Tetrahedron: Asymmetry 26 (2015) 553–559

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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy

Enantioselective synthesis of the apremilast aminosulfone using

catalytic asymmetric hydrogenation
Alexander L. Ruchelman ⇑, Terrence J. Connolly
Drug Substance Development, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA

a r t i c l e i n f o a b s t r a c t

Article history: Celgene’s OtezlaÒ 1 (apremilast) is the first and only PDE4 inhibitor approved by the US FDA for the treat-
Received 23 February 2015 ment of plaque psoriasis and psoriatic arthritis. The active pharmaceutical ingredient 1 has been histori-
Accepted 27 March 2015 cally prepared via resolution to obtain the enantioenriched aminosulfone intermediate. Herein we have
Available online 16 April 2015
investigated the use of catalytic asymmetric hydrogenation for the enantioselective synthesis of the key
aminosulfone intermediate in order to identify a higher yielding and greener synthesis route. Asymmetric
reduction of enamine 7 and ketone 11 both proceeded with high selectivity, generating their respective
products with >95% ee.
Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction OMe

Apremilast 1 (OtezlaÒ) is an inhibitor of phosphodiesterase 4 O OEt

(PDE4) approved by the US FDA for the treatment of patients with

moderate to severe plaque psoriasis for whom phototherapy or
systemic therapy is appropriate (Fig. 1).1 Apremilast has also been
approved for the treatment of adult patients with active psoriatic
arthritis.2 By virtue of its properties as a regulator of inflammatory
signaling, apremilast may have utility in various disease states,
which benefit from restored balance between pro- and anti-in-
flammatory signaling; apremilast is also being investigated as an
oral treatment for ankylosing spondylitis, Behcet’s disease, atopic
dermatitis and ulcerative colitis. The previously reported synthesis
of apremilast3 (Scheme 1) suffers from a low-yielding first step and
relies on subsequent resolution for the purification of the enan-
tioenriched (S)-isomer of the aminosulfone intermediate 8, which
is isolated as the N-Ac-L-Leu salt 4. It would be preferable to pre-
pare the aminosulfone intermediate enantioselectively for better
throughput and improved greenness.4 Herein we report our results
from the application of catalytic asymmetric hydrogenation for the
enantioselective synthesis of aminosulfone 8.
2. Results and discussion
In recent years, the development of technologies for the cat-
alytic asymmetric hydrogenation of unprotected enamines has
been reported,5 including the well-documented process for the
⇑ Corresponding author. Tel.: +1 908 673 9587; fax: +1 908 673 2792.
E-mail address: aruchelman@celgene.com (A.L. Ruchelman).
N
SO 2Me
O
O NH
apremilast 1
Figure 1. Structure of apremilast 1.
synthesis of the diabetes drug sitagliptin shown in Scheme 2.6 An
analogous enantioselective enamine reduction for the generation
of the requisite aminosulfone 8, if feasible, would comprise a con-
cise route to an enantioenriched intermediate. To explore this syn-
thesis route, the requisite enamine substrate 7 was prepared via
reaction of 3-ethoxy-4-methoxybenzonitrile with the lithium salt
of dimethylsulfone (Scheme 3). In a preliminary screening of the
asymmetric hydrogenation of enamine 7, promising results were
obtained with rhodium catalysts in 2,2,2-trifluoroethanol (TFE),
conditions similar to those reported to be optimal for various
enamine substrates.5,6 Subsequent ligand screening utilized 30
vol of TFE as solvent with 5 mol % Rh catalyst at 50 °C under
250 psig hydrogen gas for 18 h. The results are displayed in
Table 1. Excellent results were obtained with Josiphos ligands
(entries 1 and 2), which gave >99.5% conversion after 18 h and
95% ee in favor of the desired (S)-enantiomer. Me-Duphos also
provided good conversion (entry 3) but with poor enantioselectiv-
ity (25% ee). Phanephos was less active under these conditions and

http://dx.doi.org/10.1016/j.tetasy.2015.03.010
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
554 A. L. Ruchelman, T. J. Connolly / Tetrahedron: Asymmetry 26 (2015) 553–559

OMe OMe
OMe
OEt OEt
OEt a b

SO2 Me SO2Me
CHO H2N N-Ac-L-Leu .H 2 N

2 3 4

OMe
O
OMe
OEt O OEt
O c
+
N
O NH O
SO2 Me
SO2 Me
N-Ac-L-Leu.H 2N O NH O
5 4 1

Scheme 1. Reagents and conditions: (a) LiHMDS, then Me2SO2, n-BuLi, BF3Et2O, 78 °C, 41%; (b) N-Ac-L-leucine, MeOH, 44%, 98.4% ee; (c) HOAc, reflux, 75%.

