Organozirconium chemistry on cyclosporin: A novel process for the highly stereoselective synthesis of (E)-ISA247 (voclosporin) and close analogues

Article abstract of DOI:10.1055/s-0031-1289616

Application of organozirconium chemistry to cyclosporin has led to the development of a novel process for the highly stereoselective synthesis of the E-isomer of ISA247 (voclosporin), which is a potent immunosuppressive agent currently in late stage human clinical trials for treatment of psoriasis, prevention of kidney transplant rejection, and ophthalmic indications. Synthesis of deuterated analogues of ISA247 and a cyclosporin triene analogue using the same methodology is also described. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289616

PAPER
63
Organozirconium Chemistry on Cyclosporin: A Novel Process for the Highly
Stereoselective Synthesis of (E)-ISA247 (Voclosporin) and Close Analogues
a
b
a
a
b
b
S
J
tereosele
u
ctive
S
ynthe
n
sis of
(
E
)
-ISA
-
247 (V
o
H
closporin) and
C
l
o
ose
A
nalogues Maeng, Zhicai Yang,* David D. Manning, Liaqat Masih, Yeyu Cao, Kevin G. Pattamana,
b
b
Frederic Bois, Bruce F. Molino
a
Discovery R & D Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212-5098, USA
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212-5098, USA
Fax +1(518)5122079; E-mail: zhicai.yang@amriglobal.com
b
Received 3 October 2011; revised 27 October 2011
Abstract: Application of organozirconium chemistry to cyclospor-
in has led to the development of a novel process for the highly ste-
reoselective synthesis of the E-isomer of ISA247 (voclosporin),
which is a potent immunosuppressive agent currently in late stage
human clinical trials for treatment of psoriasis, prevention of kidney
transplant rejection, and ophthalmic indications. Synthesis of deu-
terated analogues of ISA247 and a cyclosporin triene analogue us-
ing the same methodology is also described.
HO
N
O
N
N
N
N
O
N
H
N
O
1
O
O
O
O
O
N
H
N
O
H
N
Key words: cyclosporin A, ISA247, voclosporin, E-diene, organo-
zirconium chemistry
N
H
O
O
ISA247 (1) is a novel semi-synthetic analogue of cy-
closporin A (CsA, 2) which was originally reported as a
mixture of cyclosporin terminal E- and Z-dienes 1, where
the E/Z ratio varies depending on the synthetic method
2
CsA
θ
η
ζ
1
employed to construct the terminal diene on the 1-amino
ε
acid side chain (Figure 1). The replacement of the termi-
nal methyl of CsA with a vinyl group is the only structural
difference between ISA247 (1) and CsA (2). CsA remains
one of the major drugs used for the prevention of organ
transplant rejection. Recent reports indicate that (E)-
ISA247 (1a) exhibits greater immunosuppressive potency
and an improved drug safety profile in human clinical tri-
δ
γ
HO
HO
HO
β
α
CsA
1
CsA
CsA
1b
1a
ISA247
(E)-ISA247
(Z)-ISA247
Figure 1 Structures of CsA and ISA247 (voclosporin) stereoiso-
2
mers
als compared with CsA. CsA’s poor therapeutic index is
attributed largely to renal toxicity, which often occurs in
patients undergoing chronic, long term treatment with this logues of 1a to elucidate structure–activity relationships
potent immunosuppressive agent. The drug name voclo- around this part of the molecule.3
sporin was recently adopted for (E)-ISA247 (1a), which is
Suzuki and co-workers developed a facile and highly E-
currently in phase II clinical trials for the prevention of or-
selective method using an organozirconium reagent for
gan rejection after kidney transplantation, and phase III
the stereoselective synthesis of terminal 1,3-dienes direct-
clinical trials for the treatment of psoriasis. It is also in
phase III clinical trials for the ophthalmic indication, uvei-
ly from simple aromatic and aliphatic aldehydes.4
2g
Our efforts toward the stereoselective synthesis of (E)-
ISA247 (1a) are summarized in Scheme 1. The known in-
termediate aldehyde 4 was prepared in two steps from cy-
closporin A following the procedure described in the
tis. The recent clinical findings and the potential phar-
maceutical utility of voclosporin warrant the development
of a highly stereoselective synthetic route for the prepara-
tion of this drug candidate.
1b
literature. Protection of the secondary alcohol of CsA (2)
with an acetyl group followed by ozonolysis of the result-
ing acetylcyclosporin A (3) provided aldehyde 4 in excel-
lent yield that was satisfactory to carry forward without
further purification. The subsequent treatment of alde-
hyde 4 with the g-trimethylsilylpropenylzirconocene
chloride complex, which was prepared in situ from bis(cy-
clopentadienyl)zirconium chloride hydride (Schwartz’s
reagent) and propargyltrimethylsilane, in the presence of
silver perchlorate produced exclusively the desired E-di-
In an effort to obtain (E)-ISA247 (1a) for benchmarking
purposes in our biological assays, we developed a novel,
highly stereoselective route for the synthesis of 1a. Our
synthetic method was also used to synthesize close ana-
SYNTHESIS 2012, 44, 63–68
x
x.
x
x
.
2
0
1
1
Advanced online publication: 22.11.2011
DOI: 10.1055/s-0031-1289616; Art ID: M94711SS
©
Georg Thieme Verlag Stuttgart · New York

6
4
J.-H. Maeng et al.
PAPER
ene 5. None of the Z-isomer of the diene was detected by
D D
1
SiMe3 or
either HPLC or H NMR analyses (the coupling constant
O
SiMe3
5
Je,z = 14.9 Hz). Finally, (E)-ISA247 (1a) was obtained by
Cp2Zr(H)Cl or Cp2Zr(D)Cl
AgClO4, CH2Cl2, r.t.
the hydrolysis of acetate 5 using potassium carbonate in
6
AcO
methanol.
CsA
4
R1
R2
R3
R1
R2
R3
Ac2O, DMAP
CH2Cl2, 0 °C to r.t.
HO
AcO
quant.
CsA
CsA
2
3
2 3
K CO , MeOH, r.t.
AcO
HO
O
i. O3, CH2Cl2
78 °C
ii. Me2S, –78 °C
to r.t.
SiMe3
–
CsA
2
CsA
2
Cp2Zr(H)Cl, AgClO4
THF, 0 °C to r.t.
