A multikilogram-scale synthesis of (R)-methyl 2-[(1r,4R)-4-(tert-butoxy- carbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate - A doubly protected building block with three points of variation

Article abstract of DOI:10.1055/s-0031-1289724

A robust and scalable synthesis of (R)-methyl 2-[(1r,4R)-4-(tert- butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfon-amido)acetate is reported. This serves as a scaffold for the preparation of trans-substituted aminocyclohexanes. The key synthetic step is the reduction of d-4-hydroxyphenylglycine, or a protected equivalent, to achieve the required regiochemistry across the cyclohexyl ring. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289724

PAPER
875
A Multikilogram-Scale Synthesis of (R)-Methyl 2-[(1r,4R)-4-(tert-Butoxy-
carbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate – A Doubly
Protected Building Block with Three Points of Variation
A
D
oubly
P
rotecte
r
d Buildi
e
ng Block
w
g
ith Three
P
o
o
ints of
V
ariat
r
ion y Carr,*a Sam Butterworth,a Phil Walker,a Folkert Reck,b Bolin Geng,b Lakshmipathi Pandarinathanb
a
Astrazeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Infection Innovative Medicines Unit, AstraZeneca R & D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA
Fax +44(1625)513910; E-mail: greg.carr@astrazeneca.com
b
Received 19 October 2011; revised 6 February 2012
OH
Abstract: A robust and scalable synthesis of (R)-methyl 2-[(1r,4R)-
4-(tert-butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfon-
amido)acetate is reported. This serves as a scaffold for the prepara-
tion of trans-substituted aminocyclohexanes. The key synthetic step
is the reduction of D-4-hydroxyphenylglycine, or a protected equiv-
alent, to achieve the required regiochemistry across the cyclohexyl
ring.
H2N
NsHN
NHBoc
CO2H
CO2Me
OH
2
3
H2N
CO2H
4
Key words: chirality, diastereoselectivity, hydrogenation, protect-
ing groups, reduction
Scheme 1 Retrosynthetic analysis of methyl (R)-2-[(1r,4R)-4-
(tert-butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonami-
do)acetate
D-4-Hydroxyphenylglycine (4) was reduced by hydro-
genolysis with rhodium under basic conditions to a 1:1
mixture of the cis/trans–diastereomers,6 5 (Scheme 2),
which were easily separated by chromatography follow-
ing esterification and amine protection to give 6 and 7.
Functionalised amino-substituted cyclohexanes are useful
building blocks for medicinal chemistry. Compounds
containing the general structure 1, where R2 is either an
amide or alkylamino group, have shown activity against
biological targets such as TACE,1 Factor Xa,2 antibacteri-
als,3 MMP,4 and dipeptidyl peptidase IV.5
OH
OH
We required access to kilogram quantities of a suitable
building block, which would allow us to vary any of the
three positions indicated by R1, R2, and R3 in structure 1
(Figure 1). We chose to focus our efforts on synthesising
a building block of structure 2 with the amines protected
as nosyl (2-nitrosulfonyl) and Boc. The presence of an es-
ter would allow access to amides and alkyl substitution.
We report herein an optimised synthesis, which has been
progressed to deliver a single trans-diastereomer 2, on a
multikilogram scale.
H
O
Na+
O–
OH
H2N
H2N
O
4
5
NsHN
NsHN
+
OH
CO2Me
CO2Me
OH
6
7
H
Scheme 2 Reduction of 4 and separation of diastereomers
NsHN
N
R1
H
NHBoc
N
R3
R2
CO2Me
Reduction of the N-Boc 87 derivative under neutral condi-
tions is reported to give predominantly the cis-
diastereomer8 and in our hands gave a 10:1 cis/trans ratio
of diastereomers 9 (Scheme 3), with cyclohexane 10 be-
ing observed as the major impurity. On scale-up to 75
grams, reactions progressed smoothly with 6 being isolat-
ed in 50% overall yield from 8, after esterification and
protecting group swap. However, when the scale was in-
creased to 750 grams, the yield reduced to 25% due to for-
mation of previously undetected decarboxylated material
11.
1
2
Figure 1 Structures of building blocks 1 and 2
Our retrosynthetic strategy is shown in Scheme 1. The key
step is the reduction of the readily available D-4-hydroxy-
phenylglycine (4) to give the cis-diastereomer 3, which
enables installation of the correct trans-orientation of the
nitrogen in 2 after esterification, protection, activation,
and displacement with an ammonia equivalent.
It was hypothesised that if the reduction were performed
on the N-Boc methyl ester 12 (Scheme 4), the formation
of the decarboxylated product 11 would be suppressed.