F F
F F
NH 2 O NH 2 O
a
N N
N N
N N
F N F N

CF3 CF3

P(t-Bu)2
Ph2 P
Fe

(R,S)-t-Bu Josiphos

Scheme 2. Reagents and conditions: (a) [Rh(cod)Cl2], NH4Cl, (R,S)-t-Bu Josiphos, 90 psi H2, MeOH, 98%, 95% ee.6

OMe OMe
OMe OMe
OEt
OEt O OEt
OEt
a b c
N
SO2 Me SO2Me
H2N SO2Me
CN N-Ac-Leu .H2 N O
O NH
6 7 4 1

d c

OMe OMe
(t-Bu)2 P P
PPh2 OEt OEt
Fe
e
O P

(S,R)-t-Bu Josiphos SO2Me SO2Me

F 3C N H2N
H (R,R)-Me 2-DuPhos
9 8

Scheme 3. Reagents and conditions: (a) Me2SO2, n-BuLi, THF, 0 °C, 83%; (b) (i) (S,R)-t-Bu Josiphos, Rh(cod)2OTf, 90 psi H2, TFE, 50 °C; (ii) N-Ac-L-Leu, MeOH, 80%, 99.2% ee; (c)
N-(phthalimid-3-yl)acetamide, HOAc, reflux, 83%, 99.4% ee; (d) TFAA, CH2Cl2, 0 °C, 85%; (e) (i) Rh(cod)2OTf, (R,R)-Me2-DuPhos, H2, TFE, 35 °C, 47%; (ii) 6 M HCl, 85 °C, 68%.

provided only 50% conversion, while the product ee was 72% catalyst with 1.0 mol % ligand under 90 psig hydrogen gas at
(entry 4); DM-segphos provided moderate conversion (70%) and 50 °C was sufficient enough to achieve >99.5% conversion within
ee (85%, entry 5). t-Bu-Josiphos and Josiphos SL-J011 are struc- 18 h. The product could be conveniently isolated by conversion
turally similar with the exception that the SL-J011 possesses two into its N-Ac-L-leucine salt using a procedure similar to the earlier
para-trifluoromethyl groups on the two phenyl rings of the phos- resolution process,3 resulting in a chiral upgrade to 99.2% ee and
phine. Since the trifluoromethyl substitution provided no benefit, 99.8% area purity (normalized area under the HPLC chromatogram
the simpler t-Bu-Josiphos was selected for further investigation. peak), and 80% isolated yield. Compared to the earlier synthesis
After preliminary optimization, it was established that 0.5 mol % route (Scheme 1), the route shown in Scheme 3 does not require
 A. L. Ruchelman, T. J. Connolly / Tetrahedron: Asymmetry 26 (2015) 553–559 555

Table 1
Asymmetric hydrogenation of enamine substratea

OMe OMe
OEt OEt
metal, ligand, H2 , TFE

SO2 Me SO2 Me
H 2N H 2N

7 8

Entry Ligand/metalb Area% of 8c Area% of 7d ee of 8c Configuration

1 (S,R)-t-Bu Josiphos/[Rh(cod)2OTf] 94.4 0.07 95.7 (S)
2 Josiphos SL-J011-2/[Rh(cod)2OTf] 95.4 0.06 94.4 (S)
3 (S,S)-Me-Duphos/[Rh(cod)2OTf] 85.7 3.3 25.1 (S)
4 (R)-Phanephos/[Rh(cod)2OTf] 47.0 44.8 72.0 (S)
5 (R)-Ru(OAc)2(DM-segphos) 70.0 27.2 86.0 (R)
a
Reaction conditions: in 30 vol. 2,2,2-Trifluoroethanol (TFE), S/C = 20, 2:1 ligand/metal, 50 °C, 250 psig H2, 18 h.
b
See Ref. 12 for the full chemical names of all metal complexes and ligands.
c
Area% observed in achiral HPLC with detector set to 278 nm.
d
Assayed by chiral HPLC.

