)-2-oxo-5-phenyltetrahydrofuran-3-
1
3
@ 7.24 ppm H NMR,
yl)hydrazine-1,2-dicarboxylate (5a) was obtained as a white
solid (49 mg) in 42% yield (47 mg, 40% yield by cat. 3i) for two
1
3
7
following abbreviations are used to indicate the multiplicity: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-
resolution mass spectra (HRMS) were obtained from the
Waters Q-Tof Ultima Global. X-ray data were obtained from
Zhongke chemical technology service center. Optical rotations
steps; mp = 89−91 °C; TLC: R
f
= 0.60 (petroleum ether/EtOAc =
1
4
:1 v/v); H NMR (500 MHz, CDCl ) δ 7.30 - 7.40 (m, 5H), 6.51
3
(s, 1H), 4.90 – 5.42 (m, 2H), 2.74 - 2.98 (m, 1H), 2.30 - 2.55 (m,
1
3
1
3
H), 1.44 (d, J = 17.5 Hz, 18H) ppm; C NMR (125 MHz, CDCl )
δ 173.3, 155.8, 154.6, 138.4, 129.1, 129.0, 126.0, 82.8, 81.9,
2
0
+
are reported as follows: [ɑ]
D
(c in g per 100 mL, solvent). All
7
C
1
8.7, 59.0, 34.4, 28.3 ppm; HRMS: [M+Na] calcd. For
20
the reactions were set up under air and using freshly distilled
solvents, without any precautions to exclude moisture, unless
otherwise noted, open air chemistry on the benchtop.
20
H
28
N
2
O
6
Na 415.1845, found: 415.1848; [α]
D
= -29.53 (c =
.00 in CHCl ); The enantiomeric excess was determined by
3
HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH
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Na 445.1951, found:
+
=
80/20, 1mL/min], λ = 210 nm, tminor = 7.19 min, tmajor = 12.53 HRMS: [M+Na] calcd. For C21
H
30
N
2
O
7
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2
0
DOI: 10.1039/C6OB00953K
min, ee = 93%. (by cat. 3i: tminor = 7.20 min, tmajor = 12.36 min, 445.1955; [α]
D
3
= -31.99 (c =1.00 in CHCl ); The enantiomeric
ee = 97%)
excess was determined by HPLC analysis on Daicel Chiralpak IC
di-tert-butyl
1-((3R,5S)-2-oxo-5-(p-tolyl)tetrahydrofuran-3- column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor
yl)hydrazine-1,2-dicarboxylate (4b) was obtained as a white = 10.10 min, tmajor = 19.03 min, ee = 91%.
solid (43 mg) in 35% yield (39 mg, 32% yield by cat. 3i) for two di-tert-butyl 1-((3R,5S)-5-(4-fluorophenyl)-2-
steps; mp = 76−78 °C; TLC: R = 0.75 (petroleum ether/EtOAc = oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (4d)
:1 v/v); H NMR (500 MHz, CDCl ) δ 7.10 - 7.19 (m, 4H), 6.52 was obtained as a colorless gum (44 mg) in 36% yield for two
s, 1H), 5.56 - 5.66 (m, 1H), 4.90 (d, J = 163.4 Hz, 1H), 2.79 - steps; TLC: R
.03 (m, 1H), 2.51 - 2.63 (m, 1H), 2.32 (s, 3H), 1.44 (d, J = 10.9 NMR (500 MHz, CDCl
f
1
4
(
3
3
1
f
= 0.74 (petroleum ether/EtOAc = 4:1 v/v);
) δ 7.21 - 7.27 (m, 2H), 7.02 - 7.09 (m,
) δ 173.6, 155.9, 154.5, 2H), 6.50 (s, 1H), 5.58 - 5.66 (m, 1H), 4.87 (d, J = 155.7 Hz, 1H),
38.4, 136.6, 129.7, 125.1, 82.5, 82.0, 78.7,56.6, 33.2, 28.3, 2.78 - 3.09 (m, 1H), 2.41 - 2.63 (m, 1H), 1.45 (d, J = 10.6 Hz,
H
3
1
3
Hz, 18H) ppm; C NMR (125 MHz, CDCl
3
1
2
4
+
13
8.3, 21.4 ppm; HRMS: [M+Na] calcd. For C21
H
30
N
2
O
6
Na 18H) ppm; C NMR (150 MHz, CDCl
3
) δ 173.7, 162.8 (d, JCF =
= +24.93 (c = 0.61 in CHCl ); 248 Hz), 155.6, 154.5, 135.3, 127.7, 116.2, 116.0, 83.0, 82.2,
2
0
29.2002, found: 429.2003; [α]
D
3
+
The enantiomeric excess was determined by HPLC analysis on 78.2, 57.2, 33.6, 28.3, 28.3 ppm; HRMS: [M+Na] calcd. For
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20,
2
D
0
C
20
H27FN
2
O
6
Na 433.1751, found: 433.1755; [α]
= +9.24 (c =
1
mL/min], λ = 210 nm, tminor = 6.82 min, tmajor = 7.73 min, ee = 0.67 in CHCl ); The enantiomeric excess was determined by
3
8
9%. (by cat. 3i: tminor = 6.95 min, tmajor = 7.80 min, ee = 94%)
HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH
di-tert-butyl
1-((3R,5R)-2-oxo-5-(p-tolyl)tetrahydrofuran-3- = 80/20, 1mL/min], λ = 210 nm, tminor = 5.64 min, tmajor = 6.53
yl)hydrazine-1,2-dicarboxylate (5b) was obtained as
colorless gum (50 mg) in 41% yield (46 mg, 38% yield by cat. 3i
for two steps; TLC: R
a
min, ee = 93%.
di-tert-butyl
)
1-((3R,5R)-5-(4-fluorophenyl)-2-
(5d)
) δ 7.19 – 7.30 (m, 4H), 6.55 (s, 1H), was obtained as a colorless gum (57 mg) in 46% yield for two
f
= 0.62 (petroleum ether/EtOAc = 4:1 v/v); oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate
H NMR (500 MHz, CDCl
1
3
1
4
2
CDCl
.94 - 5.43 (m, 2H), 2.77 - 2.99 (m, 1H), 2.41 - 2.60 (m, 1H), steps; TLC: R
f
= 0.62 (petroleum ether/EtOAc = 4:1 v/v).
.38 (s, 3H), 1.49 (d, J = 14.8 Hz, 18H) ppm; C NMR (125 MHz, NMR (500 MHz, CDCl ) δ 7.27 – 7.35 (m, 2H), 7.01 - 7.10 (m,
) δ 173.4, 155.7, 154.7, 138.8, 135.3, 129.7, 126.2, 125.5, 2H), 6.52 (s, 1H), 5.32 (dd, J = 10.8, 5.4 Hz, 1H), 5.13 (d, J =
H
1
3
3
3
+
8
2.8, 81.5, 78.8, 59.0, 34.8, 28.3, 21.4 ppm; HRMS: [M+Na]
138.5 Hz, 1H), 2.75 - 2.97 (m, 1H), 2.26 - 2.53 (m, 1H), 1.44 (d, J
2
D
0
13
calcd. For C21
H
30
N
2
O
6
Na 429.2002, found: 429.2004, [α]
3
= - = 15.0 Hz, 18H) ppm; C NMR (125 MHz, CDCl ) δ 173.1, 163.1
2
4.97 (c = 1.00 in CHCl
3
); The enantiomeric excess was (d, JCF = 248 Hz), 155.7, 154.1, 134.0, 128.0, 127.4, 116.2, 115.9,
+
determined by HPLC analysis on Daicel Chiralpak IC column [n- 82.8, 80.2, 78.1, 59.2, 34.2, 28.3 ppm; HRMS: [M+Na] calcd.