SYNTHESIS 2012, 44, 875–880
Advanced online publication: 27.02.2012
DOI: 10.1055/s-0031-1289724; Art ID: N98311SS
x
x
.x
x
.2
0
1
2
© Georg Thieme Verlag Stuttgart · New York

876
G. Carr et al.
PAPER
tion from dehydration of the partially reduced phenyl ring.
Furthermore, when our best conditions with platinum ox-
ide were scaled to 70 grams, we observed very slow reac-
tions resulting in the formation of 11 from the prolonged
reaction times. This was attributed to reduced reactor head
space on a larger scale resulting in inefficient mixing of
hydrogen gas.9
OH
OH
OH
+
+
H
BocHN
CO2H
BocHN
CO2H
BocHN
CO2H
BocHN
8
9
10
11
Scheme 3 Reduction of N-Boc acid
Using rhodium on alumina under the conditions given in
Table 1, entry 3, improved the reaction giving 90% isolat-
ed yield of 13 with little formation of 14 and an acceptable
cis/trans ratio of 4.5:1. Unfortunately, we were unable to
achieve an acceptable conversion with less than 10 wt%
of rhodium catalyst (Table 1, entry 4); lowering the cata-
lyst charge resulted in incomplete reactions and formation
of 11.
N-Boc-D-4-hydroxyphenylglycine methyl ester (12) was
prepared from 4 (Scheme 5) in two steps without chroma-
tography on a scale up to 12 kilograms. Initial experi-
ments showed that the reduction of the ester was much
slower than the acid, resulting in an increased formation
of dehydroxylated compound 14. To address this, a screen
of reaction conditions was undertaken using acetic acid as
solvent as this was found to increase the rate of reaction.
Raney nickel was reported9 to give predominantly the
trans-diastereomer and little reaction is reported with pal-
ladium or ruthenium9 so we focused on platinum and
rhodium catalysts. Table 1 summarises the findings.
The reaction was scaled successfully to 1 kilogram giving
13 in 90% yield with simple removal of 14 by flash silica
chromatography. Methanol was used for scales over
1 kilogram (Table 1, entry 5) as removal of acetic acid by
evaporation and aqueous workup was deemed impractical
for further scaling. The cis/trans ratio was found to in-
crease slightly to 5.2:1 on a larger scale using methanol as
solvent, although with slightly increased amounts of de-
hydroxylated impurity 14.
OH
OH
OH
+
+
The complete synthesis of building block 2 is shown in
Scheme 5. N-Boc-D-4-hydroxyphenylglycine methyl es-
ter (12) was prepared from 4 in two steps10 without chro-
matography on a scale up to 12 kilograms, then subjected
to the reduction conditions as described above to give 13.
H
BocHN
CO2Me
BocHN
CO2Me
BocHN
CO2Me
BocHN
12
13
14
11
Scheme 4 Reduction of N-Boc ester and associated impurities
Table 1 Screening of Reduction Conditionsa
Removing the N-Boc protection from 13 using hydrogen
chloride (Scheme 5), gave a hydrochloride salt that was
difficult to isolate, while deprotection with trifluoroacetic
acid gave significant amounts of the trifluoroacetate ester
on the free hydroxy group. To avoid these issues, the pro-
tecting group swap from N-Boc to N-nosyl was carried out
as a one-pot procedure. The excess hydrogen chloride was
neutralised with triethylamine before the addition of 2-ni-
trobenzenesulfonyl chloride. Chromatographic separation
of the cis- and trans-diastereomers provided 6 in 52%
yield. An attempt was made to activate the alcohol via
nosylation as part of the same step but this proved unsuc-
cessful. Therefore mesylate 16 was obtained in 78% yield
after filtration through a silica pad and methanol slurry.
Entry Solvent Catalyst
Catalyst
loading
Ratio of products
13:14:11
1
2
3
4
5
AcOH
PtO2
2.5 mol% 11:7:0b
5 mol% 11:9:2d
AcOHc PtO2
AcOH
Rh (5% on Al2O3) 10 wt%e
9:1:0d
7:1:5b,f
16:3:0g
AcOH
MeOH
Rh (5% on Al2O3)
5 wt%e
Rh (5% on Al2O3) 10 wt%e
a Note: All reactions were run at 30–35 °C and 5 bar H2 pressure.
b By 1H NMR spectroscopy.
c Pressure: 20 bar.
