Asymmetric synthesis of 7-aza-phomopsolide E and its C-4 epimer

Article abstract of DOI:10.1016/j.tet.2018.10.036

A flexible, enantioselective route to highly functionalized α,β-unsaturated δ-lactones has been applied to the synthesis of 7-aza-phomopsolide E and its C-4 epimer. This approach relies on the application of the Noyori asymmetric hydrogenation of furyl ketone to produce the secondary furyl alcohol in high enantioexcess, which can be stereoselectively transformed into α,β-unsaturated-δ-lactones by a short, highly diastereoselective oxidation and reduction sequence. DCC and acid chloride couplings were used to introduce the side chains of the two natural product analogues.

Full text of DOI:10.1016/j.tet.2018.10.036

Accepted Manuscript
Asymmetric synthesis of 7-aza-phomopsolide E and its C-4 epimer
Alhanouf Z. Aljahdali, Seth A. Freedman, Miaosheng Li, George A. O'Doherty
PII:
S0040-4020(18)31242-0
https://doi.org/10.1016/j.tet.2018.10.036
TET 29869
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 August 2018
Revised Date: 8 October 2018
Accepted Date: 15 October 2018
Please cite this article as: Aljahdali AZ, Freedman SA, Li M, O'Doherty GA, Asymmetric synthesis
of 7-aza-phomopsolide E and its C-4 epimer, Tetrahedron (2018), doi: https://doi.org/10.1016/
j.tet.2018.10.036.
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§
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Alhanouf Z. Aljahdali, Seth A. Freedman, Miaosheng Li* and George A. O’Doherty*
a
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA

1
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Tetrahedron
journal homepage: www.elsevier.com
Asymmetric synthesis of 7-aza-phomopsolide E and its C-4 epimer
§
§
Alhanouf Z. Aljahdali, Seth A. Freedman, Miaosheng Li* and George A. O’Doherty*
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Abstract: A flexible, enantioselective route to highly functionalized α,β-unsaturated δ-lactones
has been applied to the synthesis of 7-aza-phomopsolide E and its C-4 epimer. This approach
relies on the application of the Noyori asymmetric hydrogenation of furyl ketone to produce the
secondary furyl alcohol in high enantioexcess, which can be stereoselectively transformed into
α,β-unsaturated-δ-lactones by a short, highly diastereoselective oxidation and reduction
sequence. DCC and acid chloride couplings were used to introduce the side chains of the two
natural product analogs.
Available online
Keywords:
Phomopsolide A-E, 7-aza-analogues, asymmetric
synthesis, Noyori reduction, Achmatowicz
rearrangements, 2-acetylfuran synthesis
20XX Elsevier Ltd. All rights reserved
.
1
. Introduction
to the established antibiotics tetracycline, penicillin G, and
1,2
streptomycin.
Over the past century, American elm trees have taken the
spot of North America’s most widely-planted street tree due to
their ability to thrive on a wide range of soils and their ability to
There have been eight successful syntheses of the
phomopsolide natural products and related analogues. The first
1
survive root disturbance, drought and extreme cold. If attacked
5
synthesis was of phomopsolide B, by Noshita (1994). In 2002
by Dutch elm disease, a fungal infection caused by Ophiostoma
ulmi, a thriving 100-year-old American elm can be killed in as
6
and 2004 respectively, we synthesized phomopsolide C and
7
phomopsolide D, as well as an analogue, 7-oxa-phomopsolide E
2
little as two weeks. Dutch elm disease would be rendered
8
and its C-4 epimer. The next year, Blechert reported a synthesis
harmless if the microfungus responsible were removed from its
association with its vector, the elm bark beetle (e.g.,
Hylurgopinus rufipes). As a result, the elm bark beetle is a
potential target in the effort to protect the American elm from
Dutch elm disease.
9
of phomopsolide C. In 2012 and 2015, phomopsolide B was
10
11
synthesized by Prasad and Sabitha. Finally in 2014, the C-4,5-
12
bisepimer of phomopsolide B was synthesized by Atmakur.
3
4
Grove and Stierle found a series of five 6-substituted 5,6-
dihydro-5-hydroxypyran-2-one natural products, the
phomopsolides, in their search for antiboring/antifeeding
compounds with activity against the elm bark beetles. In 1985,
Groves discovered phomopsolide A and B in Phomopsis oblonga,
3
a fungus which co-habitates with the elm trees. Two years later,
Stierle re-isolated Phomopsolide A and B along with three new
Figure 1: The phomopsolides and related analogues
phomopsolides (C-E), from fungi lying in the bark of the Pacific
4
yew (Taxus brevifolia). In addition to their antifeeding
properties, the phomopsolides were also found to exhibit
As part of a continuing effort aimed at exploring the
stereochemical structure activity relationship (S-SAR) study of
antimicrobial activity against Staphylococcus aureus, comparable

2
Tetrahedron Letters
ACCEPTED MANUSCRIPT
1
3,14,15
nd
pyranone containing polyketide natural products,
like the
Our 2 generation route envisioned all the carbons acylfurans 7
and 8 as deriving from commercially available 2-acetylfuran 11
phomopsolides, we became interested in the synthesis of a 7-
aza-analogue of phomopsolide E, 2b and its C-4 epimer. The C-4
epimer was chosen to explore the S-SAR of the phomopsolides
and for its ease of synthesis. The route we envisioned builds on
our approach to 7-oxa-phomopsolide E and its C-4 epimer
(Scheme 3). The route began with the direct functionalization of
the C-6 methyl group of acetyl furan 11 by a bromination S 2
N
17
displacement strategy. Thus, an electrophilic bromination of the
furan ketone 11 generated a crude bromoketone 12, which after
aqueous work up could be readily displace with oxygen and
nitrogen nucleophiles to yield 7 and 8 respectively. As direct
displacement of the bromide in 12 with water led to poor yields,
we found the reaction with carboxylate nucleophiles to be quite
clean. This resulted in a three-step procedure of displacement
with NaOAc, ester hydrolysis (LiOH) followed by TBS-protection of
the crude hydroxyketone to reproduceable afford 7 in 60% overall
yield and the use of one silica gel chromatographic purification.
Similarly, when the crude bromide 12 was treated with a DMF
solution the potassium anion of t-butylcarbamate it was
converted directly into the desired acylfuran 8 in 51% overall
yields.