20
hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor = 7.72 For C20
min, tmajor = 14.41 min, ee = 89%. (by cat. 3i: tminor = 7.81 min, (c = 1.02 in CHCl
major = 14.51 min, ee = 98%) by HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-
di-tert-butyl
H
27FN
2
O
6
Na 433.1751, found: 433.1752; [α]
D
= -26.04
3
); The enantiomeric excess was determined
t
1-((3R,5S)-5-(4-methoxyphenyl)-2- PrOH = 80/20, 1mL/min], λ = 210 nm, tminor = 6.26 min, tmajor
=
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (4c) was 11.22 min, ee = 92%.
obtained as a colorless gum (47 mg) in 37% yield for two steps; di-tert-butyl
1-((3R,5S)-5-(4-chlorophenyl)-2-
1
TLC: R
f
= 0.76 (petroleum ether/EtOAc = 4:1 v/v). H NMR (500 oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate
(4e)
MHz, CDCl
3
) δ 7.17 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), was obtained as a white solid (47 mg) in 37% yield for two
6
(
.51 (s, 1H), 5.55 - 5.65 (m, 1H), 4.92 (d, J = 169.2 Hz, 1H), 3.78 steps; mp = 105-107 °C; TLC: R
f
= 0.76 (petroleum ether/EtOAc
s, 3H), 2.75 - 3.03 (m, 1H), 2.46 - 2.66 (m, 1H), 1.45 (d, J = 7.7 = 4:1 v/v); H NMR (500 MHz, CDCl ) δ 7.34 (d, J = 7.7 Hz, 2H),
) δ 173.9, 159.9, 155.8, 7.19 (d, J = 8.2 Hz, 2H), 6.50 (s, 1H), 5.55 - 5.66 (m, 1H), 4.85 (d,
54.6, 131.3, 126.7, 114.5, 82.8, 82.0, 78.6, 57.1, 55.7, 33.1, J = 149.5 Hz, 1H), 2.83 - 3.05 (m, 1H), 2.45 - 2.60 (m, 1H), 1.45
1
3
1
3
Hz, 18H) ppm; C NMR (125 MHz, CDCl
3
1
2
4
+
13
8.3, 28.3 ppm; HRMS: [M+Na] calcd. For C21
H
30
N
2
O
7
Na (d, J = 11.1 Hz, 18H) ppm; C NMR (125 MHz, CDCl
3
) δ 173.6,
2
0
45.1951, found: 445.1952; [α]
D
= +29.80 (c = 0.51 in CHCl ); 155.8, 154.5, 138.0, 134.5, 129.3, 126.5, 83.0, 82.1, 78.0, 57.0,
3
+
The enantiomeric excess was determined by HPLC analysis on 33.3, 28.3, 28.3 ppm; HRMS: [M+Na] calcd. For
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20,
2
0
C
20
H27ClN
2
O
6
Na 449.1455, found: 449.1457; [α]
D
= +27.01 (c
1
mL/min], λ = 210 nm, tminor = 8.79 min, tmajor = 10.37 min, ee = = 1.00 in CHCl
3
); The enantiomeric excess was determined by
9
3%.
HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH
di-tert-butyl
1-((3R,5R)-5-(4-methoxyphenyl)-2- = 80/20, 1mL/min], λ = 210 nm, tminor = 5.73 min, tmajor = 6.65
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (5c) was min, ee = 95%.
obtained as a colorless gum (51 mg) in 40% yield for two steps; di-tert-butyl
1-((3R,5R)-5-(4-chlorophenyl)-2-
1
TLC: R
f
= 0.63 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate
(5e)
MHz, CDCl
3
) δ 7.23 – 7.30 (m, 2H), 6.90 (dd, J = 8.6, 2.8 Hz, 2H), was obtained as a colorless gum (57 mg) in 45% yield for two
6
1
.53 (s, 1H), 4.90 –5.36 (m, 2H), 3.80 (s, 3H), 2.71 - 2.93 (m, steps; mp = 59-61 °C; TLC: R
f
= 0.63 (petroleum ether/EtOAc =
1
3
1
H), 2.32 - 2.55 (m, 1H), 1.45 (d, J = 11.6 Hz, 18H) ppm;
C
4:1 v/v); H NMR (500 MHz, CDCl ) δ 7.34 (d, J = 7.4 Hz, 2H),
3
NMR (125 MHz, CDCl
3
) δ 173.2, 160.2, 155.7, 154.5, 130.4, 7.27 (d, J = 8.0 Hz, 2H), 6.51 (s, 1H), 5.32 (dd, J = 10.6, 5.3 Hz,
1
27.8, 127.3, 114.2, 82.8, 81.3, 78.7, 59.4, 55.5, 34.7, 28.3 ppm; 1H), 5.13 (d, J = 146.1 Hz, 1H), 2.74 - 2.98 (m, 1H), 2.26 - 2.49
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 12
Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
1
3
1
(
m, 1H), 1.44 (d, J = 16.2 Hz, 18H) ppm; C NMR (125 MHz, (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz, CDCl
3
) δ
View Article Online
DOI: 10.1039/C6OB00953K
CDCl
3
) δ 173.1, 155.6, 154.5, 137.0, 135.0, 129.2, 127.5, 82.9, 8.17 - 8.26 (m, 2H), 7.69 (d, J = 5.8 Hz, 1H), 7.57 (t, J = 7.0 Hz,
2.1, 77.9, 59.1, 34.6, 28.3 ppm; HRMS: [M+Na] calcd. For 1H), 6.55 (s, 1H), 5.44 (dd, J = 10.8, 5.8 Hz, 1H), 5.13 (d, J =
Na 449.1455, found: 449.1457; [α]
.80 in CHCl ); The enantiomeric excess was determined by = 20.1 Hz, 18H) ppm; C NMR (125 MHz, CDCl ) δ 172.5, 155.8,
+
8
C
0
2
D
0
20
H27ClN
2
O
6
= -26.77 (c = 128.3 Hz, 1H), 2.90 - 3.09 (m, 1H), 2.31 - 2.55 (m, 1H), 1.43 (d, J
1
3
3
3
HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH 154.4, 148.8, 140.4, 132.1, 130.5, 124.0, 121.1, 83.2, 82.4, 59.1,
+
=
80/20, 1mL/min], λ = 210 nm, tminor = 6.39 min, tmajor = 11.15 34.4, 28.3 ppm; HRMS: [M+Na] calcd. For C20
H
27
N
3
O
8
Na
= -27.13 (c = 1.30 in CHCl );
1-((3R,5S)-5-(4-bromophenyl)-2- The enantiomeric excess was determined by HPLC analysis on
20
min, ee = 92%.
di-tert-butyl
460.1696, found: 460.1698; [α]
D
3
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (4f) was Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20,
obtained as a colorless gum (59 mg) in 42% yield for two steps; 1mL/min], λ = 210 nm, tminor = 19.61 min, tmajor = 21.69 min, ee
1
TLC: R
f
= 0.77 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 = 90%. (by cat. 3i: tminor = 19.71 min, tmajor = 21.83 min, ee =
MHz, CDCl
3
) δ 7.49 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 97%)
.51 (s, 1H), 5.51 - 5.66 (m, 1H), 4.84 (d, J = 146.7 Hz, 1H), 2.78 di-tert-butyl
3.09 (m, 1H), 2.42 - 2.62 (m, 1H), 1.45 (d, J = 10.9 Hz, 18H) oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate
6
-
1-((3R,5S)-5-(2-fluorophenyl)-2-
(4h)
1
3
ppm; C NMR (125 MHz, CDCl
3
) δ 173.3, 155.8, 154.4, 138.5, was obtained as a white solid (45 mg) in 37% yield for two
1
32.5, 126.8, 122.5, 83.0, 82.1, 78.4, 56.9, 33.4, 28.3, 28.3 ppm; steps; mp = 92-94 °C; TLC: R
f
= 0.72 (petroleum ether/EtOAc =
Na 493.0950, found: 4:1 v/v); H NMR (500 MHz, CDCl ) δ 7.28 - 7.35 (m,1H), 7.24 -
); The enantiomeric 7.28(m, 1H), 7.13 (t, J = 7.0 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H), 6.50
+
1
HRMS: [M+Na] calcd. For C20
4
H
27BrN
2
O
6
3
2
0
93.0951; [α]
D
= +23.93 (c = 0.82 in CHCl
3
excess was determined by HPLC analysis on Daicel Chiralpak IC (s, 1H), 5.74 - 5.87 (m, 1H), 4.92 (d, J = 158.1 Hz, 1H), 2.82 -
column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor 3.10 (m, 1H), 2.47 - 2.66 (m, 1H), 1.45 (d, J = 10.8 Hz, 18H) ppm;
1
3
=
5.91 min, tmajor = 6.83 min, ee = 94%.
