Synthetic Access to 3-Substituted Pyroglutamic Acids from Tetramate Derivatives of Serine, Threonine, allo-Threonine, and Cysteine

Article abstract of DOI:10.1021/acs.joc.9b01432

A general route which provides direct access to pyroglutamates from tetramates, making use of Suzuki coupling on an enol mesylate, followed by reduction, is reported. This work permits direct scaffold hopping from tetramate to substituted pyroglutamates. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria.

Full text of DOI:10.1021/acs.joc.9b01432

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Article
Synthetic Access to 3-Substituted Pyroglutamic acids from Tetramate
Derivatives of Serine, Threonine, allo-Threonine and Cysteine
Halima Bagum, Kirsten E. Christensen, Alexander Pretsch, Dagmar Pretsch, and Mark Gerard Moloney
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01432 • Publication Date (Web): 09 Jul 2019
Downloaded from pubs.acs.org on July 9, 2019
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Synthetic Access to 3-Substituted Pyroglutamic acids from Tetramate Derivatives of Serine,
Threonine, allo-Threonine and Cysteine
†
†
‡
‡
Halima Bagum, Kirsten E. Christensen, Alexander Pretsch, Dagmar Pretsch, and Mark G.
Moloney*,†,#
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†The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12
Mansfield Road, Oxford. OX1 3TA
#Oxford Suzhou Centre for Advanced Research, Building A, 388 Ruo Shui Road, Suzhou Industrial
Park, Jiangsu, 215123, P.R. China.
‡Oxford Antibiotic Group, The Oxford Science Park, Magdalen Centre, Oxford OX4 4GA, UK.
mark.moloney@chem.ox.ac.uk
_
______________________________________________________________________________
Abstract: A general route which provides direct access to pyroglutamates from tetramates, making
use of Suzuki coupling on an enol mesylate, followed by reduction, is reported. This work permits
direct scaffold hopping from tetramate to substituted pyroglutamates. Some compounds in the
library showed modest antibacterial activity against Gram-positive bacteria.
_______________________________________________________________________________
Introduction
1
Pyroglutamates are of interest particularly for their role as starting materials and in drug
discovery;2, 3 we have been interested in the application of pyroglutamic acids as a chiral starting
material, and have shown that, in a suitably protected form, it may be selectively alkylated,
hydroxylated and aminated,4, 5 as well as used for conjugate additions by carbon, oxygen and
6
7
nitrogen nucleophiles.8 While this does provide access to highly functionalised heterocyclic
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derivatives, it can require sequential activation of different positions around the heterocyclic ring
and such a multi-step sequence lacks convenience; an approach involving C-H activation for direct
9
ring functionalisation has, however, been recently reported. Of interest to us was a more efficient
entry to pyroglutamates with peripheral ring functionality, and with the potential for generalisation;
we envisaged that tetramates,10-12 readily available from malonyloxazolidines by highly
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chemoselective Dieckmann ring closures might find application in that regard. We report work
here which demonstrates that such substituted pyroglutamates are accessible from tetramate
precursors, providing a general approach for scaffold hopping between these two systems,15-17 with
scope for control of substituents around the ring periphery.
Results and Discussion
The required tetramates 4a-d were prepared from the methyl ester hydrochlorides of L-
serine 1a, L-threonine 1b, L-allo-threonine 1c and L-cysteine 1d respectively via the
oxa(thia)zolidines 2a-d and malonamides 3a-d according to methodology reported in the literature
1
8
(Scheme 1 and Table 1); the latter compounds exist predominantly in enolic form. Moreover, a
1
mixture of two different species, even after careful column chromatography, was apparent in the H
NMR spectra of malonamides 3a,b,d, but VT and gradient NOE NMR analysis confirmed that
these were due to the presence of rotamers, and that these systems were solely the cis-2,4-
diastereomer.
Table 1: Key results for the synthesis of tetramate templates 4a-d.
2
a-d
Yield
Yield
4a-d
(%)
75
Tetramate
cis:trans
Yield(%)
3a-d
(%)
4
a
1.4:1
1.0:1
2.5:1
86
88
71
80
67
66
4
b
73
4
c
75
4
d
1.5:1
95
78
74
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The tetramate derivatives 4a,b could be reacted with tosyl chloride using the literature method to
give tosylates 5a,b in 78 and 57% yield respectively but these were found to show poor reactivity
towards Suzuki coupling under a range of conditions,20-22 except with PdCl (dppb) as ligand
2
(Scheme 1 and Table 2). Suspecting that a more activated system was required for coupling in this
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extensively resonance delocalised tetramate system, mesylate 5c was prepared (64% yield), and this
was found to couple with 4-methoxyphenylboronic acid using PdCl (dppb) catalyst to give the
2
desired product 6ai with a yield of 80%. On this basis, the mesylates 5d-f were prepared (Scheme 1
and Table 3), and of immediate interest were the different values of  depending on its location on
H4
the exo- or endo face of the bicyclic system. The structure of these compounds was confirmed by
2
3
single crystal X-ray diffraction studies (ESI), which for 5d (derived from threonine) highlighted
the steric congestion on the endo-face caused by the C-4 methyl group.
O
CO2Me
O
O
CO2Me
R2
CO2Me
XH
t-BuCHO, Et3N,
Petrol, 110 C, 16h
2 2
EtOC(O)CH CO H
KOtBu, THF
reflux, 8 h
7
6
CO2Me
o
R2 DCC, DMAP, DCM
H
4
R2
N
EtO
N
-Cl +H N
O
N
3
2
R1
R1
4
R1
R2
R1
X
X
2
X
t-Bu
t-Bu
t-Bu
4a R1 = H, R2 = H, X = O
4b R = Me, R = H, X = O
4c R = H, R = Me, X = O
4d R = H, R = H, X = S
1
1
a R1 = H, R2 = H, X = O
2a R1 = H, R2 = H, X = O
2b R = Me, R = H, X = O
2c R1 = H, R2 = Me, X = O
2d R1 = H, R2 = H, X = S
3a R1 = H, R2 = H, X = O
1
2
1
2
1
2
1
2
b R = Me, R = H, X = O
3b R = Me, R = H, X = O
1c R = H, R2 = Me, X = O
1
3c R = H, R = Me, X = O
1
2
1
2
1
1
2
1
2
1
d R = H, R2 = H, X = S
3d R = H, R = H, X = S
Cl
R
CO2Me
MsCl or TsCl,
DIPEA
O
N
O
t-Bu
CO2Me
8
a R = C6H11
O
8b R = C6H4CH2OH
N
Me
O
t-Bu
6
c-vi
ArB(O)H)2,
PdCl2(dppb)
Na2CO3, toluene,
ethanol,
Ar
Ar
Ar
TFA,
OY
HSCH2CH2CH2SH,
CF3CH2OH
H2, PtO2,
EtOAc, rt
CO2Me
7
6
CO2Me
CO2Me
7
6
CO Me
reflux
7
6
2
R2
R2
R2
R2
O
N
O
O
N
4
N
O
4
R1
R1
R1
N
4
H
See Table 7
2
See Table 4
2
See Table 4
R1
HO
X
X
2
X
t-Bu
t-Bu
6a R1 = H, R2 = H, X = O
t-Bu
5a R1 = H, R2 = H, X = O, Y = Ts
5b R = Me, R = H, X = O, Y = Ts
5c R = H, R = H, X = O, Y = Ms
5d R = Me, R = H, X = O, Y = Ms
9
a R1 = H, R2 = H, X = O
7a R1 = H, R2 = H, X = O
1
2
1
2
1
2
1
2
9b R = Me, R = H, X = O
7b R = Me, R = H, X = O
6b R = Me, R = H, X = O
1
7c R1 = H, R2 = Me, X = O
1
2
1
2
9
c R = H, R2 = Me, X = O
6c R = H, R = Me, X = O
6d R = H, R = H, X = S
7
d R = H, R2 = H, X = S
1
1
2
1
2
1
2
5
5
e R = H, R = Me, X = O, Y = Ms
f R = H, R = H, X = S, Y = Ms
TFA,
1
2
HSCH2CH2CH2SH,
CF3CH2OH
6a only
endo- path
R1
C H p-OMe
6 4
Ph
CO2Me
O
R2
N
X
O
CO Me
N
H
exo path
2
HO
16
Scheme 1
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Table 2: Suzuki coupling reactions of tosylates 5a,b with arylboronic acids ArB(OH)2.
Compound
Y
Ar
Conditions
(dppf), Cs CO , THF/H
NiCl (PPh , THF, rt, 15h
(PPh , Cs CO , THF, 65°C, 15h
(dppb), Na CO
Product (Yield)
5a
5a
H
H
4-MeOC
6
H
4
PdCl
2
2
3
2
O, 65°C, 6h
6ai (18%)
4- MeOC
4- MeOC
4- MeOC
Ph
6
6
6
H
H
H
4
4
4
2
3
)
2
-
0
1
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3
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0
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0
1
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9
0
5
5
5
5
5
a
a
a
a
a
H
NiCl
2
3
)
2
2
3
-
H
PdCl
2
2
3
, Toluene/EtOH, 110°C, 8h
6ai (56%)
H
PdCl
PdCl
PdCl
2
2
2
(dppf), Cs
(dppf), Cs
(dppf), Cs
2
2
2
CO
CO
CO
3
3
3
, THF/H
, THF/H
, THF/H
2
2
2
O, 65°C, 12h
O, 65°C, 12h
O, 65°C, 12h
-
H
4-BrC
2-Thienyl
4- MeOC
6
H
4
-
H
-
5
b
Me
6
H
4
PdCl
2
(dppb), Na
2
CO
3
, Toluene/EtOH, 110°C, 20h
6bi (<14%)
Table 3: Mesylation of tetramates 4a-d and characteristic chemical shifts for H4 (δH4).
1
2
Entry
X, R , R
Product Yield (%)
δH4 (ppm)
3.45, 4.74
5.01
4
a
O, H, H
5c
5d
5e
5f
64
25
52
44
4
b
O, Me, H
O, H, Me
S, H, H
4
c
3.72
4
d
2.81, 3.60
The Suzuki-Miyaura cross-coupling reactions of 5c-f were explored using the optimal
conditions established earlier with a range of commercially available arylboronic acids (Table 4).
Of interest is that the coupling of serine derivative 5c proceeded successfully, although less
efficiently for electron-poor boronic acids, but by contrast the L-threonine system 5d gave a poor
yield (14%) of 6bi from a sluggish reaction. Attempts to optimise this outcome using the catalyst
24
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ) ) by Zhang’s conditions
or Gauler’s
3
4
2
5
conditions gave complex mixtures. Suspecting that the root cause of the low reactivity was likely
to be the steric effect of the endo-methyl substituent, the allo-L-threonine system 5e was examined,
and was found to give excellent conversion (Scheme 1 and Table 4), except for electron-poor
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boronic acids (using p-chlorophenylboronic acid also gave a low yield of 6cvi). X-ray crystal
structures for the 4-methoxyphenyl adducts obtained from L-serine, L-threonine, and L-allo-
threonine23 confirmed their structure but also indicated that the endo-Me group of threonine
derivative 6bi leads to greater steric hindrance as compared to endo-H for the serine 6ai and allo-
threonine 6ci systems (ESI).23 With the cysteine-derived mesylate 5f, coupling was also successful,
giving adducts 6di - 6dvii in 15-62% yields (Table 4). This methodology provides an alternative
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5
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coupling approach to the recently reported nickel-catalyzed cross-coupling of β-carbonyl alkenyl
pivalates with arylzinc chlorides.26
Table 4: Suzuki coupling and reduction reactions for tetramates 5c-f and 6a-d.