It was found that the crude reaction mixture from the re-
duction step containing a mix of cis/trans-diastereomers
13 and cyclohexyl impurity 14, could be taken through the
protecting group swap and mesylation steps with standard
workup conditions and no purification. Mesylate 16 could
then be isolated cleanly via a slurry with methanol to re-
move cyclohexyl impurity 14 and other organic impuri-
ties, followed by recrystallisation from methyl tert-butyl
ether (MTBE) to remove the trans-diastereomer. This re-
moved the need for chromatography on a large scale, but
with a 15% drop in overall yield.
d Isolated.
e Wt% compared to quantity of starting material used.
f Remaining starting material: 45%.
g By HPLC after protecting group swap.
Reactions with platinum oxide resulted in the formation of
a large amount of 14 (Table 1, entry 1) and increasing the
catalyst loading and pressure (Table 1, entry 2) also had a
detrimental effect resulting in increased quantities of 14.
This prompted investigations into how 14 may be formed.
Subjecting 13 to identical reduction conditions resulted in
no further reaction, therefore we concluded that 14 was
not formed from dehydration of 13, but during the reduc-
The cis-mesylate 16 was converted to the trans-N-Boc
amine 2 via a three stage, one-pot telescoped procedure.
At first, the mesylate 16 was displaced with sodium azide
Synthesis 2012, 44, 875–880
© Thieme Stuttgart · New York

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A Doubly Protected Building Block with Three Points of Variation
877
OH
OH
OH
OH
NsHN
d
a
b
c
e
CO2Me
H
OH
6
H2N
HCl
CO2Me
H2N
CO2H
BocHN
CO2Me
BocHN
CO2Me
4
15
12
13
N–
+
N
NsHN
f (ii)
f (iii)
f (i)
NsHN
CO2Me
NsHN
NsHN
N
NH2
NHBoc
CO2Me
16
CO2Me
18
CO2Me
OMs
17
2
Scheme 5 Synthesis of 2. Reagents and conditions: (a) AcCl, MeOH, 0 to 55 °C, 18 h, 99%; (b) Boc2O, Et3N, CH2Cl2, 25 °C, 20 h, 88%; (c)
Rh/Al2O3, AcOH, H2, 5 bar, 35 °C, 18 h, 90%; (d) i. HCl, 1,4-dioxane, 25 °C, 3 h, ii. 2-nitrobenzenesulfonyl chloride, Et3N, CH2Cl2, 20 °C, 18
h, 52%; (e) MsCl, Et3N, CH2Cl2, 20 °C, 1 h, 78%; (f) i. NaN3, DMF, 55 °C, 16 h, ii. Ph3P, EtOAc, H2O, 65 °C, 3 h, iii. Boc2O, Et3N, CH2Cl2,
25 °C, 18 h, 69%.
NsHN
NsHN
a
NHBoc
NHBoc
NHBoc
CO2Me
CO2Me
CO2H
19
2
2
NsHN
HO
NsHN
b
c
NHBoc
NHBoc
NsN
20
21
Scheme 6 Further functionalisation of 2. Reagents and conditions: (a) 2 M aq NaOH, MeOH, 50 °C, 1 h, 86%; (b) DIBAL-H, CH2Cl2, 0 °C,
2 h, 66%; (c) DIAD, Ph3P, THF, 0 to 20 °C, 2 h, 65%.
in DMF giving the trans-azide 17. Isolation of 17 was 2 can be selectively diversified in each functionalised po-
avoided by drowning out the reaction mixture into water sition providing a versatile building block for medicinal
and then extracting the azide into ethyl acetate before sub- chemistry.
jecting it to reduction using Staudinger conditions11 to
give amine 18. The triphenylphosphine oxide formed in
CAUTION: The handling and use of low-molecular-weight nitro
the reaction proved difficult to remove by chromatogra-
phy on a large scale, so was removed by aqueous extrac-
tion. The amine 18 was extracted into aqueous
hydrochloric acid leaving the triphenylphosphine oxide
remaining in the organic phase.
compounds (e.g., 2-nosyl) can be dangerous due to their potentially
energetic character. Compounds containing nitro functionality
should be first prepared on a small scale and their properties tested
for safety by appropriate means (Differential Scanning Calorimetry,
BAM Fallhammer test, Carius tube test, etc.). It is recommended
that anyone wishing to replicate this chemistry should perform their
own safety testing and further testing should most definitely be per-
The aqueous extract was neutralised with ammonia and
amine 18 was extracted into dichloromethane. This solu- formed prior to any scale-up.
tion was treated directly with di-tert-butyl dicarbonate to
give 2 in 69% yield. This removal of chromatography was
significant as building block 2 could be synthesised on
large scale without any chromatographic stages.