C NMR (125 MHz, CDCl
3
) δ 174.0, 159.8 (d, JCF = 245 Hz),
di-tert-butyl
1-((3R,5R)-5-(4-bromophenyl)-2- 155.7, 154.5, 130.5, 126.3, 124.7, 116.2, 116.1, 82.9, 82.0, 74.6,
+
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (5f) was 57.0, 32.6, 28.4, 28.3 ppm; HRMS: [M+Na] calcd. For
20
obtained as a colorless gum (62 mg) in 44% yield for two steps;
C
20
H27FN
2
O
6
Na 433.1751, found: 433.1752; [α]
= 0.63 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 0.80 in CHCl ); The enantiomeric excess was determined by
MHz, CDCl ) δ 7.50 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH
.51 (s, 1H), 4.89 – 5.40 (m, 2H), 2.76 - 2.99 (m, 1H), 2.24 - = 80/20, 1mL/min], λ = 210 nm, tminor = 6.37 min, tmajor = 7.83
D
= +17.61 (c =
1
TLC: R
f
3
3
6
2
1
3
.49 (m, 1H), 1.44 (d, J = 16.2 Hz, 18H) ppm; C NMR (125 min, ee = 95%.
MHz, CDCl
3
) δ 172.9, 155.7, 154.5, 137.5, 132.2, 127.7, 123.0, di-tert-butyl
1-((3R,5R)-5-(2-fluorophenyl)-2-
+
8
2.9, 82.0, 77.7, 59.0, 34.2, 28.3 ppm; HRMS: [M+Na] calcd. oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate
(5h)
2
0
For C20
H
27BrN
2
O
6
Na 493.0950, found: 493.0952; [α]
D
= -30.18 was obtained as a white solid (52 mg) in 42% yield for two
(
c = 1.00 in CHCl
3
); The enantiomeric excess was determined steps; mp = 120-122 °C; TLC: R
f
= 0.64 (petroleum ether/EtOAc
) δ 7.42 (t, J = 7.2 Hz, 1H),
1
by HPLC analysis on Daicel Chiralpak IC column [n-hexane/i- = 4:1 v/v); H NMR (500 MHz, CDCl
3
PrOH = 80/20, 1mL/min], λ = 210 nm, tminor = 6.59 min, tmajor
1.53 min, ee = 91%.
di-tert-butyl
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (4g) was = 17.9 Hz, 18H) ppm; C NMR (125 MHz, CDCl
obtained as a yellow solid (50 mg) in 38% yield (43 mg, 33% 155.7, 154.5, 130.7, 127.3, 124.7, 116.0, 82.9, 82.0, 73.5, 58.9,
=
7.28 - 7.36 (m, 1H), 7.16 (t, J = 6.5 Hz, 1H), 7.05 (t, J = 9.1 Hz,
1
1H), 6.50 (s, 1H), 5.61 (dd, J = 10.6, 5.6 Hz, 1H), 5.16 (d, J =
1-((3R,5S)-5-(3-nitrophenyl)-2- 139.1 Hz, 1H), 2.86 - 3.04 (m, 1H), 2.26 - 2.54 (m, 1H), 1.44 (d, J
1
3
3
) δ 173.1, 161.1,
+
yield by cat. 3i) for two steps; mp = 80-82 °C; TLC: R
f
= 0.69 33.7, 28.3 ppm; HRMS: [M+Na] calcd. For C20
H
27FN
2
O
6
Na
1
20
(
petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz, CDCl
3
) δ 433.1751, found: 433.1750; [α]
D
= -25.30 (c = 0.99 in CHCl );
3
8
1
1
.19 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.53 – 7.66 (m, 2H), 6.55 (s, The enantiomeric excess was determined by HPLC analysis on
H), 5.61-5.81 (m, 1H), 4.82 (d, J = 106.0 Hz, 1H), 2.90 - 3.21 (m, Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20,
1
3
H), 2.49 – 2.64 (m, 1H), 1.46 (d, J = 12.8 Hz, 18H) ppm;
) δ 173.1, 155.6, 154.4, 148.9, 141.5, 94%.
31.3, 130.5, 123.6, 120.4, 83.3, 82.3, 57.2, 33.6, 28.3, 28.3 di-tert-butyl
C
1mL/min], λ = 210 nm, tminor = 7.40 min, tmajor = 9.99 min, ee =
NMR (150 MHz, CDCl
1
ppm; HRMS: [M+Na] calcd. For C20
3
1-((3R,5S)-5-(naphthalen-2-yl)-2-
+
H
27
N
3
O
8
Na 460.1696, oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (4i) was
20
found: 460.1695; [α]
D
= +11.51 (c = 1.47 in CHCl
3
); The obtained as a white solid (45 mg) in 34% yield for two steps;
= 0.66 (petroleum ether/EtOAc = 4:1
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20, v/v); H NMR (500 MHz, CDCl ) δ 7.79 - 7.89 (m, 3H), 7.73 (s,
enantiomeric excess was determined by HPLC analysis on mp = 129-131 °C; TLC: R
f
1
3
1
=
9
mL/min], λ = 210 nm, tminor = 15.93 min, tmajor = 20.79 min, ee 1H), 7.46 – 7.53 (m, 2H), 7.32 (d, J = 8.5 Hz, 1H), 6.52 (s,1H),
88%. (by cat. 3i: tminor = 15.93 min, tmajor = 20.78 min, ee = 5.75 - 5.87 (m, 1H), 4.94 (d, J = 157.6 Hz, 1H), 2.89 - 3.16 (m,
1
3
8%)
1H), 2.57 - 2.76 (m, 1H), 1.46 (d, J = 16.4 Hz, 18H) ppm;
C
di-tert-butyl
1-((3R,5S)-5-(3-nitrophenyl)-2- NMR (125 MHz, CDCl ) δ 174.0, 155.8, 154.6, 136.8, 133.3,
3
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (5g) was 129.2, 128.3, 127.9, 126.9, 126.7, 123.8, 123.0, 82.9, 82.1, 78.7,
+
obtained as a yellow gum (51 mg) in 39% yield (54 mg, 41% 57.0, 33.3, 28.4, 28.3 ppm; HRMS: [M+Na] calcd. For
20
yield by cat. 3i) for two steps; mp = 52-53 °C; TLC: R
f
= 0.60
C
24
H
30
N
2
O
6
Na 465.2002, found: 465.2001; [α]
D
= +54.29 (c =
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 8 of 12
ARTICLE
Journal Name
+
0
.99 in CHCl
3
View Article Online
); The enantiomeric excess was determined by 57.2, 41.6, 30.0, 28.3 ppm; HRMS: [M+Na] calcd. For
2
0
DOI: 10.1039/C6OB00953K
HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH
C
21
H
30
N
2
O
6
Na 429.2002, found: 429.2003; [α]
D
= +7.25 (c =
=
80/20, 1mL/min], λ = 210 nm, tminor = 7.26 min, tmajor = 8.06 0.48 in CHCl ); The enantiomeric excess was determined by
3
min, ee = 94%.
di-tert-butyl
HPLC analysis on Daicel Chiralpak IB column [n-hexane/i-PrOH
1-((3R,5R)-5-(naphthalen-2-yl)-2- = 85/15, 1mL/min], λ = 210 nm, tmajor = 7.65 min, tminor = 9.21
oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (5i) was min, ee = 94%.
obtained as a colorless gum (55 mg) in 41% yield for two steps; di-tert-butyl
1-((3R,5S)-5-benzyl-2-oxotetrahydrofuran-3-
1
TLC: R
f
= 0.56 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 yl)hydrazine-1,2-dicarboxylate (5k) was obtained as
a
MHz, CDCl
3
) δ 7.78 - 7.89 (m, 4H), 7.46 - 7.54 (m, 2H), 7.42 (d, J colorless gum (34 mg) in 28% yield for two steps; TLC: R
f
= 0.64
1
=
8.4 Hz, 1H), 6.53 (s, 1H), 5.53 (dd, J = 10.9, 5.5 Hz, 1H), 5.21 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz, CDCl
3
) δ
(
d, J = 161.5 Hz, 1H), 2.92 - 3.09 (m, 1H), 2.40 - 2.67 (m, 1H), 7.25 - 7.33 (m, 2H), 7.21 - 7.24 (m, 1H), 7.19 (d, J = 7.0 Hz, 2H),
1
3
1
1
1
.44 (d, J = 28.2 Hz, 18H) ppm; C NMR (125 MHz, CDCl
3
) δ 6.40 (s, 1H), 4.97 (d, J = 173.5 Hz, 1H), 4.49 - 4.62 (m, 1H), 3.07
73.5, 155.7, 154.5, 135.7, 133.5, 133.2, 129.0, 128.3, 128.0, (dd, J = 13.6, 5.8 Hz, 1H), 2.92 (dd, J = 13.4, 4.8 Hz, 1H), 2.45 -
1
3
26.8, 125.3, 123.3, 82.8, 81.9, 78.5, 59.0, 34.3, 28.3 ppm; 2.60 (m, 1H), 1.94 - 2.28 (m, 1H), 1.44 (s, 18H) ppm; C NMR
+
HRMS: [M+Na] calcd. For C24
H
30
N
2
O
6
Na 465.2002, found: (125 MHz, CDCl
= -37.75 (c = 1.00 in CHCl ); The enantiomeric 127.3, 82.9, 81.9, 78.3,58.5, 42.0, 31.9, 28.3 ppm; HRMS:
excess was determined by HPLC analysis on Daicel Chiralpak IC [M+Na] calcd. For C21
3
) δ 174.0, 155.7, 154.6, 135.8, 129.6, 129.0,
2
0
4
65.2004; [α]
D
3
+
H
30
2
N O
6
Na 429.2002, found: 429.2005;
2
D
0
column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor [α]
8.35 min, tmajor = 15.47 min, ee = 92%.