the use of cryogenic conditions and provides a better yield.
Additionally, chemical greenness is improved since there is no
need to discard half of the process stream comprising the dys-
tomer, as is the case in the resolution process.
The reduction of N-acyl enamines, a historically well estab-
lished reaction, is reported to be catalyzed by a broader range of
catalysts in comparison with unprotected enamine reduction.7 A
non-proprietary catalytic system might provide for a better syn-
thesis pathway in spite of the greater number of steps for the acyl
enamine synthesis pathway. The trifluoroacetyl enamine 9 deriva-
tive was selected as a representative acyl enamine due to its docu-
mented mild deprotection.8 Table 2 shows the results of the
reduction using a variety of ligands. Screening was conducted in
30 vol of TFE with 5 mol % rhodium catalyst and 10 mol % ligand
under 250 psig hydrogen gas at 50 °C for 18 h. However, none of
the results exceeded the previous finding with unprotected enam-
ine. While many ligands provided good conversion to N-acyl
aminosulfone 10, the enantioselectivity was modest to poor. The
best conditions were obtained using methyl-Duphos/
[Rh(cod)2OTf], which gave 85 Area% and 50% ee under the screen-
ing conditions (entry 2). It was subsequently found that the ee
increased to 80% when the reaction was run at 35 °C under 90 psig
hydrogen with 2 mol % Rh(cod)2OTf and 3 mol % (R,R)-methyl-
Duphos. From this reaction mixture, the poorly soluble trifluoroac-
etamide could be isolated by filtration, providing 40–48% yield;
hydrolysis of the trifluoroacetamide then provided the aminosul-
fone in 68% yield, in 99.5% area purity, and with 96% ee. Ketone
asymmetric hydrogenation9 was also investigated as a path for
the enantioselective synthesis of aminosulfone 8. Various catalytic
systems reported to be effective for enantioselective ketone reduc-
tion were screened using 1 mol % of catalyst under 450 psig hydro-
gen gas at 50 °C for 18 h (Table 3). Complete conversion of
substrate 11 was not achieved with any of the catalysts after
18 h; at best 85% conversion was achieved with 15 A% starting
material remaining. No attempt was made to lengthen the reaction
time in this screen. The best results were obtained with RuCl(p-
cymene)[(S,S)-Ts-DPEN] in the presence of t-BuOK, which provided
75% conversion and 82% ee (entry 4). The other catalysts investi-
gated gave poor conversion, poor ee, or both. Better results were
obtained by the application of Noyori’s asymmetric transfer hydro-
genation using RuCl(p-cymene)[(S,S)-Ts-DPEN] and formic acid–
TEA.10 Product 12 was obtained in 87% yield and 99.8% purity

Table 2
Asymmetric hydrogenation of N-trifluoroacetyl enamine substratea

OMe OMe
OEt OEt
metal, ligand, H2 , TFE

O O
SO2 Me SO2 Me
F3 C N F3 C N
H H
9 10

Entry Ligand/metalb A% of 10 A% of 9 ee of 10c (%) Configuration

1 (S,R)-t-Bu Josiphos/[Rh(cod)2OTf] 90.2 0.5 6.3 (S)
2 (S,S)-Methyl-Duphos/[Rh(cod)2OTf] 81.3 0.8 50.1 (R)
3 (S,S)-Chiraphos/[Rh(cod)2OTf] 85.6 5.0 9.7 (S)
4 (R)-Phanephos/[Rh(cod)2OTf] 43.3 51.4 50.7 (R)
5 (S)-(DM-Segphos)/[Rh(cod)2OTf] 88.0 6.1 9.5 (S)
6 [(R,R)-Me-BPE]Rh(cod)BF4 28.8 60.4 6.1 (R)
7 (R)-C3-TunePhos/[Rh(cod)2OTf] 91.9 2.2 11.6 (S)
8 (R)-[Rh(cod)TCFP]BF4 97.4 0.4 8.6 (R)
a
Reaction conditions: in 30 vol. 2,2,2-Trifluoroethanol (TFE), S/C = 20, 2:1 ligand/metal, 250 psig H2, 50 °C, 18 h.
b
See Ref. 12 for the full chemical names of all metal complexes and ligands.
c
Assayed by chiral HPLC.
556 A. L. Ruchelman, T. J. Connolly / Tetrahedron: Asymmetry 26 (2015) 553–559

Table 3
Asymmetric hydrogenation of the ketone substratea

OMe OMe
OEt M-L (1 mol%), 450 psig H2 , OEt
solvent, 50 oC

SO2 Me SO2 Me
O HO
11 12

Entry M-L12 Solvent Additive A% of 12b A% of 11b ee of 12c (%)

