Formal synthesis of tamiflu: Conversion of tamiflu into tamiphosphor

Article abstract of DOI:10.1055/s-0031-1290356

A short, enantiomeric, synthesis of Shibasakis 3rd generation intermediate to form (-)-oseltamivir phosphate (Tamiflu) has been achieved in eight steps with the use of inexpensive starting materials. A formal synthetic route to convert tamiflu into tamiphosphor via Fangs tamiphosphor intermediate has been accomplished. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290356

LETTER
573
Formal Synthesis of Tamiflu: Conversion of Tamiflu into Tamiphosphor
Formal Synthesis
o
i
f
T
am
n
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Fax +1(765)4940265; E-mail: dgunasek@purdue.edu
Received 6 October 2011
with significant resistance to tamiflu, it is prudent to de-
velop and test additional neuraminidase inhibitors.6 Re-
cently, Fang et al.7 synthesized tamiphosphor (2;
Figure 1), which was reported to be more active than 1 by
Abstract: A short, enantiomeric, synthesis of Shibasaki’s 3rd gen-
eration intermediate to form (–)-oseltamivir phosphate (Tamiflu®)
has been achieved in eight steps with the use of inexpensive starting
materials. A formal synthetic route to convert tamiflu into tami-
phosphor via Fang’s tamiphosphor intermediate has been accom- 19- and 7-folds in NA inhibition and antiflu assays, re-
plished.
spectively. The phosphonate group in tamiphosphor has
been shown to form strong interactions with three arginine
residues of neuraminidase, making it a more potent inhib-
itor against the wild-type neuraminidases of H1N1 and
H5N1 viruses.8 Moreover, preliminary studies have
shown that 2 is also orally bioavailable.8 Therefore, devel-
opment of synthetic protocols to convert tamiflu into
tamiphosphor would be timely and would reduce costs in
the event that a switch between drugs is required.
In Shibasaki’s 3rd generation synthesis of tamiflu, the op-
tically active intermediate 8 was obtained by the use of
chiral HPLC.9 Herein, we describe a short enantioselec-
tive pathway for the synthesis of 8, using benzene as an in-
expensive starting material. Furthermore, we have shown
for the first time, a concise route to convert tamiflu (1)
into tamiphosphor (2) by synthesizing 11, the key inter-
mediate of Fang’s tamiphosphor synthesis.8 Converting
tamiflu (1) into tamiphosphor (2) might be advantageous
if influenza viruses develop resistance to tamiflu (1).
Key words: hydrolysis, epoxide, oxidation, amides, enantioselec-
tivity
Influenza is a highly contagious respiratory virus that
poses a serious threat to public health. On average, sea-
sonal influenza epidemics cause 36000 deaths and over
200,000 hospitalizations annually in the US.1 In addition,
emergence of novel influenza strains could lead to pan-
demics resulting in millions of hospitalizations and deaths
worldwide.2,3 Currently, the leading drugs available to
treat influenza infections are the neuraminidase inhibitors
Relenza® (zanamivir) and Tamiflu® [(–)-oseltamivir
phosphate; Figure 1). Since neuraminidases play a key
role in the life cycle of all influenza viruses, these drugs
represent an efficient molecular weapon to protect hu-
mans against epidemic and pandemic influenza.4 Due to
its ability to be administered orally, tamiflu has become
the agent of choice for treating severe influenza infec-
tions.4
Scheme 1 shows the synthetic approach used to construct
functionalized Shibasaki’s intermediate 8.10 While this