Entry
Ar
Reaction
Time (h)
Product
Yield (%) Product Yield
(%)
5c
4-Methoxyphenyl
Phenyl
4
5
12
11
6ai
6aii
6aiii
6aiv
6av
-
6avi
6avii
6bi
80
64
47
28
7ai
7aii
7aiii
8b
7av
-
-
-
-
7ci
7cii
7ciii
7civ
7cv
98
88
28
76
33
-
-
-
-
71
94
67
79
84
5
5
c
c
2-Furyl
5c
4-Formylphenyl
4-Chlorophenyl
4-Bromophenyl
trans-2-Phenylvinyl
2-Phenyl-1-ethynyl
4-Methoxyphenyl
4-Methoxyphenyl
Phenyl
a
5
5
c
c
7
49 (16)
overnight
-
5c
48
12
4
4
25
20
14
70
80
28
36
71a
5
5
c
5
d
5e
6ci
5
5
5
5
e
e
e
e
4
6cii
6ciii
6civ
6cv
2-Furyl
4-Formylphenyl
4-Chlorophenyl
overnight
28
4
6
cvi
5
5
5
5
5f
5
5
f
f
f
f
4-Methoxyphenyl
Phenyl
3
3
6di
6dii
6diii
6div
6dv
-
62
58
22
25
43a
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2-Furyl
20
overnight
4-Formylphenyl
4-Chlorophenyl
4-Bromophenyl
trans-2-Phenylvinyl
2-Phenyl-1-ethynyl
6
f
f
20
24
24
6dvi
6dvii
20
15
5f
a
1
.05 eq 4-Chlorophenyl boronic acid
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Having been able to synthesise a library of pyrrolinones 6a-d, reduction of the C6-C7
double bond to achieve a library of pyrrolidinones was examined; this could not be achieved using
2
7, 28
29
the NaBH in AcOH conditions of Castro
or the NaBH CN in AcOH of Pinheiro. However,
3
4
30
hydrogenation using PtO as a catalyst gave more success. Thus, treatment of serine derivatives
2
6a with atmospheric hydrogen and PtO catalyst over 1-6h efficiently furnished the desired products
2
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a (Scheme 1 and Table 4), and the allo-threonine derivatives 6c under the same reaction
conditions similarly provided derivatives 7c; delivery of hydrogen to the endo- face of the bicyclic
system was clearly preferred. Over-reduction was observed for aldehyde 6aiv giving benzyl
alcohol 8b (76%) while a shorter reaction time (1h) gave partially reduced lactam 6a (Ar =
C H CH OH) resulting from preferential reduction of the aldehyde over the alkene system; in the
6
4
2
case of chlorophenyl derivative 6av, in addition to the expected product 7av (33%), the over-
reduced cyclohexyl derivative 8a (35%) was also obtained. The stereochemistry of pyroglutamates
7
a and 7c was assigned by NOE analysis (Figure 1) and further confirmed by determination of the
X-ray crystal structure of 7aii and 7cii (ESI).23 However, of interest is that for hydrogenation of
threonine derivative 6bi under similar conditions, only unreacted starting material was recovered,
further confirming the steric hindrance of the C4-methyl group.
OMe
CHO
Cl
O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O
H
H
O
H
O
H
O
H
H
O
H
H
O
H
N
N
N
N
N
N
H
H
H
O
O
O
O
O
O
t-Bu
H
t-Bu
H
t-Bu
H
t-Bu
H
t-Bu
H
t-Bu
H
7ai
7aii
7aiii
7aiv
7av
8
OMe
CHO
Cl
H
O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O
H
O
H
O
H
O
H
O
H
N
N
N
N
N
Me
Me
Me
Me
Me
O
O
O
O
O
t-Bu
H
t-Bu
H
t-Bu
H
t-Bu
H
t-Bu
H
7ci
7cii
7ciii
7civ
7cv
Figure 1. NOE data for selected compounds
By contrast, the cysteine-derived system 6d was unreactive under these reductive
conditions; this is consistent with catalyst poisoning from the heterocyclic sulphur atom.31 In order
32
33
to overcome this problem, sulfone systems were examined; Keith et al. reported the conversion
of the sulfur to sulfone system in lactams by using m-chloroperbenzoic acid (m-CPBA) and after
application of these conditions to tetramate 4d, the product could not be isolated, possibly due to its
high polarity which prevented its isolation on silica. However, m-CPBA oxidation of mesylate 5f
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furnished desired product 10 in 77% yield (Scheme 2), and its structure was confirmed by single-
crystal X-ray diffraction analysis (ESI).23
This sulfone was subjected to the optimal conditions for Suzuki coupling, and gave sulfone
adducts 11i-v in good yield (Table 5), consistent with the S-analogues 6d. The formation of by-
product 13 was also observed for the Suzuki coupling with 4-chlorophenylboronic acid, giving
increased yields of this product for higher equivalents of the boronic acid (Scheme 2 and Table 5).
These adducts were subjected to hydrogenation which proceeded in good yield and
diastereoselectivity to give pyroglutamates 12i-v (Table 5); of interest is the conservation of NMR
1
1
1
1
1
1
1
1
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
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
and [] values in each compound series, but in particular the complete inversion of the sign of
D
[] in going from the Suzuki coupled product to the reduced system. The stereochemistry of the
D
newly formed chiral centre C6 was assigned by NOESY analysis which displayed a strong
interaction between endo-H4-H6-H2 for all synthesised products in this series. The absolute
stereochemistry was further confirmed by X-ray crystal structure determination of 12v (ESI).23
Table 5: Suzuki coupling and subsequent hydrogenation of sulfone: representative values for 11i-v
and 12i-v.
[]D25 (c 1.0 in DCM)
Ar
Products, Yield
δH6 (ppm)
δH7 (ppm)
4-MeOC H
11i, 56%
12i, 83%
11ii, 53%
12ii, 82%
11iii, 20%
12iii, 37%
11iv, 26%
12iv, 54%
11v, 48%
-
3.79
-
6.52
2.57, 3.26
6.65
+129.2
-87.6
6
4
4
-MeOC H
6
4
C H
+132.3
-89.8
6
5
C H
3.84
-
2.60, 3.32
6.47
6
5
2
2
-Furyl
-Furyl
+88.3
-65.1
3.90
-
2.62, 3.18
6.80
4
-CHOC H
+103.0
-72.7
6
4
4-HOCH C H
3.82
-
2.54, 3.29
6.65
2
6
4
4
-ClC H
+105.4
6
4
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4
-ClC H C H
4
13, 8%
-
6.70
2.60, 3.26
+70.2
-65.1
6
4
6
4
-ClC H
12v, 77%
3.81
6
4
Given the successful hydrogenation of sulfones 11iv, preparation of the corresponding
sulfoxide using a limiting amount of m-CPBA was attempted; use of 1.3 equivalents gave a yield
of 52% for sulfoxide 14 (Scheme 2) in a reaction which proceeded with complete stereoselectivity,
and whose structure was determined by single crystal X-ray diffraction studies (ESI);23 the
sulfoxide oxygen was positioned towards the endo-face of the bicyclic ring system, anti- to the
bulky adjacent t-butyl group.
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
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9
0
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2
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5
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7
8
9
0
OMs
CO Me
Ar
Ar
ArB(O)H)2,
PdCl2(dppb)
H2, PtO2,
EtOAc, RT
7
6
7
6
MCPBA
3 equiv.
2
CO2Me
CO2Me
5f
O
O
O
N
N
4
N
4
Na CO , toluene,
ethanol, reflux
2
3
2
2
S
S
S
O
O
O
7
7%
t-Bu
t-Bu
t-Bu
O
O
O
1
1i Ar = 4-MeOC6H4-
11ii Ar = C6H5-
1iii Ar = 2-C4H3S-
1iv Ar = 4-OCHC6H4-
1
0
12i Ar = 4-MeOC6H4-
2ii Ar = C6H5-
12iii Ar = 2-C4H3S-
1
MCPBA
.3 equiv.
1
1
59%
1
1
2iv Ar = 4-OCHC6H4-
2v Ar = 4-ClC6H4-
1
11v Ar = 4-ClC6H4-
Cl
OMs
Ar
S
ArB(OH)2,
PdCl2(dppb)
CO Me
CO Me
2
2
O
O
N
N
Na2CO3, toluene,
ethanol, reflux
S
O
O
t-Bu
t-Bu
1
1
5i Ar = 4-MeOC6H4- (18%)
5ii Ar = C6H5- (18%)
14
CO Me
2
O
N
15iii Ar = 4-ClC6H4- (8%)
S
O
t-Bu
O
13
Scheme 2
Of interest was that Suzuki coupling of sulfoxide 14 with boronic acids gave adducts 15i-iii
Scheme 2) although less efficiently than for the sulfone. In this case, it seems that the endo-face
(
suffers from the steric hindrance caused by the endo-sulfoxide, and in this sense is similar to the
threonine-derived system 5d. The structure of sulfoxide adduct 15i was confirmed by single crystal
X-ray diffraction studies (ESI).23 Attempted hydrogenation of 15i resulted in quantitative recovery
of starting material, similar to that observed in the threonine series.
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3
4
Application of Corey-Reichard protocol to representative analogues efficiently removed
the N,O-protecting group (Table 7), giving the product pyroglutaminol systems but this approach
was not successful for the equivalent N,S-system 7dv.
Table 7: N, O-acetal deprotection (see Scheme 1).
1
1
1
1
1
1
1
1
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
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
Starting Compound
Product
Yield (%)
6
a
16
94
80
79
90
81
0
7ai
aii
9ai
9aii
7
8
b
9a, R = C H CH OH
6
4
2
7ci
9ci
6
dv
-
Broth assay of these compounds against a small panel of Gram positive (Methicillin
resistant Staphylococcus aureus) and Gram negative (Escherichia coli (EC 34), Klebsiella
pneumonia (KL 18) and Pseudomonas aeruginosa (PS 23)) bacteria mostly showed no activity,
confirming earlier results that simple lactam systems do not display such activity.35 The exceptions
were 6civ, 6div, 7ai, and 15iii which showed modest activity against Methicillin resistant
Staphylococcus aureus with MIC values of 15.6, 15.6, 62.0, 31.3 g/mL respectively (assays
3
6
conducted using reported methodology ).