CAUTION: The handling and use of sodium azide can be danger-
ous due its potentially explosive character. Before use, users should
consult the handbook on chemical hazards.14
Solvents were not dried before use. The catalyst used for the phenyl
ring reduction was 5% Rh on Al2O3, powder type 524, purchased
from Johnson Matthey. Reactions were monitored by either TLC,
LC-MS, or GC-MS. Glass plates precoated with silica gel 60 F254
to a thickness of 0.5 mm (Merck) were used for TLC analyses. LC-
MS spectra were recorded using a Waters 2790 separation module
fitted with a Waters 2996 photodiode array detector and a Waters
micromass ZQ mass detector. GC-MS were recorded using Agilent
Technologies 6890N network GC system fitted with an Agilent
Technologies 5975 inert XL mass selective detector. 1H NMR spec-
tra were recorded at 400, 500, and 700 MHz using TMS as an inter-
nal standard in CDCl3. All HRMS were recorded on a Thermo
Fisher LTQ-FT fitted with a 7.2T magnet. Reactions were per-
formed in either 10 L, 20 L, or 50 L jacketed glass vessels, or 250 L
glass-lined reactors for the larger scale reactions. The phenyl ring
reduction was performed in a 5 L or 20 L glass jacketed vessels ca-
pable of withstanding the pressure required or a 300 L autoclave for
the largest scale reaction. All reactors used an appropriately sized
Protected building block 2 can be further functionalised in
a number of ways and serves as a versatile intermediate,
which has three handles for derivatisation (Scheme 6).
The carboxylic acid 19 can be released by simple hydrol-
ysis in 86% yield, and the ester can be reduced with di-
isobutylaluminum hydride to afford the alcohol 20 in 66%
yield after chromatography. The nosyl and Boc groups
can be removed independently12 giving flexibility as to
which nitrogen is unveiled first. The nosyl group also
makes the nitrogen acidic allowing aziridine 21 to be syn-
thesised via Mitsunobu13 chemistry.
In conclusion, we have shown a practical and scaleable
synthesis of 2, allowing kilogram quantities to be pre-
pared in good yield with no chromatography. Compound
© Thieme Stuttgart · New York
Synthesis 2012, 44, 875–880

878
G. Carr et al.
PAPER
heater/chiller unit to provide reaction temperature control. Racemic
samples of 16 and 20 were prepared using the same route and the
chirality was checked via chiral HPLC using an Agilent 1100 sys-
tem fitted with a photodiode array detector and a 5 mm Chiralpak
AD-H column. No racemisation was found and none of the cis-
diastereomer was detected, copies of the spectra can be found in the
Supporting Information. As the chirality was checked part way
through and at the end of the synthesis with no found degradation,
it was deemed unnecessary to perform a check on chirality at every
stage in the synthesis.
sphere of H2 at 5 bar and 35 °C for 18 h. The reaction mixture was
filtered through dicalite and the solvent was evaporated under vac-
uum to give the title compound 13 (3.4 kg, 66%), which was used
in the next step without further purification.
Methyl (R)-2-[(1s,4S)-4-Hydroxycyclohexyl]-2-(2-nitrophenyl-
sulfonamido)acetate (6)
A solution of 4 M HCl in 1,4-dioxane (4.10 L, 16.43 mol) was add-
ed dropwise to 13 (944 g, 3.28 mol) in 1,4-dioxane (1.90 L) and
stirred at 25 °C for 3 h. The reaction mixture was diluted with
CH2Cl2 (6.60 L) and cooled to 5 °C. Et3N (3.21 L, 23.00 mmol) was
slowly added over a period of 20 min, then the mixture was stirred
at 5 °C for 15 min. 2-Nitrobenzenesulfonyl chloride (874 g, 3.94
mol) was added portionwise over a period of 5 min at 5 °C, then the
reaction mixture was warmed to 20 °C, and stirred for 18 h. The
mixture was washed with H2O (14.5 L) and the aqueous layer was
re-extracted with CH2Cl2 (9.50 L). The combined organics were
washed with 50% sat. brine (9.50 L) and dried (MgSO4), then fil-
tered, and the solvents evaporated. Purification by flash chromatog-
raphy (isohexane–acetone, 13:7) gave the title compound 6 as a
cream solid; yield: 636 g (52%); mp 78–84 °C.
Methyl (R)-2-Amino-2-(4-hydroxyphenyl)acetate Hydrochlo-
ride (15)
AcCl (1.85 L, 26.02 mol) was added dropwise over a period of 1 h
to D-(–)-4-hydroxyphenylglycine (1.45 kg, 8.67 mol) suspended in
MeOH (14 L) and cooled to 0 °C under N2. The resulting solution
was stirred at 0 °C for 30 min, then heated to 55 °C, and stirred at
this temperature for 18 h. The reaction mixture was cooled to 20 °C
and the solvent evaporated under vacuum to give the title compound
15 as a white solid; yield: 1.87 kg (99%); mp 180 °C (dec.).