manuscript was in preparation, Hayashi and co-workers
independently reported a similar synthetic approach to
8.11 However, our approach is more straightforward, effi-
cient and robust. The synthesis began with the preparation
of optically pure epoxide 3 from benzene in 21% yield
over three steps.12,13 Azido alcohol 4 was obtained in mod-
erate yield by cesium chloride promoted ring opening of
epoxide 3 using NaN3–MeCN conditions.14 A convenient
way of transforming azido alcohols to aziridines was re-
ported by Ittah et al.15 This methodology was successfully
applied to obtain N-protected aziridine 5 from 4 in 76%
yield. Regioselective ring opening of aziridine 5 was ac-
complished by the use of tetramethylguanidinium azide
(TMGA) to give 6 in excellent yield.16 Reduction of azide
6 followed by N-Boc protection gave diamide 7 in 91%
yield. Base hydrolysis of 7, followed by oxidation using
standard Dess–Martin periodinane conditions gave enan-
tiopure Shibasaki’s intermediate 8 in 86% yield.17 Com-
pound 8 proved to be a single stereoisomer as determined
by HPLC (OD-H CHIRALCEL column). Shibasaki’s in-
termediate 8 could be easily converted into tamiflu with
seven steps.9 It is worth mentioning that, to date, this ap-
O
CO2Et
O
PO(ONH4)2
AcHN
AcHN
NH2⋅H3PO4
NH2
tamiphosphor (2)
Tamiflu (1)
Figure 1 Structures of tamiflu and tamiphosphor
At present, large-scale industrial syntheses of tamiflu re-
quire either (–)-shikimic acid or (–)-quinic acid.5 These
processes are time consuming and expensive due to the
low natural abundance of these starting materials.5a,b De-
velopment of alternate syntheses of tamiflu from readily
available and less expensive starting materials is manda-
tory to meet the growing demand for this drug, cost-effec-
tively.5 In addition, since constant evolutionary pressure
could result in the development of novel influenza strains
SYNLETT 2012, 23, 573–576
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 13.02.2012
DOI: 10.1055/s-0031-1290356; Art ID: S52211ST
© Georg Thieme Verlag Stuttgart · New York

574
D. S. Gunasekera
LETTER
O
O
1. Ph3P, MeCN
70 °C, 3 h
2. Ac2O, Et3N
py, 6 h
NaN3, CeCl3
MeCN, 70 °C
5 h
O
O
ref. 12, 13
OH
N3
O2N
O2N
O
74%
76%
3 (>99 ee)
4
O
O
1. Ph3P, MeCN
60 °C, 2 h
2. Boc2O, Et3N
CH2Cl2, 0 °C, 3 h
O
O
TMGN3, MeCN
70 °C, 7 h
NHAc
N3
O2N
O2N
NAc
83%
91%
5
6
O
1. NaOMe, MeOH
26 °C, 1 h
2. DMP, CH2Cl2
5 °C, 4 h
O
O
O
CO2Et
ref. 9
NHAc
NHAc
O2N
86%
AcHN
NHBoc
NHBoc
7
8
NH2⋅H3PO4
Tamiflu (1)
Scheme 1 Enantioselective synthesis of intermediate 8
S
S
O
1. KOH, H2O–MeOH
O
CO2Et
O
CO2H
O
N
26 °C, 5 h
2. Boc2O, CH2Cl2
0 °C, 3 h
O
12, DABCO, PAAA
0 °C, 7 h
AcHN
AcHN
AcHN
97%
81%
NH2⋅H3PO4
Tamiflu (1)
NHBoc
9
NHBoc
10
AIBN, BrCCl3
105 °C, 1 h
S
O
Br
O
PO(ONH4)2
ref. 7
HO
S
N
76%
AcHN
AcHN
NHBoc
11
NH2
tamiphosphor (2)
12
Scheme 2 Conversion of tamiflu into tamiphosphor
proach is the shortest synthesis of enantiomerically pure In summary, a short (eight steps from benzene, 8% overall
intermediate 8 from benzene.
yield), and practical synthesis of the intermediate 8 was
achieved. This key intermediate 8 could easily be trans-
formed to enantiomerically pure (–)-oseltamivir phos-
phate.9 Moreover, we have presented a convenient
approach to convert tamiflu into its more potent counter-
part tamiphosphor, by synthesizing intermediate 11 in
three steps with an overall yield of 59%. The proposed
synthetic routes are straightforward, flexible and cost ef-
fective.