Conclusion
Diasterocontrol in the reactions of bicyclic lactams37-39 is governed by several phenomena
including steric,40, 41 electronic and hydrogen bonding effects. The work described here adds a
further aspect of steric control in the facial selectivity of bicyclic lactams, showing that ring
substituents may critically influence stereochemical outcome in such functionally dense bicyclic
ring systems. It has direct implications for the stereocontrolled synthesis of the recently identified
clausenamide group of natural products.43 This work complements other approaches which permit
scaffold hopping from tetramate to pyroglutamates, by providing a general route to more highly
substituted systems. 44, 45
42
7
Experimental Section
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General methods. All reagents were obtained from commercial sources and used without further
purification. Anhydrous solvents were dried by pre-storing them over activated 3 Å molecular
sieves before being passed through an activated alumina column on a solvent tower under N2
pressure. Analytical thin-layer chromatography (TLC) was carried out on Merck aluminum foil
backed sheets precoated with 0.2 mm Kielselgel 60 F254. The spots were visualized by UV
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
1
2
3
4
5
6
7
8
9
0
irradiation (λ 254 nm) and by staining with a KMnO solution followed by heating. Flash column
4
chromatography was performed on Kielselgel 60 silica gel (230−400 mesh particle size). Optical
rotations were recorded at 25 °C on a polarimeter using the D line of sodium (589 nm) and a path
length of 1 dm. Concentrations (c) are given in g/100 mL, and specific rotations (
) are quoted in
0 deg cm g . Melting points were measured with a capillary melting point apparatus and are
uncorrected. Infrared spectra were recorded on an FT-IR spectrometer; absorption maxima (νmax
−
1
2
−1
1
)
−
1
1
are reported in wavenumbers (cm ) and only selected peaks are reported. H NMR spectra were
1
3
recorded 400, 500 and 600 MHz, and C NMR spectra at 100 and 125 MHz. Chemical shifts (δ
H
and δ ) are reported in parts per million (ppm) and are referenced to the residual solvent peak.
C
Coupling constants (J) are quoted in hertz. Two-dimensional COSY, NOESY, HSQC and HMBC
experiments were recorded at 500 MHz. Assignment of the NMR spectra have been made using
DEPTQ, COSY and HSQC and confirmation of stereochemistry was made using NOESY and X-
ray crystallography. Low-resolution mass spectra (m/z) were recorded using electrospray ionization
(ESI); selected peaks are reported in daltons and their intensities given as percentages of the base
peak. High-resolution mass spectra (HRMS) were recorded using TOF (ESI, EI or CI).
Synthesis of Methyl Ester Hydrochloride: General Method A46
SOCl (1.5 eq) was added dropwise to stirring anhydrous MeOH (2 M) at 0 °C, followed by ʟ-
2
amino acid (1 eq) portion-wise. The mixture was heated to 40 °C and stirred at this temperature for
3
h. The solvent was then evaporated under reduced pressure to give methyl ester hydrochlorides
1
a-d.
Synthesis of Oxazolidine and Thiazolidine Compounds: General Method B47
The ester hydrochloride of the ʟ-amino acid 1a-d (1.0 eq) was suspended in petroleum ether.
Triethylamine (1.5 eq) and trimethylacetaldehyde (1.2 eq) were then added. The mixture was heated
at reflux with continuous removal of water using a Dean-Stark apparatus for 18 h. The white
precipitate was then filtered and washed with Et O. The combined filtrates were concentrated under
2
reduced pressure to furnish the oxazolidines or thiazolidine 2a-d.
1
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N-Acylation of Oxazolidine and Thiazolidine Compounds: General Method C13
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8
9
1
1
1
1
1
1
1
1
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
DMAP (0.05 eq) and DCC (1.05 eq) were added to a solution of oxazolidine or thiazolidine 2a-d
(1.0 eq) in anhydrous DCM. The mixture was cooled to 0 °C and ethyl malonate (1.05 eq) was
added. The reaction mixture was then stirred 30 min at 0 °C and 5 h at room temperature. A white
precipitate was formed, which was filtered and washed with DCM. The combined filtrates were
concentrated in vacuo and purified by flash column chromatography to give the required N-acyl
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
oxazolidines or thiazolidine 3a-d.
Dieckmann Cyclisation: General Method D13
To a solution of N-acyl oxazolidine or thiazolidine 3a-d (1.0 eq) in anhydrous THF was added
potassium tert-butoxide (1.05 eq). The mixture was heated at reflux for 3 h. The reaction mixture
was separated between Et O and water, the aqueous phase was acidified with 2 M aqueous HCl and
2
extracted with EtOAc. The organic layer was washed with a 1 M aqueous solution of NaH PO and
2
4
brine, dried over anhydrous Na SO and concentrated under reduced pressure to give the tetramic
2
4
acids 4a-d.
Synthesis of Tosylate/Mesylate: General Method E19
Tetramic acid 4a-d (1.0 eq) was dissolved in DCM under nitrogen atmosphere. p-Toluenesulfonyl
chloride or methanesulfonyl chloride (1 eq) and DIPEA (2 eq) were added to this solution. The
resulting mixture was stirred for 2-6 h at room temperature until total consumption of the starting
material. The reaction mixture was washed with 5% HCl, 5% NaHCO , and brine, dried over
3
MgSO , and filtered. The solvent was removed in vacuo, and the residue was chromatographed on
4
silica gel using ethyl acetate:petroleum ether as eluants to give tosylates 5a,b or mesylates 5c-f.
Attempted Methods for Suzuki Coupling
2
0
Procedure 1: Tosylate/mesylate (1.0 eq) and boronic acid (1.2 eq) were dissolved in THF (0.1 M).
Pd(dppf)Cl (5 mol%) and a solution of Cs CO (3.0 eq) in water (1/10 THF) was added
2
2
3
1
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1
1
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2
2
2
2
2
2
2
2
3
3
3
3
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4
4
4
4
4
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5
5
5
6
subsequently to this solution. The reaction mixture was then stirred at room temperature for 40
minutes and refluxed until total consumption of the starting material. After completion, the reaction
mixture was filtered through Celite and washed with ethyl acetate. The organic layer was washed
with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated in
vacuo to give crude material, which was purified by flash column chromatography.
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
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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
Procedure 2: 21 To a suspension of the boronic acid (227 mg, 1.50 mmol) and the NiCl (PPh ) (24
2
3 2
mg, 0.04 mmol) in THF (10 mL) was added tosylate (153 mg, 0.37 mmol) in THF (0.1 M). The
reaction mixture was stirred at room temperature or refluxed for 15 h and quenched using saturated
sodium bicarbonate. The product was extracted with EtOAc, the organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give crude material, which was purified by
flash column chromatography.
Procedure 3: General Method F22
A mixture of 1,4-bis(diphenylphosphino)butane (0.06 eq) and bis(benzonitrile)palladium(II)
chloride (0.05 eq) in dry toluene was stirred at room temperature under nitrogen atmosphere for 30
minutes to form a creamy orange slurry of [1,4-bis(diphenylphosphino)butane] palladium(II)
chloride. Tosylate/mesylate (1.0 eq), boronic acid (1.05-1.8 eq), ethanol (7.0 eq), 1 M aqueous
sodium carbonate solution (9-18 eq) and dry toluene were added to the catalyst and the mixture was
refluxed for 3-30 hours. After cooling, water was added, and the mixture was diluted with ethyl
acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic
phases were dried and evaporated in vacuo to find the crude product, which was then purified to
give the product by flash column chromatography.
Procedure 4: 48 To a solution of aryl chloride (1.0 eq) in DMA:water (20/1) was added Pd/C (5
mol%), 4-methoxyphenylboronic acid (1.2 eq), and K CO (2.0 eq) under a N atmosphere. The
2
3
2
reaction mixture was degassed and allowed to stir at 80 °C. The catalyst was filtered, washed with
1
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5
6
acetonitrile, and evaporated to find crude material, which was then purified by flash column
chromatography.
2
4
Procedure 5: A mixture of tosylate (1.0 eq) and tetrakis(triphenylphosphine)palladium(0) (0.05
eq) in DME was degassed and then stirred with gentle heating until it turned into a clear solution. 4-
Methoxyphenylboronic acid (1.0 eq) and potassium tert-butoxide (2.0 eq) in tert-butyl alcohol (2.0
M) were then added. The reaction mixture was degassed again and refluxed at 95 °C for 15 minutes
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
under N atmosphere. The reaction mixture was filtered through Celite and washed with DCM. The
2
solvent was removed in vacuo and the crude material was purified by flash column
chromatography.
Procedure 6: 25 The mesylate (1.0 eq) was dissolved in a mixture of dry DMF and toluene. To this
solution was added K CO (7.6 eq), tetrakis(triphenylphosphine)palladium(0) (10 mol%) and 4-
2
3
methoxyphenylboronic acid (3.8 eq). The reaction mixture was heated at 95 °C for 18 h under N2
atmosphere. After being cooled to room temperature, water was added, and the solution was
extracted with DCM. The organic layer was washed with water, dried over anhydrous Na SO ,
2
4
concentrated in vacuo. The resulting crude product was purified by flash column chromatography.
Hydrogenation: 30 General Method G
To a solution of α,β-unsaturated lactam (1 eq) in EtOAc (0.05 M), platinum(IV) oxide (0.15 eq) was
added. The reaction mixture was stirred at room temperature under H atmosphere for 1-48 h,
2
filtered through Celite, evaporated under reduced pressure, and then purified by flash column
chromatography on silica gel using ethyl acetate/petroleum ether as eluents to give pure
pyrrolidinones.
Preparation of sulfone and sulfoxide: General Method H33
A solution of cysteine-derived mesylate 5f (1 eq) in CHCl (0.086 M) was cooled to 0°C. A solution
3
of m-chloroperbenzoic acid (1.3-3.0 eq) in CHCl (0.15 M) was added dropwise. The reaction
3
1
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2
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5
6
mixture was stirred at room temperature for 12-17 hours. After completion, the mixture was poured
into EtOAc (0.01 M) and the resultant solution was washed with sat. aq. solution of NaHCO and
3
brine. The organic layer was dried over Na SO and concentrated in vacuo to get crude sulfone or
2
4
sulfoxide. The sulfone 10 or sulfoxide 14 was purified by flash column chromatography using 35-
0% EtOAc in petroleum ether.
0
1
2
3
4
5
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8
9
0
1
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9
0
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1
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7
8
9
0
4
N,O-Acetal deprotection: 34 General Method I
Under a nitrogen atmosphere, the pyrrolinone or pyrrolidinone (1 eq) was treated with propane-1,3-
dithiol (2.1-4.0 eq) followed by a freshly prepared 1.5% solution of HCl in 2,2,2-trifluoroethanol.
The solution was stirred at room temperature for 24-36 h or at 50 °C for 12-17 h. The reaction
mixture was concentrated in vacuo, the crude residue was dissolved in MeOH, washed with
petroleum ether and concentrated under reduced pressure to give N,O-acetal deprotected amides.