1H NMR (400 MHz, DMSO-d6, 100 °C): d = 3.73 (s, 3 H), 5.00 (s,
1 H), 6.83 (d, J = 8.6 Hz, 2 H), 7.28 (d, J = 8.6 Hz, 2 H), 8.72 (s, 2
H), 9.53 (s, 1 H).
IR (mull): 3495–3160, 3050–2790, 1740, 1555, 1480, 1395, 1180
cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C9H12NO3: 182.08117; found:
182.08115.
1H NMR (500 MHz, C6D6): d = 1.04–1.24 (m, 4 H), 1.31–1.40 (m,
1 H), 1.47–1.65 (m, 5 H), 2.96 (s, 3 H), 3.59–3.67 (m, 1 H), 4.06–
4.16 (m, 1 H), 6.29 (d, J = 9.9 Hz, 1 H), 6.63 (dt, J = 7.7, 1.4 Hz, 1
H), 6.76 (dt, J = 7.7, 1.3 Hz, 1 H), 7.06 (dd, J = 7.9, 1.3 Hz, 1 H),
7.79 (dd, J = 7.9, 1.4 Hz, 1 H)
(R)-Methyl 2-(tert-Butoxycarbonylamino)-2-(4-Hydroxyphe-
nyl)acetate (12)
Et3N (1.25 L, 9.01 mol) was added dropwise to 15 (1.87 kg, 8.58
mol) suspended in CH2Cl2 (15 L). The mixture was warmed to
25 °C and stirred for 5 min; then a solution of di-tert-butyl dicar-
bonate (1.97 kg, 9.01 mol) in CH2Cl2 (4 L) was added dropwise
over a period of 45 min. The reaction mixture was stirred at 25 °C
for 20 h and then washed with H2O (19 L). The organic layer was
dried (MgSO4), filtered, and the solvent evaporated under vacuum.
The resulting solid was slurried with MTBE (3.80 L) for 1 h, the
precipitate collected by filtration, washed with further MTBE (2 L),
and dried under vacuum to give the title compound 12 (1.82 kg).
The mother liquors were evaporated under vacuum and the solid
was triturated with MTBE (850 mL). The precipitate was collected
by filtration, washed with further MTBE (850 mL), and dried under
vacuum to give a second crop of title compound 12 (297 g); total
yield: 2.11 kg (88%); white solid; mp 139 °C.
13C NMR (175 MHz, DMSO-d6, 69 °C): d = 170.44, 147.05,
133.64, 132.74, 131.88, 129.56, 123.73, 63.73, 60.01, 51.14, 38.20,
31.37, 31.29, 22.78, 22.17.
HRMS (ESI): m/z [M + H]+ calcd for C15H21N2O7S: 373.10640;
found: 373.10660.
Larger-Scale Method: A solution of 4 M HCl in 1,4-dioxane (12.90
L, 51.52 mol) was added dropwise to 13 (3.0 kg, 10.44 mol) in 1,4-
dioxane (5.90 L) and the reaction mixture was stirred at 25 °C for 2
h. The mixture was diluted with CH2Cl2 (20.70 L) and cooled to
5 °C. Et3N (10.06 L, 72.10 mmol) was slowly added over a period
of 1 h, followed by the addition of 2-nitrobenzenesulfonyl chloride
(2.74 kg, 12.31 mol) portionwise over a period of 30 min at 5 °C.
The reaction mixture was warmed to 20 °C and stirred for 3 h. The
mixture was washed with H2O (44.5 L) and the aqueous layer was
re-extracted with CH2Cl2 (29.6 L). The combined organics were
washed with 50% sat. brine (29.6 L), dried (MgSO4), filtered, and
the solvents evaporated to give the title compound 6 (3.5 kg, 90%),
which was used in the next step without further purification.
1H NMR (400 MHz, DMSO-d6, 100 °C): d = 1.39 (s, 9 H), 3.63 (s,
3 H), 5.06 (d, J = 7.7 Hz, 1 H), 6.73 (d, J = 8.6 Hz, 2 H), 6.91 (s, 1
H), 7.15 (d, J = 8.6 Hz, 2 H), 9.08 (s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO5: 282.13360;
found: 282.13361.