1 (S)-Ru(OAc)2(BINAP) TFE — 12.4 87.3 28.5
2 (S)-Ru(OAc)2(BINAP) TFE t-BuOK- 32.8 66.5 23.3
3 (S)-Ru(OAc)2(DM-segphos) TFE — 22.2 77.3 36.2
4 RuCl(p-cymene)[(S,S)-Ts-DPEN] i-PrOH t-BuOK 74.4 23.0 82.0
5 RuCl(p-cymene)[(S,S)-Ts-DPEN] TFE 57.2 42.5 66.9
6 RuCl(p-cymene)[(S,S)-Ts-DPEN] MeCN 12.7 86.7 —
7 RuCl2[(R)-(DM-segphos)[(R,R)-(DPEN)] i-PrOH t-BuOK 61.8 16.2 63.1
a
Reaction conditions: in 10 vol of the indicated solvent, S/C = 100, 450 psig H2, 50 °C, 18 h.
b
Area% observed in achiral HPLC with detector set to 278 nm.
c
Assayed by chiral HPLC.

OMe OMe OMe OMe

OEt OEt OEt OEt
a b c

SO 2 Me SO2Me SO2Me SO 2Me

O HO N3 N-Ac-Leu.H 2N
11 12 13 4

O
O
S Ru Cl
N NH 2

Ph Ph

RuCl(p-cymene)[(S,S)-Ts-DPEN]

Scheme 4. Reagents and conditions: (a) RuCl(p-cymene)[(S,S)-Ts-DPEN], HCO2H–TEA, MeCN, 87%, 99.4% ee; (b) (i) HN3, PBu3, DIAD, PhCH3, 81%, 41.7% ee; (c) (i) H2, 10% Pd–C,
TFE; (ii) N-Ac-L-Leu, TFE, MeOH, 44%, 94.4% ee.