(Scheme 1). This convergent approach relies on the serial
coupling of three components: tiglic acid 3, protected lactic acid
chloride 4, and pyranone 6. The desired pyranone 6 with a Boc-
protected C-6 amino-group could be easily be prepared in either
enantiomeric series from acylfuran 8. Key to the success of this
approach is the careful control of the degree of protonation of
the amine intermediate, generated from a Boc-deprotection, as
it enters into the amide coupling, such as to prevent any
migration of the C-4 tigliate group. The success of this approach
is demonstrated by the synthesis of the desired 7-aza-analogue
2
b, as well as its C-4 epimer 2c (vide infra).
Scheme 3: Development route to protected furan 7 and 8
Scheme 1: Retrosynthesis toward 2a and 2b
Reagents and conditions: (a) t-butyl carbamate, KHMDS, DMF, 0
ºC, 51%; (b) CH CO Na, TBAB, acetone, 0 ºC-rt; (c) LiOH,
3
2
THF/H O, 0 ºC-rt; (d) TBSCl, cat. DMAP, Et N, CH Cl , 0 ºC-rt, 60%
2
3
2
2
2
. Results and Discussion
over 4 steps.
Previously, we have disclosed that acylfurans 7 and 8 could be
readily prepared by an addition of 2-lithiofuran to TBS-protected
The conversion of acylfuran 8 into the desired pyranone 6 began
8
16
amide 9 and the lithium salt of N-Boc-protected glycine 10,
with an asymmetric Noyori hydrogen transfer reduction
respectively (Scheme 2). While we have found these two
approaches to be both reproduceable and scalable, the
requirements for handling significant quantities of n-BuLi
inspired us to investigate an alternative process for the synthesis
of furans 7 and 8. In particular, we were hoping to find a general
approach that would be amenable for the scalable synthesis of
both acylfurans 7 and 8 from inexpensive commercially available
starting material.
(
HCO H/Et N, (S,S)-Noyori) of furan ketone 8 to form furan
2 3
alcohol 13 in excellent yield (92%) and enantiomeric excess
(>95% ee). The furan alcohol 13 was oxidatively hydrated into
pyranone 14 upon exposure to the Achmatowicz conditions (NBS
in buffered THF/H O). The crude pyranone 14 further oxidized
2
with the Jones reagent to give enedione 15. Because enedione
1
5 is prone to enolization, it is unstable to silica gel
chromatography. Analytically pure samples of 15 can be
prepared by recrystallization (CH Cl /hexanes). The crude
2
2
enedione 15 could be reduced under Luche conditions
NaBH /CeCl CH Cl /MeOH) without further purification to give
(
4
3
2
2
a 3.2:1 ratio of C-4 epimers 6 and 16 (Scheme 4).
Scheme 2: Synthesis of protected furan 7 and 8

3
ACCEPTED MANUSCRIPT
Scheme 6: Synthesis of 4-Epi-7-aza-phomopsolide E
Reagents and conditions: (a) Tiglic Acid 3, DCC, DMAP, CH Cl , rt,
Scheme 4: Synthesis of pyranones 6 and 16
2
2
8
6%; (b) i. HCl (4M), dioxane, rt, ii. NaHCO , 4, rt, 72%; (c) HF-Py
3
Reagents and conditions: (a) HCO H/Et N, (S,S)-Noyori,CH Cl ,
(2:1), CH Cl , rt, 92%.
2 2
2
3
2
2
9
2%; (b) NBS, THF, H O, 0 ºC, 89%; (c) Jones reagent, acetone, 0
2
3
. Experimental section
ºC, 84%; (d) NaBH , 0.4 M CeCl /MeOH, CH Cl , 74%.
4
3
2
2
Section A: General methods
The major diastereomer pyranone 6 was converted into the
desired analogue 2b via a coupling/deprotection/coupling
Air- and/or moisture-sensitive reactions were carried out under an
atmosphere of argon or nitrogen using oven-dried glassware and
standard syringe/septa techniques. Ether, tetrahydrofuran,
methylene chloride and methanol were dried by passing through
activated alumina column with argon. Hexanes refer to the
petroleum fraction of boiling point 40-60 °C. Commercial
reagents were used without purification unless otherwise noted.
Flash chromatography was performed using the indicated solvent
/
deprotection sequence (Scheme 5). A DCC coupling between
pyranone 6 and tiglic acid gave pyranone 17 via DCC mediated
coupling. Deprotection of pyranone 17 occurred upon treatment
with HCl(aq) to remove the Boc-protecting group to form the HCl
salt of a primary amine, which, when exposed to acid chloride 4
in the presence of NaHCO , afforded 18. Finally, the TBDPS group
3
was removed with HF/Py to give the desired 7-aza-
phomopsolide E (2b) in excellent overall yield (90%).
system on silica gel standard grade 60 (230-400 mesh). R values
are reported for analytical TLC using the specified solvents and
f
0
.25 mm silica gel 60 F254 plates that were visualized by UV
irradiation (254 nm) or by KMnO or anisaldehyde staining.
4
Optical rotations were obtained using a digital polarimeter at
sodium D line (589 nm) and were reported in concentration of
1
13
g/100 mL at 25 °C. H and C spectra were recorded on 600
MHz and 400 MHz spectrometer. Chemical shifts are reported
1
relative to CHCl (δ 7.26 ppm) for H and CHCl (δ 77.0 ppm)
3
3
13
for C. IR was recorded on FT-IR spectrometer; thin film was
formed in CHCl solution. Melting points are uncorrected.
3
2
-Bromo-1-(2-furyl)ethanone (12)
To a solution of 2-acetyl furan 11 (1 g, 9.09 mmol) in diethyl
ether (10 mL) at 0ºC, the bromine (0.515 mL, 9.99 mmol) was
added slowly over 15 minutes. The reaction continued to stir at
rt for 24 hours. The reaction was diluted with EtOAc and
quenched with sodium bisulfite to reduce excess bromine. The
Scheme 5: Synthesis of 7-Aza-phomopsolide E
Reagents and conditions: (a) Tiglic Acid 3, DCC, DMAP, CH Cl , rt,
2
2
HBr was neutralized with saturated NaHCO aq and the mixture
3
8
3%; (b) i. HCl (4 M), dioxane, rt, ii. NaHCO , 4, rt, 76%; (c) HF-Py
3
extracted with ethyl acetate. The organic layer was dried over
Na SO then concentrated under reduced pressure. The crude
(
2:1), CH Cl , rt, 90%.