(2R,5S)- and (2S,5S)-2-(tert-Butyl)-5-methoxycarbonyl-1,3-oxazolidine, 2a
According to General Method B, ʟ-serine methyl ester hydrochloride 1a (7.40 g,
MeO C
2
47.5 mmol) was reacted with triethylamine (9.9 mL, 71 mmol) and
HN O
(
CH ) CCHO (6.2 mL, 57 mmol). Yield 86% (7.6 g); yellow oil; 1.4:1 mixture
3 3
-1
of diastereomers; R (85% EtOAc in DCM) 0.60; ν /cm 3316 (N-H), 2957
f
max
(C-H), 2871 (C-H), 1740 (C=O); δ (400 MHz, CDCl ) major isomer (2R): 0.95 (9H, s, C(CH ) ),
H
3
3 3
2
.48 (1H, br s, NH), 3.64-3.67 (1H, m, C(4)H H ), 3.72 (3H, s, CO CH ), 3.84-3.88 (2H, m,
A B 2 3
(
C(4)H H ) + (C(5)H)), 4.04 (1H, s, C(2)H); minor isomer (2S): 0.87 (9H, s, C(CH ) ), 2.48 (1H,
A
B
3
3
br s, NH), 3.67-3.69 (1H, m, C(4)H H ), 3.70 (3H, s, CO CH ), 3.89-3.93 (1H, m, C(5)H), 4.07
A
B
2
3
(1H, dd, J 8.0, 7.3, C(4)H H ), 4.28 (1H, s C(2)H); δ (100 MHz, CDCl ) major isomer (2R): 25.2
A
B
C
3
(
C(CH ) ), 33.2 (C(CH ) ), 52.5 (CO CH ), 59.6 (C(5)), 68.3 (C(4)), 99.9 (C(2)), 172.9 (CO CH );
3 3 3 3 2 3 2 3
minor isomer (2S): 24.9 (C(CH ) ), 34.6 (C(CH ) ), 52.4 (CO CH ), 59.4 (C(5)), 68.9 (C(4)), 99.2
3
3
3 3
2
3
+
+
+
(C(2)), 173.1 (CO CH ); m/z ([ESI] ) 188.1 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for
2
3
C H NO 188.1281; Found 188.1282.
9
18
3
(2R,4R,5S)- and (2S,4R,5S)-2-(tert-Butyl)-5-methoxycarbonyl-4-methyl-1,3-oxazolidine, 2b
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According to General Method B, ʟ-threonine methyl ester hydrochloride 1b
Me
MeO C
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
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
2
(
9.7 g, 57 mmol) was reacted with triethylamine (11.9 mL, 85.8 mmol) and
HN
O
trimethylacetaldehyde (7.46 mL, 68.6 mmol). Yield 88% (10.1 g); yellow oil;
-1
1:1 mixture of diastereomers; R (50% EtOAc in DCM) 0.62; ν /cm 3341
f
max
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
(
N-H), 2957 (C-H), 2870 (C-H), 1741 (C=O); δ (400 MHz, CDCl ) isomer (2R): 0.96 (9H, s,
H 3
C(CH ) ), 1.31 (3H, d, J 6.0, C(4)CH ), 2.67 (1H, br s, NH), 3.34 (1H, d, J 7.2, C(5)H), 3.75 (3H, s,
3
3
3
CO CH ), 3.78-3.85 (1H, m, C(4)H), 4.27 (1H, s, C(2)H); isomer (2S): 0.88 (9H, s, C(CH ) ), 1.35
2
3
3 3
(
3H, d, J 6.0, C(4)CH ), 2.67 (1H, br, NH), 3.45 (1H, d, J 7.2, C(5)H), 3.74 (3H, s, CO CH ), 3.78-
3
2
3
3
.85 (1H, m, C(4)H), 4.36 (1H, s, C(2)H); δ (100 MHz, CDCl ) isomer (2R): 19.9 (C(4)CH ), 25.2
C 3 3
(
C(CH ) ), 34.6 (C(CH ) ), 52.4 (OCH ), 65.7 (C(5)), 76.2 (C(4)), 98.2 (C(2)), 171.9 (CO CH );
3 3 3 3 3 2 3
isomer (2S): 18.9 (C(4)CH ), 24.8 (C(CH ) ), 33.5 (C(CH ) ), 52.3 (OCH ), 67.1 (C(5)), 77.3
3
3 3
3 3
3
+
+
+
(
C(4)), 98.8 (C(2)), 172.7 (CO CH ); m/z ([ESI] ) 202.1 ([M+H] , 100%); HRMS (ESI ) m/z:
2 3
[
MH]+ Calcd for C H NO 202.1438; Found 202.1438.
1
0
20
3
(2R,4S,5S)- and (2S,4S,5S)-2-(tert-Butyl)-5-methoxycarbonyl-4-methyl-1,3-oxazolidine, 2c
According to General Method B, ʟ-allo-threonine methyl ester
Me
MeO C
2
hydrochloride 1c (2.96 g, 17.5 mmol) was reacted with triethylamine (3.65
HN O
mL, 26.2 mmol) and trimethylacetaldehyde (2.27 mL, 20.9 mmol). Yield
7
1% (2.5 g); colourless oil; 2.5:1 mixture of diastereomers; R (50%
f
-1
EtOAc in DCM) 0.60; νmax/cm 3313 (N-H), 2956 (C-H), 2872 (C-H), 1742 (C=O); δ (400 MHz,
H
CDCl ) major isomer (2R): 0.94 (9H, s, C(CH ) ), 1.01 (3H, d, J 6.4, C(4)CH ), 2.49 (1H, br s,
3
3 3
3
NH), 3.70 (3H, s, CO CH ), 3.88-3.92 (1H, m, C(5)H), 4.02 (1H, s, C(2)H), 4.16 (1H, dq, J 8.2,
2
3
6
.4, C(4)H); minor isomer (2S): 0.82 (9H, s, C(CH ) ), 1.00 (3H, d, J 6.4, C(4)CH ), 2.49 (1H, br,
3 3 3
NH), 3.68 (3H, s, CO CH ), 3.88-3.92 (1H, m, C(5)H), 4.28-4.39 (1H, m, C(4)H), 4.54 (1H, s,
2
3
C(2)H); δ (100 MHz, CDCl ) major isomer (2R): 16.8 (C(4)CH ), 25.3 (C(CH ) ), 32.8 (C(CH ) ),
C
3
3
3 3
3 3
5
2.1 (OCH ), 63.3 (C(5)), 73.4 (C(4)), 98.5 (C(2)), 171.7 (CO CH ); minor isomer (2S): 16.0
3 2 3
(
C(4)CH ), 24.7 (C(CH ) ), 35.7 (C(CH ) ), 52.0 (OCH ), 63.2 (C(5)), 74.6 (C(4)), 98.1 (C(2)),
3 3 3 3 3 3
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5
5
5
5
5
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+
+
+
171.8 (CO CH ); m/z ([ESI] ) 202.2 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for
2
3
C H NO 202.1438; Found 202.1438.
1
0
20
3
(
2R,5S)- and (2S,5S)-2-(tert-Butyl)-5-methoxycarbonyl-1,3-thiazolidine, 2d
MeO C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
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1
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8
9
0
2
According to General Method B, L-cysteine methyl ester hydrochloride 1d
5.0 g, 29 mmol) was reacted with triethylamine (6.09 mL, 43.7 mmol) and
(
HN S
trimethylacetaldehyde (3.8 mL, 35.0 mmol). Yield 95% (5.62 g); yellow oil;
1.5:1 mixture of diastereomers; R (75% EtOAc in DCM) 0.58; ν /cm-1
f
max
3
317 (N-H), 2954 (C-H), 2868 (C-H), 1740 (C=O); δ (400 MHz, CDCl ) major isomer (2R): 1.01
H 3
(
9H, s, C(CH ) ), 2.19 (1H, br s, NH), 2.62 (1H, t, J 10.0, C(4)H H ), 3.20 (1H, dd, J 10.2, 6.7,
3 3 A B
C(4)H H ), 3.72 (3H, s, CO CH ), 4.72-3.78 (1H, m, C(5)H), 4.40 (1H, s, C(2)H); minor isomer
A
B
2
3
(2S): 0.92 (9H, s, C(CH ) ), 2.19 (1H, br s, NH), 2.96 (1H, dd, J 10.6, 5.6, C(4)H H ), 3.05 (1H,
3
3
A
B
dd, J 10.2, 6.4, C(4)H H ), 3.69 (3H, s, CO CH ), 4.08 (1H, dd, J 6.3, 5.6, C(5)H), 4.47 (1H, s,
A
B
2
3
C(2)H); δ (100 MHz, CDCl ) major isomer (2R): 27.0 (C(CH ) ), 34.0 (C(CH ) ), 37.5 (C(4)), 52.5
C
3
3 3
3 3
(CO CH ), 65.5 (C(5)), 81.9 (C(2)), 171.9 (CO CH ); minor isomer (2S): 26.6 (C(CH ) ), 35.9
2
3
2
3
3 3
+
(
C(CH ) ), 37.1 (C(4)), 52.5 (CO CH ), 65.1 (C(5)), 79.9 (C(2)), 172.5 (CO CH ); m/z ([ESI] )
3 3 2 3 2 3
+
+
2
04.1 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO S 204.1053; Found
9 18 2
204.1055.
(
2R,5S)-2-(tert-Butyl)-1-ethoxycarbonylacetyl-5-methoxycarbonyl-1,3-oxazolidine, 3a
MeO C
2
According to General Method C, oxazolidine 2a (10.6 g, 56.5 mmol),
DCC (12.2 g, 59.3 mmol), and DMAP (345 mg, 2.80 mmol) was
reacted with ethyl hydrogen malonate (7.0 mL, 59.3 mmol) in DCM.
O
EtO
N
O O
Yield 80% (13.6 g); colourless oil; R (10% EtOAc in DCM) 0.52;
-62.4 (c 1.0 in DCM);
f
-1
νmax/cm 2958 (C-H), 1741 (C=O), 1672 (C=O); δ (400 MHz, CDCl ): 0.83 (9H, s, C(CH ) ),
H
3
3 3
1.23 (3H, t, J 7.1, OCH CH ), 3.46 (1H, d, J 15.5, C(7)H H ), 3.65 (1H, d, J 15.5, C(7)H H ), 3.74
2
3
A
B
A
B
(
3H, s, CO CH ), 3.89-4.06 (1H, m, C(4)H H ), 4.14 (2H, q, J 7.1, OCH CH ), 4.42-4.53 (1H, m,
2 3 A B 2 3
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5
5
5
5
5
5
6
C(4)H H ), 4.60-4.68 (1H, m, C(5)H), 5.22 (1H, s, C(2)H); δ (100 MHz, CDCl ): 13.9
A B C 3
(OCH CH ), 25.4 (C(CH ) ), 37.1 (C(CH ) ), 42.9 (C(7)), 52.6 (CO CH ), 59.3 (C(5)), 61.4
2 3 3 3 3 3 2 3
+
(
OCH CH ), 67.5 (C(4)), 96.4 (C(2)), 167.4 (C(8)), 167.6 (CO CH ), 169.8 (C(6)); m/z ([ESI] )
2
3
2
3
+
+
+
302.2 ([M+H] , 55%), 324.1 ([M+Na] , 65%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO
6
1
4
24
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
3
02.1598; Found 302.1594.
(2R,4R,5S)-2-(tert-Butyl)-1-ethoxycarbonylacetyl-5-methoxycarbonyl-4-methyl-1,3-
oxazolidine, 3b
MeO C
Me
2
According to General Method C, oxazolidine 2b (9.95 g, 49.4 mmol),
DCC (10.7 g, 51.9 mmol), and DMAP (302 mg, 2.5 mmol) was
reacted with ethyl hydrogen malonate (6.12 mL, 51.9 mmol) in DCM.