= -18.09 (c = 0.42 in CHCl ); The enantiomeric excess was
3
=
determined by HPLC analysis on Daicel Chiralpak IB column [n-
di-tert-butyl
1-((3R,5S)-2-oxo-5-(thiophen-2- hexane/i-PrOH = 85/15, 1mL/min], λ = 210 nm, tminor = 12.47
yl)tetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (4j) was min, tmajor = 18.74 min, ee = 89%.
obtained as a white solid (36 mg) in 30% yield for two steps; di-tert-butyl 1-((3R,5R)-5-methyl-2-oxotetrahydrofuran-3-
mp = 117-118 °C; TLC: R = 0.77 (petroleum ether/EtOAc = 4:1 yl)hydrazine-1,2-dicarboxylate (4l) was obtained as a white
v/v); H NMR (500 MHz, CDCl ) δ 7.31 (s, 1H), 7.04 (s, 1H), 6.98 solid (38 mg) in 38% yield for two steps; mp = 94-96 °C; TLC: R
f
1
3
f
1
(
s, 1H), 6.48 (s, 1H), 5.76 - 5.88 (m, 1H), 5.06 (d, J = 134.5 Hz, = 0.72 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz,
1
H), 2.83 - 3.06 (m, 1H), 2.69 – 2.81 (m, 1H), 1.46 (s, 18H) ppm; CDCl
3
) δ 6.42 (s, 1H), 5.99 – 5.26 (m, 1H), 4.68 – 4.80 (m, 1H),
1
3
C NMR (125 MHz, CDCl
26.5, 125.6, 83.0, 82.1, 75.7, 57.3, 33.7, 28.4, 28.3 ppm; = 6.5 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
) δ 173.3, 155.6, 154.5, 142.1, 127.7, 2.48 - 2.73 (m, 1H), 2.12 - 2.25 (m, 1H), 1.45 (s, 18H), 1.37 (d, J
1
3
1
3
) δ 173.8, 155.7,
SNa 421.1409, found: 154.6, 82.8, 82.0, 75.1, 57.1, 32.1, 28.3, 21.8 ppm; HRMS:
+
HRMS: [M+Na] calcd. For C18
H
26
N
2
O
6
2
0
+
4
21.1408; [α]
excess was determined by HPLC analysis on Daicel Chiralpak IC [α]
column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor determined by HPLC analysis on Daicel Chiralpak IC column [n-
7.50 min, tmajor = 9.01 min, ee = 94%. hexane/i-PrOH = 80/20, 1mL/min], λ = 230 nm, tminor = 7.65
1-((3R,5R)-2-oxo-5-(thiophen-2- min, tmajor = 9.21 min, ee = 96%.
D
= +21.71 (c = 0.21 in CHCl
3
); The enantiomeric [M+Na] calcd. For C15
H
26
2
N O
6
Na 353.1689, found: 353.1688;
2
0
D
= +2.31 (c = 0.59 in CHCl ); The enantiomeric excess was
3
=
di-tert-butyl
yl)tetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (5j) was di-tert-butyl
1-((3R,5S)-5-methyl-2-oxotetrahydrofuran-3-
obtained as a white solid (37 mg) in 31% yield for two steps; yl)hydrazine-1,2-dicarboxylate (5l) was obtained as a white
mp = 132-134 °C; TLC: R = 0.64 (petroleum ether/EtOAc = 4:1 solid (45 mg) in 45% yield for two steps; mp = 48-49 °C; TLC: R
f
f
1
1
v/v); H NMR (500 MHz, CDCl
3
) δ 7.36 (s, 1H), 7.12 (d, J = 2.6 = 0.68 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz,
) δ 6.43 (s, 1H), 5.00 (d, J = 185.3 Hz, 1H), 4.42 – 4.53 (m,
.13 (d, J = 199.2 Hz, 1H), 2.90 – 3.03 (m, 1H), 2.45 - 2.65 (m, 1H), 2.45 - 2.70 (m, 1H), 1.89 - 2.17 (m, 1H), 1.45 (s, 18H), 1.42
Hz, 1H), 7.00 (s, 1H), 6.49 (s, 1H), 5.57 (dd, J = 11.0, 5.5 Hz, 1H), CDCl
3
5
1
1
1
3
13
3 3
H), 1.46 (s, 18H) ppm; C NMR (125 MHz, CDCl ) δ 172.6, (d, J = 6.4 Hz, 3H) ppm; C NMR (125 MHz, CDCl ) δ 173.6,
55.8, 154.5, 140.6, 127.4, 82.9, 82.0, 74.4, 58.8, 34.7, 28.3 155.8, 154.6, 82.7, 81.9, 74.6, 58.9, 33.5, 28.3, 21.1 ppm;
+
+
ppm; HRMS: [M+Na] calcd. For C18
H
26
N
2
O
6
SNa 421.1409, HRMS: [M+Na] calcd. For C15
H
26
N
2
O
6
Na 353.1689, found:
= -17.61 (c = 1.07 in CHCl ); The enantiomeric
2
0
20
found: 421.1409; [α]
D
= -54.47 (c = 0.45 in CHCl
3
); The 353.1689; [α]
D
3
enantiomeric excess was determined by HPLC analysis on excess was determined by HPLC analysis on Daicel Chiralpak IC
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20, column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor
1
9
mL/min], λ = 210 nm, tminor = 8.39 min, tmajor = 14.13 min, ee = = 7.62 min, tmajor = 12.23 min, ee = 93%.
2%. diethyl 1-((3R,5S)-2-oxo-5-phenyltetrahydrofuran-3-
1-((3R,5R)-5-benzyl-2-oxotetrahydrofuran-3- yl)hydrazine-1,2-dicarboxylate (4m) was obtained as a
yl)hydrazine-1,2-dicarboxylate (4k) was obtained as a white colorless gum (39 mg) in 39% yield (41 mg, 41% yield by cat. 3i
solid (35 mg) in 29% yield for two steps; mp = 104-106 °C; TLC: for two steps; TLC: R = 0.74 (petroleum ether/EtOAc = 3:1 v/v);
= 0.69 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz, H NMR (500 MHz, CDCl ) δ 7.38 (t, J = 7.2 Hz, 2H), 7.30 – 7.35
CDCl ) δ 7.30 (t, J = 7.3 Hz, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.19 (d, (m, 1H), 7.26 (d, J = 7.5 Hz, 2H), 6.74 (s, 1H), 5.60 - 5.73 (m, 1H),
J = 7.2 Hz, 2H), 6.37 (s, 1H), 4.64 - 5.05 (m, 2H), 2.95 - 3.07 (m, 5.00 (d, J = 64.1 Hz, 1H), 4.15 - 4.26 (m, 4H), 2.89 - 3.03 (m, 1H),
di-tert-butyl
)
f
1
1
R
f
3
3
1
3
1
1
1
H), 2.85 - 2.95 (m, 1H), 2.43 - 2.60 (m, 1H), 2.30 – 2.41 (m, 2.56 – 2.69 (m, 1H), 1.26 (dt, J = 14.1, 7.2 Hz, 6H) ppm;
C
1
3
H), 1.42 (s, 18H) ppm; C NMR (125 MHz, CDCl
3 3
) δ 173.5, NMR (125 MHz, CDCl ) δ 173.3, 156.7, 155.6, 139.3, 129.1,
55.6, 154.4, 135.6, 130.0, 129.7, 129.5, 127.4, 82.8, 81.5, 78.8, 128.7, 125.1, 78.6, 63.6, 62.7, 57.8, 33.2, 14.7 ppm; HRMS:
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 9 of 12
Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
+
13
[
[
M+Na] calcd. For C16
H
20
N
2
O
6
Na 359.1219, found: 359.1217; 1H), 1.96 – 2.10 (m, 2H), 1.45 (d, J = 9.5 Hz, 18H) ppm;
C
View Article Online
2
0
DOI: 10.1039/C6OB00953K
) δ 171.8, 155.5, 155.2, 138.6, 128.9,
α]
D
= +19.32 (c = 1.00 in CHCl
3
); The enantiomeric excess NMR (150 MHz, CDCl
3
was determined by HPLC analysis on Daicel Chiralpak IC 128.7, 126.7, 82.5, 81.2, 79.4, 54.8, 29. 9, 29.7, 28.4, 28.2 ppm;
+
column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor HRMS: [M+Na] calcd. For C21
H
30
N
2
O
6
Na 429.2002, found:
= -20.14 (c = 0.50 in CHCl ); The enantiomeric
excess was determined by HPLC analysis on Daicel Chiralpak IA
2
0
=
1
20.01 min, tmajor = 21.39 min, ee = 87%. (by cat. 3i: tminor
9.67 min, tmajor = 20.90 min, ee = 89%)
=
429.2005; [α]
D
3
diethyl
1-((3R,5R)-2-oxo-5-phenyltetrahydrofuran-3- column [n-hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tmajor
yl)hydrazine-1,2-dicarboxylate (5m) was obtained as a white = 8.47 min, tminor = 11.11 min, ee = 93%.