1
7a: R , R = H, R3 = D, 47%
1
6
6
a: R , R = H, R3 = D, 25%
b: R , R = D, R = H, 37%
AcO
1
2
3
1
2
3
7b: R , R = D, R = H, 59%
1
2
3
1
2
3
95%
74%
6c: R , R , R = D, 25%
7c: R , R , R = D, 43%
CsA
4
Scheme 2 Synthesis of deuterated ISA247 analogues
TFA (v/v). Aldehyde 8 was treated with a mixture of
Schwartz’s reagent and propargyltrimethylsilane in the
K2CO3, MeOH, r.t.
60%
presence of silver perchlorate to produce acetyltriene 9 in
AcO
HO
9
2
9% yield. The structure of the triene 9 was confirmed to
CsA
5
CsA
1a
be an E,E-triene (Je,z = 14.6 Hz and Jh,q = 14.8 Hz) by
NMR studies. Hydrolysis of the acetyltriene 9 with potas-
sium carbonate provided the final compound 10 in 75%
yield.
Scheme 1 Synthesis of (E)-ISA247 (voclosporin)
Interestingly, the corresponding deuterated diene ana-
logues, which have been reported to change both the phys-
icochemical and pharmacokinetic profile and improve the
therapeutic index, can be synthesized utilizing the same
strategy by employing deuterated reagents (Scheme 2).
OMe
OMe
O
SiMe3
7
Cp Zr(H)Cl, AgClO
2
4
Grubbs II
CH2Cl2, r.t.
AcO
AcO
Reaction of aldehyde 4 with the zirconium complex pre-
CH2Cl2, 60 °C
sealed tube
29%
pared in situ from the commercially available Cp Zr(D)Cl
2
CsA
CsA
6
4%
and propargyltrimethylsilane in the presence of silver per-
3
8
chlorate provided exclusively the E-isomer of deuterated
diene 6a by H NMR analyses (the coupling constant
Je,z = 15.2 Hz). Similarly, deuterated E-dienes 6b and 6c
were synthesized by employing deuterated propargyltri-
κ
ι
1
θ
η
ζ
γ
methylsilane, which was prepared following a two-step
ε
8
δ
literature procedure, with either Cp Zr(H)Cl (for 6b) or
2
2 3
K CO , MeOH, r.t.
9
Cp Zr(D)Cl (for 6c). No corresponding Z-isomers of 6b
AcO
HO
2
β
1
75%
and 6c were observed by H NMR analyses (the coupling
α
CsA
CsA
10
constants Je,z from 6b and 6c are 14.3 Hz and 15.2 Hz, re-
spectively). Hydrolysis of the acetates 6a–c with potassi-
um carbonate in methanol provided E-dienes 7a–c
smoothly.
9
Scheme 3 Synthesis of cyclosporin triene
In conclusion, we have successfully developed an effi-
cient synthetic approach to the immunosuppressive drug
candidate voclosporin (1a). The four-step novel process
provides a highly stereocontrolled conversion from cy-
closporin A to voclosporin (1a) in 42% overall yield. Uti-
lizing this method, the corresponding deuterated ISA247
and triene analogues have also been prepared.
With these successes in hand, we next investigated the
synthesis of a novel cyclosporin triene analogue by uti-
lizing the organozirconium chemistry (Scheme 3). The E-
1
0
a,b-unsaturated aldehyde 8 (J = 15.5 Hz) was prepared
e,z
from acetylcyclosporin A (3) via olefin cross-metathesis
1
1
using Grubbs’ second-generation catalyst. The resulting
acetal from the reaction was hydrolyzed to provide the
corresponding aldehyde in the course of the purification
by semi-preparative HPLC on a C18 column at 70 °C us- Unless otherwise noted, reagents and solvents were used as re-
ceived from commercial suppliers. Optical rotations were measured
ing a solvent system of acetonitrile and water with 0.05%
1
13
on a Perkin-Elmer 343 polarimeter at r.t. H and C NMR spectra
Synthesis 2012, 44, 63–68
© Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (E)-ISA247 (Voclosporin) and Close Analogues
(E)-Acetyl-ISA 247 (5)
65
were recorded at 300 and 75 MHz or 500 and 125 MHz, respective-
ly. Spectra are given in ppm (d) and coupling constants, J, are re-
ported in hertz. Tetramethylsilane was used as an internal standard
for proton spectra and the solvent peak was used as the reference
peak for carbon spectra. Mass spectra were obtained on a Perkin-
Elmer Sciex 100 atmospheric pressure ionization (APCI) mass
spectrometer or a Finnigan LCQ Duo LCMS ion trap electrospray
ionization (ESI) mass spectrometer. High-resolution mass spec-
trometry (HRMS) was performed in ESI positive mode on a Waters
Q-Tof Micro mass spectrometer. HPLC analyses were obtained us-
ing a Dynamax C18 column (200 × 4.5 mm) or Phenomenex Luna
C18(2) column (250 × 4.6 mm) with UV detection at 210 nm and
oven temperature at 65 °C. Semi-preparative HPLC purifications
were performed on a Luna C18(2) column (250 × 21.2 mm) with
To a suspension of Cp Zn(H)Cl (620 mg, 2.4 mmol) in THF (10
2
mL) at 0 °C was added propargyltrimethylsilane (280 mg, 2.5
mmol). The mixture was stirred at 0 °C for 30 min and then warmed
to r.t. for 2 h. The mixture was cooled to 0 °C again, and a solution
of aldehyde 4 (300 mg, 0.24 mmol) in THF (2 mL) was added. The
mixture was stirred at 0 °C for 10 min and then warmed to r.t.
AgClO (10 mg, 0.05 mmol) was added and the resulting mixture
4
was stirred at r.t. for 12 h. The mixture was poured into sat. aq
NaHCO (10 mL). The organic layer was separated, and the aque-
3
ous layer was extracted with EtOAc (3 × 20 mL). The combined or-
ganics were washed with brine (20 mL), dried (Na SO ), filtered,
2
4
and concentrated under reduced pressure. The crude product was
purified by Combi-Flash chromatography on a silica gel column (0
to 50% EtOAc–hexanes) to afford 5; yield: 223 mg (74%); white
oven temperature at 70 °C using a solvent system of MeCN and H O
2
2
5
with 0.05% TFA (v/v). Combi-Flash chromatography was per-
formed using Combi-Flash Companion (Isco, Inc.) with either a sil-
ica gel column or a C18 column.