2 2
2
4
product was used without further purification. The product
could be purified by silica gel flash chromatography eluting with
Following the same four step protocol, the minor diastereomer
pyranone 16 was converted to the epimeric analogue 2c
3
% EtOAc/hexanes to give 2-bromo-1-(2-furyl)ethanone (12) as
(
Scheme 6). A DCC coupling of 19 and tiglic acid 3 gave 19 (86%).
A similar Boc-deprotection acid chloride coupling reaction gave
0 (72%), which, when exposed to the TBDPS deprotection
brown solid (1.7 g, 9.04 mmol, 87%): R (30% EtOAc/hexane) =
f
0
.55. Our spectroscopic data are matched with a literature
18 19
,
2
report of this compound.
The reported data are; mp 34.5-36
1
conditions, (HF/Py, 92%) converted it into 4-epi-7-aza-
phomopsolide E (2c).
°
C; H NMR (300 MHz, CDCl3): δ = 7.64 (dd, J=1.6, 0.6 Hz, 1H),
7
2
1
.34 (dd, J=3.7, 0.6 Hz, 1H), 6.55 (dd, J=3.6, 1.8 Hz, 1H), 4.32 (s,
H). C NMR (75 MHz, CDCl3): δ = 180.36, 150.36, 147.29,
19.13, 112.87, 30.01.
1
3

4
Tetrahedron Letters
ACCEPTED MANUSCRIPT
(
2-Furan-2-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester (8):
187.8, 150.3, 147.3, 118.1, 112.8, 65.2. This spectroscopic data
2
1
are matched with a literature report of this compound.
t-butyl carbamate (0.9 g, 8 mmol) was dissolved in 1 ml of DMF.
The solution was cooled to −20 °C and KHDMS (5 mL, 20 mmol)
was added dropwise to the solution. Then, a solution of furan
bromide 12 (1 g, 5 mmol) in 1.5 ml of DMF was added slowly.
The red solution formed was stirred 30 min at −20 °C followed
by warming and stirred at 0 °C for an additional 4h. The reaction
mixture was poured into ice water (200 mL) and extracted with
ether (2 x 100 ml). The organic layers were combined, washed
with cold 1 N NaOH (30 ml) and brine, dried over Na SO , and
2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(2-furanyl)-
Ethanone (7)
A solution of furan alcohol (52.4 g, 415 mmol) in CH Cl (790 ml)
2
2
was cooled to 0 °C. Triethylamine (50.4 ml, 498.9 mmol) was
added then the reaction was stirred for 15 min at rt. Solid t-
butyldimethylsilyl chloride (TBSCl) (74.5 g, 498 mmol) and 4-
dimethylaminopyridine (DMAP) (5.07 g, 41.57 mmol) were
added and the solution was stirred for 24 h at rt and monitored
by TLC until the reaction was complete. The reaction was
quenched with 1 N HCl solution (200 mL), and extracted with
ethyl acetate. The combined organic layers were dried over
2
4
concentrated under reduced pressure. Flash chromatography
30% EtOAc/hexane) on silica gel yielded 0.59 g (2.6 mmol, 51%)
of ketone 8 as a light yellow solid: mp 122-124 °C; R (50%
(
f
-1
EtOAc/hexanes) = 0.58; IR (thin film, cm ) 3338, 3119, 2975,
1
1
7
1
714, 1666, 1530, 1279, 1253, 909; H NMR (270 MHz, CDCl ) δ
3
.60 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 3.0 Hz, 1H), 6.55 (dd, J = 3.5,
.7 Hz, 1H), 5.39 (br/s, 1H), 4.49 (d, J = 5.0 Hz, 2H), 1.44 (s, 6H);
C NMR (68 MHz, CDCl ) δ 183.9, 155.7, 150.8, 146.9, 117.7,
12.4, 77.5, 46.9, 28.3; ESI HRMS Calcd for [C H O + Na] :
Na SO then concentrated under reduced pressure. The crude
2
4
1
3
product was purified using column chromatography eluting with
-4% EtOAc/hexane to give 2-((tert-butyldimethylsilyl)oxy)-1-
3
+
3
1
2
11
15
4
(
furan-2-yl)ethan-1-one 7 as yellow oil (72 g, 300 mmol, 73%): Rf
48.0893, Found: 248.0888.
(
40% EtOAc/hexane) = 0.8. Our spectroscopic data are matched
2
2,8
with a literature report of this compound. The reported data
are IR (thin film, cm ) 2952, 2929, 2856, 1698, 1471, 1255, 1150,
1
−
1
1
017, 839; H NMR (270 MHz, CDCl
) δ 7.58 (dd, J=1.7, 0.7 Hz,
3
1
H), 7.32 (dd, J=3.5, 0.7 Hz, 1H), 6.54 (dd, J=3.5, 1.7 Hz, 1H), 4.73
1
3
2
-(2-Furyl)-2-oxoethyl acetate
(s, 2H), 0.94 (s, 9H), 0.13 (s, 6H); C NMR (68 MHz,
CDCl ) δ 187.0, 150.9, 146.3, 118.0, 112.1, 67.1, 25.8, 18.5, −5.4;
3
+
+
To a solution of 12 (37 g, 196 mmol) in acetone (365 mL), a
CI HRMS calcd for [C H O Si Na] : 263.1074, found: 263.1076.
12
20
3
solution of sodium acetate (62 g, 787.2 mmol, in 40 mL H O) was
2
added to the solution drop-wise at 0 °C, followed by the addition
of TBAB (3.5 g, 5 mol%). The reaction was stirred at rt for 3 hr
and monitored by TLC until the reaction was complete. The
reaction was quenched with 1 N HCl solution (50 mL), and
extracted with ethyl acetate. The combined organic layers were
dried over Na SO then concentrated under reduced pressure.
(
2S)-(2-Furan-2-yl-2-hydroxy-ethyl)-carbamic acid tert-butyl
ester (13):
To a 10 mL flask was added ketone 8 (0.27 g, 1.2 mmol), formic
acid-triethylamine (1:1, 3 mL), CH Cl2 (1 mL), and Noyori
asymmetric transfer hydrogenation catalyst (R)-Ru(η -
Mesitylene)-(S,S)-TsDPEN·HCl ((S,S)-Noyori) (3.5 mg, 0.5%mol).
The resulting solution was stirred at room temperature for 24 h.