In order to transform tamiflu to tamiphosphor, we pre-
pared the N-Boc-protected acid 9 by hydrolyzing enantio-
merically pure (–)-oseltamivir phosphate 1,18 as outlined
in Scheme 2. Conversion of 9 directly into Fang’s tami-
phosphor intermediate 11 using Hunsdiecker-type bromo-
decarboxylation conditions was unsuccessful.19 However,
treatment of 9 with cyclic thiohydroxamic acid 12, pro-
pane phosphonic acid anhydride (PPAA), and 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) afforded 10 in 81%
yield.20 Conversion of 10 into 11 was achieved by slow
addition of 10 to a solution of AIBN in bromotrichlo-
romethane to produce 11, which is the key intermediate of
Fang’s tamiphosphor synthesis.21
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
In all three transformations, we did not observe any ero-
sion in enantiopurity compared to the starting (–)-oselta-
mivir phosphate.22 The intermediate 11 could be
converted into tamiphosphor (2) in two operations.8
The author thanks Professor Philip. L. Fuchs for his intellectual
contributions; Dr. Douglas Lantrip for his technical support and
help with the chiral HPLC; and Dr. Arlene Rothwell and Dr. Karl
Wood for the MS data; and the Purdue University for support of this
research.
Synlett 2012, 23, 573–576
© Thieme Stuttgart · New York

LETTER
Formal Synthesis of Tamiflu
575
J = 4.1 Hz, 4 H), 5.70–5.95 (m, 2 H), 5.50–5.70 (m, 1 H),
3.13–3.38 (m, 1 H), 2.88–3.15 (m, 1 H), 2.64 (dd, J = 19.9,
4.4 Hz, 1 H), 2.29–2.54 (m, 1 H), 2.07 (s, 3 H). 13C NMR
(400 MHz, CDCl3): d = 182.74, 164.35, 150.96, 135.20,
131.07, 126.69, 123.66, 122.15, 68.22, 37.37, 34.79, 24.51,
23.31. HRMS (CI): m/z [M + H] calcd for C15H14N2O5:
303.0981; found: 303.0986.
References and Notes
(1) Molinari, N. A.; Ortega-Sanchez, I. R.; Messonnier, M. L.;
Thompson, W. W.; Wortley, P. M.; Weintraub, E.; Bridges,
C. B. Vaccine 2007, 25, 5086.
(2) Cheam, A. L.; Barr, I. G.; Hampson, A. W.; Mosse, J.; Hurt,
A. C. Antiviral Res. 2004, 63, 177.
(3) Smith, B. J.; McKimm-Breshkin, J. L.; McDonald, M.;
Fernley, R. T.; Varghese, J. N.; Colman, P. M. J. Med.
Chem. 2002, 45, 2207.
(4) De Clercq, E. Nat. Rev. Drug Discov. 2006, 5, 1015.
(5) (a) Johnson, D. S.; Li, J. J. The Art of Drug Synthesis; John
Wiley & Sons: Hoboken, NJ, 2007, 95. (b) Werner, L.;
Machara, A.; Sullivan, B.; Carrera, I.; Moser, M.; Adams, D.
R.; Hudlicky, T. J. Org. Chem. 2011, 76, 10050.
(6) Thorlund, K.; Awad, T.; Boivin, G.; Thabane, L. BMC
Infectious Diseases 2011, 11, 134.
(7) Shie, J. J.; Fang, J. M.; Wang, S. Y.; Tsai, K. C.; Cheng, Y.
S.; Yang, A. S.; Hsiao, S. C.; Su, C. Y.; Wong, C. H. J. Am.
Chem. Soc. 2007, 129, 11892.
(8) Shie, J. J.; Fang, J. M.; Wong, C. H. Angew. Chem. Int. Ed.