and with 99.4% ee (Scheme 4). Thus, transfer hydrogenation was
superior to hydrogen gas for this reduction with this particular
catalyst and solvent. Subsequent conversion of hydroxysulfone
12 into aminosulfone 8 was achieved using the Mitsunobu reaction
as shown in Scheme 4. It was hoped that Mitsunobu reaction with
phthalimide would provide a protected aminosulfone, but the
attempted reaction with phthalimide gave only the vinylsulfone
elimination product. With alternative coupling partner hydrazoic
acid, the Mitsunobu reaction successfully delivered azide 13; how-
ever the conversion was accompanied by a significant erosion of
ee. Racemization of ortho- and para-alkoxybenzyl alcohols during
the Mitsunobu reaction has been described11 and is believed to
be a consequence of the increased carbocation character of the
Mitsunobu phosphonium intermediate resulting from the strong
electron-donating properties of the alkoxy substituent. Thus, it is
suspected that the reaction products arise partly from an SN1-type
reaction pathway. Herein, the partially racemized azide was car-
ried forward and the synthesis was completed (Scheme 4).
Reduction to the amine was followed by conversion into the N-
Ac-Leu salt and crystallization of the product to afford enantioen-
riched 4 (94.4% ee). Thus, diastereomeric salt formation was used
to rescue the ee at the cost of yield. The enantiomeric purity was
somewhat lower than that normally obtained using the N-Ac-L-
Leu chiral resolution, possibly a result of the modified solvent
system; in this experiment, the resolution was performed in a mix-
ture of TFE and methanol rather than simply methanol.
3. Conclusion
In conclusion, the application of catalytic asymmetric hydro-
genation to a key intermediate to the synthesis of apremilast 1
resulted in the discovery of enantioselective synthesis pathways
involving asymmetric reduction of either an enamine or ketone
as the key step. The unprotected enamine hydrogenation gave
the aminosulfone intermediate in good yield and with high purity
(>99% ee), and is a promising alternative synthesis route. The N-
acyl enamine and ketone substrates 9 and 11, respectively, under-
went asymmetric reduction under hydrogen gas, however the yield
and selectivity were not comparable to the reduction of the unpro-
tected enamine 7. Ketone 11 could be reduced in good yield and
with high ee using a transfer hydrogenation process, but subse-
quent conversion of alcohol 12 into amine 4 occurred with partial
epimerization under the conditions studied. Of the routes studied,
the unprotected enamine reduction is the most promising. In the
previous synthesis route (Scheme 1),3 enantioenriched (S)-
aminosulfone is obtained in 2 steps from 3-ethoxy-4-methoxyben-
zaldehyde in 18% overall yield. The enamine asymmetric reduction
provides enantioenriched (S)-aminosulfone in two steps from
 A. L. Ruchelman, T. J. Connolly / Tetrahedron: Asymmetry 26 (2015) 553–559
3-ethoxy-4-methoxybenzonitrile in 66% combined yield, a nearly
four-fold improvement. Both routes provide material of similar
enantiomeric purity. The improvement in yield can translate into
a lower cost of goods, improved process throughput and greenness.
4. Experimental
4.1. General
Commercial reagents and solvents were used as received with-
out further purification. Reactions were run under a nitrogen
atmosphere, unless noted otherwise. Column chromatography
refers to flash chromatography using Isco brand prepacked silica
gel cartridges. Proton (1H NMR) and carbon (13C NMR) nuclear
magnetic resonance were recorded on a Bruker 300 spectrometer.
NMR spectra (300 MHz 1H and 75 MHz 13C) were recorded in the
deuterated solvent indicated with chemical shifts reported in d
units downfield from tetramethylsilane (TMS). Coupling constants
are reported in Hertz (Hz). The purity of compounds was also ana-
lyzed by reverse phase HPLC using the solvent systems indicated.
Enantiomeric purity was analyzed by normal phase HPLC with a
chiral column using the solvent systems indicated. Elemental
analyses were obtained from QTI Intertek, Whitehouse, NJ.
Elemental analyses were within 0.4% of theory.
4.2. 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethen-
amine 7
A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 mL)
was treated with a 1.6 M solution of n-butyllithium in hexane
(505 ml, 808 mmol) at 0–5 °C. The resulting mixture was agitated
for 1 h then a solution of 3-ethoxy-4-methoxybenzonitrile (80 g,
451 mmol) in THF (240 mL) was added at 0–5 °C. The mixture
was agitated at 0–5 °C for 0.5 h, warmed to 25–30 °C over 0.5 h
and then agitated for 1 h. Water (1.4 L) was added at 25–30 °C
and the reaction mass was agitated overnight at room temperature
(20–30 °C). The solid was filtered and subsequently washed with a
2:1 mixture of water:THF (200 mL), water (200 mL) and heptane
(2  200 mL). The solid was dried under reduced pressure at 40–
45 °C to provide the product as a white solid (102 g, 83% yield);
1
H NMR (DMSO-d6) d 1.34 (t, J = 7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s,
3H), 4.08 (q, J = 7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d,
J = 8.5 Hz, 1H), 7.09–7.22 (m, 2H).
4.3. (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-
ethanamine N-Ac-L-Leu salt 4
A solution of bis(1,5-cyclooctadiene)rhodium(I) trifluo-
romethanesulfonate (17 mg, 0.037 mmol) and (S)-1-[(R)-2-
(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg,
0.037 mmol) in 10 mL of 2,2,2-trifluoroethanol was prepared
under nitrogen. To this solution was added 1-(3-ethoxy-4-methox-
yphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The