solid (44 mg) 44% yield (45 mg, 45% yield by cat. 3i) for two di-tert-butyl 1-((3R,6R)-2-oxo-6-phenyltetrahydro-2H-pyran-
steps; mp = 108-109 °C; TLC: R
=
f
= 0.65 (petroleum ether/EtOAc 3-yl)hydrazine-1,2-dicarboxylate (5o) was obtained as a white
3:1 v/v); H NMR (500 MHz, CDCl ) δ 7.30 - 7.41 (m, 5H), 6.74 solid (35 mg) in 29% yield for two steps; mp = 110-111 °C; TLC:
s, 1H), 5.38 (dd, J = 11.1, 5.5 Hz, 1H), 5.26 (d, J = 86.0 Hz, 1H),
1
3
1
(
R
f
= 0.70 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz,
.06 – 4.29 (m, 4H), 2.85 - 3.02 (m, 1H), 2.32 - 2.51 (m, 1H), CDCl ) δ 7.27 – 7.39 (m, 5H), 6.49 (s, 1H), 5.30 – 5.42 (m, 1H),
) δ 173.0, 4.71 (d, J = 166.7 Hz, 1H), 2.34 - 2.50 (m, 1H), 2.20 – 2.32 (m,
4
1
1
3
3
3
1
3
.21 - 1.27 (m, 6H) ppm; C NMR (125 MHz, CDCl
56.6, 155.7, 138.1, 129.1, 129.0, 126.0, 78.7, 63.6, 62.7, 59.6, 2H), 2.03 – 2.11 (m, 1H), 1.46 (s, 18H) ppm; C NMR (150 MHz,
3
1
3
+
4.6, 14.6 ppm; HRMS: [M+Na] calcd. For C16
59.1219, found: 359.1218; [α]
H
20
N
2
O
6
Na CDCl
3
) δ 169.5, 155.7, 154.9, 139.4, 129.0, 128.9, 128.7, 125.9,
20
D
= -26.42 (c = 1.00 in CHCl ); 125.8, 83.5, 82.5, 81.5, 58.7, 31.1, 29.9, 28.3 ppm; HRMS:
3
+
The enantiomeric excess was determined by HPLC analysis on [M+Na] calcd. For C21
H
30
N
2
O
6
Na 429.2002, found: 429.2003;
); The enantiomeric excess was
mL/min], λ = 210 nm, tminor = 8.07 min, tmajor = 16.69 min, ee = determined by HPLC analysis on Daicel Chiralpak IC column [n-
4%. (by cat. 3i: tminor = 7.93 min, tmajor = 15.80 min, ee = 88%) hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor = 7.70
1-((3R,5S)-2-oxo-5-phenyltetrahydrofuran-3- min, tmajor = 9.06 min, ee = 95%.
yl)hydrazine-1,2-dicarboxylate (4n) was obtained as di-tert-butyl 1-((3R,5S)-2-oxo-5-phenyl-1-tosylpyrrolidin-3-
colorless gum (45 mg) in 41% yield (45 mg, 41% yield by cat. 3i yl)hydrazine-1,2-dicarboxylate (4p) was obtained as a white
for two steps; TLC: R = 0.70 (petroleum ether/EtOAc = 4:1 v/v); solid (59 mg, 36% yield by cat. 3i) for two steps; mp = 84-85 °C;
2
0
Daicel Chiralpak IB column [n-hexane/i-PrOH = 80/20, [α]
D
= -2.88 (c = 0.78 in CHCl
3
1
8
diisopropyl
a
)
f
1
1
H NMR (500 MHz, CDCl
3
) δ 7.35 - 7.41 (m, 2H), 7.29 - 7.35 (m, TLC: R
H), 7.26 (d, J = 7.5 Hz, 2H), 6.63 (s, 1H), 5.61 - 5.71 (m, 1H), MHz, CDCl
.79 – 5.17 (m, 3H), 2.89 - 3.04 (m, 1H), 2.56 – 2.67 (m, 1H), 7.19 (m, 2H), 6.98 – 7.12 (m, 2H), 6.31 (s, 1H), 5.44 (d, J = 8.4
f
= 0.20 (petroleum ether/EtOAc = 6:1 v/v); H NMR (500
1
4
1
1
3
3
3
) δ 7.51 - 7.59 (m, 2H), 7.25 – 7.31 (m, 3H), 7.13 –
1
3
.22 – 1.29 (m, 12H) ppm; C NMR (150 MHz, CDCl
56.5, 155.1, 139.4, 129.2, 128.6, 125.1, 78.7, 71.6, 70.7, 57.4, Hz, 1H), 2.38 (s, 3H), 2.32 (dd, J = 12.2, 5.7 Hz, 1H), 1.42 (d, J =
3.6, 22.2, 22.1 ppm; HRMS: [M+Na] calcd. For C18
87.1532, found: 387.1534; [α]
3
) δ 173.6, Hz, 1H), 5.36 (d, J = 63.1 Hz, 1H), 2.65 (ddd, J = 31.1, 19.1, 9.1
+
13
H
24
N
2
O
6
Na 26.8 Hz, 18H) ppm; C NMR (125 MHz, CDCl
3
) δ 170.3, 155.7,
2
0
D
= +19.56 (c = 1.00 in CHCl ); 154.7, 145.5, 139.7, 135.2, 129.4, 129.1, 128.8, 128.4, 126.2,
3
The enantiomeric excess was determined by HPLC analysis on 82.8, 81.8, 60.1, 58.4, 53.7, 32.6, 28.2, 21.9 ppm; HRMS:
+
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20, [M+Na] calcd. For C27
H
35
N
3
O
7
SNa 568.2093, found: 568.2095;
= -43.55 (c = 1.00 in CHCl ); The enantiomeric excess was
determined by HPLC analysis on Daicel Chiralpak IC column [n-
2
0
1
mL/min], λ = 210 nm, tminor = 9.82 min, tmajor = 11.38 min, ee = [α]
0%. (by cat. 3i: tminor = 9.73 min, tmajor = 11.23 min, ee = 94%.)