Methyl (R)-2-[(1s,4S)-4-(Methylsulfonyloxy)cyclohexyl]-2-(2-
nitrophenylsulfonamido)acetate (16)
Methyl (R)-2-(tert-Butoxycarbonylamino)-2-(4-hydroxycyclo-
hexyl)acetate (13)
A solution of MsCl (249 mL, 3.22 mol) in CH2Cl2 (900 mL) was
added dropwise over a period of 30 min to a stirred solution of 6
(1.09 kg, 2.92 mol) and Et3N (610 mL, 4.38 mol) in CH2Cl2 (10 L)
cooled to 5 °C under N2. The solution was warmed to 20 °C and
stirred for 1 h, and then washed with H2O (10 L). The aqueous layer
was re-extracted with CH2Cl2 (10 L) and the combined organics
were washed with 50% sat. brine (10 L), dried (MgSO4), filtered,
and the solvents evaporated. The crude product was slurried with
MeOH (3.40 L) for 10 min, the precipitate was collected by filtra-
tion, washed with MeOH (1.0 L) and Et2O (1.70 L), and dried under
vacuum to give the title compound 16 as a white solid; yield: 1.02
kg (78%); mp 117–119 °C.
Compound 12 (1.05 kg, 3.73 mol) and 5% Rh on Al2O3 (105 g) in
AcOH (10 L) were stirred under an atmosphere of H2 at 5 bar and
35 °C for 18 h. The reaction mixture was filtered through dicalite
and the solvent was evaporated under vacuum. The residue was dis-
solved in CH2Cl2 (10 L) and washed with sat. aq NaHCO3 (10 L).
The aqueous layer was re-extracted with CH2Cl2 (5 L), then the
combined organic layers were dried (MgSO4), filtered, and evapo-
rated. The residue was passed through a silica pad, washing first
with 10% EtOAc in isohexane, then eluting the desired product with
10% MeOH in CH2Cl2. Solvents were evaporated under vacuum to
give the title compound 13 as a yellow gum, which was used with-
out further purification; yield: 965 g (90%).
Chiral HPLC: 1 mg/mL; UV: lmax = 254 nm; Chiralpak AS column,
5 mm silica, 4.6 mm diameter, 250 mm length; eluent: 50:50:0.1
mixture of heptanes–EtOH–Et3N; 100% chirally pure.
IR (mull): 3305, 3050–2790, 1740, 1550, 1470, 1355, 1180 cm–1.
Larger-Scale Method: Compound 12 (5.0 kg, 17.8 mol) and 5% Rh
on Al2O3 (0.5 kg) in MeOH (100 L) were stirred under an atmo-
Synthesis 2012, 44, 875–880
© Thieme Stuttgart · New York

PAPER
A Doubly Protected Building Block with Three Points of Variation
879
1H NMR (400 MHz, CDCl3): d = 1.36–1.65 (m, 6 H), 1.66–1.87 (m,
1 H), 2.01–2.10 (m, 2 H), 2.96 (s, 3 H), 3.37 (s, 3 H), 3.86–4.08 (m,
1 H), 4.92 (s, 1 H), 6.00 (d, J = 9.7 Hz, 1 H), 7.57–7.78 (m, 2 H),
7.83–7.91 (m, 1 H), 7.95–8.10 (m, 1 H).
13C NMR (175 MHz, DMSO-d6, 69 °C): d = 170.13, 147.02,
133.69, 132.69, 131.91, 129.59, 123.72, 77.46, 59.92, 51.28, 37.74,
37.54, 29.24, 29.22, 22.67, 21.93.
IR (mull): 3480–3150, 3050–2790, 1690, 1540, 1455, 1365, 1170
cm–1.
1H NMR (700 MHz, pyridine-d5, 67 °C): d = 1.25–1.38 (m, 2 H),
1.44–1.71 (m, 11 H), 1.96–2.11 (m, 2 H), 2.11–2.21 (m, 3 H), 3.61
(s, 1 H), 4.45 (d, J = 5.66 Hz, 1 H), 6.63 (s, 1 H), 7.45–7.59 (m, 2
H), 7.79 (d, J = 7.34 Hz, 1 H), 8.34 (d, J = 7.27 Hz, 1 H).
13C NMR (175 MHz, DMSO-d6, 69 °C): d = 171.04, 154.46,
147.12, 133.42, 133.06, 131.98, 129.58, 123.85, 77.00, 60.84,
48.95, 31.86, 31.80, 27.96, 27.54, 26.44.
HRMS (ESI): m/z [M + H]+ calcd for C16H23N2O9S2: 451.08395;
found: 451.08447.