resulting mixture was heated to 50 °C and hydrogenated under
90 psig hydrogen pressure. After 18 h, the mixture was cooled to
ambient temperature and removed from the hydrogenator.
Ecosorb C-941 (200 mg) was then added and the mixture was
stirred at ambient temperature for 3 h. The mixture was filtered
through Celite, and the filter was washed with additional
trifluoroethanol (2 mL). Next, the mixture was heated to 55 °C,
and a solution of N-acetyl-L-leucine (1.3 g, 7.5 mmol) was added
dropwise over the course of 1 h. Stirring proceeded at the same
temperature for 1 h following completion of the addition, and then
the mixture was cooled to 22 °C over 2 h and stirred at this tem-
perature for 16 h. The crystalline product was filtered, rinsed with
methanol (2  5 mL), and dried under vacuum at 45 °C to provide
557
the product as a white solid (2.6 g, 80% yield); achiral HPLC
(Hypersil BDS C8, 5.0 lm, 250  4.6 mm, 1.5 mL/min, 278 nm, 90/
10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then
gradient to 10/90 0.1% aqueous TFA/MeOH over the next
15 min): 8.57 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 lm
Daicel, 250  4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane–i-
PrOH–diethylamine): 7.37, (0.4%), 8.35 (99.6%); 1H NMR (DMSO-
d6) d 0.84 (d, 3H), 0.89 (d, J = 6.6 Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H),
1.41–1.52 (m, 2H), 1.62 (dt, J = 6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94
(s, 3H), 3.28 (dd, J = 4.0, 14.4 Hz, 1H), 3.44 (dd, J = 9.1, 14.4 Hz,
1H), 3.73 (s, 3H), 4.02 (q, J = 6.9 Hz, 2H), 4.18 (q, J = 7.7 Hz, 1H),
4.29 (dd, J = 4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s,
1H), 8.04 (d, J = 7.9 Hz, 1H); Anal. (C20H34N2O7S) C, H, N. Calcd: C,
53.79; H, 7.67; N 6.27. Found: C, 53.78; H, 7.57; N 6.18.
4.4. N-(1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-
vinyl)-2,2,2-trifluoroacetamide 9
A solution of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsul-
fonyl)ethenamine (2 g, 7.37 mmol) in methylene chloride (20 ml)
was cooled on ice, and then 2,2,2-trifluoroacetic anhydride
(1.127 mL, 8.11 mmol) was added followed by triethylamine
(1.229 mL, 8.85 mmol). The mixture was stirred and allowed to
warm to room temperature over 2 h. The mixture was evaporated
and the residue was loaded directly onto a silica gel column, elut-
ing with a hexanes–ethyl acetate gradient. The appropriate frac-
tions were pooled and evaporated under vacuum, and the
residue was slurried with heptane (40 mL). After 1 h, the solids
were filtered, washed with additional heptane (25 mL), and dried
under vacuum, to afford the product as a white solid (2.3 g, 85%
yield); HPLC (Waters BEH C18, 1.7 lm, 2.1  50 mm, 0.8 mL/min,
240 nm, 5/95 gradient to 85/15 CH3CN 0.1% FA/H2O 0.1% FA in
5 min then 85/15 CH3CN 0.1%FA/H2O 0.1% FA for 1 min): 2.03
(5.71%), 2.26 (94.29%); 1H NMR (DMSO-d6) d 1.35 (t, 3H), 3.12 (s,
3H), 3.81 (s, 3H), 4.08 (q, J = 6.9 Hz, 2H), 7.02–7.14 (m, 2H), 7.14–
7.21 (m, 2H), 11.18 (s, 1H).
4.5. (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-
ethanamine 8
Step 1: To a solution of bis(1,5-cyclooctadiene)rhodium(I)
trifluoromethanesulfonate (0.025 g, 0.054 mmol), and 1,2-bis-
[(2R,5R)-2,5-dimethylphospholano]benzene (0.025 g, 0.082 mmol)
in 2,2,2-trifluoroethanol (20 mL) was added N-(1-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)vinyl)-2,2,2-trifluoroacetamide
(1 g, 2.72 mmol). The resulting mixture was hydrogenated at 35 °C
under 90 psig hydrogen gas for 18 h. Next, the mixture was cooled
to 25 °C and methanol (7 mL) was added dropwise over 15 min,
and the mixture was stirred at the same temperature for 2 h. The
solids were filtered and rinsed with 1:1 MeOH–TFE (5 mL), and
dried under vacuum to provide the reduction product as a white
solid (0.47 g, 47% yield); HPLC (Hypersil BDS C8, 5.0 lm,
250  4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1%
aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aque-
ous TFA/MeOH over the next 15 min): 16.43 (99.5%); 1H NMR
(DMSO-d6) d 1.33 (t, 3H), 2.97 (s, 3H), 3.59–3.79 (m, 5H), 4.02 (q,
J = 7.0 Hz, 2H), 5.38 (m, J = 4.9, 8.8 Hz, 1H), 6.85–6.98 (m, 2H),
7.07 (d, J = 1.5 Hz, 1H), 10.03 (d, J = 8.5 Hz, 1H).
Step 2: To the product from Step 1 (0.30 g, 0.81 mmol) was
added 6 M HCl (15 mL), and the resulting mixture was heated at
85 °C for 16 h, and then cooled to 20 °C. The mixture was filtered,
and the filtrate was evaporated. The residue was partitioned
between 10% K2CO3 (8 mL) and CH2Cl2 (8 mL). The lower organic
phase was removed and washed with CH2Cl2 (2  8 mL). To the
organic phase was added CH2Cl2 (25 mL), and the resulting organic
phase was washed with 10% K2CO3 (2  25 mL) and water (25 mL),
558 A. L. Ruchelman, T. J. Connolly / Tetrahedron: Asymmetry 26 (2015) 553–559
dried (MgSO4), and evaporated under vacuum to provide the pro-
duct as a white solid (150 mg, 68% yield); achiral HPLC (Hypersil
BDS C8, 5.0 lm, 250  4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient
to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/
90 0.1% aqueous TFA/MeOH over the next 15 min): 8.68 (99.5%);
chiral HPLC (Chiralpak AD-H 5.0 lm Daicel, 250  4.6 mm,
1.0 mL/min, 280 nm, 70:30:0.1 heptane–i-PrOH–diethylamine):
7.17 (1.9%), 8.06 (98.1%); 1H NMR (DMSO-d6) d 1.32 (t, J = 7.0 Hz,
3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J = 3.6, 14.4 Hz, 1H), 3.41
(dd, J = 9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J = 7.0 Hz, 2H), 4.26
(dd, J = 3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); Anal.
(C12H19NO4S) C, H, N. Calcd: C, 52.73; H, 7.01; N, 5.12. Found: C,
53.03; H, 6.78; N, 4.98.