solid; [a]D –298.8 (c 0.3, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 8.46 (d, J = 9.1 Hz, 1 H), 8.05 (d,
3
J = 7.1 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H),
6
5
4
3
.21 (dt, J = 16.8, 10.3 Hz, 1 H), 5.90 (dd, J = 14.9, 10.8 Hz, 1 H),
.69 (dd, J = 10.7, 3.6 Hz, 1 H), 5.54 (s, 2 H), 5.40–4.75 (m, 7 H),
.65 (d, J = 14.2 Hz, 1 H), 4.46 (t, J = 7.3 Hz, 1 H), 3.44 (s, 3 H),
.25 (s, 3 H), 3.19 (s, 6 H), 3.11 (s, 3 H), 2.69 (s, 6 H), 2.48–2.33
Acetylcyclosporin A (3)
A mixture of cyclosporin A (2; 40 g, 33.3 mmol), Ac O (31.3 mL,
2
3
32 mmol), pyridine (40.2 mL, 498 mmol), DMAP (0.405 g, 3.32
mmol), and anhyd CH Cl (250 mL) was stirred under N at 0 °C
2
2
2
(
m, 1 H), 2.22–2.09 (m, 5 H), 2.02 (s, 3 H), 1.75–0.70 (m, 65 H).
and allowed to warm to r.t. for 2 days. After this time, the mixture
was poured slowly into sat. aq NaHCO (1 L) and stirred for 1 h
1
3
C NMR (125 MHz, CDCl ): d = 173.7, 173.2, 173.0, 172.9, 171.6
3
3
(
2 C), 171.4, 171.1, 170.6, 170.5, 170.2, 168.1, 136.8, 133.1, 132.3,
(
Caution: there was vigorous production of CO when the reaction
2
1
4
3
15.1, 73.1, 58.4, 57.5, 56.2, 55.4, 54.9, 54.4, 50.2, 48.9, 48.4, 48.0,
5.0, 40.9, 39.2, 39.1, 37.0, 35.7, 34.0, 33.3, 32.3, 31.7, 31.5, 31.4,
0.2, 30.1, 29.7, 29.5, 25.0, 24.8, 24.7 (2 C), 24.5, 24.1, 23.7, 23.4
was quenched). The organic layer was separated and the aqueous
layer was extracted with CH Cl (2 × 100 mL). The combined or-
2
2
ganic layers were washed with aq 1 M HCl (2 × 500 mL), sat. aq
(
1
2 C), 22.5, 21.7, 21.2, 21.1, 20.6, 20.3, 19.4, 18.5, 18.1, 17.9, 17.5,
5.1, 9.8.
NaHCO (500 mL), and brine (500 mL). The organics were then
3
dried (Na SO ), filtered, and concentrated under reduced pressure to
2
4
give acetylcyclosporin A (3); yield: 41.4 g (quant); off-white solid.
+
HRMS (ESI): m/z calcd for C H N O [M + H] : 1256.8597;
found: 1256.8447.
6
5
114 11 13
1
H NMR (300 MHz, CDCl ): d = 8.57 (d, J = 9.9 Hz, 1 H), 8.05 (d,
3
J = 6.9 Hz, 1 H), 7.50 (d, J = 9.6 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H),
(
E)-ISA 247 (1a)
To a stirred solution of E-acetyldiene 5 (75 mg, 0.06 mmol) in
MeOH (8 mL) was added K CO (205 mg, 1.48 mmol) at r.t. After
5
.67 (dd, J = 10.8, 3.9 Hz, 1 H), 5.45–5.60 (m, 1 H), 5.38 (dd,
J = 11.7, 3.6 Hz, 1 H), 5.10–5.35 (m, 6 H), 4.97 (d, J = 11.1 Hz, 2
H), 4.84 (t, J = 7.2 Hz, 1 H), 4.76 (t, J = 9.9 Hz, 1 H), 4.65 (d,
J = 13.8 Hz, 1 H), 4.41 (t, J = 7.2 Hz, 1 H), 3.44 (s, 3 H), 3.26 (s, 3
H), 3.24 (s, 3 H), 3.21 (s, 3 H), 3.09 (s, 3 H), 2.67 (s, 3 H), 2.65 (s,
2
3
stirring for 12 h at r.t., the reaction mixture was diluted with EtOAc
50 mL) and then washed with sat. aq NH Cl (15 mL). The aqueous
(
4
layer was further extracted with EtOAc (2 × 50 mL). The combined
organics were dried (Na SO ), filtered, and concentrated under re-
duced pressure. The crude product was purified by Combi-Flash
chromatography on a C18 column (10 to 100% MeCN–H O) to af-
ford 1a; yield: 44 mg (60%); white solid; [a]D –220.0 (c 0.3,
CHCl3).
3
1
H), 2.33–2.48 (m, 1 H), 2.09–2.22 (m, 5 H), 2.02 (s, 3 H), 0.70–
.75 (m, 64 H).
2
4
ESI-MS: m/z = 1244 [C H N O + H]+.
6
4
113 11 13
2
2
5
Acetylcyclosporin A Aldehyde (4)
A mixture of acetylcyclosporin A (3; 41.4 g, 33.2 mmol) and anhyd
1
H NMR (500 MHz, CDCl ): d = 7.95 (d, J = 10.2 Hz, 1 H), 7.60 (d,
CH Cl (200 mL) was cooled to –78 °C, and ozone was bubbled
3
2
2
J = 6.2 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 7.9 Hz, 1 H),
through the mixture until a light blue color appeared. N was bub-
bled through the mixture for 10 min and then Me S (20 mL, 272
mmol) was added at –78 °C. The mixture was allowed to warm to
r.t. and stirred overnight under N . The mixture was concentrated,
2
6
5
.30 (dt, J = 17.0, 10.3 Hz, 1 H), 5.99 (dd, J = 15.4, 10.3 Hz, 1 H),
.53–5.73 (m, 2 H), 5.50 (d, J = 5.7 Hz, 1 H), 5.33 (dd, J = 11.6, 3.9
2
Hz, 1 H), 4.92–5.16 (m, 5 H), 4.82 (t, J = 7.3 Hz, 1 H), 4.77 (d,
J = 13.3 Hz, 1 H), 4.65 (t, J = 8.7 Hz, 1 H), 4.53 (t, J = 7.2 Hz, 1 H),
3
2
2
and the residue was dissolved in Et O (2 L), washed with 10% aq
2
.52 (s, 3 H), 3.40 (s, 3 H), 3.23 (s, 3 H), 3.11 (s, 3 H), 3.10 (s, 3 H),
.70 (s, 3 H), 2.69 (s, 3 H), 1.98–2.52 (m, 8 H), 0.65–1.82 (m, 63 H).
Na CO (2 × 500 mL) and brine (1 L), dried (Na SO ), filtered, and
2
3
2
4
concentrated to dryness to give aldehyde 4; yield: 38.8 g (95%);
white solid.