2008, 47, 5788.
(1S,5R,6S)-6-Acetamido-5-azidocyclohex-2-en-1-yl 4-
Nitrobenzoate (6): To a solution of 5 (2.11 g, 6.98 mmol) in
MeCN (4.2 mL), tetramethylguanidinium azide (TMGA;
2.18 g, 13.96 mmol, 2 equiv) was added and the mixture was
stirred at 60 °C for 13 h. After completion of the reaction,
MeCN was removed under reduced pressure. HCl (5%, 20
mL) was added and the solution was extracted with Et2O (3
× 15 mL). The combined organic layer was washed with
brine, dried over Na2SO4 and concentrated and purified by
column chromatography (hexane–EtOAc) to afford 6 (2.23
g) in 83% yield as a white solid; mp 181–183 °C; [a]26D +42
(c = 0.12, CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.23 (dd,
J = 51.0, 8.8 Hz, 4 H), 5.89–6.17 (m, 2 H), 5.66 (d, J = 3.3
Hz, 2 H), 4.35–4.73 (m, 1 H), 3.74–4.04 (m, 1 H), 2.71 (dd,
J = 18.1, 4.0 Hz, 1 H), 2.36 (dd, J = 18.1, 9.0 Hz, 1 H), 2.01
(s, 3 H). 13C NMR (400 MHz, CDCl3): d = 170.25, 163.83,
150.74, 135.25, 130.73, 123.73, 70.37, 56.34, 50.82, 30.93,
23.59. HRMS (ESI): m/z [M + Na] calcd for C15H15N5O5:
368.0971; found: 368.0974.
(9) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2007, 48, 1403.
(10) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
(11) Tanaka, T.; Tan, Q.; Kawakubo, H.; Hayashi, M. J. Org.
Chem. 2011, 76, 5477.
(1S,5R,6S)-6-Acetamido-5-tert-butoxycarbonylamino-2-
en-1-yl 4-Nitrobenzoate (7): To a solution of 6 (1.24 g, 3.6
mmol) in MeCN (6 mL), Ph3P (1.16 g, 3.96 mmol, 1.1 equiv)
was added and the mixture was stirred at 60 °C for 3 h. H2O
(2 mL) was added and the reaction mixture was stirred at 45
°C for 2 h. Solvent was removed under reduced pressure
followed by the addition of CH2Cl2 (6 mL), Et3N (1.5 mL,
10.8 mmol), and Boc2O (1.57 g, 7.2 mmol), and the mixture
was stirred at r.t. for 2 h. Deionised H2O (6 mL) was added
and the aqueous layer was extracted with CH2Cl2 (2 × 10
mL) and the combined organic layer was dried over Na2SO4.
The solvent was removed under reduced pressure and the
residue was purified by column chromatography (silica gel,
hexane–EtOAc, 1:1) to afford 7 (1.27 g, 3.28 mmol) in 91%
yield (2 steps) as a white solid; mp 196–198 °C; [a]26D +154
(c = 0.16, CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.09–
8.46 (m, 4 H), 6.38 (d, J = 7.7 Hz, 1 H), 5.98 (s, 2 H), 5.59
(s, 1 H), 4.73 (d, J = 7.5 Hz, 2 H), 3.89–4.43 (m, 2 H), 2.65
(d, J = 18.7 Hz, 1 H), 2.10 (dd, J = 17.6, 9.6 Hz, 1 H), 1.91
(s, 3 H), 1.44 (s, 9 H). 13C NMR (400 MHz, CDCl3): d =
170.51, 163.77, 156.90, 150.57, 135.19, 131.99, 130.80,
123.56, 80.08, 70.50, 53.54, 45.56, 32.65, 28.21, 23.13.