The mixture was diluted with water (20 mL) and extracted with
EtOAc (3 x 15 mL). The organic layers were combined, washed
2
4
2
The crude product was purified using column chromatography
eluting with 7-8% EtOAc/hexane to give 2-(2-Furyl)-2-oxoethyl
acetate as yellow oil (30 g, 159 mmol, 91%): Rf (30%
EtOAc/hexane) = 0.4; Our spectroscopic data are matched with a
6
20
literature report of this compound. The reported data are IR
(
KBr): 3422, 3131, 2929, 2856, 1730, 1688, 1570, 1468, 1399,
-1 1
with sat. NaHCO
3
and brine, dried over Na SO , and
2 4
1
1
3
=
276, 1161, 1021 cm ; H NMR (600 MHz, CDCl3): δ =8.23 (s,
H), 7.65 (d, J = 1.2 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.6 (dd, J =
concentrated under reduced pressure to afford the crude
alcohol. Flash chromatography (30% EtOAc/hexane) on silica gel
yielded 0.25 g (1.1 mmol, 92%) of alcohol 13 as a light yellow oil:
13
.5, 1.7 Hz, 1H), 5.29 (s, 2H); C NMR (150 MHz, CDCl3): δ
180.5, 159.9, 150.1, 146.9, 117.9, 112.5, 64.4; HRMS (ESI): m/z
25
o
R (30% EtOAc/hexanes) = 0.62; [α] = −14 (c 1.02, MeOH); IR
f
D
[M + H]+ calcd for C7H6O4: 192.9930; found: 192.9979.
-1
(thin film, cm ) 3356, 2980, 2940, 1695, 1520, 1367, 1252, 1172,
1
7
39; H NMR (270 MHz, CDCl ) δ 7.37 (d, J = 1.7 Hz, 1H), 6.33 (dd,
3
J = 3.0, 2.0 Hz, 1H), 6.29 (d, J = 3.2 Hz, 1H), 5.02 (s, br, 1H), 4.80
ddd, J = 8.2, 4.2, 4.2 Hz, 1H), 3.62-3.37 (m, 2H), 3.31 (d, J = 4.2
(
1
-(2-Furanyl)-2-hydroxyethanone
13
Hz, 1H), 1.43 (s, 9H); C NMR (68 MHz, CDCl ) δ 156.8, 154.3,
3
1
42.2, 110.2, 106.7, 79.9, 67.6, 45.2, 28.3.
To a solution of furan acetate (38 g, 226 mmol) in THF/H O (231
2
mL, 10:1), a solution of lithium hydroxide (14.22 g, 339 mmol, 21
mL H O) was added drop-wise at 0 °C. The reaction was stirred
2
at rt for 15-20 min and monitored by TLC, until the reaction was
complete. The reaction was quenched with 1 N HCl solution (300
mL), and extracted with ethyl acetate. The combined organic
layers were dried over Na SO , then concentrated under
(
2S)-2-(tert-Butyloxycarbonylaminomethyl)-6-hydroxy-2H-
pyran-3-(6H)-one (14):
2
4
Alcohol 13 (913 mg, 4.04 mmol), THF (12 mL), and H O (3 mL)
were added to a 50 mL round bottom flask and cooled to 0 °C.
NaHCO3 (680 mg, 8.09 mmol), NaOAc•3H O (550 mg, 4.04
mmol), and NBS (720 mg, 4.04 mmol) were added to the
solution and the mixture was stirred for 1h at 0 °C. The reaction
2
reduced pressure. The crude product was purified using column
chromatography eluting with 12-15% EtOAc/hexane to give 1-(2-
furanyl)-2-hydroxyethanone as yellow oil (28 g, 220 mmol, 98%):
2
1
R (30% EtOAc/hexane) = 0.3 H NMR (400 MHz, CDCl ) δ = 7.63
f
3
(
1
d, J = 1.6 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.6 (dd, J = 3.6, 1.8 Hz,
H), 4.74 (s, 2H), 3.25 (broad s, 1H); C NMR (100 MHz, CDCl ) δ
3
13
was quenched with saturated aqueous NaHCO
extracted with EtOAc (3 x 50 mL), dried (Na SO ), concentrated
3
(20mL),
2
4

5
ACCEPTED MANUSCRIPT
1
3
under reduced pressure. Flash chromatography (EtOAc/hexane,
2.4 Hz, 1H), 1.45 (s, 9H); C NMR (150 MHz, CDCl ) δ 163.3,
3
3
:7) on silica gel yielded enone 14 (873 mg, 89%) as colorless
158.1, 151.2, 119.4, 81.9, 81.0, 63.1, 40.3, 28.2; ESI HRMS Calcd
25
o
+
oils: R (50% EtOAc/hexanes) = 0.35; [α]
CH Cl ); IR (thin film, cm ) 3356, 2979, 2931, 1692, 1523, 1368,
1
= −12 (c 1.25,
for [C H NO + Na] : 264.0999, Found: 266.0984.
f
D
11 17
5
-1
2
2
1
251, 1168, 1035; H NMR (600 MHz, CDCl ) major isomer δ 6.92
3
(
4
4
dd, J = 10.2, 3.0 Hz, 1H), 6.10 (d, J = 10.4 Hz, 1H), 5.66 (dd, J =
(
5S,6S)-5-(2-Methyl-2-butenoyloxy)-6-(tert-
.2, 4.2 Hz, 1H), 5.07 (br/s, 1H), 4.66 (dd, J = 5.4, 5.4 Hz, 1H),
.33 (br/s, 1H), 4.19 (dd, J = 7.2, 4.8 Hz, 1H), 3.56 (dd, J = 6.6, 6.6
butyloxycarbonylaminomethyl)-5,6-dihydropyran-2-one (17):
1
3
Hz, 2H), 1.44 (s, 9H); C NMR (150 MHz, CDCl ) δ 195.5, 156.5,
1
[
3
To a 10 mL round bottom flask was added alcohol 6 (358 mg,
1.47 mmol), CH Cl (5 mL), tiglic acid (294 mg, 2.94 mmol),
45.2, 127.3, 90.2, 87.8, 77.7, 72.5, 28.4; ESI HRMS Calcd for
+
2
2
C H NO + Na] : 266.0999, Found: 266.1000.