13
C NMR (125 MHz, CDCl ): d = 173.8 (2 C), 173.6, 173.4, 171.5,
3
1
171.2, 171.1, 170.4, 170.3, 170.1, 170.0, 137.3, 133.5, 132.6, 114.5,
H NMR (300 MHz, CDCl ): d = 9.60 (d, J = 3.3 Hz, 1 H), 8.56 (d,
3
7
4
2
4.6, 58.8, 57.8, 57.5, 55.5, 55.4, 55.3, 50.3, 48.7, 48.5, 48.2, 45.1,
0.6, 39.4, 38.9, 37.3, 36.1, 35.9, 35.8, 34.0, 31.5, 31.3, 31.1, 29.8,
9.7, 29.5, 29.0, 25.4, 24.8 (2 C), 24.6, 24.4, 23.8, 23.7, 23.6, 23.4
J = 9.6 Hz, 1 H), 7.97 (d, J = 6.9 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H),
7
.46 (d, J = 9.0 Hz, 1 H), 5.66 (dd, J = 11.1, 3.6 Hz, 1 H), 5.45–5.60
(
(
m, 3 H), 5.32 (dd, J = 12.6, 3.6 Hz, 1 H), 5.10–5.23 (m, 6 H), 4.83
t, J = 7.2 Hz, 1 H), 4.73 (t, J = 9.6 Hz, 1 H), 4.65 (d, J = 13.8 Hz,
(
2 C), 21.9, 21.8, 21.0, 20.2, 19.8, 18.6, 18.3, 18.1, 16.8, 15.9, 9.8.
1
H), 4.41 (t, J = 6.9 Hz, 1 H), 3.46 (s, 3 H), 3.29 (s, 6 H), 3.21 (s, 3
H), 3.08 (s, 3 H), 2.67 (s, 3 H), 2.65 (s, 3 H), 2.33–2.48 (m, 1 H),
.09–2.22 (m, 5 H), 2.01 (s, 3 H), 0.70–1.75 (m, 59 H).
ESI-MS: m/z = 1232 [C H N O + H]+.
+
HRMS (ESI): m/z calcd for C H N O [M + H] : 1214.8492;
found: 1214.8394.
6
3
112 11 12
2
(E)-Acetyl-(h-d)-ISA247 (6a)
To a suspension of Cp Zn(D)Cl (410 mg, 1.60 mmol) in CH Cl (3
6
2
109 11 14
2
2
2
mL) at r.t. was added propargyltrimethylsilane (0.25 mL, 1.7
mmol). The mixture was stirred at r.t. for 10 min. A solution of al-
©
Thieme Stuttgart · New York
Synthesis 2012, 44, 63–68

6
6
J.-H. Maeng et al.
PAPER
dehyde 4 (200 mg, 0.160 mmol) in CH Cl (1 mL) was added, fol-
ers were dried (Na SO ), filtered, and concentrated under reduced
2
2
2
4
lowed by AgClO (7.0 mg, 0.03 mmol). The resulting mixture was
pressure. The residue was purified by semi-preparative HPLC on a
4
2
5
stirred at r.t. for 12 h. The mixture was poured into sat. aq NaHCO3
C18 column to afford 6c; yield: 51 mg (25%); white solid; [a]D
–258.7 (c 0.1, CHCl3).
(
10 mL). The organic layer was separated and the aqueous layer was
extracted with CH Cl (3 × 20 mL). The combined organic layers
1
2
2
H NMR (300 MHz, CDCl ): d = 8.53 (d, J = 9.2 Hz, 1 H), 8.06 (d,
3
were dried (Na SO ), filtered, and concentrated under reduced pres-
2
4
J = 6.8 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H),
5
2
Hz, 1 H), 3.45 (s, 3 H), 3.26 (s, 3 H), 3.24 (s, 6 H), 3.11 (s, 3 H),
2.68 (s, 3 H), 2.67 (s, 3 H), 2.45–2.35 (m, 1 H), 2.28–2.05 (m, 5 H),
2.02 (s, 3 H), 1.95–0.65 (m, 65 H).
sure. The residue was purified by semi-preparative HPLC on a C18
.90 (d, J = 15.2 Hz, 1 H), 5.69 (dd, J = 11.2, 3.7 Hz, 1 H), 5.54 (s,
H), 5.42–4.75 (m, 5 H), 4.66 (d, J = 13.9 Hz, 1 H), 4.44 (t, J = 7.1
2
5
column to afford 6a; yield: 50 mg (25%); white solid; [a]D –255.8
(
c 0.3, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 8.53 (d, J = 9.6 Hz, 1 H), 8.04 (d,
3
J = 6.9 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1 H),
5
5
1
3
5
.90 (d, J = 15.2 Hz, 1 H), 5.69 (d, J = 6.8 Hz, 1 H), 5.53 (s, 2 H),
.40–4.72 (m, 7 H), 4.64 (d, J = 13.3 Hz, 1 H), 4.43 (t, J = 6.6 Hz,
H), 3.45 (s, 3 H), 3.26 (s, 3 H), 3.21 (s, 3 H), 3.20 (s, 3 H), 3.10 (s,
H), 2.68 (s, 3 H), 2.66 (s, 3 H), 2.48–2.33 (m, 1 H), 2.22–2.09 (m,
H), 2.02 (s, 3 H), 1.92–0.70 (m, 65 H).
+
HRMS (ESI): m/z calcd for C H D N O [M + H] : 1259.8783;
found: 1259.8857.
6
5
111
3
11 13
(
E)-(h-d)-ISA247 (7a)
To a stirred solution of E-acetyldiene 6a (43 mg, 0.03 mmol) in
MeOH (4 mL) was added K CO (104 mg, 0.750 mmol) at r.t. After
stirring for 12 h at r.t., the reaction mixture was diluted with H O
(20 mL), and extracted with EtOAc (3 × 50 mL). The combined or-
ganics were dried (Na SO ), filtered, and concentrated under re-
duced pressure. The crude product was purified by semi-preparative
1
3
C NMR (125 MHz, CDCl ): d = 173.7, 173.2, 173.1, 172.9, 171.9,
3
2
3
1
1
4
3
71.8, 171.7, 171.4, 170.8, 170.7, 170.2, 168.2, 136.8, 133.4, 131.9,
15.0, 73.2, 58.5, 57.6, 56.2, 55.5, 55.0, 54.3, 50.3, 48.9, 48.4, 48.1,
5.0, 40.9, 39.2, 39.1, 37.0, 35.7, 34.0, 33.3, 32.3, 31.7, 31.5, 31.4,
0.2, 30.1, 29.7, 29.5, 25.0, 24.8, 24.7 (2 C), 24.5, 24.0, 23.6, 23.4
2
2
4
(
1
2 C), 22.5, 21.7, 21.2, 21.1, 20.6, 20.3, 19.4, 18.5, 18.1, 17.8, 17.5,
5.1, 9.8.