HRMS (ESI): m/z [M + H] calcd for C20H25N3O7: 420.1771;
found: 420.1774.
tert-Butyl [(1R,6S)-6-Acetamido-5-oxocyclohex-3-en-1-
yl]carbamate (8): To a solution of 7 (635 mg, 1.63 mmol)
in MeOH (3.26 mL) was added solid NaOMe (44 mg, 0.81
mmol) under argon atmosphere. After stirring at r.t. for 1 h,
glacial AcOH (47 mL) was added to quench the reaction.
MeOH was removed by rotary evaporation and CH2Cl2 (3
mL) was added to the residue. After cooling to 4 °C Dess–
Martin periodinane (1.03 g, 2.44 mmol, 1.5 equiv) was
added. After 1 h, sat. aq Na2S2O3 was added and the organic
layer was separated. The aqueous layer was extracted with
EtOAc (3 × 5 mL). The combined organic layer was washed
with sat. aq NaHCO3 and brine, and then dried over Na2SO4.
The solvent was removed under reduced pressure and was
purified by column chromatography (silica gel, hexane–
EtOAc, 2:1) to afford 8 (332.4 mg, 1.4 mmol) in 86% yield
as a white solid; mp 143–144 °C; [a]26D –132 (c = 0.08,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 6.85–7.08 (m, 1
(12) (a) Brandsma, L.; Vansoolingen, J.; Andringa, H. Synth.
Commun. 1990, 20, 2165. (b) Ruggles, E.; Deker, P.;
Hondal, R. Tetrahedron 2009, 65, 1257.
(13) Tan, Q. T.; Hayashi, M. Org. Lett. 2009, 11, 3314.
(14) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Yadav, J. S. Org.
Lett. 2002, 4, 343.
(15) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J.
J. Org. Chem. 1978, 43, 4271.
(16) Ballereau, S.; McCort, I.; Dureault, A.; Depezay, J. C.
Tetrahedron 2001, 57, 1935.
(17) (1S,5R,6S)-5-Azido-6-hydroxycyclohex-2-en-1-yl 4-
Nitrobenzoate(4): CeCl3·7H2O (1 mmol) and NaN3 (1.1
mmol) were added to epoxide 3 (1 mmol) in a mixture of
MeCN and H2O (9:1, 10 mL). The reaction mixture was
stirred at reflux temperature until the disappearance of
starting material as indicated by TLC. The reaction mixture
was extracted with EtOAc, and the combined organic layers
were washed with H2O and brine, dried over anhyd Na2SO4,
and evaporated under reduced pressure. The residue was
subjected to flash chromatography on silica gel (hexane–
EtOAc) to provide the pure azidohydrin 4 in 74% yield as a
white foam; [a]26D +27 (c = 0.05, CHCl3). 1H NMR (400
MHz, CDCl3): d = 8.20–8.33 (m, 4 H), 5.81–5.90 (m, 1 H),
5.62–5.75 (m, 2 H), 3.94 (dd, J = 10.4, 7.5 Hz, 1 H), 3.76 (td,
J = 10.4, 5.9 Hz, 1 H), 2.93 (s, 1 H), 2.61 (dt, J = 17.6, 5.5
Hz, 1 H), 2.23 (ddd, J = 17.8, 10.3, 2.5 Hz, 1 H). 13C NMR
(400 MHz, CDCl3): d = 164.94, 158.39, 150.93, 135.12,
130.93, 127.81, 124.86, 123.57, 76.79, 74.22, 61.22, 30.39.
HRMS (CI): m/z [M + H] calcd for C13H12N4O5: 305.0886;
found: 305.0883.
(1S,2S,6S)-7-Acetyl-7-azabicyclo[4.1.0]hept-3-en-2-yl 4-
Nitrobenzoate (5): A solution of 4 (0.82 g, 2.6 mmol) and
triphenylphosphine (0.85 g, 2.9 mmol) in anhyd MeCN (5.2
mL) was refluxed for 2 h. After cooling to r.t., the solvent
was removed under reduced pressure, and pyridine (5.2 mL)
and Ac2O (490 mL, 5.2 mmol, 2 equiv) were added at r.t.