Larger-Scale Method: MsCl (0.62 L, 7.98 mol) was added dropwise
over a period of 30 min to a stirred solution of 6 (3.5 kg, 9.40 mol)
and Et3N (1.51 L, 10.88 mol) in CH2Cl2 (27 L) cooled to 5 °C under
N2. The solution was warmed to 20 °C and stirred for 1 h, and then
washed with H2O (27 L). The aqueous layer was re-extracted with
CH2Cl2 (27 L) and the combined organics were washed with 50%
sat. brine (27 L), dried (MgSO4), filtered, and the solvents evaporat-
ed. The crude product was slurried with MeOH (5.4 L) for 1 h at
25 °C, then the precipitate was collected by filtration, and washed
with MeOH (2.1 L) and MTBE (2.7 L). The solid was recrystallised
from a mixture of MTBE (13.5 L) and EtOAc (5.4 L) to give the title
compound 16 as a white solid; yield: 1.54 kg (38%).
HRMS (ESI): m/z [M + H]+ calcd for C19H28N3O8S: 458.15916;
found: 458.15976.
tert-Butyl (1R,4r)-4-[(R)-2-Hydroxy-1-(2-nitrophenylsulfon-
amido)ethyl]cyclohexylcarbamate (20)
DIBAL-H (1 M solution in toluene, 567 mL, 0.57 mol) was added
dropwise over 30 min to 2 (63.6 g, 0.13 mol) in CH2Cl2 (640 mL)
cooled to –10 °C under N2. The resulting solution was stirred at
0 °C for 2 h, then quenched by dropwise addition of MeOH (64
mL). The mixture was cooled to 0 °C and a 4.5% w/v aq solution of
Rochelle’s salt (800 mL) was added. The mixture was warmed to
20 °C and stirred for 1 h, then diluted with CH2Cl2 (320 mL), and
filtered through Celite. The organic layer was separated and dried
(MgSO4), filtered, and the solvent evaporated under vacuum. Puri-
fication by flash chromatography (isohexane–EtOAc, gradient of
100:0 to 60:40) gave the title compound 20 as a yellow solid; yield:
39.5 g (66%); mp 196 °C (dec.).
Methyl (R)-2-[(1r,4R)-4-(tert-Butoxycarbonylamino)cyclohex-
yl]-2-(2-nitrophenylsulfonamido)acetate (2)
NaN3 (780 g, 11.97 mol) was added to 16 (3.00 kg, 6.66 mol) in
DMF (15 L) and heated to 55 °C for 16 h. The reaction mixture was
cooled to 20 °C, diluted with H2O (45 L), and extracted with EtOAc
(30 L). The aqueous layer was re-extracted with EtOAc (30 L), then
the combined organics were dried (MgSO4), and filtered. To the fil-
trate was added Ph3P (2.10 kg, 7.99 mol) and the solution was heat-
ed to 65 °C for 90 min. H2O (6 L) was added and the reaction
mixture was stirred at 65 °C for a further 90 min, then cooled to
20 °C, and extracted with 1.5 M aq HCl (4 × 12 L). The combined
aqueous layers were washed with CH2Cl2 (3 × 30 L) then the aque-
ous layer was basified with liquid ammonia (9 L) and extracted with
CH2Cl2 (30 L). The CH2Cl2 layer was dried (MgSO4), filtered, and
then treated with Et3N (1.39 L, 9.99 mol) and di-tert-butyl dicarbon-
ate (1.60 kg, 7.33 mol). The mixture was stirred at 25 °C for 18 h
and washed with H2O (30 L). The aqueous layer was re-extracted
with CH2Cl2 (30 L), then the combined organics were dried
(MgSO4), filtered, and the solvent evaporated under vacuum. The
crude solid was slurried with isohexane (9 L) and the precipitate
collected by filtration and dried under vacuum to give the title com-
pound 2 as a yellow solid; yield: 2.10 kg (69%); mp 108–118 °C.
Chiral HPLC: 1 mg/mL; UV: lmax = 254 nm; Chiralpak AS column,
5 mm silica, 4.6 mm diameter, 250 mm length; eluent: 80:20:0.1
mixture of heptanes–EtOH–Et3N; 100% chirally pure.
IR (mull): 3600–3120, 3050–2790, 1685, 1530, 1450, 1370–1320,
1250, 1170 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.75–1.13 (m, 4 H), 1.35 (s, 9 H),
1.40–1.51 (m, 1 H), 1.59–1.65 (m, 1 H), 1.67–1.83 (m, 2 H), 1.83–
1.99 (m, 2 H), 3.13–3.29 (m, 2 H), 3.44–3.64 (m, 2 H), 4.26 (s, 1 H),
5.49 (d, J = 8.3 Hz, 1 H), 7.61–7.71 (m, 2 H), 7.73–7.85 (m, 1 H),
8.00–8.11 (m, 1 H).
13C NMR (175 MHz, DMSO-d6, 69 °C): d = 154.44, 147.09,
133.82, 133.24, 131.81, 129.61, 123.64, 76.98, 60.90, 59.74, 49.11,
37.32, 32.05, 32.03, 27.95, 27.58, 26.48.