HPLC on a C18 column to afford 7a; yield: 17 mg (47%); white sol-
id; [a]D –194.0 (c 0.3, CHCl3).
2
5
+
1
HRMS (ESI): m/z calcd for C H DN O [M + H] : 1257.8659;
found: 1257.8561.
H NMR (300 MHz, CDCl ): d = 7.95 (d, J = 9.0 Hz, 1 H), 7.62 (d,
6
5
113
11 13
3
J = 6.8 Hz, 1 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.17 (d, J = 7.7 Hz, 1 H),
5
.98 (d, J = 14.8 Hz, 1 H), 5.74–5.54 (m, 2 H), 5.50 (d, J = 5.1 Hz,
(
E)-Acetyl-(q,q-d,d)-ISA247 (6b)
1 H), 5.33 (d, J = 7.9 Hz, 1 H), 5.17–4.88 (m, 5 H), 4.82 (t, J = 6.6
Hz, 1 H), 4.74 (d, J = 14.1 Hz, 1 H), 4.65 (t, J = 8.7 Hz, 1 H), 4.53
(t, J = 7.2 Hz, 1 H), 3.52 (s, 3 H), 3.40 (s, 3 H), 3.24 (s, 3 H), 3.11
(s, 3 H), 3.10 (s, 3 H), 2.71 (s, 3 H), 2.69 (s, 3 H), 2.55–1.95 (m, 8
H), 1.80–0.65 (m, 63 H).
To a suspension of Cp Zn(H)Cl (410 mg, 1.60 mmol) in CH Cl (3
2
2
2
mL) at r.t. was added 1,1-d,d-propargyltrimethylsilane (190 mg,
.70 mmol). The mixture was stirred at r.t. for 10 min. A solution of
aldehyde 4 (200 mg, 0.160 mmol) in CH Cl (1 mL) was added, fol-
1
2
2
lowed by AgClO (7.0 mg, 0.03 mmol). The resulting mixture was
stirred at r.t. for 12 h. The mixture was poured into sat. aq NaHCO3
13
4
C NMR (125 MHz, CDCl ): d = 173.8, 173.7, 173.6, 173.0, 172.0,
3
1
7
4
3
2
71.7, 171.4, 170.8, 170.6, 170.5, 170.1, 137.3, 133.4, 132.7, 114.5,
4.7, 58.7, 58.5, 58.0, 57.7, 55.6, 55.4, 54.5, 50.4, 48.9, 48.7, 48.4,
5.5, 40.6, 39.4, 38.9, 38.6, 37.2, 36.1, 35.9, 35.8, 34.0, 31.5, 31.3,
1.1, 29.9, 29.8, 29.5, 29.0, 25.4, 24.7, 24.6, 24.4, 23.8, 23.7, 23.6,
3.1, 22.9, 21.8, 21.0, 20.2, 19.8, 18.6, 18.3, 17.5, 16.7, 16.0, 9.8.
+
(
10 mL). The organic layer was separated, and the aqueous layer
was extracted with CH Cl (3 × 20 mL). The combined organic lay-
2
2
ers were dried (Na SO ), filtered, and concentrated under reduced
2
4
pressure. The residue was purified by semi-preparative HPLC on a
2
5
C18 column to afford 6b; yield: 75 mg (37%); white solid; [a]
D
HRMS (ESI): m/z calcd for C H DN O [M + H] : 1215.8553;
–
300.4 (c 0.2, CHCl ).
63 111
11 12
3
found: 1215.8457.
1
H NMR (300 MHz, CDCl ): d = 8.46 (d, J = 9.2 Hz, 1 H), 8.06 (d,
3
J = 6.5 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 7.1 Hz, 1 H),
(
E)-(q,q-d,d)-ISA247 (7b)
6
.20 (d, J = 10.4 Hz, 1 H), 5.90 (dd, J = 14.3, 10.4 Hz, 1 H), 5.69 (d,
To a stirred solution of E-acetyldiene 6b (70 mg, 0.06 mmol) in
J = 7.3 Hz, 1 H), 5.54 (s, 2 H), 5.40–4.75 (m, 5 H), 4.65 (d, J = 13.6
Hz, 1 H), 4.46 (t, J = 7.1 Hz, 1 H), 3.43 (s, 3 H), 3.25 (s, 3 H), 3.19
MeOH (8 mL) was added K CO (190 mg, 1.40 mmol) at r.t. After
stirring for 12 h at r.t., the reaction mixture was diluted with H O
2
3
2
(s, 6 H), 3.12 (s, 3 H), 2.70 (s, 3 H), 2.68 (s, 3 H), 2.45–2.28 (m, 1
(
30 mL) and extracted with EtOAc (3 × 50 mL). The combined or-
H), 2.22–2.05 (m, 5 H), 2.03 (s, 3 H), 1.75–0.70 (m, 65 H).
ganics were dried (Na SO ), filtered, and concentrated under re-
2
4
1
3
C NMR (125 MHz, CDCl ): d = 173.7, 173.3, 173.0, 172.9, 171.5,
duced pressure. The crude product was purified by semi-preparative
HPLC on a C18 column to afford 7b; yield: 40 mg (59%); white sol-
id; [a]D –181.5 (c 0.3, CHCl3).
3
1
1
4
3
71.4, 171.2, 171.0, 170.5, 170.3, 170.2, 168.1, 136.7, 133.0, 132.4,
15.0, 73.1, 58.3, 57.4, 56.2, 55.3, 54.8, 54.3, 50.1, 48.8, 48.3, 47.9,
4.8, 40.9, 39.2, 39.1, 37.0, 35.8, 34.0, 33.2, 32.3, 31.7, 31.5, 31.4,
0.2, 30.0, 29.7, 29.5, 25.0, 24.8, 24.7 (2 C), 24.5, 24.1, 23.7, 23.4
2
5
1
H NMR (300 MHz, CDCl ): d = 7.98 (d, J = 9.2 Hz, 1 H), 7.61 (d,
3
J = 6.7 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.17 (d, J = 7.7 Hz, 1 H),
(
1
2 C), 22.5, 21.8, 21.2, 21.1, 20.6, 20.3, 19.4, 18.5, 18.1, 18.0, 17.6,
5.0, 9.8.