EtO
N O
O
O
Yield 67% (10.5 g); yellow oil; R (10% EtOAc in DCM) 0.42;
-37.5 (c 1.0 in DCM);
f
-1
νmax/cm 2977 (C-H), 2958 (C-H), 1741 (C=O), 1669 (C=O); δ (400 MHz, CDCl ): 0.84 (9H, s,
H
3
C(CH ) ), 1.22 (3H, t, J 7.1, OCH CH ), 1.30 (3H, d, J 6.0, C(4)CH ), 3.38 (1H, d, J 15.4,
3 3
2
3
3
C(7)H H ), 3.52 (1H, d, J 15.4, C(7)H H ), 3.74 (3H, s, CO CH ), 4.14 (2H, q, J 7.1, OCH CH ),
A
B
A
B
2
3
2
3
4
.23-4.27 (1H, m, C(5)H), 4.68-4.75 (1H, m, C(4)H), 5.37 (1H, s, C(2)H); δ (100 MHz, CDCl ):
C 3
1
4.1 (OCH CH ), 20.1 (C(4)CH ), 25.8 (C(CH ) ), 37.9 (C(CH ) ), 42.9 (C(7)), 52.9 (CO CH ),
2
3
3
3 3
3 3
2
3
61.7 (OCH CH ), 65.5 (C(5)), 76.1 (C(4)), 96.2 (C(2)), 167.3, 167.4 (C(6), C(8)), 170.0 (CO CH );
2
3
2
3
+
+
+
m/z ([ESI] ) 316.2 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO 204.1053;
1
5
26
6
Found 316.1752.
(2R,4S,5S)-2-(tert-Butyl)-1-ethoxycarbonylacetyl-5-methoxycarbonyl-4-methyl-1,3-
oxazolidine, 3c
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According to General Method C, oxazolidine 2c (3.50 g, 17.4 mmol),
DCC (3.77 g, 18.3 mmol), and DMAP (106 mg, 0.9 mmol) was
reacted with ethyl hydrogen malonate (2.15 mL, 18.3 mmol) in DCM.
MeO C
Me
2
EtO
N O
O O
Yield 66% (1.83 g); colourless oil; R (40% EtOAc in Petrol) 0.35;
f
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
-
50.3 (c 1.0 in DCM); νmax/cm-1 2981 (C-H), 2958 (C-H), 1743 (C=O), 1677 (C=O); δH
(
400 MHz, CDCl ): 0.91 (9H, s, C(CH ) ), 1.21 (3H, t, J 7.2, C(10)CH ), 1.35 (3H, d, J 6.4,
3
3 3
3
C(4)CH ), 3.33 (1H, d, J 15.3, C(7)H H ), 3.42 (1H, d, J 15.3, C(7)H H ), 3.70 (3H, s, CO CH ),
3
A
B
A
B
2
3
4
.08-4.18 (3H, m, C(9)H + C(4)H), 4.44 (1H, d, J 6.6, C(5)H), 5.13 (1H, s, C(2)H); δ (100 MHz,
2 C
CDCl ): 14.1 (C(10)), 15.4 (C(4)CH ), 26.3 (C(CH ) ), 36.9 (C(CH ) ), 43.7 (C(7)), 52.0
3
3
3 3
3 3
(CO CH ), 61.7 (C(9)), 62.8 (C(5)), 74.9 (C(4)), 96.5 (C(2)), 167.4 (C(8)), 167.8 (CO CH ), 168.9
2
3
2
3
+
+
+
(
C(6)); m/z ([ESI] ) 338.2 ([M+Na] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO
15 26 6
3
16.1755; Found 316.1746.
(
2R,5R)-2-(tert-Butyl)-1-ethoxycarbonylacetyl-5-methoxycarbonyl-1,3-thiazolidine, 3d
MeO C
2
According to General Method C, thiazolidine 2d (5.54 g, 27.3 mmol),
DCC (5.9 g, 28.6 mmol), and DMAP (167 mg, 1.4 mmol) was reacted
with ethyl hydrogen malonate (3.38 mL, 28.6 mmol) in DCM. Yield
S
EtO
N
O O
78% (5.88 g); colourless oil; R (10% EtOAc in DCM) 0.71;
-102.5 (c 1.0 in CHCl ); 1.5:1
3
f
-1
mixture of rotamers, major A and minor B; νmax/cm 2958 (C-H), 1740 (C=O), 1664 (C=O); δ
H
(
400 MHz, CDCl ): 0.92 (9H, s, C(CH ) A), 1.01 (9H, s, C(CH ) B), 1.22 (3H, t, J 7.1, CH CH ),
3 3 3 3 3 2 3
3.21-3.52 (4H, m, (C(4)H H + C(7)H H )), 3.70 (3H, s, CO CH B), 3.75 (3H, s, CO CH A),
A
B
A
B
2
3
2
3
4
.14 (2H, q, J 7.1, OCH CH ), 4.74 (1H, s, C(2)H B), 4.83 (1H, t, J 8.0, C(5)H A), 5.05 (1H, t, J
2 3
9
.5, C(5)H B), 5.48 (1H, s, C(2)H A); δ (100 MHz, CDCl ): 14.1 (OCH CH ), 26.9 (C(CH ) A),
C
3
2
3
3 3
27.2 (C(CH ) B), 32.9 (C(4) B), 34.2 (C(4) A), 39.4 (C(CH ) A), 40.1 (C(CH ) B), 42.4 (C(7)),
3
3
3 3
3 3
5
2.5 (CO CH B), 53.0 (CO CH A), 61.6 (OCH CH B), 61.7 (OCH CH A), 64.2 (C(5)), 73.3
2 3 2 3 2 3 2 3
+
(
C(2) A), 74.7 (C(2) B), 166.8, 167.0 (C(8), CO CH ), 170.6 (C(6) B), 170.8 (C(6) A); m/z (ESI )
2
3
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5
5
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5
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318.1 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO S 318.1370; Found
1
4
24
5
3
18.1367.
(
2R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-3-oxa-6,8-dioxobicyclo[3.3.0]-octane, 4a
O
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
According to General Method D, malonamide 3a (7.06 g, 23.4 mmol)
was refluxed with potassium tert-butoxide (2.76 g, 24.6 mmol) in THF
CO Me
2
O
N
1
6
(
0.2 M). Yield 75% (4.49 g); yellow solid, m. p. 118-120°C (lit. m. p.
131-133°C); R (25% MeOH in EtOAc) 0.30; +111.3 (c 1.2 in
DCM); νmax/cm 2960 (C-H), 1747 (C=O), 1724 (C=O), 1621 (C=O); δ (400 MHz, CDCl ): 0.84
O
f
-1
H
3
(9H, s, C(CH ) ), 3.11 (1H, d, J 21.2, C(7)H H ), 3.56 (1H, d, J 9.0, C(4)H H ), 3.68 (1H, d, J
3 3 A B A B
21.2, C(7)H H ), 3.76 (3H, s, CO CH ), 4.73 (1H, d, J 9.0, C(4)H H ), 5.01 (1H, s, C(2)H); δ
C
A
B
2
3
A
B
(100 MHz, CDCl ): 24.7 (C(CH ) ), 35.6 (C(CH ) ), 44.8 (C(7)), 53.7 (CO CH ), 67.9 (C(4)), 80.5
3 3 3 3 3 2 3
-
-
(C(5)), 98.3 (C(2)), 166.9 (CO CH ), 172.3 (C(8)), 198.3 (C(6)); m/z ([ESI] ) 254.1 ([M-H] ,
2 3
-
-
1
00%); HRMS (ESI ) m/z: ([M-H] ) Calcd for C H NO 254.1034; Found 254.1032.
12 16 5
(2R,4R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-3-oxa-6,8 dioxobicyclo [3.3.0]-
octane, 4b
O
According to General Method D, malonamide 3b (5.23 g, 16.6 mmol) was
refluxed with potassium tert-butoxide (1.95 g, 17.4 mmol) in THF (0.2
CO Me
2
Me
O
N
16
M). Yield 73% (3.25 g); yellow solid, m. p. 134-136°C (lit. m. p. 132-
O
1
34°C); R (20% MeOH in EtOAc) 0.38;
+41.3 (c 1.1 in DCM);
f
-1
νmax/cm 2960 (C-H), 2874 (C-H), 1782 (C=O), 1749 (C=O), 1617 (C=O); δ (400 MHz, CDCl ):
H
3
0
2
.83 (9H, s, C(CH ) ), 0.98 (3H, d, J 6.7, C(4)CH ), 3.08 (1H, d, J 21.7, C(7)H H ), 3.58 (1H, d, J
3 3 3 A B
1.7, C(7)H H ), 3.74 (3H, s, CO CH ), 5.02 (1H, q, J 6.7, C(4)H), 5.05 (1H, s, C(2)H); δ (100
A
B
2
3
C
MHz, CDCl ): 15.1 (C(4)CH ), 24.7 (C(CH ) ), 35.5 (C(CH ) ), 45.1 (C(7)), 53.6 (CO CH ), 75.0
3
3
3 3
3 3
2
3
+
(C(4)), 83.6 (C(5)), 95.9 (C(2)), 167.1 (CO CH ), 172.9 (C(8)), 199.4 (C(6)); m/z ([ESI] ) 270.1
2 3
+
+
([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO 270.1336; Found 270.1336.
1
3
20
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1
1
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1
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
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5
5
5
5
5
5
5
6
(2R,4S,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-3-oxa-6,8-dioxobicyclo [3.3.0]-
octane, 4c
O
According to General Method D, malonamide 3c (1.84 g, 5.80 mmol) was
refluxed with potassium tert-butoxide (685 mg, 6.1 mmol) in THF (0.2
CO Me
2
Me
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
O
N
M). Yield 75% (1.17 g); yellow solid, m. p. 118-120; R (20% MeOH in
O
f
-1
EtOAc) 0.38;
+76.9 (c 1.0 in DCM); νmax/cm 2959 (C-H), 2872
(C-H), 1755 (C=O), 1723 (C=O), 1623 (C=O); δ (400 MHz, CDCl ): 0.87 (9H, s, C(CH ) ), 1.60
H
3
3 3
(
3H, d, J 6.5, C(4)CH ), 3.07 (1H, d, J 21.2, C(7)H H ), 3.65 (1H, d, J 21.2, C(7)H H ), 3.71 (3H,
3 A B A B
s, CO CH ), 3.75 (1H, q, J 6.5, C(4)H), 4.90 (1H, s, C(2)H); δ (100 MHz, CDCl ): 14.6
2
3
C
3
(C(4)CH ), 25.0 (C(CH ) ), 35.3 (C(CH ) ), 45.1 (C(7)), 52.9 (CO CH ), 76.6 (C(4)), 80.1 (C(5)),
3
3 3
3 3
2
3
+
+
9
6.8 (C(2)), 165.7 (CO CH ), 172.6 (C(8)), 198.3 (C(6)); m/z ([ESI] ) 270.2 ([M+H] , 80%), 292.1
2 3
+
+
(
[M+Na] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO 270.1336; Found 270.1336.
13 20 5
(2R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-6,8-dioxo-3-thiabicyclo[3.3.0]-octane, 4d
According to General Method D, malonamide 3d (5.81 g, 18.3 mmol) was
O
CO Me
2
refluxed with potassium tert-butoxide (2.16 g, 19.2 mmol) in THF (0.2 M).