After 5 h, the reaction mixture was concentrated in vacuum.
The residue was purified by column chromatography (silica
gel, hexane–EtOAc, 3:1 → 1:1) to afford 5 (60 mg, 0.976
mmol) in 76% yield as a pale yellow semisolid; [a]26D +36 (c
= 0.11, CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.26 (d,
© Thieme Stuttgart · New York
Synlett 2012, 23, 573–576

576
D. S. Gunasekera
LETTER
(3R,4R,5S)-4-Methyl-2-thioxothiazol-3 (2H)-yl-4-
H), 6.38 (d, J = 6.4 Hz, 1 H), 6.12 (dd, J = 10.1, 3.0 Hz, 1 H),
5.70 (d, J = 7.8 Hz, 1 H), 4.59 (dd, J = 13.0, 7.1 Hz, 1 H),
3.75–4.03 (m, 1 H), 2.93 (dt, J = 18.7, 5.5 Hz, 1 H), 2.29–
2.52 (m, 1 H), 2.07 (s, 3 H), 1.40 (s, 9 H). 13C NMR (101
MHz, CDCl3): d = 194.98, 172.50, 156.09, 148.65, 128.51,
79.73, 59.70, 53.49, 34.11, 28.31, 23.11. HRMS (CI): m/z
[M+] calcd for C13H20N2O4: 268.1423; found: 268.1425.
acetamido-5-[(tert-butoxycarbonyl)amino]-3-(pentan-3-
loxy)cyclohex-1-enecarboxylate (10): DABCO (112 mg,
1.43 mmol) and thiohydroxamic acid (12; 84 mg, 0.572
mmol) were added to a cold (0 °C), magnetically stirred
solution of 9 (110 g, 0.286 mmoL) in anhyd CH2Cl2 (1.43
mL), and the reaction mixture was stirred for 45 min at 0–5
°C, and treated with propane phosphonic acid anhydride
[PPAA; 0.5 mL, 50% (w/w) solution of PPAA in DMF]. The
reaction mixture was stirred for 5 h at r.t. All volatiles were
removed at 20 °C under reduced pressure to afford a residue
which was taken up in Et2O (2 mL) and H2O (2 mL). The
combined ethereal layers were washed with H2O (2 mL),
dried with anhyd Na2SO4, filtered, and evaporated. Column
chromatography (elution with 25–50% Et2O and hexane)
gave the ester 10 (119 mg, 81%) as a semisolid; [a]26D –59
(c = 0.06, CHCl3). 1H NMR (400 MHz, MeOD): d = 6.61 (s,
1 H), 4.24 (d, J = 7.5 Hz, 1 H), 3.95 (t, 1 H), 3.84 (td, J =
10.3, 5.4 Hz, 1 H), 3.40–3.52 (m, 1 H), 2.84 (d, J = 17.4 Hz,
1 H), 2.31–2.59 (m, 1 H), 2.19 (s, 3 H), 1.98 (s, 3 H), 1.48–
1.63 (m, 6 H), 1.45 (s, 9 H), 0.92 (dt, J = 15.4, 7.4 Hz, 6 H).
13C NMR (400 MHz, MeOD): d = 182.38, 173.72, 157.96,
138.94, 126.34, 104.20, 83.72, 80.41, 77.15, 55.87, 49.99,
31.62, 28.71, 27.22, 26.72, 22.99, 13.14, 9.94, 9.59. HRMS
(ESI): m/z [M + Na] calcd for C23H35N3O6S2: 536.1865;
found: 536.1873.
(18) Tamiflu® was purchesed from Hangzhou DayangChem Co.
Ltd. and LGM Pharma.
(19) Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369.
(20) Hartung, J.; Schwarz, M. Synlett 2000, 371.
(21) Paquette, L. A.; Dahnke, K.; Doyon, J.; He, W.; Wyant, K.;
Friedrich, D. J. Org. Chem. 1991, 56, 6199.