6
5
.29 (d, J = 10.5 Hz, 1 H), 5.99 (dd, J = 15.2, 10.5 Hz, 1 H), 5.73–
.53 (m, 2 H), 5.50 (d, J = 5.2 Hz, 1 H), 5.32 (d, J = 8.9 Hz, 1 H),
+
HRMS (ESI): m/z calcd for C H D N O [M + H] : 1258.8721;
5.16–4.90 (m, 3 H), 4.82 (t, J = 6.8 Hz, 1 H), 4.74 (d, J = 14.2 Hz,
1 H), 4.64 (t, J = 8.6 Hz, 1 H), 4.53 (t, J = 7.0 Hz, 1 H), 3.52 (s, 3
H), 3.40 (s, 3 H), 3.25 (s, 3 H), 3.12 (s, 3 H), 3.10 (s, 3 H), 2.70 (s,
3 H), 2.69 (s, 3 H), 2.59–2.35 (m, 2 H), 2.20–1.92 (m, 6 H), 1.82–
0.65 (m, 63 H).
6
5
112
2
11 13
found: 1258.8801.
(
E)-Acetyl-(h,q,q-d,d,d)-ISA247 (6c)
To a suspension of Cp Zn(D)Cl (410 mg, 1.60 mmol) in CH Cl (3
2
2
2
mL) at r.t. was added 1,1-d,d-propargyltrimethylsilane (190 mg,
.70 mmol). The mixture was stirred at r.t. for 10 min. A solution of
aldehyde 4 (200 mg, 0.160 mmol) in CH Cl (1 mL) was added, fol-
13
C NMR (125 MHz, CDCl ): d = 173.8, 173.7, 173.6, 173.4, 171.6,
3
1
1
7
4
3
2
71.4, 171.2, 170.4 (2 C), 170.2, 170.1, 137.2, 133.5, 132.7, 114.5,
4.7, 58.7, 58.5, 58.1, 57.5, 55.6, 55.4, 55.3, 50.4, 48.9, 48.7, 48.4,
5.2, 40.6, 39.4, 38.9, 38.6, 37.3, 36.1, 35.9, 35.8, 34.0, 31.5, 31.3,
1.1, 29.9, 29.8, 29.5, 29.0, 25.4, 24.9, 24.8, 24.6, 23.8, 23.7, 23.6,
3.1, 22.9, 21.8, 21.0, 20.2, 19.8, 18.6, 18.3, 18.0, 16.8, 16.0, 9.8.
2
2
lowed by AgClO (7.0 mg, 0.03 mmol). The resulting mixture was
4
stirred at r.t. for 12 h. The mixture was poured into sat. aq NaHCO3
(
10 mL). The organic layer was separated, and the aqueous layer
was extracted with CH Cl (3 × 20 mL). The combined organic lay-
2
2
Synthesis 2012, 44, 63–68
© Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (E)-ISA247 (Voclosporin) and Close Analogues
67
+
HRMS (ESI): m/z calcd for C H D N O [M + H] : 1216.8615;
found: 1216.8608.
mmol). The mixture was stirred at r.t. for 10 min. A solution of al-
dehyde 8 (100 mg, 0.08 mmol) in CH Cl (1 mL) was added, fol-
6
3
110
2
11 12
2
2
lowed by AgClO (3.0 mg, 0.016 mmol). The resulting mixture was
4
(
E)-(h,q,q-d,d,d)-ISA247 (7c)
stirred at r.t. for 12 h. The mixture was poured into sat. aq NaHCO3
(10 mL). The organic layer was separated, and the aqueous layer
was extracted with CH Cl (3 × 20 mL). The combined organic lay-
To a stirred solution of E-acetyldiene 6c (45 mg, 0.04 mmol) in
MeOH (5 mL) was added K CO (120 mg, 0.900 mmol) at r.t. After
stirring for 12 h at r.t., the reaction mixture was diluted with H O
2
3
2
2
ers were dried (Na SO ), filtered, and concentrated under reduced
2
2 4
(
20 mL) and extracted with EtOAc (3 × 50 mL). The combined or-
pressure. The residue was purified by semi-preparative HPLC on a
2
5
ganics were dried (Na SO ), filtered, and concentrated under re-
duced pressure. The crude product was purified by semi-preparative
C18 column to afford 9; yield: 30 mg (29%); white solid; [a]D
2
4
–297.8 (c 0.3, CHCl ).
3
HPLC on a C18 column to afford 7c; yield: 19 mg (43%); white sol-
id; [a]D –221.6 (c 0.3, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 8.53 (d, J = 9.6 Hz, 1 H), 8.05 (d,
25
3
J = 6.7 Hz, 1 H), 7.70 (d, J = 9.1 Hz, 1 H), 7.52 (d, J = 7.5 Hz, 1 H),
6.36 (dt, J = 16.8, 9.8 Hz, 1 H), 6.17 (dd, J = 14.8, 9.9 Hz, 1 H), 6.08
(dd, J = 14.7, 9.7 Hz, 1 H), 5.92 (dd, J = 14.6, 9.7 Hz, 1 H), 5.69
(dd, J = 10.7, 3.6 Hz, 1 H), 5.53 (s, 2 H), 5.40–4.75 (m, 7 H), 4.65
(d, J = 14.2 Hz, 1 H), 4.44 (t, J = 7.3 Hz, 1 H), 3.45 (s, 3 H), 3.25 (s,
3 H), 3.21 (s, 3 H), 3.20 (s, 3 H), 3.11 (s, 3 H), 2.68 (s, 3 H), 2.67 (s,
3 H), 2.48–2.33 (m, 1 H), 2.25–2.10 (m, 4 H), 2.03 (s, 3 H), 1.75–
0.70 (m, 66 H).
1
H NMR (300 MHz, CDCl ): d = 7.98 (d, J = 9.6 Hz, 1 H), 7.61 (d,
3
J = 7.2 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 1 H),
5
1
.99 (d, J = 15.0 Hz, 1 H), 5.74–5.55 (m, 2 H), 5.50 (d, J = 5.9 Hz,
H), 5.30 (dd, J = 10.9, 3.2 Hz, 1 H), 5.16–4.90 (m, 3 H), 4.82 (t,
J = 7.2 Hz, 1 H), 4.73 (d, J = 13.9 Hz, 1 H), 4.65 (t, J = 9.3 Hz, 1
H), 4.53 (t, J = 7.3 Hz, 1 H), 3.52 (s, 3 H), 3.40 (s, 3 H), 3.25 (s, 3
H), 3.11 (s, 3 H), 3.10 (s, 3 H), 2.70 (s, 3 H), 2.69 (s, 3 H), 2.57–2.40
(
1
m, 2 H), 2.20–1.94 (m, 6 H), 1.82–0.65 (m, 63 H).