O
N
1
6
Yield 74% (3.7 g); yellow solid, m. p. 114-116 (lit. m. p. 114-116°C); R
f
S
(25% MeOH in EtOAc) 0.38;
+150.1 (c 1.0 in DCM); νmax/cm-1
2
2
957 (C-H), 1748 (C=O), 1714 (C=O), 1626 (C=O); δ (400 MHz, CDCl ): 0.89 (9H, s, C(CH ) ),
H
3
3 3
.95 (1H, d, J 11.6, C(4)H H ), 3.07 (1H, d, J 21.5, C(7)H H ), 3.56 (1H, d, J 21.5, C(7)H H ),
A
B
A
B
A
B
3.72 (1H, d, J 11.6, C(4)H H ), 3.76 (3H, s, CO CH ), 5.26 (1H, s, C(2)H); δ (100 MHz, CDCl ):
A
B
2
3
C
3
2
1
6.4 (C(CH ) ), 33.8 (C(4)), 37.2 (C(CH ) ), 42.9 (C(7)), 53.9 (CO CH ), 73.7 (C(2)), 84.9 (C(5)),
3 3 3 3 2 3
-
-
+
67.1 (CO CH ), 170.6 (C(8)), 199.5 (C(6)); m/z ([ESI] ) 270.1 ([M-H] , 100%); HRMS (ESI )
2
3
m/z: [MH]+ Calcd for C H NO S 272.0951; Found 272.0951.
1
2
18
4
(2R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-3-oxa-8-oxo-6-tosyloxybicyclo[3.3.0]-oct-6-
ene, 5s
2
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According to General Method E, tetramic acid 4a (2.37 g, 9.30
mmol) was reacted with TsCl (1.77 g, 9.30 mmol) and DIPEA (3.20
mL, 18.6 mmol) in DCM (0.1 M). Yield 78% (2.97 g); white solid,
Me
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
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
3'
O
2
'
S
O O
7
CO Me
2
m. p. 144-148°C; R (20% EA in PE) 0.26;
+72.9 (c 1.3 in
DCM); νmax/cm 2959 (C-H), 2873 (C-H), 1723 (C=O), 1629
C=O); δ (400 MHz, CDCl ): 0.78 (9H, s, C(CH ) ), 2.43 (3H, s,
f
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
4
N
1
-1
O
O
3
(
H
3
3 3
Ar-CH ), 3.21 (1H, d, J 8.6, C(4)H H ), 3.50 (3H, s, CO CH ), 4.58 (1H, s, C(2)H), 4.63 (1H, d, J
3
A
B
2
3
8
.6, C(4)H H ), 5.77 (1H, s, C(7)H), 7.35 (2H, d, J 8.6, C(3')H), 7.74 (2H, d, J 8.6, C(2')H); δ
A B C
(
100 MHz, CDCl ): 21.9 (Ar-CH ), 24.6 (C(CH ) ), 35.1 (C(CH ) ), 53.3 (CO CH ), 69.4 (C(4)),
3 3 3 3 3 3 2 3
75.0 (C(5)), 96.9 (C(2)), 107.5 (C(7)), 128.7 (C(2')), 130.3 (C(3')), 130.8 (C(4')), 147.2 (C(1')),
+
+
+
1
63.6 (CO CH ), 166.8 (C(8)), 175.6 (C(6)); m/z ([ESI] ) 410.2 ([M+H] , 100%); HRMS (ESI )
2 3
m/z: [MH]+ Calcd for C H NO S 410.1268; Found 410.1277.
1
9
24
7
(
2R,4R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-3-oxa-8-oxo-6-tosyloxy
bicyclo[3.3.0]-oct-6-ene, 5b
Me
According to General Method E, tetramic acid 4b (56.0 mg, 0.2
mmol) was reacted with TsCl (40.0 mg, 0.20 mmol) and DIPEA
(0.07 mL, 0.4 mmol) in DCM (0.1 M). Yield 57% (50 mg);
3
'
O
2
'
S
O O
7
CO Me
2
Me
Colourless oil; R (20% EA in PE) 0.35;
f
+79.4 (c 1.1 in
N
1
O
-1
O 3
DCM); νmax/cm 2960 (C-H), 2874 (C-H), 1720 (C=O), 1627
(C=O); δ (400 MHz, CDCl ): 0.76 (9H, s, C(CH ) ), 0.85 (3H, d, J
H
3
3 3
6
.8, C(4)CH ), 2.43 (3H, s, ArCH ), 3.45 (3H, s, CO CH ), 4.66 (1H, s, C(2)H), 4.94 (1H, q, J 6.8,
3 3 2 3
C(4)H), 5.84 (1H, s, C(7)H), 7.35 (2H, d, J 8.2, C(3')H), 7.75 (2H, d, J 8.4, C(2')H); δ (100 MHz,
C
CDCl ): 14.3 (C(4)CH ), 21.9 (Ar-CH ), 24.6 (C(CH ) ), 35.1 (C(CH ) ), 53.2 (CO CH ), 73.5
3
3
3
3 3
3 3
2
3
(
(
(
C(4)), 78.1 (C(5)), 94.0 (C(2)), 107.7 (C(7)), 128.7 (C(2')), 130.3 (C(3')), 130.8 (C(4')), 147.2
+
+
C(1')), 161.9 (CO CH ), 167.3 (C(8)), 175.4 (C(6)); m/z ([ESI] ) 424.2 ([M+H] , 60%), 446.0
2
3
+
+
[M+Na] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H O NS 424.1425; Found 424.1419.
2
0
26
7
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2
2
2
2
2
2
2
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5
5
6
(2R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-6-((methylsulfonyl)oxy)-3-oxa-8-
oxobicyclo[3.3.0]-oct-6-ene, 5c
OMs
According to General Method E, tetramic acid 4a (6.83 g, 26.8 mmol) was
reacted with MsCl (2.10 mL, 26.8 mmol) and DIPEA (9.30 mL, 53.6
mmol) in DCM (0.1 M). Yield 64% (5.7 g); white solid, m. p. 186-188°C;
CO Me
2
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
O
N
O
-1
R (50% EA in PE) 0.50;
f
+144.3 (c 1.1 in DCM); νmax/cm 2980 (C-
H), 2885 (C-H), 1721 (C=O), 1632 (C=O); δ (400 MHz, CDCl ): 0.85 (9H, s, C(CH ) ), 3.17 (3H,
H
3
3 3
s, OSO CH ), 3.45 (1H, d, J 8.6, C(4)H H ), 3.76 (3H, s, CO CH ), 3.67 (1H, s, C(2)H), 4.75 (1H,
2
3
A
B
2
3
d, J 8.6, C(4)H H ), 5.86 (1H, s, C(7)H); δ (100 MHz, CDCl ): 23.6 (C(CH ) ), 34.2 (C(CH ) ),
A
B
C
3
3 3
3 3
37.2 (OSO CH ), 52.5 (CO CH ), 68.5 (C(4)), 74.0 (C(5)), 96.0 (C(2)), 107.0 (C(7)), 161.9
2
3
2
3
+
+
+
(
CO CH ), 166.3 (C(8)), 174.2 (C(6)); m/z ([ESI] ) 356.0 ([M+Na] , 100%); HRMS (ESI ) m/z:
2 3
[
M+Na]+ Calcd for C H NNaO S 356.0774; Found 356.0774.
1
3
19
7
(2R,4R,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-6-((methylsulfonyl)oxy)-3-oxa-
8-oxobicyclo[3.3.0]-oct-6-ene, 5d
OMs
According to General Method E, tetramic acid 4b (3.45 g, 12.8 mmol)
CO Me
2
was reacted with MsCl (0.99 mL, 12.8 mmol) and DIPEA (4.45 mL, 25.6
O
Me
N
mmol) in DCM (0.1 M). Yield 25% (1.1 g); white solid, m. p. 138-140°C;
O
-1
R (40% EA in PE) 0.38;
f
+150.0 (c 1.1 in DCM); νmax/cm 2961
(
C-H), 2875 (C-H), 1720 (C=O), 1629 (C=O); δ (400 MHz, CDCl ): 0.82 (9H, s, C(CH ) ), 1.01
H 3 3 3
(3H, d, J 6.7, C(4)CH ), 3.17 (3H, s, OSO CH ), 3.75 (3H, s, CO CH ), 4.73 (1H, s, C(2)H), 5.01
3
2
3
2
3
(
1H, q, J 6.7, C(4)H), 5.90 (1H, s, C(7)H); δ (100 MHz, CDCl ): 14.6 (C(4)CH ), 24.6 (C(CH ) ),
C 3 3 3 3
3
5.2 (C(CH ) ), 38.2 (OSO CH ), 53.5 (CO CH ), 73.6 (C(4)), 78.1 (C(5)), 94.1 (C(2)), 108.6
3 3 2 3 2 3
+
+
+
(C(7)), 161.4 (CO CH ), 167.7 (C(8)), 175.0 (C(6)); m/z ([ESI] ) 348.2 ([M+H] ), 370.0 ([M+Na] ,
2
3
+
9
0%); HRMS (ESI ) m/z: [M+Na]+ Calcd for C H NNaO S 370.0931; Found 370.0918.
14 21 7
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2
2
2
2
2
2
2
2
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3
3
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(2R,4S,5R)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-6-((methylsulfonyl)oxy)-3-oxa-
-oxobicyclo[3.3.0]-oct-6-ene, 5e
According to General Method E, tetramic acid 4c (478 mg, 1.80 mmol)
8
OMs
CO Me
2
was reacted with MsCl (0.14 mL, 1.8 mmol) and DIPEA (0.62 mL, 3.6
mmol) in DCM (0.1 M). Yield 52% (320 mg); white solid, m. p. 88-90°C;
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
Me
O
N
O
-1
R (40% EA in PE) 0.35;
f
+71.5 (c 1.0 in DCM); νmax/cm 2980 (C-
H), 2884 (C-H), 1719 (C=O), 1630 (C=O); δ (400 MHz, CDCl ): 0.87 (9H, s, C(CH ) ), 1.58 (3H,
H
3
3 3
d, J 6.5, C(4)CH ), 3.19 (3H, s, OSO CH ), 3.71 (3H, s, CO CH ), 3.72 (1H, q, J 6.5, C(4)H), 4.61
3
2
3
2
3
(
1H, s, C(2)H), 5.83 (1H, s, C(7)H); δ (100 MHz, CDCl ): 14.7 (C(4)CH ), 25.1 (C(CH ) ), 35.0
C 3 3 3 3
(C(CH ) ), 38.0 (OSO CH ), 52.7 (CO CH ), 75.1 (C(5)), 79.5 (C(4)), 96.8 (C(2)), 107.3 (C(7)),
3
3
2
3
2
3
+
+
+
1
63.9 (CO CH ), 166.1 (C(8)), 175.8 (C(6)); m/z ([ESI] ) 348.2 ([M+H] , 100%); HRMS (ESI )
2 3
m/z: [MH]+ Calcd for C H NO S 348.1112; Found 348.1110.