11 17 5
dicyclohexylcarbodiimide (608 mg, 2.94 mmol), and DMAP (17
mg, 0.0147 mmol). The reaction mixture was stirred at room
temperature for 6 h. Then it was filtered through a pad of celite
and concentrated. The crude product was purified by silica gel
chromatography (EtOAc/hexane, 2:8) to yield ester 17 (396 mg,
(
(
6S)-6-(tert-Butyloxycarbonylaminomethyl)-pyran-2,5-dione
15):
2
5
8
3%) as a colorless oil: R (50% EtOAc/hexanes) = 0.51; [α]
=
D
f
o
-1
Pyranone 14 (872.8 mg, 3.6 mmol) was dissolved in 15 mL of
acetone and cooled to 0 °C. Jones reagent (2.97 M, 1.21 mL, 3.6
mmol) was added dropwise into the solution. After 15 min the
starting material was no longer visible by TLC and the solution
was filtered through a pad of celite and washed with 100 ml of
Et O. The organic layer was washed with saturated NaHCO (50
+229 (c 2.30, CH Cl ); IR (thin film, cm ) 3376, 2979, 2928,
2 2
1717, 1653, 1521, 1368, 1251, 1171, 1066; H NMR (600 MHz,
1
CDCl ) δ 6.96 (dd, J = 9.6, 5.4 Hz, 1H), 6.82 (qq, J = 7.2, 1.2 Hz,
3
1H), 6.15 (d, J = 10.2 Hz, 1H), 5.27 (dd, J = 6.0, 3.0 Hz, 1H), 5.17
(br, 1H), 4.60 (dd, J = 3.0, 3.0 Hz, 1H), 3.47 (ddd, J = 13.2, 7.2, 4.8
Hz, 1H), 3.35 (ddd, J = 13.8, 7.8, 4.8 Hz, 1H), 1.74 (d, J = 1.2 Hz,
2
3
13
mL) and brine (50 ml), dried (NaSO ), and concentrated to afford
3H), 1.72 (d, J = 7.2 Hz, 3H), 1.35 (s, 9H); C NMR (150 MHz,
4
dione 15 (730 mg, 84%) as light yellow solid: mp 106-108 °C; R
CDCl ) δ 166.5, 162.2, 155.6, 140.4, 139.6, 127.3, 124.7, 79.6,
f
3
25
(
50% EtOAc/hexanes) = 0.42; [α] = −51 ° (c 1.23, CH Cl ); IR
77.5, 61.7, 40.4, 28.1, 14.3, 14.0; ESI HRMS Calcd for [C H NO
+ Na] : 348.1418, Found: 348.1409.
D
2
2
16 23
6
-
1
+
(thin film, cm ) 3367, 2976, 1738, 1699, 1618, 1524, 1368, 1252,
1
1
6
1
1
167, 1113; H NMR (600 MHz, CDCl ) δ 6.85 (d, J = 9.6 Hz, 1H),
3
.80 (d, J = 10.2 Hz, 1H), 5.05 (br/s, 1H), 4.96 (dd, J = 4.2, 4.2 Hz,
13
H), 3.65 (m, 2H), 1.39 (s, 9H); C NMR (150 MHz, CDCl ) δ
3
(5R,6S)-5-(2-Methyl-2-butenoyloxy)-6-(tert-
91.1, 160.1, 155.6, 139.1, 134.6, 82.5, 80.3, 43.4, 28.2; ESI
+
butyloxycarbonylaminomethyl)-5,6-dihydropyran-2-one (19):
HRMS Calcd for [C H NO + Na] : 264.0842, Found: 266.0844.
11
15
5
The procedure was the same as that for the preparation of 17.
Thus alcohol 16 (102 mg, 0.42 mmol) was used to afford ester 19
(
5
5S, 6S)-5-Hydroxy-6-(tert-butyloxycarbonylaminomethyl)-
,6-dihydropyran-2-one (6) and (5R, 6S)-5-hydroxy-6-(tert-
(118 mg, 86%) as a colorless oil: R (50% EtOAc/hexanes) = 0.54;
f
25 o
-1
[α] = −138 (c 1.15, CH Cl ); IR (thin film, cm ) 3372, 2975,
D 2 2
1
butyloxycarbonylaminomethyl)-5,6-dihydropyran-2-one (16):
1737, 1713, 1651, 1516, 1367, 1249, 1168, 1078; H NMR (600
MHz, CDCl ) δ 6.92 (qq, J = 6.6, 1.2 Hz, 1H), 6.81 (dd, J = 10.2, 3.0
3
Pyrandione 15 (692 mg, 2.87 mmol) was dissolved in 9 mL of
Hz, 1H), 6.06 (dd, J = 9.6, 1.2 Hz, 1H), 5.49 (d, J = 8.4 Hz, 1H), 5.00
(br, 1H), 5.46 (dd, J = 9.6, 7.8 Hz, 1H), 3.54 (ddd, J = 15.0, 6.6, 4.2
Hz, 1H), 3.40 (ddd, J = 15.0, 6.6, 6.6 Hz, 1H), 1.84 (d, J = 1.2 Hz,
CH Cl , cooled to 0 °C, and 9 mL of a 0.4 M solution of CeCl in
2
2
3
MeOH was added to the solution. NaBH (136 mg, 3.58 mmol)
4
13
was added and the solution was stirred for 20 min. 80 mL of
EtOAc and 100 mL of water were added. The phases were
separated and the aqueous layer was extracted with EtOAc (3 x
3H), 1.81 (d, J = 7.2 Hz, 3H), 1.41 (s, 9H); C NMR (150 MHz,
CDCl ) δ 166.6, 161.8, 155.6, 144.7, 139.7, 127.5, 121.6, 79.9,
3
79.0, 64.3, 41.4, 28.3, 14.5, 12.0; ESI HRMS Calcd for [C H NO
+ Na] : 348.1418, Found: 348.1410.