13
C NMR (125 MHz, CDCl ): d = 173.7, 173.4, 172.9, 172.8, 171.4,
3
3
C NMR (125 MHz, CDCl ): d = 173.8 (2 C), 173.6, 173.4, 171.5,
171.2, 170.9, 170.8, 170.5, 170.3, 170.0, 168.0, 137.3, 133.6, 133.4,
132.2, 131.0, 116.0, 73.2, 58.3, 57.3, 56.2, 55.3, 54.8, 54.2, 50.0,
48.7, 48.2, 47.9, 44.7, 41.0, 39.3, 39.2, 37.1, 35.9, 34.5, 33.3, 32.3,
31.7, 31.4, 31.3, 30.1, 29.8, 29.7, 29.5, 25.0, 24.8, 24.7 (2 C), 24.5,
24.2, 23.7, 23.5 (2 C), 22.5, 21.8, 21.2, 21.1, 20.7, 20.4, 19.6, 18.6,
18.2, 18.1, 17.6, 15.0, 9.9.
3
1
7
4
3
2
71.2, 171.1, 170.4, 170.3, 170.1, 170.0, 137.2, 133.4, 132.5, 114.5,
4.6, 58.7, 58.5, 57.9, 57.5, 55.6, 55.4, 55.3, 50.3, 48.7, 48.6, 48.2,
5.1, 40.6, 39.4, 38.9, 38.6, 37.3, 36.1, 35.9, 35.8, 34.0, 31.5, 31.3,
1.1, 29.7 (2 C), 29.5, 29.0, 25.4, 24.9 (2 C), 24.6, 23.8, 23.7, 23.6,
3.3, 22.9, 21.8, 21.1, 20.2, 19.8, 18.7, 18.3, 18.1, 16.8, 16.0, 9.9.
+
+
HRMS (ESI): m/z calcd for C H D N O [M + H] : 1217.8677;
HRMS (ESI): m/z calcd for C H N O [M + H] : 1282.8754;
6
3
109
3
11 12
67 116 11 13
found: 1217.8644.
found: 1282.8892.
cyclo-{[(2S,3R,4R,6E)-3-Acetoxy-4-methyl-2-(methylamino)-8-
oxoct-6-enoyl]-L-2-aminobutyryl-N-methyl-glycyl-N-methyl-L-
leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-
L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl} (8)
A mixture of acetylcyclosporin A (3; 100 mg, 0.08 mmol), acrolein
dimethyl acetal (0.018 mL, 0.16 mmol), Grubbs II catalyst (25 mg,
cyclo-{[(2S,3R,4R,6E,8E)-3-Hydroxy-4-methyl-2-(methylami-
no)-6,8,10-undecatrienoyl]-L-2-aminobutyryl-N-methyl-glycyl-
N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-ala-
nyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl}
(10)
To a stirred solution of E,E-acetyltriene 9 (25 mg, 0.019 mmol) in
0
.029 mmol), and CH Cl (1 mL) was heated at 60 °C in a sealed
MeOH (2 mL) was added K CO (65 mg, 0.47 mmol) at r.t. After
2 2
2
3
tube for 12 h. After that time, additional Grubbs II catalyst (25 mg)
and acrolein dimethyl acetal (0.018 mL) were added, and the mix-
ture was stirred at the same temperature for an additional 12 h. The
mixture was cooled to r.t. and concentrated under reduced pressure.
The residue was purified by semi-preparative HPLC to afford 8;
stirring for 12 h at r.t., the reaction mixture was diluted with H O
2
(15 mL), and extracted with EtOAc (3 × 30 mL). The combined or-
ganics were dried (Na SO ), filtered, and concentrated under re-
2
4
duced pressure. The crude product was purified by semi-preparative
HPLC on a C18 column to afford 10; yield: 18 mg (75%); white sol-
2
5
25
yield: 65 mg (64%); off-white solid; [a]D –278.1 (c 0.2, CHCl3).
id; [a]D –201.1 (c 0.1, CHCl3).
1
1
H NMR (300 MHz, CDCl ): d = 9.42 (d, J = 7.9 Hz, 1 H), 8.55 (d,
H NMR (300 MHz, CDCl ): d = 8.02 (d, J = 8.7 Hz, 1 H), 7.59 (d,
3
3
J = 9.6 Hz, 1 H), 8.02 (d, J = 6.8 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1
H), 7.53 (d, J = 7.5 Hz, 1 H), 6.73 (ddd, J = 15.5, 10.0, 4.5 Hz, 1 H),
J = 7.4 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H),
6.37 (dt, J = 16.8, 9.8 Hz, 1 H), 6.19–5.95 (m, 4 H), 5.72–5.60 (m,
2 H), 5.48 (d, J = 6.0 Hz, 1 H), 5.32 (dd, J = 11.4, 3.7 Hz, 1 H),
5.25–5.02 (m, 7 H), 4.93 (dd, J = 10.1, 5.8 Hz, 1 H), 4.82 (t, J = 7.2
Hz, 1 H), 4.78–4.62 (m, 3 H), 4.51 (t, J = 7.2 Hz, 1 H), 3.84 (t,
J = 6.8 Hz, 1 H), 3.51 (s, 3 H), 3.39 (s, 3 H), 3.24 (s, 3 H), 3.11 (s,
3 H), 3.10 (s, 3 H), 2.70 (s, 3 H), 2.69 (s, 3 H), 2.52–2.35 (m, 1 H),
5
3
2
.60 (dd, J = 15.5, 7.9 Hz, 1 H), 5.70–4.40 (m, 12 H), 3.46 (s, 3 H),
.27 (s, 3 H), 3.22 (s, 3 H), 3.21 (s, 3 H), 3.13 (s, 3 H), 2.68 (s, 3 H),
.66 (s, 3 H), 2.50–1.50 (m, 10 H), 2.04 (s, 3 H), 1.40–0.75 (m, 58
H).
1
3
C NMR (125 MHz, CDCl ): d = 193.2, 173.2, 173.1, 173.0, 172.5,
3
2
.20–2.00 (m, 4 H), 1.75–0.70 (m, 60 H).