4.6. (R)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-
ethanol 12
A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsul-
fonyl)ethanone (1.2 g, 4.4 mmol), RuCl(p-cymene)[(S,S)-Ts-DPEN]
(28 mg, 0.044 mmol), and 5:2 formic acid–triethylamine complex
(2.2 mL) in acetonitrile (7.2 mL) was stirred at 20–25 °C for 40 h.
The mixture was then evaporated to dryness and the residue was
chromatographed on a silica gel column, using a hexanes–ethyl
acetate gradient. The appropriate fractions were pooled and evapo-
rated. The residue was triturated with heptane (25 mL) and the
resulting slurry was filtered and dried under vacuum to provide
the product as a white solid (1.05 g, 87% yield); achiral HPLC
(Hypersil BDS C8, 5.0 lm, 250  4.6 mm, 1.5 mL/min, 278 nm, 90/
10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then
gradient to 10/90 0.1% aqueous TFA/MeOH over the next
15 min): 12.37 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 lm
Daicel, 250  4.6 mm, 1.0 mL/min, 280 nm, 85:15 heptane–i-
PrOH): 18.07 (0.51%), 20.43 (99.4%); 1H NMR (CHCl3-d) d 1.48 (t,
J = 7.0 Hz, 3H), 2.77 (dd, J = 1.1, 2.6 Hz, 1H), 3.05 (s, 3H), 3.17 (dd,
J = 0.9, 14.7 Hz, 1H), 3.46 (dd, J = 10.1, 14.6 Hz, 1H), 3.88 (s, 3H),
4.11 (q, J = 7.0 Hz, 2H), 5.27–5.32 (m, 1H), 6.82–6.95 (m, 3H).
4.7. (S)-4-(1-Azido-2-(methylsulfonyl)ethyl)-2-ethoxy-1-meth-
oxybenzene 13
A mixture of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsul-
fonyl)ethanol (0.94 g, 3.4 mmol) in toluene (280 mL) and THF
(20 mL) was sparged with nitrogen for 15 min, and then a
1.1 M solution of hydrazoic acid in toluene (13.8 mL, 15 mmol)
was added. The flask was cooled in a dry ice-acetone bath. When
the internal temperature reached <60 °C, tributylphosphine
(1.7 mL, 6.9 mmol), and then diisopropyl azodicarboxylate
(1.6 mL, 7.9 mmol) were added. The cooling bath was charged with
dry ice for the next 4 h in order to maintain the reaction tempera-
ture at <60 °C, and then the temperature was allowed to gradu-
ally rise. After 16 h, the internal temperature had reached 2 °C.
Then, silica gel (20 g) was added and the resulting slurry was
evaporated. The residue was chromatographed on a silica gel col-
umn, using a hexanes–EtOAc gradient. After pooling and evaporat-
ing the appropriate fractions, the residue was triturated with
heptane (25 mL) and the slurry was filtered. The solids were dried
under vacuum to provide the product as a white solid (0.84 g, 81%
yield); achiral HPLC (Hypersil BDS C8, 5.0 lm, 250  4.6 mm,
1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/
MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/
MeOH over the next 15 min): 17.77 (99.9%); chiral HPLC
(Chiralpak AD-H 5.0 lm Daicel, 250  4.6 mm, 1.0 mL/min,
280 nm, 85:15 heptane–i-PrOH): 6.07 (31.83%), 6.65 (68.17%); 1H
NMR (DMSO-d6) d 1.33 (t, 3H), 2.99 (s, 3H), 3.55 (dd, J = 4.0,
14.7 Hz, 1H), 3.77 (s, 3H), 3.90 (dd, J = 9.6, 14.7 Hz, 1H), 3.98–
4.13 (m, 2H), 5.01–5.21 (m, 1H), 6.90–7.05 (m, 2H), 7.08 (s, 1H).
4.8. (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-
ethanamine N-acetyl-L-leucine salt 4
(S)-4-(1-Azido-2-(methylsulfonyl)ethyl)-2-ethoxy-1-methoxy-
benzene (0.5 g, 1.670 mmol) was dissolved in TFE, and then 10%
Pd–C (0.05 g) was added. The resulting mixture was hydrogenated
at ambient temp under 40 psig hydrogen for 9 h, and then the mix-
ture was filtered through Celite. The filtrate was warmed to 55 °C
with stirring, and a solution of N-acetyl-L-leucine (0.29 g,
1.67 mmol) in MeOH (10 mL) was added dropwise to the mixture
over 1 h. The mixture was stirred at the same temperature for
2 h and then cooled to 20 °C over 2 h and stirred at this tempera-
ture for 16 h. The mixture was filtered and rinsed with 1:1 (v/v)
TFE–MeOH (10 mL), and the solids were dried under vacuum to
provide the product as a white solid (0.33 g, 44% yield); achiral
HPLC (Hypersil BDS C8, 5.0 lm, 250  4.6 mm, 1.5 mL/min,
278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over
10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the
next 15 min): 7.26 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 lm
Daicel, 250  4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane–i-
PrOH–diethylamine): 7.10 (2.8%), 8.02 (97.2%); 1H NMR (DMSO-
d6) d 0.84 (d, 3H), 0.89 (d, J = 6.6 Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H),
1.41–1.52 (m, 2H), 1.62 (dt, J = 6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94
(s, 3H), 3.28 (dd, J = 4.0, 14.4 Hz, 1H), 3.44 (dd, J = 9.1, 14.4 Hz,
1H), 3.73 (s, 3H), 4.02 (q, J = 6.9 Hz, 2H), 4.18 (q, J = 7.7 Hz, 1H),
4.29 (dd, J = 4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s,
1H), 8.04 (d, J = 7.9 Hz, 1H).
References
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12. The full chemical names of the metal complexes and ligands used herein are as
follows. Rh(cod) 2OTf: Bis(1,5-cyclooctadiene)rhodium(I) trifluoromethane-
sulfonate. (S,R)-t-Bu Josiphos: (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]
ethyldi-tert-butylphosphine. Josiphos SL-J011-2: (S)-1-{(RP)-2-[Bis[4-
(trifluoromethyl)phenyl]phosphino]ferrocenyl}ethyldi-tert-butylphosphine.
(S,S)-Me-Duphos: (+)-1,2-bis[(2S,5S)-2,5-Dimethylphospholano]benzene.
(R)-Phanephos: (R)-()-4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane.
(R)-Ru(OAc)2(DM-segphos): Diacetato[(R)-5,50 -Bis[di(3,5-xylyl)phosphino]-
4,40 -bi-1,3-benzodioxole]ruthenium(II). (S,S)-Chiraphos: (2S,3S)-()-Bis-
(diphenylphosphino)butane. [(R,R)-Me-BPE]Rh(cod)BF4: 1,2-Bis[(2R,5R)-2,5-
(Dimethylphospholano]ethane(cyclooctadiene)rhodium(I) tetrafluoroborate.
 A. L. Ruchelman, T. J. Connolly / Tetrahedron: Asymmetry 26 (2015) 553–559 559