D
3
9
diisopropyl
yl)hydrazine-1,2-dicarboxylate (5n) was obtained as a white min, tmajor = 18.85 min, ee = 97%.
solid (48 mg) in 44% yield (44 mg, 40% yield by cat. 3i) for two di-tert-butyl 1-((3R,5R)-2-oxo-5-phenyl-1-tosylpyrrolidin-3-
steps; mp = 147-148 °C; TLC: R = 0.62 (petroleum ether/EtOAc yl)hydrazine-1,2-dicarboxylate (5p) was obtained as a white
4:1 v/v); H NMR (500 MHz, CDCl ) δ 7.30 – 7.40 (m, 5H), solid (57 mg, 35% yield by cat. 3i) for two steps; mp = 176-
.61 (s, 1H), 5.06 - 5.43 (m, 2H), 4.83 - 5.01 (m, 2H), 2.78 - 2.99 177 °C; TLC: R
1-((3R,5R)-2-oxo-5-phenyltetrahydrofuran-3- hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor = 11.81
f
1
=
6
3
1
f
= 0.15 (petroleum ether/EtOAc = 6:1 v/v);
) δ 7.45 (d, J = 52.3 Hz, 2H), 7.06 – 7.32
) δ 173.1, 156.6, 155.2, 138.2, 129.1, 126.0, (m, 7H), 6.41 (s, 1H), 4.83 – 5.34 (m, 2H), 2.82 (s, 1H), 2.39 (s,
H
1
3
(
(
m, 1H), 2.27 - 2.52 (m, 1H), 1.18 - 1.31 (m, 12H) ppm; C NMR NMR (500 MHz, CDCl
125 MHz, CDCl
3
3
+
13
7
8.7, 71.5, 70.6, 59.4, 34.7, 22.2, 22.2 ppm; HRMS: [M+Na]
3H), 2.16 (s, 1H), 1.41 (dd, J = 17.2, 13.0 Hz, 18H) ppm;
= - NMR (125 MHz, CDCl ) δ 170.6, 155.6, 154.4, 145.2, 141.0,
3
); The enantiomeric excess was 135.7, 129.5, 128.8, 128.5, 127.6, 127.2, 82.6, 81.8, 60.4, 59.0,
C
2
0
calcd. For C18
2
H
24
N
2
O
6
Na 387.1532, found: 387.1535; [α]
D
3
4.83 (c = 1.00 in CHCl
+
determined by HPLC analysis on Daicel Chiralpak IC column [n- 53.6, 32.3, 28.3, 21.9 ppm; HRMS: [M+Na] calcd. For
hexane/i-PrOH = 80/20, 1mL/min], λ = 210 nm, tminor = 10.83
2
0
C
27
H
35
N
3
O
7
SNa 568.2093, found: 568.2096; [α]
D
= -12.21 (c =
min, tmajor = 23.17 min, ee = 86%. (by cat. 3i: tminor = 10.79 min, 1.00 in CHCl ); As compound rac-5p couldn’t be separated by
3
t
major = 22.95 min, ee = 93%.)
di-tert-butyl 1-((3R,6S)-2-oxo-6-phenyltetrahydro-2H-pyran- excess of product N-Boc-5p was determined by HPLC analysis
-yl)hydrazine-1,2-dicarboxylate (4o) was obtained as a white on Daicel Chiralpak IC column [n-hexane/i-PrOH = 70/30,
solid (29 mg) in 24% yield for two steps; mp = 105-107 °C; TLC: 1mL/min], λ = 210 nm, tminor = 31.81 min, tmajor = 35.97 min, ee
chiral HPLC, N-Boc-5q was obtained and the enantiomeric
3
1
R
f
= 0.73 (petroleum ether/EtOAc = 4:1 v/v); H NMR (500 MHz, = 98%.
CDCl ) δ 7.29 – 7.39 (m, 5H), 6.62 (s, 1H), 5.37 (dd, J = 9.9, 2.7 di-tert-butyl
Hz, 1H), 4.88 - 5.34 (m, 1H), 2.33 - 2.48 (m, 1H), 2.22 - 2.30 (m, butyldimethylsilyl)oxy)methyl)-2-oxo-1-tosylpyrrolidin-3-
3
1-((3R,5S)-5-(((tert-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 10 of 12
ARTICLE
Journal Name
yl)hydrazine-1,2-dicarboxylate (4q) was obtained as a white Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20,
View Article Online
DOI: 10.1039/C6OB00953K
solid (53 mg, 29% yield by cat. 3i) for two steps; mp = 52-53 °C; 1mL/min], λ = 210 nm, tmajor = 7.24 min, tminor = 12.50 min, ee =
1
TLC: R
f
= 0.20 (petroleum ether/EtOAc = 8:1 v/v); H NMR (500 -92%.
MHz, CDCl
3
) δ 7.91 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), General procedure for the synthesis of α-amino lactone
.21 (s, 1H), 5.08 (d, J = 148.9 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), derivatives. To a solution of 5a (35 mg, 0.089 mmol) in
6
3
2
=
1
2
C
0
o
.97 – 4.12 (m, 1H), 3.69 (d, J = 9.3 Hz, 1H), 2.40 (s, 3H), 2.23 – dichloromethane (1 mL) was added TFA (0.5 mL) at 0 C. After
.37 (m, 2H), 1.40 (d, J = 20.5 Hz, 18H), 0.78 (s, 9H), -0.00 (d, J stirring at room temperature for 3h, the mixture was
1
3
33.1 Hz, 6H) ppm; C NMR (125 MHz, CDCl
3
) δ 171.2, 155.8, concentrated and desolved in etanol/aceticacid (0.6 mL/0.2
54.2, 145.2, 136.2, 129.7, 128.4, 82.1, 81.5, 65.0, 58.3, 42.2, mL), then Raney Ni (89 mg) was added and purging with H
2
,
+
8.3, 27.8, 26.0, 21.8, 18.3, -5.3 ppm; HRMS: [M+H] calcd. For the mixture was stirred overnight. Then the mixture was
20
28
H
48
N
3
O
8
SSi 614.2931, found: 614.2933; [α]
D
= -35.44 (c = filtered and concentrated and dissolved in dichloromethane (1
.50 in CHCl ); The enantiomeric excess was determined by mL), Triethylamine (10mg, 0.1 mmol), DMAP (4.4 mg, 0.036
3
HPLC analysis on Daicel Chiralpak IC column [n-hexane/i-PrOH mmol) and di-tert-butyl dicarbonate (21.8mg, 0.1 mmol) was
o
=
80/20, 1mL/min], λ = 210 nm, tminor = 6.33 min, tmajor = 8.11 added at 0 C. After stirring for 10h at room temperature, 1M
min, ee = 93%.
HCl solution was added into the mixture, which was then
di-tert-butyl
1-((3R,5R)-5-(((tert- extracted with dichloromethane. The combined organic layer
butyldimethylsilyl)oxy)methyl)-2-oxo-1-tosylpyrrolidin-3-
yl)hydrazine-1,2-dicarboxylate (5q) was obtained as a white give a residue which was purified by flash chromatography to
solid (52 mg, 28% yield by cat. 3i) for two steps; mp = 67-68 °C; give . For the synthesis of compound 4a (59 mg, 0.15 mmol)
= 0.15 (petroleum ether/EtOAc = 8:1 v/v); H NMR (500 was added instead of 5a, following the first step of the
MHz, CDCl ) δ 7.87 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), procedure above and then recrystallized from
.24 (s, 1H), 4.77 (d, J = 117.3 Hz, 1H), 3.82 – 4.21 (m, 3H), 2.35 dichloromethane.
2.47 (m, 4H), 2.11 – 2.22 (m, 1H), 1.41 (d, J = 9.9 Hz, 18H), tert-butyl
2 4
was dried over Na SO , filtered and concentrated in vacuo to
8
9,
1
TLC: R
f
3
6
–
0
1
5
((3R,5R)-2-oxo-5-phenyltetrahydrofuran-3-
) δ yl)carbamate (8) was obtained as white solid (4.6 mg) in 19%
1
3
.83 (s, 9H), 0.03 (s, 6H) ppm; C NMR (125 MHz, CDCl
3
71.3, 155.7, 154.7, 145.5, 135.6, 129.8, 128.5, 82.5, 81.7, 64.1, yield; mp = 166-168 °C ; TLC: R
f
=0.55 (petroleum ether/EtOAc =
8.1, 42.3, 28.3, 28.3, 26.1, 24.9, 21.9, 18.4, -5.2, -5.3 ppm; 3:1 v/v); H NMR (500 MHz, CDCl ) δ 7.32–7.41 (m, 5H), 5.38
SSi 614.2931, found: (dd, J=11.2, 5.2 Hz, 1H), 5.05–5.17 (m, 1H), 4.51-4.61 (m, 1H),
= -2.69 (c = 1.00 in CHCl ); The enantiomeric 3.05–3.19 (m, 1H), 2.13 (dd, J=23.8, 11.9 Hz, 1H), 1.44 (s, 9H)
excess was determined by HPLC analysis on Daicel Chiralpak IB ppm; C NMR (125MHz, CDCl
column [n-hexane/i-PrOH = 90/10, 1mL/min], λ = 210 nm, tminor 129.0, 126.0, 80.9, 78.9, 52.2, 39.6, 28.5 ppm; HRMS: [M+Na]
1
3
+
48 3 8
HRMS: [M+H] calcd. For C28H N O
6
20
14.2935; [α]
D
3
1
3
3
) δ 174.7, 155.6, 138.0, 129.1+,
20
=
9.53 min, tmajor = 11.55 min, ee = 94%.
di-tert-butyl 1-((3S,5R)-2-oxo-5-phenyltetrahydrofuran-3- 7.17 (c = 0.18 in CHCl
yl)hydrazine-1,2-dicarboxylate ((-)-4a) was obtained by cat. (- determined by HPLC analysis on Daicel Chiralpak IB column [n-
3d as a white solid (43 mg) in 37% yield for two steps; mp = hexane/i-PrOH=80/20, 1mL/min], λ=210 nm, tmajor=7.19 min,
12-113 °C; TLC: R = 0.75 (petroleum ether/EtOAc = 4:1 v/v); minor=8.34 min, ee = 93%.