1
7
4
2
2
9
72.1, 170.6 (2 C), 170.3, 169.8, 169.7, 169.5, 167.1, 156.0, 134.1,
2.0, 57.8, 56.7, 55.3, 54.9, 54.6, 53.5, 49.5, 48.1, 47.6, 47.3, 44.2,
0.3, 38.6 (2 C), 36.8, 35.3, 33.5, 32.1, 31.6, 31.0, 30.8 (2 C), 29.6,
9.3, 29.1, 28.9, 24.4, 24.2, 24.1, 24.0, 23.9, 23.5, 23.1, 22.9, 22.7,
1.6, 21.2, 20.7, 20.3, 20.0, 19.8, 19.0, 18.0, 17.4 (2 C), 16.9, 14.4,
.2.
1
3
C NMR (125 MHz, CDCl ): d = 173.8, 173.7, 173.6, 173.4, 171.5,
3
171.2, 171.1, 170.4, 170.3, 170.1, 170.0, 137.3, 134.1, 133.7, 131.8,
130.9, 116.0, 74.4, 58.7, 57.9, 57.5, 55.5, 55.4, 55.3, 50.3, 48.7,
48.6, 48.2, 45.1, 40.6, 39.5, 38.9, 37.3, 36.1, 35.9, 35.8, 34.0, 31.5,
31.3, 31.1, 29.7 (2 C), 29.5, 29.0, 25.4, 24.9 (2 C), 24.6, 24.4, 23.8,
23.7, 23.6, 23.4, 23.3, 21.9, 21.8, 21.1, 20.2, 19.8, 18.7, 18.3, 18.1,
+
HRMS (ESI): m/z calcd for C H N O [M + H] : 1258.8390;
6
4
112 11 14
1
6.9, 16.0, 9.9.
found: 1258.8439.
+
HRMS (ESI): m/z calcd for C H N O [M + H] : 1240.8648;
6
5
114 11 12
cyclo-{[(2S,3R,4R,6E,8E)-3-Acetoxy-4-methyl-2-(methylami-
no)-6,8,10-undecatrienoyl]-L-2-aminobutyryl-N-methyl-glycyl-
N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-ala-
nyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl}(9)
To a suspension of Cp Zn(H)Cl (206 mg, 0.80 mmol) in CH Cl (2
found: 1240.8602.
2
2
2
mL) at r.t. was added propargyltrimethylsilane (0.13 mL, 0.84
©
Thieme Stuttgart · New York
Synthesis 2012, 44, 63–68

6
8
J.-H. Maeng et al.
PAPER
References
(4) (a) Suzuki, K.; Hasegawa, T.; Imai, T.; Maeta, H.; Ohba, S.
Tetrahedron 1995, 51, 4483. (b) Maeta, H.; Suzuki, K.
Tetrahedron Lett. 1992, 33, 5969.
(
1) (a) Naicker, S.; Yatscoff, R.; Foster, R.; Abel, M.;
Jayaraman, S.; Mair, H.-J.; Adam, J.-M.; Lohri, B. PCT Int.
Pub. No. WO 2003/033526, 2003. (b) Naicker, S.; Yatscoff,
R.; Foster, R. PCT Int. Pub. No. WO 2003/033527, 2003.
(
(
(
5) The coupling constant Je,z of the corresponding Z-isomer is
11.0 Hz.
6) Preparation of 1a was conducted up to 10 g scale without
reducing the E-selectivity.
7) (a) Naicker, S.; Yatscoff, R. W.; Foster, R. T. PCT Int. Pub.
No. WO 1999/18120, 1999. (b) Lazarova, T.; Weng, Z.
Expert Opin. Ther. Pat. 2003, 13, 1327.
(
c) Adam, J.-M.; Abel, M.; Jayaraman, S. PCT Int. Pub. No.
WO 2004/089960, 2004.
(
2) (a) Aspeslet, L.; Freitag, D.; Trepanier, D.; Abel, M.;
Naicker, S.; Kneteman, N.; Foster, R.; Yatscoff, R.
Transplant. Proc. 2001, 33, 1048. (b) Abel, M. D.;
Aspeslet, L. J.; Freitag, D. G.; Naicker, S.; Trepanier, D. J.;
Kneteman, N. M.; Foster, R. T.; Yatscoff, R. W. J. Heart
Lung Transpl. 2001, 20, 161. (c) Naicker, S.; Yatscoff, R.
W.; Foster, R. T. US Patent No 6605593, 2000.
(
(
8) Rajagopalan, S.; Zweifel, G. Synthesis 1984, 111.
9) The organozirconium chemistry also worked well in
CH Cl . The desired product was the major portion of the
2
2
crude product (typically 60–70%) by LC/MS or analytical
HPLC analysis. However, the isolated yields were low in
some cases after purification by semi-preparative HPLC. We
usually got less than 70% recovery from semi-preparative
HPLC purification.
(
d) Naicker, S.; Yatscoff, R. W.; Foster, R. T. US Patent
6613739, 2000. (e) Dumont, F. J. Curr. Opin. Invest. Drugs
2004, 5, 542. (f) Bissonnette, R.; Papp, K.; Poulin, Y.;
Lauzon, G.; Aspeslet, L.; Huizinga, R.; Mayo, P.; Foster, R.
T.; Yatscoff, R. W.; Maksymowych, W. P. J. Am. Acad.
Dermatol. 2006, 54, 472. (g) Luveniq (oral voclosporin)
completed in July 2008 a phase III LUMINATE clinical trial
for treatment of uveitis. Details can be found at
(
(
10) For pharmaceutical utilities of similar cyclosporin triene
analogues, see the recent US Patent: Wu, F. X. H.; Or, Y. S.
US Patent 2004/266669, 2004.
11) Recent publications that reported the synthetic efforts on
olefin metathesis of cyclosporin A: (a) Lazarova, T.; Chen,
J. S.; Hamann, B.; Kang, J. M.; Houth-Trombino, D.; Han,
F.; Hoffmann, E.; McClure, C.; Eckstein, J.; Or, Y. S.
J. Med. Chem. 2003, 46, 674. (b) Smulik, J.; Diver, S. T.
Org. Lett. 2002, 4, 2051.
www.clinicaltrials.gov.
(
3) (a) Molino, B. F.; Yang, Z.; Maeng, J.-H.; Manning, D. D.
US Patent 7799756, 2010. (b) Molino, B. F.; Yang, Z. US
Patent 7378391, 2008. (c) Molino, B. F.; Yang, Z. US Patent
7361636, 2008.
Synthesis 2012, 44, 63–68
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