16
23
6
+
5
0 mL). The organic fractions were combined, washed with brine
(
30 ml), dried (Na SO ) and concentrated. Purification on silica
2
4
gel (EtOAc/hexane, 3:7) yielded pyranone 6 (391.2 mg, 56%) as a
25
o
colorless oil: R (50% EtOAc/hexanes) = 0.19; [α] = +43 (c
f
D
-
1
(
5S, 6S)-5-(2-Methyl-2-butenoyloxy)-6-[(2S)-2-(tert-
1
1
.20, MeOH); IR (thin film, cm ) 3372, 2980, 2933, 1712, 1523,
1
butyldiphenylsilanyloxy)propionylaminomethyl]-5,6-
dihydropyran-2-one (18):
455, 1368, 1253, 1169, 1060; H NMR (600 MHz, CDCl ) δ 6.96
3
(dd, J = 9.0, 5.7 Hz, 1H), 6.08 (d, J = 9.6 Hz, 1H), 5.20 (dd, J = 5.4,
5
8
.4 Hz, 1H), 4.68 (br/s, 1H), 4.29 (m, 1H), 3.73 (ddd, J = 15.0, 8.4,
13
To a 25 mL round bottom flask was added ester 17 (102.7 mg,
.316 mmol), dioxane (5 mL) and HCl (2 mL, 4 M). The reaction
mixture was stirred at room temperature for 4 h. Then it was
concentrated under reduced pressure to afford the crude
ammonium salt which was then dissolved in water (3 mL) and
.4 Hz, 1H), 3.37 (ddd, J = 14.4, 10.8, 5.4 Hz, 1H), 1.43 (s, 9H);
C
0
NMR (150 MHz, CDCl ) δ 163.1, 157.4, 144.1, 122.7, 80.8, 78.9,
5
Found: 266.0981.
3
+
9.8, 39.7, 28.2; ESI HRMS Calcd for [C H NO + Na] : 264.0999,
11 17 5
dioxane (7 mL). NaHCO (106 mg, 1.26 mmol) and then acid
Minor isomer 16 (122.3 mg, 18%) is a colorless oil: R (50%
3
f
25
o
chloride 4 (219.0 mg, 0.632 mmol) were added. The reaction
mixture was stirred at room temperature for 2 h then extracted
with EtOAc (3 x 50 mL). The organic fractions were combined,
EtOAc/hexanes) = 0.32; [α] = −34 (c 1.10, MeOH); IR (thin
D
-1
film, cm ) 3380, 2979, 2930, 1714, 1526, 1368, 1251, 1167,
062; H NMR (600 MHz, CDCl ) δ 6.96 (d, J = 10.2 Hz, 1H), 5.92
1
1
3
washed with brine (30 mL), dried (Na SO ) and concentrated.
(dd, J = 10.2, 2.4 Hz, 1H), 5.20 (br, 1H), 4.61 (d, J = 4.8 Hz, 1H),
2
4
Purification on silica gel (EtOAc/hexane, 2:8) yielded amide 18
4
1
.35 (ddd, J = 7.8, 4.8, 2.4 Hz, 1H), 4.17 (ddd, J = 10.8, 2.4, 2.4 Hz,
H), 3.28 (ddd, J = 15.6, 5.4, 2.4 Hz, 1H), 3.83 (ddd, J = 15.6, 7.8,
(
128 mg, 76%) as a colorless oil: R (50% EtOAc/hexanes) =
f
25
o
-1
0
.59; [α] = +101 (c 0.91, CH Cl ); IR (thin film, cm ) 3420,
D 2 2

6
Tetrahedron Letters
ACCEPTED MANUSCRIPT
1
2
932, 2858, 1742, 1716, 1682, 1651, 1522, 1251, 1113; H
The procedure was the same as that for the preparation of 7-aza-
phomopsolide E (2b). Thus, ester 20 (95 mg, 0.178 mmol) was
used to afford 4-epi-7-aza-phomopsolide E (2c) (49 mg, 92%) as
NMR (600 MHz, CDCl ) δ 7.62 (m, 4H), 7.39 (m, 6H), 7.27 (dd,
J = 7.8, 3.6 Hz, 1H), 7.01 (dd, J = 10.2, 6.0 Hz, 1H), 6.91 (qq, J =
3
25
o
7
.2, 1.2 Hz, 1H), 6.24 (d, J = 10.2 Hz, 1H), 5.25 (dd, J = 6.0, 3.0
a colorless oil: R (EtOAc) = 0.41; [α]
= +160 (c 1.21,
f
D
-
1
Hz, 1H), 4.37 (ddd, J = 8.4, 4.2, 2.4 Hz, 1H), 4.28 (q, J = 6.6 Hz,
MeOH); IR (thin film, cm ) 3349, 2985, 2932, 1737, 1716, 1651,
1
1
9
=
1
1
3
H), 3.74 (ddd, J = 14.4, 7.8, 4.2 Hz, 1H), 3.46 (ddd, J = 13.8,
1538, 1256, 1127, 1076; H NMR (600 MHz, CDCl ) δ 7.27 (dd,
3
.0, 4.2 Hz, 1H), 1.82 (s, 3H), 1.80 (d, J = 7.2 Hz, 3H), 1.27 (d, J
J = 6.0, 6.0 Hz, 1H), 6.93 (qq, J = 7.2, 1.8 Hz, 1H), 6.83 (dd, J =
10.8, 3.0 Hz, 1H), 6.01 (dd, J = 10.2, 1.8 Hz, 1H), 5.45 (ddd, J =
7.8, 3.0, 1.8 Hz, 1H), 4.61 (ddd, J = 10.8, 6.6, 5.6 Hz, 1H), 4.25
(q, J = 6.6 Hz, 1H), 3.74 (ddd, J = 14.4, 6.6, 3.6 Hz, 1H), 3.61
(br/s, 1H), 3.48 (ddd, J = 14.4, 6.0, 6.0 Hz, 1H), 1.84 (dd, J = 1.2,
1.2 Hz, 3H), 1.81 (dd, J = 7.2, 1.2 Hz, 3H), 1.40 (d, J = 6.6 Hz,
13
6.6 Hz, 3H), 1.13 (s, 9H); C NMR (150 MHz, CDCl ) δ
3
97.5, 174.7, 166.5, 161.8, 140.2, 139.9, 135.7, 135.6, 132.8,
32.3, 130.1, 130.0, 127.9, 127.7, 127.3, 125.0, 77.3, 70.8, 61.8,
8.9, 26.9, 21.7, 19.0, 14.5, 12.0; ESI HRMS Calcd for
+
[
C H NO Si+ Na] : 558.2282, Found: 558.2254.
3
0
37
6
13
3
1
H); C NMR (150 MHz, CDCl ) δ 175.5, 166.7, 161.9, 144.7,
40.0, 127.4, 121.7, 78.8, 68.4, 64.2, 39.7, 20.9, 14.6, 12.0; ESI
3
+
HRMS Calcd for [C H NO + Na] : 320.1104, Found:
14
19
6
(
5R, 6S)-5-(2-Methyl-2-butenoyloxy)-6-[(2S)-2-(tert-
butyldiphenylsilanyloxy)-propionylaminomethyl]-5,6-
dihydropyran-2-one (20):
3
40.1091.