1
4
22
7
(2R,5R)-1-Aza-2-(tert-butyl)-6-((methylsulfonyl)oxy)-5-methoxycarbonyl-8-oxa-3-thiabicyclo
[3.3.0]-oct-6-ene, 5f
OMs
According to General Method E, tetramic acid 4d (5.54 g, 20.4 mmol) was
CO Me
2
reacted with MsCl (1.58 mL, 20.4 mmol) and DIPEA (7.11 mL, 40.8 mmol)
O
N
S
in DCM (0.1 M). Yield 44% (3.16 g); white solid, m. p. 140-142°C; Rf
-1
(50% EA in PE) 0.48;
+232.3 (c 1.2 in DCM); νmax/cm 3010 (C-H),
2
960 (C-H), 1714 (C=O), 1639 (C=O); δ (400 MHz, CDCl ): 0.91 (9H, s, C(CH ) ), 2.81 (1H, d, J
H 3 3 3
11.2, C(4)H H ), 3.20 (3H, s, OSO CH ), 3.60 (1H, d, J 11.2, C(4)H H ), 3.78 (3H, s, CO CH ),
A
B
2
3
A
B
2
3
4
.91 (1H, s, C(2)H), 5.79 (1H, s, C(7)H); δ (100 MHz, CDCl ): 26.4 (C(CH ) ), 33.0 (C(4)), 36.8
C 3 3 3
(
C(CH ) ), 38.2 (OSO CH ), 53.6 (CO CH ), 71.5 (C(2)), 79.6 (C(5)), 105.5 (C(7)), 162.7
3 3 2 3 2 3
+
+
+
(CO CH ), 167.3 (C(8)), 173.1 (C(6)); m/z ([ESI] ) 372.0 ([M+Na] , 100%); HRMS (ESI ) m/z:
2
3
[
MH]+ Calcd for C H NO S 350.0727; Found 350.0724.
13 20 6 2
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2
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(2R,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-6-(4-methoxyphenyl)-3-oxa-8-
oxobicyclo[3.3.0]-oct-6-ene, 6ai
OMe
According to General Method F, mesylate 5c (623 mg, 1.90 mmol) was
reacted with 4-methoxyphenylboronic acid (369 mg, 2.40 mmol),
PdCl (dppb), 1 M aqueous Na CO solution (1.8 mL, 16.6 mmol) in ethanol
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
CO Me
2
2
2
3
O
N
(0.8 mL, 13.1 mmol) and toluene (15 mL) for 4 h. PdCl (dppb) was
2
O
prepared from (C H ) P(CH ) P(C H ) (48 mg, 0.1 mmol) and
6
5 2
2 4
6
5 2
(
C H CN) PdCl (35 mg, 0.1 mmol) in toluene (3 mL). Yield 80% (513 mg); white solid, m. p.
6 5 2 2
-1
1
36-138°C; R (50% EA in PE) 0.58;
+155.1 (c 1.0 in DCM); νmax/cm 2958 (C-H), 2870 (C-
f
H), 1742 (C=O), 1707 (C=O); δ (400 MHz, CDCl ): 0.89 (9H, s, C(CH ) ), 3.41 (1H, d, J 8.4,
H
3
3 3
C(4)H H ), 3.57 (3H, s, CO CH ), 3.77 (3H, s, OCH ), 4.68 (1H, s, C(2)H), 5.05 (1H, d, J 8.4,
A
B
2
3
3
C(4)H H ), 6.19 (1H, s, C(7)H), 6.86 (2H, d, J 9.0, C(3')H), 7.31 (2H, d, J 9.0, C(2')H); δ (100
A
B
C
MHz, CDCl ): 24.8 (C(CH ) ), 35.3 (C(CH ) ), 53.2 (CO CH ), 55.5 (OCH ), 70.4 (C(4)), 77.4
3
3 3
3 3
2
3
3
(C(5)), 96.3 (C(2)), 114.7 (C(3')), 119.1 (C(7)), 122.5 (C(1')), 128.7 (C(2')), 159.2 (C(6)), 161.9
+
+
+
(
C(4')), 170.0 (CO CH ), 177.8 (C(8)); m/z ([ESI] ) 346.2 ([M+H] , 100%); HRMS (ESI ) m/z:
2 3
[
MH]+ Calcd for C H NO 346.1649; Found 346.1642.
1
9
24
5
(2R,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-3-oxa-8-oxo-6-phenylbicyclo[3.3.0]-oct-6-ene,
aii
6
According to General Method F, mesylate 5c (741 mg, 2.20 mmol) was
reacted with phenylboronic acid (351 mg, 2.90 mmol), PdCl (dppb), 1 M
2
CO Me
2
aqueous Na CO solution (2.1 mL, 20.0 mmol) in ethanol (0.9 mL, 15.5
2
3
N
O
O
mmol) and toluene (15 mL) for 5 h. PdCl (dppb) was prepared from
2
(
C H ) P(CH ) P(C H ) (57 mg, 0.13 mmol) and (C H CN) PdCl (43 mg,
6 5 2 2 4 6 5 2 6 5 2 2
0.1 mmol) in toluene (3 mL). Yield 64% (300 mg); white solid, m. p. 162-164°C; R (20% EA in
f
-1
PE) 0.25;
+153.8 (c 1.0 in DCM); νmax/cm 2958 (C-H), 2866 (C-H), 1742 (C=O), 1699
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5
6
(C=O); δ (400 MHz, CDCl ): 0.89 (9H, s, C(CH ) ), 3.44 (1H, d, J 8.4, C(4)H H ), 3.57 (3H, s,
H 3 3 3 A B
CO CH ), 4.70 (1H, s, C(2)H), 5.08 (1H, d, J 8.4, C(4)H H ), 6.33 (1H, s, C(7)H), 7.36 (5H, s,
2
3
A
B
ArH); δ (100 MHz, CDCl ): 24.8 (C(CH ) ), 35.3 (C(CH ) ), 53.2 (CO CH ), 70.4 (C(4)), 77.4
C
3
3 3
3 3
2
3
(C(5)), 96.3 (C(2)), 121.6 (C(7)), 126.9-131.2 (ArC), 159.5 (C(6)), 169.7 (CO CH ), 177.4 (C(8));
2
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
+
+
+
m/z ([ESI] ) 316.2 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for C H NO 316.1543;
1
8
22
4
Found 316.1543.
(2R,5S)-1-Aza-2-(tert-butyl)-6-(2-furyl)-5-methoxycarbonyl-3-oxa-8-oxobicyclo[3.3.0]-oct-6-
ene, 6aiii
According to General Method F, mesylate 5c (513 mg, 1.5 mmol) was
O
reacted with 2-furylboronic acid (206 mg, 1.80 mmol), PdCl (dppb), 1 M
CO Me
2
2
aqueous Na CO solution (1.47 mL, 13.8 mmol) in ethanol (0.62 mL, 10.8
2
3
N
O
O
mmol) and toluene (15 mL) for 12 h. PdCl (dppb) was prepared from
2
(
C H ) P(CH ) P(C H ) (39 mg, 0.09 mmol) and (C H CN) PdCl (29 mg,
6 5 2 2 4 6 5 2 6 5 2 2
0.08 mmol) in toluene (3 mL). Yield 47% (219 mg); yellow solid, m. p. 98-102°C; R (30% EA in
f
-1
PE) 0.43;
+47.3 (c 1.0 in DCM); νmax/cm 2959 (C-H), 2871 (C-H), 1711 (C=O), 1627
(
C=O); δ (400 MHz, CDCl ): 0.88 (9H, s, C(CH ) ), 3.33 (1H, d, J 8.5, C(4)H H ), 3.64 (3H, s,
H 3 3 3 A B
CO CH ), 4.67 (1H, s, C(2)H), 4.92 (1H, d, J 8.5, C(4)H H ), 6.15 (1H, s, C(7)H), 6.43 (1H, dd, J
2
3
A
B
3
.6, 1.8, C(3')H), 6.59 (1H, d, J 3.6, C(4')H). 7.49 (1H, d, J 1.8, C(5')H); δ (100 MHz, CDCl ):
C 3
2
4.7 (C(CH ) ), 35.3 (C(CH ) ), 53.3 (CO CH ), 70.3 (C(4)), 75.9 (C(5)), 96.7 (C(2)), 112.7
3
3
3 3
2
3
(C(3')), 113.8 (C(4')), 118.1 (C(7)), 145.9 (C(5')), 146.1 (C(2')), 147.8 (C(6)), 169.6 (CO CH ),
2
3
+
+
+
1
77.6 (C(8)); m/z ([ESI] ) 328.0 ([M+Na] , 20%); HRMS (ESI ) m/z: [MH]+ Calcd for C H O N
16 20 5
3
06.1336; Found 306.1336.
(2R,5S)-1-Aza-2-(tert-butyl)-6-(4-formylphenyl)-5-methoxycarbonyl-3-oxa-8-oxobicyclo
[3.3.0]-oct-6-ene, 6aiv
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6
According to General Method F, mesylate 5c (676 mg, 2.0 mmol) was reacted
CHO
with 4-formylphenylboronic acid (396 mg, 2.60 mmol), PdCl (dppb), 1 M
2
aqueous Na CO solution (1.9 mL, 18.3 mmol) in ethanol (0.82 mL, 14.2
2
3
CO Me
2
mmol) and toluene (15 mL) for 11 h. PdCl (dppb) was prepared from
2
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
N
O
O
(
C H ) P(CH ) P(C H ) (39.0 mg, 0.09 mmol) and (C H CN) PdCl (29 mg,
6 5 2 2 4 6 5 2 6 5 2 2
0
.08 mmol) in toluene (3 mL). Yield 28% (194 mg); white solid, m. p. 154-
-1
158°C; R (10% EA in DCM) 0.46;
+119.5 (c 1.0 in DCM); νmax/cm 2959 (C-H), 2871 (C-
f
H), 1743 (C=O), 1702 (C=O); δ (400 MHz, CDCl ): 0.90 (9H, s, C(CH ) ), 3.47 (1H, d, J 8.4,
H
3
3 3
C(4)H H ), 3.58 (3H, s, CO CH ), 4.72 (1H, s, C(2)H), 5.10 (1H, d, J 8.4, C(4)H H ), 6.47 (1H, s,
A
B
2
3
A
B
C(7)H), 7.53 (2H, d, J 8.6, C(2')H), 7.88 (2H, d, J 8.6, C(3')H). 9.98 (1H, s, CHO); δ (100 MHz,
C
CDCl ): 24.7 (C(CH ) ), 35.4 (C(CH ) ), 53.4 (CO CH ), 70.4 (C(4)), 77.4 (C(5)), 96.5 (C(2)),
3
3 3
3 3
2
3
1
24.4 (C(7)), 127.5 (C(2')), 130.4 (C(3')), 135.1 (C(4')), 137.6 (C(1')), 157.8 (C(6)), 169.4
+
+
+
(
CO CH ), 176.6 (C(8)), 191.1 (CHO); m/z ([ESI] ) 344.2 ([M+H] , 30%), 366.2 ([M+Na] , 50%);
2 3
+
HRMS (ESI ) m/z: [M+Na]+ Calcd for C H O NNa 366.1312; Found 366.1309.