(22) (3R,4R,5S)-4-Acetamido-5-[(tert-butoxycarbonyl)-
amino]-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic
Acid (9): Solid 1 (163 mg, 0.413 mmol) was dissolved in sat.
NaHCO3 (10 mL) and was extracted with EtOAc (2 × 10
mL). The combined organic layer was dried with Na2SO4.
After complete removal of the solvent, the residue was
dissolved in H2O–MeOH (1 mL; 1:1) mixture and solid
KOH (46.3 mg, 0.826 mmol) was added, and the mixture
was stirred at r.t. overnight. After most of the MeOH was
removed under reduced pressure, H2O was removed by
azeotropic evaporation with benzene. The residue was
dissolved in CH2Cl2 (1 mL) and treated with Et3N (287 uL,
2.06 mmol, 5 equiv), and Boc2O (180 mg, 8826 mmol, 2
equiv), and the mixture was stirred at r.t. for 4 h. The reaction
mixture was quenched with a sat. aq NH4Cl solution and
extracted with EtOAc (3 × 5 mL). The organic extracts were
combined, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to
give pure product 9 as a white solid in 97% yield; mp 206–
208 °C; [a]26D –53 (c = 0.12, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 6.82 (s, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 5.78 (d,
J = 9.6 Hz, 1 H), 3.86–4.10 (m, 2 H), 3.66–3.84 (m, 1 H),
3.26–3.34 (m, 1 H), 2.69 (dd, J = 17.6, 4.7 Hz, 1 H), 2.24 (dd,
J = 17.4, 10.8 Hz, 1 H), 1.98 (s, 3 H), 1.46 (t, J = 6.6 Hz, 4
H), 1.40 (s, 9 H), 0.77 –0.93 (m, 6 H). 13C NMR (400 MHz,
CDCl3): d= 171.36, 169.00, 156.72, 139.30, 128.92, 82.08,
79.65, 76.00, 55.10, 49.27, 30.72, 28.34, 26.15, 25.49,
23.22, 9.63, 9.00. HRMS (ESI): m/z [M + Na] calcd for
C19H32N2O6: 407.2158; found: 407.2153.
tert-Butyl-[(1S,5R,6R)-6-acetamido-3-bromo-5-(pentan-
3-yloxy)cyclohex-3-en-1-yl]carbamate (11):
Thiohydroxamic ester 10 (96 mg, 0.187 mmol) and AIBN
(1.5 mg) were dissolved in bromotrichloromethane (935 mL)
and heated to 70 °C. The reaction was stirred for an
additional 1 h, cooled, and chromatographed directly on
silica gel (hexane–EtOAc) to give 21 (59 mg, 76%) as a
white solid; mp 153–155 °C; [a]26D –42 (c = 0.32, CHCl3).
All spectroscopic data was identical to the previously
reported data of 11. 1H NMR (400 MHz, CDCl3): d = 6.05
(s, 1 H), 5.65 (d, J = 9.0 Hz, 1 H), 5.36 (d, J = 8.9 Hz, 1 H),
4.08 (q, J = 9.2 Hz, 1 H), 3.74–3.92 (m, 2 H), 3.19–3.34 (m,
1 H), 2.76 (dd, J = 17.8, 5.2 Hz, 1 H), 2.57 (dd, J = 15.7, 8.1
Hz, 1 H), 1.97 (s, 3 H), 1.36–1.53 (m, 13 H), 0.87 (t, J = 6.4
Hz, 6 H). 13C NMR (400 MHz, CDCl3): d = 170.66, 155.91,
129.25, 121.57, 81.89, 79.71, 76.37, 52.74, 49.52, 40.41,
28.30, 26.15, 25.87, 23.35, 9.61, 9.43. HRMS (ESI): m/z [M
+ H] calcd for C18H31BrN2O4: 419.1545; found: 419.1550.
Synlett 2012, 23, 573–576
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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.