H NMR (500 MHz, CDCl ) 7.28 – 7.41 (m, 3H), 7.25 (d, J = 8.0 2-((3R,5S)-2-oxo-5-phenyltetrahydrofuran-3-yl)hydrazin-1-
Hz, 2H), 6.47 (s, 1H), 5.59 – 5.69 (m, 1H), 4.91 (d, J = 164.9 Hz, ium 2,2,2-trifluoroacetate (9) was obtained as white solid
calcd. For C15
H
19NO
4
Na 300.1212, found: 300.1213; [α]
D
-
3
); The enantiomeric excess was
)
-
1
f
t
1
3
1
1
1
2
H), 2.80 – 3.09 (m 1H), 2.48 – 2.65 (m, 1H), 1.45 (d, J = 12.0 Hz, (45.8 mg) in 70% yield; TLC: R
f
=0.35 (CH
-DMSO) δ 9.27 (s, 3H), 7.41–7.46 (m, 2H),
39.4, 129.2, 128.6, 125.6, 82.8, 82.1, 78.6, 56.7, 33.6, 28.3, 7.36–7.41 (m, 3H), 6.16 (s, 1H), 5.74 (dd, J=7.3, 5.8 Hz, 1H),
2 2
Cl :MeOH = 20:1 v/v);
1
3
1
8H) ppm; C NMR (150 MHz, CDCl
3
) δ 173.5, 155.8, 154.5,
H NMR (500 MHz, d
6
+
28 2 6
8.3 ppm; HRMS: [M+Na] calcd. For C20H N O Na 415.1845, 4.07 (t, J=7.4 Hz, 1H), 2.60 (dt, J=14.1, 7.2 Hz, 1H), 2.53 (dd,
20
13
found: 415.1846; [α]
D
3 6
= -16.17 (c = 1.00 in CHCl ); The J=8.2, 5.5 Hz, 1H) ppm; C NMR (125MHz, d -DMSO) δ 174.2,
enantiomeric excess was determined by HPLC analysis on 139.0, 128.7, 128.5, 125.7, 78.9, 56.1, 34.6 ppm; HRMS:
+
Daicel Chiralpak IC column [n-hexane/i-PrOH = 80/20, [M+H] calcd. For C10
H
13
N
2
O
2
193.0977, found: 193.0979;
+24.43 (c = 0.30 in DMSO).
General procedure for the synthesis of bicyclic oxazolidinone
1-((3S,5S)-2-oxo-5-phenyltetrahydrofuran-3- 12. Compound 10 and 13 were prepared following the general
yl)hydrazine-1,2-dicarboxylate ((-)-5a) was obtained by cat. (- procedure of the first step. 10 (39.5 mg, 0.1 mmol) was
3d as a white solid (48 mg) in 41% yield for two steps; mp = dissolved in dichloromethane (1 ml), and BF •OEt (42.6 mg,
7-88 °C; TLC: R = 0.60 (PE:EA, 4:1 v/v); H NMR (500 MHz, 0.3 mmol) was added at 0 C. After stirring at 0 C for 1.5h, the
2
0
1
9
mL/min], λ = 210 nm, tmajor = 6.27 min, tminor = 7.31 min, ee = - [α]
2%.
D
=
di-tert-butyl
)
8
-
3
2
1
o
o
f
CDCl
3
) δ 7.29 – 7.41 (m, 5H), 6.49 (s, 1H), 4.93 – 5.48 (m, 2H), mixture was concentrated in vacuo and purified by flash
2
1
1
.75 – 3.01 (m, 1H), 2.24 – 2.54 (m, 1H), 1.44 (d, J = 18.2 Hz, chromatography to afford compound 11. To a solution of 11
1
3
8H) ppm; C NMR (150 MHz, CDCl
3
) δ 173.9, 155.8, 154.5, (22 mg, 0.1 mmol) in methanol (1 mL) was added Raney Ni
. After stirring at room
Na 415.1845, temperature for 12h, the mixture was filtered and
= +22.57 (c = 1.00 in CHCl ); The concentrated in vacuo, and compound 12 was obtained after
enantiomeric excess was determined by HPLC analysis on flash chromatography.
39.0, 129.0, 129.0, 126.1, 83.0, 82.0, 78.7, 59.0, 34.5, 28.3 (100 mg) and purging with H
2
+
28 2 6
ppm; HRMS: [M+Na] calcd. For C20H N O
found: 415.1845; [α]
20
D
3
1
0 | J. Name., 2012, 00, 1-3
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Page 11 of 12
Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
2
012, 48, 3336-3338. For review, see: (c) L. C.VMiewillAertriclaenOdnliRne.
(
2
3aR,5S,6aR)-1-amino-5-phenyltetrahydrofuro[3,2-d]oxazol-
(3aH)-one (11) was obtained as white solid (19.5 mg) in 89%
yield; mp =59-61 °C ; TLC: R =0.20 (petroleum ether/EtOAc =
:1 v/v); H NMR (600 MHz, CDCl ) δ 7.29–7.37 (m, 5H), 6.12 (d,
J=5.5 Hz, 1H), 5.13 (dd, J=11.1, 4.6 Hz, 1H), 4.46 (t, J=5.7 Hz,
H), 4.04 (s, 2H), 2.64 (dd, J=13.6, 4.6 Hz, 1H), 1.89 (ddd,
Sarpong, Chem. Soc. Rev. 2011, 40, 4550-4562.
DOI: 10.1039/C6OB00953K
2
3
For selected reviews, see: (a) M. Teplitski, U. Mathesius and
K. P. Rumbaugh, Chem. Rev. 2011, 111, 100-116; (b) D. M.
Stacy, M. A. Welsh, P. N. Rather and H. E. Blackwell, ACS
Chem. Biol. 2012, 7, 1719-1728; (c) M. Schuster, D. J. Sexton,
S. P. Diggle and E. P. Greenberg, Annu. Rev. Microbiol. 2013
67, 43-63.
(a) S. R. Donohue, J. H. Krushinski, V. W. Pike, E. Chernet, L.
Phebus, A. K. Chesterfield, C. C. Felder, C. Halldin and J. M.
Schaus, J. Med. Chem. 2008, 51, 5833-5842; (b) K. R. Campos,
A. Klapars, Y. Kohmura, D. Pollard, H. Ishibashi, S. Kato, A.
Takezawa, J. H. Waldman, D. J. Wallace, C. Chen and N.
Yasuda, Org. Lett. 2011, 13, 1004-1007.
M. Jacob, M. L. Roumestant, P. Viallefont and J. Martinez,
Synlett 1997, 6, 691-692.
M. Venkataiah, G. Reddipalli, L. S. Jasti and N. W. Fadnavis,
Tetrahedron: Asymmetry 2011, 22, 1855-1860.
A. R. Healy, M. Izumikawa, A. M. Z. Slawin, K. Shin-ya and N. J.
Westwood, Angew. Chem. Int. Ed. 2015, 54, 4046-4050.
W. Li, J. Gan and D. Ma, Angew. Chem. Int. Ed. 2009, 48,
f
1
1
3
,
1
1
3
J=13.7, 11.1, 5.9 Hz, 1H); C NMR(125MHz, CDCl
1
3
) δ 157.7,
38.2, 128.8, 128.6, 126.3, 100.6, 79.9, 63.8, 38.5 ppm; HRMS:
+
[
[
(
M+H] calcd. For C11
α]
H
13
N
2
O
3
3
221.0926, found: 221.0928;
2
D
0
=
-107.43 (c=0.21 in CHCl
).