1
9
21
5
(
2R,5S)-1-Aza-2-(tert-butyl)-6-(4-chlorophenyl)-5-methoxycarbonyl-3-oxa-8-oxobicyclo
[
3.3.0]-oct-6-ene, 6av
Cl
According to General Method F, mesylate 5c (676 mg, 2.00 mmol) was
reacted with 4-chlorophenylboronic acid (201 mg, 0.60 mmol),
CO Me PdCl (dppb), 1 M aqueous Na CO solution (0.60 mL, 5.4 mmol) in
2
2
2
3
O
N
ethanol (0.24 mL, 4.2 mmol) and toluene (15 mL) for 7 h. PdCl (dppb)
2
O
was prepared from (C H ) P(CH ) P(C H ) (15 mg, 0.04 mmol) and
6
5 2
2 4
6
5 2
(
C H CN) PdCl (11.5 mg, 0.03 mmol) in toluene (2 mL). Yield 49% (103
6 5 2 2
mg); white solid, m. p. 168-172°C; R (20% EA in PE) 0.32;
+133.2 (c 1.0 in DCM);
f
-1
νmax/cm 2958 (C-H), 2870 (C-H), 1743 (C=O), 1709 (C=O); δ (400 MHz, CDCl ): 0.88 (9H, s,
H
3
C(CH ) ), 3.42 (1H, d, J 8.4, C(4)H H ), 3.57 (3H, s, CO CH ), 4.69 (1H, s, C(2)H), 5.05 (1H, d, J
3
3
A
B
2
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5
5
6
8.4, C(4)H H ), 6.32 (1H, s, C(7)H), 7.29 (2H, d, J 8.9, C(2')H), 7.33 (2H, d, J 8.9, C(3')H); δ
A B C
(100 MHz, CDCl ): 24.7 (C(CH ) ), 35.3 (C(CH ) ), 53.3 (CO CH ), 70.3 (C(4)), 77.4 (C(5)), 96.4
3 3 3 3 3 2 3
(C(2)), 122.1 (C(7)), 128.2 (C(2')), 128.3 (C(4')), 129.7 (C(3')), 137.4 (C(1')), 158.1 (C(6)), 169.6
+
+
35
+ 37
(CO CH ), 177.0 (C(8)); m/z ([ESI] ) 372.0 ([M+Na] , Cl, 100%), 374.0 ([M+Na] , Cl, 25%);
2
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
+
35
HRMS (ESI ) m/z: [M+Na], Cl]+ Calcd for C H O NClNa 372.0973; Found 372.0970.
1
8
20
4
(2R,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-3-oxa-8-oxo-6-((E)-styryl)bicyclo[3.3.0]-oct-
6-ene, 6avi
According to General Method F, mesylate 5c (101 mg, 0.30 mmol) was
reacted with trans-2-phenylvinylboronic acid (67 mg, 0.45 mmol),
PdCl (dppb), 1 M aqueous Na CO solution (0.3 mL, 2.7 mmol) in ethanol
2
2
3
CO Me
2
(0.12 mL, 2.1 mmol) and toluene (10 mL) for 48 h. PdCl (dppb) was
2
O
N
O
prepared from (C H ) P(CH ) P(C H ) (7.7 mg, 0.018 mmol) and
6
5 2
2 4
6
5 2
(
C H CN) PdCl (5.8 mg, 0.015 mmol) in toluene (1 mL). Yield 25% (26
6 5 2 2
mg); yellow solid, m. p. 218-220°C; R (30% EA in PE) 0.45;
+6.4 (c 0.9 in DCM); νmax/cm-1
958 (C-H), 1742 (C=O), 1707 (C=O); δ (500 MHz, CDCl ): 0.98 (9H, s, C(CH ) ), 3.44 (1H, d, J
f
2
8
H
3
3 3
.5, C(4)H H ), 3.77 (3H, s, CO CH ), 4.76 (1H, s, C(2)H), 5.08 (1H, d, J 8.5, C(4)H H ), 6.09
A
B
2
3
A
B
(1H, s, C(7)H), 6.84 (1H, d, J 16.7, C(10)H), 6.94 (1H, d, J 16.7, C(9)H), 7.36-7.53 (5H, m, ArH);
δ (125 MHz, CDCl ): 24.7 (C(CH ) ), 35.3 (C(CH ) ), 53.3 (CO CH ), 70.1 (C(4)), 76.7 (C(5)),
C
3
3 3
3 3
2
3
9
6.3 (C(2)), 119.2 (C(10)), 123.8 (C(7)), 127.5-135.1 (ArC), 137.4 (C(9)), 157.3 (C(6)), 170.1
+
+
+
(CO CH ), 177.6 (C(8)); m/z ([ESI] ) 342.2 ([M+H] , 100%); HRMS (ESI ) m/z: [MH]+ Calcd for
2
3
C H NO 342.1700; Found 342.1699.
2
0
24
4
(2R,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-3-oxa-8-oxo-6-(phenylethynyl)bicyclo [3.3.0]-
oct-6-ene, 6avii
According to General Method F, mesylate 5c (276 mg, 0.830 mmol) was reacted with 2-phenyl-1-
ethynylboronic acid (303 mg, 1.33 mmol), PdCl (dppb), 1 M aqueous Na CO solution (0.8 mL, 7.5
2
2
3
2
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol) in ethanol (0.34 mL, 5.8 mmol) and toluene (13 mL) for 12 h.
PdCl (dppb) was prepared from (C H ) P(CH ) P(C H ) (21 mg, 0.05
2
6
5 2
2 4
6
5 2
mmol) and (C H CN) PdCl (16 mg, 0.04 mmol) in toluene (1 mL). Yield
6
5
2
2
CO Me 20% (55.0 mg); yellow sticky material; R (20% EA in PE) 0.32;
f
2
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
-1
+
11.5 (c 1.0 in DCM); νmax/cm 2959 (C-H), 2871 (C-H), 1748 (C=O),
O
N
O
1
716 (C=O); δ (400 MHz, CDCl ): 0.88 (9H, s, C(CH ) ), 3.36 (1H, d, J
H 3 3 3
8.5, C(4)H H ), 3.73 (3H, s, CO CH ), 4.68 (1H, s, C(2)H), 4.85 (1H, d, J
A
B
2
3
8
.5, C(4)H H ), 6.16 (1H, s, C(7)H), 7.25-7.45 (5H, m, ArH); δ (100 MHz, CDCl ): 24.7
A B C 3
(
C(CH ) ), 35.4 (C(CH ) ), 53.3 (CO CH ), 70.4 (C(4)), 78.9 (C(5)), 79.5 (C(9)), 97.4 (C(2)), 105.2
3 3 3 3 2 3
(C(10)), 120.9, 128.6, 130.3, 132.2 (ArC), 129.4 (C(7)), 141.9 (C(6)), 168.3 (CO CH ), 177.3
2
3
+
+
+
(
C(8)); m/z ([ESI] ) 362.2 ([M+Na] , 20%); HRMS (ESI ) m/z: [M+Na]+ Calcd for C H NNaO
20 21 4
3
62.1363; Found 362.1362.
2R,4R,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-6-(4-methoxyphenyl)-4-methyl-3-oxa-8-
(
oxobicyclo [3.3.0]-oct-6-ene, 6bi
OMe
According to General Method F, mesylate 5d (106.0 mg, 0.30 mmol)
was reacted with 4-methoxyphenylboronic acid (60 mg, 0.40 mmol),
PdCl (dppb), 1 M aqueous Na CO solution (0.3 mL, 2.8 mmol) in
O
CO Me
2
N
2
2
3
Me
O
ethanol (0.13 mL, 2.2 mmol) and toluene (10 mL) for 50 h.
PdCl (dppb) was prepared from (C H ) P(CH ) P(C H ) (8.0 mg, 0.018 mmol) and
2
6
5 2
2 4
6
5 2
(C H CN) PdCl (6.0 mg, 0.015 mmol) in toluene (1 mL). Yield 14% (15 mg); white solid, m. p.
6
5
2
2
-1
1
50-152°C; R (40% EA in PE) 0.50;
+193.5 (c 1.0 in DCM); νmax/cm 2959 (C-H), 2872 (C-
f
H), 1743 (C=O), 1707 (C=O); δ (500 MHz, CDCl ): 0.95 (9H, s, C(CH ) ) 0.96 (3H, d, J 6.6,
H
3
3 3 ,
C(4)CH ), 3.65 (3H, s, CO CH ), 3.86 (3H, s, OCH ), 4.83 (1H, s, C(2)H), 5.40 (1H, q, J 6.6,
3
2
3
3
C(4)H), 6.35 (1H, s, C(7)H), 6.95 (2H, d, J 8.9, C(3')H), 7.41 (2H, d, J 8.9, C(2')H); δ (125 MHz,
C
CDCl ): 14.0 (C(4)CH ), 24.8 (C(CH ) ), 35.3 (C(CH ) ), 53.1 (CO CH ), 55.5 (OCH ), 74.3
3
3
3 3
3 3
2
3
3
(
C(4)), 80.3 (C(5)), 93.3 (C(2)), 114.7 (C(3')), 120.2 (C(7)), 122.3 (C(1')), 128.7 (C(2')), 157.3
2
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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
(C(6)), 161.8 (C(4')), 170.4 (CO CH ), 177.3 (C(8)); m/z ([ESI] ) 360.2 ([M+H] , 100%); HRMS
2 3
+
(
ESI ) m/z: [MH]+ Calcd for C H NO 360.1806; Found 360.1808.
20 26 5
(
2R,4S,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-6-(4-methoxyphenyl)-4-methyl-3-oxa-8-
oxobicyclo [3.3.0]-oct-6-ene, 6ci
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
OMe
According to General Method F, mesylate 5e (264.0 mg, 0.730 mmol)
was reacted with 4-methoxyphenylboronic acid (166 mg, 1.10 mmol),
PdCl (dppb), 1 M aqueous Na CO solution (0.7 mL, 6.6 mmol) in
CO Me
2
O
2
2
3
N
Me
O
ethanol (0.3 mL, 5.1 mmol) and toluene (13 mL) for 4 h. PdCl (dppb)
2
was prepared from (C H ) P(CH ) P(C H ) (18.7 mg, 0.043 mmol) and
6
5 2
2 4
6
5 2
(
C H CN) PdCl (14.0 mg, 0.037 mmol) in toluene (2 mL). Yield 70% (183 mg); white solid, m. p.
6 5 2 2
-
1
1
74-176°C; R (40% EA in PE) 0.50;
-86.8 (c 1.0 in DCM); νmax/cm 2956 (C-H), 2870 (C-
f
H), 1710 (C=O), 1607 (C=O); δ (400 MHz, CDCl ): 0.90 (9H, s, C(CH ) ), 1.71 (3H, d, J 6.6,
H
3
3 3
C(4)CH ), 3.51 (1H, q, J 6.6, C(4)H), 3.61 (3H, s, CO CH ), 3.78 (3H, s, OCH ), 4.67 (1H, s,
3
2
3
3
C(2)H), 6.23 (1H, s, C(7)H), 6.86 (2H, d, J 9.0, C(3')H), 7.37 (2H, d, J 9.0, C(2')H); δ (100 MHz,
C
CDCl ): 14.7 (C(4)CH ), 25.1 (C(CH ) ), 35.1 (C(CH ) ), 52.5 (CO CH ), 55.5 (OCH ), 76.7
3
3
3 3
3 3
2
3
3
(
C(5)), 80.3 (C(4)), 95.9 (C(2)), 114.5 (C(3')), 119.9 (C(7)), 122.9 (C(1')), 128.5 (C(2')), 159.0
+
+
(C(4’)), 161.6 (C(6)), 169.4 (CO CH ), 178.0 (C(8)); m/z ([ESI] ) 360.2 ([M+H] , 100%); HRMS
2
3
+
(
ESI ) m/z: [MH]+ Calcd for C H NO 360.1806; Found 360.1803.
20 26 5
(
2R,4S,5S)-1-Aza-2-(tert-butyl)-5-methoxycarbonyl-4-methyl-3-oxa-8-oxo-6-phenylbicyclo
[3.3.0]-oct-6-ene, 6c-ii
2
9
ACS Paragon Plus Environment