The procedure was the same as that for the preparation of 18.
Thus ester 19 (90 mg, 0.28 mmol) was used to afford amide 20
4. Acknowledgements: We gratefully acknowledge the NSF
(CHE-1565788) for their support of our research program.
(
107 mg, 72%) as a colorless oil: R (50% EtOAc/hexanes) =
§
f
25
o
-1
5. Author Contributions: Co-first authors, the order is
alphabetical.
0
3
1
7
.63; [α] = −128 (c 1.23, CH Cl ); IR (thin film, cm ) 3426,
D 2 2
058, 2953, 2931, 2858, 1741, 1716, 1681, 1651, 1519, 1249,
1
112; H NMR (600 MHz, CDCl ) δ 7.63 (m, 4H), 7.39 (m, 6H),
3
6. Supplementary data:
.24 (dd, J = 6.0, 6.0 Hz, 1H), 6.94 (qq, J = 7.2, 1.2 Hz, 1H), 6.81
Supplementary
data
(experimental
procedures
and
(dd, J = 10.2, 3.0 Hz, 1H), 5.43 (ddd, J = 9.0, 2.4, 2.4 Hz, 1H),
characterization for the synthesis of all compounds, and copies of
H NMR, C NMR for all new compounds can be found in the
supplementary data) associated with this article can be found, in
the online version, at…
4
3
.42 (ddd, J = 10.8, 7.2, 3.0 Hz, 1H), 4.27 (q, J = 6.6 Hz, 1H),
.75 (ddd, J = 14.4, 7.2, 3.6 Hz, 1H), 3.44 (ddd, J = 14.4, 7.2, 5.4
1
13
Hz, 1H), 1.85 (s, 3H), 1.81 (d, J = 7.2 Hz, 3H), 1.27 (d, J = 6.6
Hz, 3H), 1.13 (s, 9H); C NMR (150 MHz, CDCl ) δ 174.5,
13
3
1
1
2
66.6, 161.3, 144.8, 139.9, 135.7, 135.6, 132.9, 132.4, 130.1,
30.0, 127.9, 127.7, 127.5, 121.6, 78.8, 70.9, 64.5, 39.5, 26.9,
1.7, 19.1, 14.6, 12.0; ESI HRMS Calcd for [C H NO Si+
7
. References and notes
30
37
6
1. Becker, H. Agricultural Research 1996, 44, 4-8.
2. Santamour, F. S. and Bentz, S. E. J. of Arboriculture 1995, 21,
+
Na] : 558.2282, Found: 558.2307.
1
22-131.
3
4
.
.
Grove, J. F. J. Chem. Soc., Perkin Trans. 1 1985, 865-869.
Stierle, D. B.; Stierle, A. A.; Ganser, B. J. Nat. Prod. 1997, 60,
1
207-1209.
7
-Aza-phomopsolide E (2b):
5
.
Noshita, T.; Sugiyama, T.; Yamashita, K.; Oritani, T. Biosci.
Biotech. Biochem. 1994, 58, 740-744.
Ester 18 (113 mg, 0.21 mmol), 1 mL of CH CN, and HF-Py (2:1)
6. Harris, J. M.; O'Doherty, G. A. Tetrahedron Lett. 2002, 43, 8195-
3
(
2.5 M, 1.5 mL, ~3.7 mmol) were added to a plastic vial and
8199.
7
8
.
.
Li, M.; O'Doherty, G. A. Tetrahedron Lett. 2004, 45, 6407-6411.
Li, M.; Scott, J. G.; O'Doherty, G. A. Tetrahedron Lett. 2004, 45,
stirred at rt for 24 h. The reaction was quenched with saturated
NaHCO3 (5 mL), and the aqueous layer was extracted with
EtOAc (2 x 40 mL). The organic layer was washed with HCl (1
M, 10 mL), dried over Na SO , and concentrated under reduced
pressure to afford the crude alcohol. Flash chromatography (70%
EtOAc/hexane) on silica gel yielded 56 mg (0.19 mmol, 90%) of
1
005-1009.
9
.
Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513-5516.
2
4
10. Prasad, K. R.; Gutala, P. Tetrahedron 2012, 68, 7489–7493.
11. Reddy, D. V.; Sabitha, G.; Yadav, J. S. Tetrahedron Lett. 2015,
5
6, 4112-4114.
o
12. Emmadi, N. R.; Bingi, C.; Kumar, C. G.; Yedla, P.; Atmakur, K.
7
-aza-phomopsolide E (2b) as a colorless solid: mp 156-158 C;
Synthesis 2014, 46, 2945–2950
25
D
o
R (100% EtOAc) = 0.35; [α] = +231 (c 1.02, MeOH); IR
f
1
1
3. (a) Wang, Y.; Xing, Y.; Zhang, Q.; O’Doherty, G. A. Chem.
Commun. 2011, 47, 8493-8505. (b) Aljahdali, A. Z.; Foster, K. A.;
O’Doherty, G. A. Chem. Commun. 2018, 54, 3428-3435.
4. (a) C. M. Goins, T. D. Sudasinghe, X. Liu, Y. Wang, G. A.
O’Doherty, D. R. Ronning, Biochemistry, 2018, 57, 2383-2393.
-
1
(thin film, cm ) 3434, 3388, 2767, 1733, 1706, 1647, 1533, 1263,
1
1
1
6
6
127; H NMR (600 MHz, DMSO-d ) δ 7.92 (dd, J = 6.0, 6.0 Hz,
6
H), 7.12 (dd, J = 9.6, 5.4 Hz, 1H), 6.81 (qq, J = 7.2, 1.8 Hz, 1H),
.22 (d, J =9.0 Hz, 1H), 5.55 (d, J = 4.8 Hz, 1H), 5.26 (dd, J =
.0, 2.4 Hz, 1H), 4.74 (m, 1H), 3.97 (q, J = 7.2 Hz, 1H), 3.51
(b) Liu, X.; Wang, Y.; Duclos, R. I.; O’Doherty, G. A, ACS Med.
Chem. Lett. 2018, 9, 274-278. (c) Liu, X.; Wang, Y.; O’Doherty,
G. A. AsianJOC. 2015, 4, 994-1009. (d) Mulzer, M.; Tiegs, B.;
Yanping Wang, Y.; Coates, G. W.; O’Doherty, G. A. J. Am. Chem.