(R)-C3-TunePhos: (R)-1,13-Bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo- RuCl(p-cymene)[(S,S)-Ts-DPEN]: [N-[(1S,2S)-2-(amino-jN)-1,2-diphenylethyl]-

[f,h][1,5]dioxonin. (R)-[Rh (cod)TCFP]BF4: R-(tert-Butylmethylphosphino-di-
tert-butylphosphinomethane)-g4-(1,5-cyclooctadiene)rhodium(I) tetrafluo-
roborate. (S)-Ru(OAc)2(BINAP): Diacetato[(S)-()-2,20 -Bis(diphenylphos-
phino)-1,10 -binaphthyl]ruthenium(II). (S)-Ru(OAc)2(DM-segphos): Diacetato-
[(S)-()-5,50 -Bis[di(3,5-xylyl)phosphino]-4,40 -bi-1,3-benzodioxole]ruthenium(II).
4-methylbenzenesulfonamidato-jN]chloro[(1,2,3,4,5,6-g)-1-methyl-4-(1-methy-
lethyl)benzene]-ruthenium. RuCl2[(R)-(DM-segphos)[(R,R)-(DPEN)]: Dichloro-
[(R)-5,50 -Bis[di(3,5-xylyl)phosphino]-4,40 -bi-1,3-benzodioxole][(1R,2R)-1,2-
diphenylethylenediamine]ruthenium(II).