3aR,5S,6aR)-5-phenyltetrahydrofuro[3,2-d]oxazol-2(3aH)-
one (12) was obtained as white solid (13.4 mg) in 65% yield;
mp =159-160 °C ; TLC: R =0.3 (petroleum ether/EtOAc = 1:1 v/v);
H NMR (500 MHz, CDCl ) δ 7.28–7.38 (m, 5H), 6.38 (s, 1H),
.28 (d, J=5.5 Hz, 1H), 5.26 (dd, J=11.1, 4.4 Hz, 1H), 4.57 (t,
J=5.7 Hz, 1H), 2.37 (dd, J=13.4, 4.5 Hz, 1H), 1.93 (ddd, J=13.4,
4
5
6
7
8
f
1
3
6
1
3
1
1
1.2, 6.0 Hz, 1H) ppm; C NMR(125MHz, CDCl
3
) δ 159.0, 138.2,
28.9, 128.6, 126.3, 104.3, 79.8, 57.9, 42.0 ppm; HRMS:
8
891-8895.
+
[M+Na] calcd. For C11
H
11NO
3
Na 228.0637, found: 228.0639;
Z. Yang, Z. Wang, S. Bai, K. Shen, D. Chen, X. Liu, L. Lin and X.
Feng, Chem.—Eur. J. 2010, 16, 6632-6637.
2
D
0
[
α]
-46.36 (c=0.90 in CHCl ); The enantiomeric excess was
3
9
1
N. A. Aslam and S. A. Babu, Tetrahedron 2014, 70, 6402-6419.
0 (a) S. De Lamo Marin, C. Catala, S. R. Kumar, A. Valleix, A.
Wagner and C. Mioskowski, Eur. J. Org. Chem. 2010, 3985–
determined by HPLC analysis on Daicel Chiralpak IC column [n-
hexane/i-PrOH=80/20, 1mL/min], λ=210 nm, tminor=10.427 min,
tmajor=11.567 min, ee = 97%.
3
989; (b) S. K. Ghosh, B. Somanadhan, K. S.-W. Tan, M. S.
General procedure for the synthesis of amino alcohol:
Compound 13 (29.0 mg, 0.074 mmol) was dissolved in
methanol (1mL), and sodium borohydride (22.7 mg, 0.6 mmol)
Butler and M. J. Lear, Org. Lett. 2012, 14, 1560-1563; (c) T.-Y.
Yuen, S. E. Eaton, T. M. Woods, D. P. Furkert, K. W. Choi and
M. A. Brimble, Eur. J. Org. Chem. 2014, 1431-1437.
o
o
11 (a) Y.-K. Liu, Z.-L. Li, J.-Y. Li, H.-X. Feng and Z.-P. Tong, Org.
Lett. 2015, 17, 2022-2025; (b) H.-X. Feng, R. Tan and Y.-K. Liu,
Org. Lett. 2015, 17, 3794-3797; (c) X.-L. Sun, Y.-H. Chen, D.-Y.
Zhu, Y. Zhang and Y.-K. Liu, Org. Lett. 2016, 18, 864-867; (d)
J.-Y. Li, Z.-L. Li, W.-W. Zhao, Y.-K. Liu, Z.-P. Tong and R. Tan,
Org. Biomol. Chem. 2016, 14, 2444-2453; (e) P.-W. Cai, Z.-H.
You, L.-H. Xie, R. Tan, Z.-P. Tong and Y.-K. Liu, Synthesis, 2016
DOI: 10.1055/s-0035-1561972; (f) Z.-L. Li, C. Liu, R. Tan, Z.-P.
Tong and Y.-K. Liu, Catalysts 2016, 6, 65-78.
was added at 0 C. After stirring at 0 C for 0.5h, the mixture
was concentrated in vacuo and purified by flash
chromatography to afford compound 14
di-tert-butyl 1-((2R,4R)-1,4-dihydroxy-4-phenylbutan-2-
yl)hydrazine-1,2-dicarboxylate (14) was obtained as colorless
gum (22 mg) in 75% yield; TLC: R =0.35 (petroleum
ether/EtOAc = 3:1 v/v); H NMR (500 MHz, CDCl ) δ 7.32 (s, 4H),
.24 (s, 1H), 6.06 (d, J=110.5 Hz, 1H), 4. 32–4. 73 (m, 2H), 3.36–
.57 (m, 2H), 1.68–1.83 (m, 1H), 1.56–1.67 (m, 1H), 1.46 (d,
.
,
f
1
3
7
3
1
2 (a) Y. Zhu, P. Qian, J. Yang, S. Chen, Y. Hu, P. Wu, W. Wang,
W. Zhang and S. Zhang, Org. Biomol. Chem. 2015, 13, 4769-
1
3
4
775; (b) J. Wang, P. Qian, Y. Hua, J. Yang, J. Jiang, S. Chen, Y.
J=7.2 Hz, 18H) ppm; C NMR (125MHz, CDCl
3
) δ 157.9, 155.9,
Zhang and S. Zhang, Tetrahedron Lett. 2015, 56, 2875-2877.
13 B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.
000, 122, 2395-2396.
1
5
C
43.9, 128.8, 128.7, 128.0, 127.7, 125.8, 82.8, 82.4, 71.4, 62.6,
+
6.4, 37.6, 28.4, 28.3 ppm; HRMS: [M+H] calcd. For
2
20
20
H
33
N
2
O
6
397.2339, found: 397.2339; [α]
D
-7.22 (c=0.86 in
1
4 A. Msutu and R. Hunter, Tetrahedron Lett. 2014, 55, 2295-
2298.
CHCl
3
); The enantiomeric excess was determined by HPLC
1
5 (a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2005, 44, 794-797; (b) Y. Hayashi, H.
analysis on Daicel Chiralpak IA column [n-hexane/i-
PrOH=85/15, 1mL/min], λ=210 nm, tminor=6.30 min, tmajor=16.05
min, ee = 91%.
Gotoh, T. Hayashi and M. Shoji, Angew. Chem. Int. Ed. 2005
4, 4212-4215.
6 For reviews, see: (a) F. Zhou, F.-M. Liao, J.-S. Yu and J. Zhou,
Synthesis 2014, 46, 2983-3003; (b) C.-B. Ji, Y.-L. Liu, X.-L. Zhao,
Y.-L. Guo, H.-Y. Wang and J. Zhou, Org. Biomol. Chem. 2012
0, 1158-1161; For selected examples, see: (c) N.
,
4
1
Acknowledgements
We thank the National Nature Science Foundation of China
,
1
Kumaragurubaran, K. Juhl, W. Zhuang, A. Bøgevig and K. A.
Jørgensen, J. Am. Chem. Soc. 2002, 124, 6254-6255; (d) A.
Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang and K. A.
Jørgensen, Angew. Chem. Int. Ed. 2002, 41, 1790-1793; (e) B.
List, J. Am. Chem. Soc. 2002, 124, 5656-5657.
(
No. 21302156), NSFC-Shandong Joint Fund for Marine Science
Research Centers (No. U1406402) and Ocean University of
China (OUC 201562031) for generous financial support.
1
1
7 J.-Y. Fu, X.-Y. Xu, Y.-C. Li, Q.-C. Huang and L.-X. Wang, Org.
Biomol. Chem. 2010, 8, 4524-4526.
8 N. S. Chowdari and C. F. Barbas III, Org. Lett. 2005, 7, 867-
870.
Notes and references
1
(a) G. Bergonzini and P. Melchiorre, Angew. Chem. 2012, 124,
9
95-998; Angew. Chem. Int. Ed. 2012, 51, 971-974; (b) M. 19 (a) S. T. Tong, P. W. R. Harris, D. Barker and M. A. Brimble,
Retini, G. Bergonzini and P. Melchiorre, Chem. Commun.
Eur. J. Org. Chem. 2008, 164-170; (b) Z. P. Demko and K. B.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 12 of 12
ARTICLE
Journal Name
Sharpless, Org. Lett. 2002, 4, 2525-2527; (c) A. Hartikka and
P. I. Arvidsson, Eur. J. Org. Chem. 2005, 4287-4295.
0 CCDC 1436994 ( ) and CCDC 1437043 (11) contain the
View Article Online
DOI: 10.1039/C6OB00953K
2
9
supplementary crystallographic data for these compounds.
These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
1 D. A. Evans, Aldrichimica Acta 1982, 15, 23-32.
2 See the ESI† for more details.
2
2
2
3 (a) H. Iwamura, S. P. Mathew and D. G. Blackmond, J. Am.
Chem. Soc. 2004, 126, 11770-11771; (b) H. Iwamura, D. H.
Wells, Jr., S. P. Mathew, M. Klussmann, A. Armstrong and D.
G. Blackmond, J. Am. Chem. Soc. 2004, 126, 16312-16313; (c)
J. E. Hein, A. Armstrong and D. G. Blackmond, Org. Lett. 2011
,
1
3, 4300-4303.
1
2 | J. Name., 2012, 00, 1-3
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