Soc. 2014, 136, 10814-10820.
(ddd, J = 13.2, 6.0, 6.0 Hz, 1H), 3.39 (ddd, J = 13.2, 7.2, 5.4 Hz,
1
3
1
1
3
H), 1.79 (d, J = 6.0 Hz, 3H), 1.78 (s, 3H), 1.21 (d, J = 7.2 Hz,
13
H); C NMR (150 MHz, DMSO-d ) δ 174.9, 165.9, 162.2,
6
1
5. (a) Hunter, T. J.; Wang, Y.; Zheng, J.; O’Doherty, G. A. Synthesis
2016, 48, 1700-1710. (b) Cuccarese, M. F.; Wang, Y.; Beuning, P.
J.; O’Doherty, G. A. ACS Med. Chem. Lett. 2014, 5, 522-526. (c)
Wang, Y.; O’Doherty, G. A. J. Am. Chem. Soc. 2013, 135, 9334–
41.4, 138.8, 127.3, 124.2, 76.6, 67.2, 61.8, 38.0, 21.0, 14.2,
+
1.9; ESI HRMS Calcd for [C H NO + Na] : 320.1104, Found:
14
19
6
40.1094.
9
337.
1
1
6. Haukaas, M. H.; Li, M.; Starosotnikov, A. M.; O’Doherty, G. A.
Heterocycles, 2008, 76 (2), 1549-1559.
7. Amador, A. G.; Sherbrook, E. M.; Yoon, T. P. J. of the American
4
-Epi-7-aza-phomopsolide E (2c):
Chemical Society 2016, 138(14), 4722-4725
.

7
ACCEPTED MANUSCRIPT
8. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. Bulletin of
1
the Chemical Society of Japan 1987, 60, 1159
1
2
9. Pirtsch, M.; Chem. A Eur. J., 2012, 18, 7336-7340.
0. Zhu, Y. P., Gao, Q. H., Lian, M., Yuan, J. J., Liu, M. C., Zhao, Q.,
&
Wu, A-X, Chem. Commun. 2011, 47, 12700-12702
2
2
1. Matsumoto, Toshihiko; J. Org. Chem. 1985, 50, 603-606
2. Babu, R.; Chen, Q.; Kang, S.; Zhou, M.; O’Doherty, G., J. Am.
Chem. Soc. 2012, 134, 11952.

8
Tetrahedron Letters
ACCEPTED MANUSCRIPT
1
2
.
.
Becker, H. Agricultural Research 1996, 44, 4-8.
Santamour, F. S. and Bentz, S. E. J. of Arboriculture 1995, 21,
22-131.
1
3
4
.
.
Grove, J. F. J. Chem. Soc., Perkin Trans. 1 1985, 865-869.
Stierle, D. B.; Stierle, A. A.; Ganser, B. J. Nat. Prod. 1997, 60,
1
207-1209.
5
6
.
.
Noshita, T.; Sugiyama, T.; Yamashita, K.; Oritani, T. Biosci.
Biotech. Biochem. 1994, 58, 740-744.
Harris, J. M.; O'Doherty, G. A. Tetrahedron Lett. 2002, 43, 8195-
8
199.
7
8
.
.
Li, M.; O'Doherty, G. A. Tetrahedron Lett. 2004, 45, 6407-6411.
Li, M.; Scott, J. G.; O'Doherty, G. A. Tetrahedron Lett. 2004, 45,
1
005-1009.
9
1
1
.
Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513-5516.
0. Prasad, K. R.; Gutala, P. Tetrahedron 2012, 68, 7489–7493.
1. Reddy, D. V.; Sabitha, G.; Yadav, J. S. Tetrahedron Lett. 2015,
5
6, 4112-4114.
1
2. Emmadi, N. R.; Bingi, C.; Kumar, C. G.; Yedla, P.; Atmakur, K.
Synthesis 2014, 46, 2945–2950
1
3. (a) Wang, Y.; Xing, Y.; Zhang, Q.; O’Doherty, G. A. Chem. Commun.
2
011, 47, 8493-8505. (b) Aljahdali, A. Z.; Foster, K. A.; O’Doherty,
G. A. Chem. Commun. 2018, 54, 3428-3435.
1
4. (a) C. M. Goins, T. D. Sudasinghe, X. Liu, Y. Wang, G. A. O’Doherty,
D. R. Ronning, Biochemistry, 2018, 57, 2383-2393. (b) Liu, X.;
Wang, Y.; Duclos, R. I.; O’Doherty, G. A, ACS Med. Chem. Lett.
2
2
018, 9, 274-278. (c) Liu, X.; Wang, Y.; O’Doherty, G. A. AsianJOC.
015, 4, 994-1009. (d) Mulzer, M.; Tiegs, B.; Yanping Wang, Y.;
Coates, G. W.; O’Doherty, G. A. J. Am. Chem. Soc. 2014, 136,
0814-10820.
1
1
5. (a) Hunter, T. J.; Wang, Y.; Zheng, J.; O’Doherty, G. A. Synthesis
016, 48, 1700-1710. (b) Cuccarese, M. F.; Wang, Y.; Beuning, P.
2
J.; O’Doherty, G. A. ACS Med. Chem. Lett. 2014, 5, 522-526. (c)
Wang, Y.; O’Doherty, G. A. J. Am. Chem. Soc. 2013, 135, 9334–
9
337.
1
1
6. Haukaas, M. H.; Li, M.; Starosotnikov, A. M.; O’Doherty, G. A.
Heterocycles, 2008, 76 (2), 1549-1559.
7. Amador, A. G.; Sherbrook, E. M.; Yoon, T. P. J. of the American
Chemical Society 2016, 138(14), 4722-4725
.
1
8. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. Bulletin of
the Chemical Society of Japan 1987, 60, 1159
1
2
9. Pirtsch, M.; Chem. A Eur. J., 2012, 18, 7336-7340.
0. Zhu, Y. P., Gao, Q. H., Lian, M., Yuan, J. J., Liu, M. C., Zhao, Q.,
&
Wu, A-X, Chem. Commun. 2011, 47, 12700-12702
2
2
1. Matsumoto, Toshihiko; J. Org. Chem. 1985, 50, 603-606
2. Babu, R.; Chen, Q.; Kang, S.; Zhou, M.; O’Doherty, G., J. Am.
Chem. Soc. 2012, 134, 11952