HRMS (ESI): m/z [M + H]+ calcd for C19H30N3O7S: 444.17990;
found: 444.18042.
tert-Butyl (1R,4r)-4-[(R)-1-(2-Nitrophenylsulfonyl)aziridin-2-
yl)cyclohexylcarbamate (21)
IR (mull): 3020–2790, 1690, 1555, 1520, 1470, 1365, 1190 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86–1.27 (m, 4 H), 1.37 (s, 9 H),
1.53–1.85 (m, 3 H), 1.85–2.10 (m, 2 H), 3.19–3.35 (m, 1 H), 3.36
(s, 3 H), 3.84–4.03 (m, 1 H), 4.28 (s, 1 H), 5.99 (d, J = 9.9 Hz, 1 H),
7.62–7.73 (m, 2 H), 7.81–7.90 (m, 1 H), 7.94–8.04 (m, 1 H).
13C NMR (175 MHz, DMSO-d6, 69 °C): d = 170.26, 154.43,
147.01, 133.62, 132.77, 131.86, 129.56, 123.69, 77.04, 60.24,
51.22, 48.69, 38.53, 31.57, 31.54, 27.92, 27.27, 26.67.
Diisopropyl azodicarboxylate (DIAD, 21.0 mL, 107 mmol) was
added dropwise to 20 (39.4 g, 89 mmol) and Ph3P (28.0 g, 107
mmol) in THF (400 mL) cooled to –5 °C under N2. The resulting so-
lution was stirred at 0 °C for 1 h, then warmed to 20 °C, and stirred
for 30 min. Further Ph3P (14.0 g, 53.5 mmol) and DIAD (10.5 mL,
53.5 mmol) were added and the mixture was stirred at 20 °C for 10
min, then the solvents were evaporated under vacuum (water bath
kept below 35 °C). Purification by flash chromatography (isohex-
ane–EtOAc, gradient of 100:0 to 70:30) gave the title compound 21
as a white solid; yield: 24.5 g (65%); mp 152 °C (dec.).
HRMS (ESI): m/z [M + H]+ calcd for C20H30N3O8S: 472.17481;
found: 472.17554.
IR (mull): 3050–2790, 1700, 1550, 1470, 1390 cm–1.
(R)-2-[(1r,4R)-4-(tert-Butoxycarbonylamino)cyclohexyl]-2-(2-
nitrophenylsulfonamido)acetic Acid (19)
1H NMR (400 MHz, DMSO-d6): d = 0.98–1.10 (m, 5 H), 1.35 (s, 9
H), 1.43–1.55 (m, 1 H), 1.56–1.65 (m, 1 H), 1.64–1.81 (m, 2 H),
2.58–2.70 (m, 1 H), 2.66–2.75 (m, 1 H), 3.09 (s, 1 H), 6.63 (d,
J = 7.7 Hz, 1 H), 7.86–7.94 (m, 1 H), 7.94–8.01 (m, 1 H), 7.99–8.09
(m, 1 H), 8.09–8.17 (m, 1 H).
13C NMR (175 MHz, DMSO-d6, 69 °C): d = 154.44, 147.78,
135.21, 132.11, 130.42, 129.23, 124.02, 77.02, 48.78, 44.91, 37.24,
33.47, 31.34, 31.25, 27.91, 27.56, 27.32.
Aq 2 M NaOH (5.30 mL, 10.60 mmol) was added dropwise to 2 (1
g, 2.12 mmol) suspended in MeOH (5 mL). The resulting solution
was stirred at 50 °C for 1 h, then cooled to 20 °C, and the MeOH
evaporated under vacuum. The aqueous residues were acidified to
pH 4 with 1 M aq citric acid and the resulting precipitate was col-
lected by filtration, washed with H2O (10 mL), and dried under vac-
uum to give the title compound 19 as a white solid; yield: 0.84 g
(86%); mp 225 °C (dec.).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 875–880

880
G. Carr et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C19H28N3O6S: 426.16933;
Zumbrunn Acklin, C. Patent PCT Int. Appl. WO
found: 426.16916.
2008078305, 2008; Chem. Abstr. 2008, 149, 153099.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Colwell, L.; Eiermann, G.; Feeney, W. P.; Habulihaz, B.;
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Acknowledgment
The authors would like to thank Howard Beeley for obtaining the
NMR data, and Antonio Cirillo and Alex Brough for helping with
the chiral HPLC analysis.
(7) Hirai, Y.; Yokota, K.; Momose, T. Heterocycles 1994, 39,
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