Dynamic kinetic resolution for the catalytic asymmetric total synthesis of antithrombotic agents M58163 and M58169

Article abstract of DOI:10.1002/adsc.200600611

Dynamic kinetic resolution is one of the most synthetically useful phenomena for asymmetric synthesis. Dynamic kinetic resolution for the catalytic asymmetric synthesis of a spiro[imidazo[1,2-a]pyrazine-2(3H),4′- piperidin]-5(1H)-one scaffold with a lanth

Full text of DOI:10.1002/adsc.200600611

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DOI: 10.1002/adsc.200600611
Dynamic Kinetic Resolution for the Catalytic Asymmetric Total
Synthesis of Antithrombotic Agents M58163 and M58169
Fumihiko Saitoh,a,c,* Hidemitsu Nishida,a Takafumi Mukaihira,a
Kohsuke Aikawa,b and Koichi Mikamib,*
a
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8524, Japan
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
b
Fax : (+81)-3-5734-2776; e-mail: kmikami@o.cc.titech.ac.jp
On leave from Mochida Pharmaceutical Co., Ltd.
c
Received: November 28, 2006
In the honor of Professor Masakatsu Shibasaki on the occasion of his 60th birthday (Kanreki in Japanese).
Abstract: Dynamic kinetic resolution is one of the cies of the lanthanum complex.The catalytic asym-
most synthetically useful phenomena for asymmetric metric total syntheses of our antithrombotic agents
synthesis.Dynamic kinetic resolution for the catalyt-
ic asymmetric synthesis of a spiro[imidazo[1,2-a]pyr- namic kinetic resolution.
azine-2(3H),4’-piperidin]-5(1H)-one scaffold with a
lanthanum-linked BINOL complex is described.It is
M58163 and M58169 have thus been achieved via dy-
A
ACHTREUNG
AHCTREUNG
also clarified that starting materials, diamine 1 and Keywords: antithrombotic agents; dynamic kinetic
keto ester 2, play important roles not only as sub- resolution; enantioselective acetal formation;
strates but also as additives to modify an active spe- M58163; M58169
Introduction
M58169 (IC50 = 0.58 nM)] than M55529 (IC50
2.0 nM).Cyclic N,N-acetals are widely found in natu-
=
Factor Xa (FXa), a trypsin-like serine protease, occu- ral and unnatural products[6] and are employed as a
pies a central position in the blood coagulation cas- protective group for carbonyl compounds,[7] as syn-
cade in linking the intrinsic and extrinsic mechanisms. thetic intermediates of N-containing heterocyclic
FXa is known to activate prothrombin to thrombin. compounds,[8] or as chiral compounds prepared from
Compared to a thrombin inhibitor, an FXa inhibitor chiral diamine and/or chiral carbonyl compounds, for
as an anticoagulant has been suggested to result in a synthon, an optical resolution, an asymmetric cata-
less risk of bleeding and, hence, to lead to a more fa- lyst, and so on.[9] However, the enantioselective syn-
vorable safety/efficacy ratio.[1] Therefore the design of thesis of cyclic N,N-acetals using achiral substrates
a new drug as an FXa inhibitor has been a challenge has never been reported so far.We report here the
for the treatment and prevention of thrombosis dis- full account of the dynamic kinetic resolution in the
eases.[2]
amide formation step following formation of a cyclic
During the course of our development of an FXa N,N-acetal leading to the tricyclic key intermediate of
inhibitor as an antithrombotic agent, we have report- M58163 and M58169 (Scheme 2).[10]
ed the unique FXa inhibitor M55529, containing a
cyclic N,O-acetal structure,[3] and an asymmetric syn-
thesis of M55529 based on the enantioselective cyclic Results and Discussion
N,O-acetal formation using a chiral salen-manganese
complex (Scheme 1).[4]
Enantioselective Cyclic N,N-Acetal Formation
Quite recently, we also reported other oral FXa in-
hibitors M58163 and M58169,[5] with characteristic First, the chiral Brønsted acids and salen-manganese
features of a spiro unit and an imidazopyrazinone as complex, by which the cyclic N,O-acetal had been ob-
a cyclic N,N-acetal structure instead of the cyclic N,O- tained enantioselectively,[4] were examined.The re-
acetal of M55529.These compounds exhibit higher
sults are summarized in Table 1.While the enantioen-
FXa inhibitory activity [M58163 (IC50 = 0.61 nM), riched N,O-acetal was obtained with these chiral
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Scheme 1. Enantioselective cyclic N,O-acetal formation and the asymmetric synthesis of the antithrombotic agent M55529.
Scheme 2.
acids, the cyclic N,N-acetal 3 was also obtained, albeit used in a catalytic amount.In contrast, the Lewis
in 0% ee.However, the tricyclic compound 4 was ob- acidic salen-manganese complex gave moderate enan-
tained in situ in up to 48% ee in low to moderate tioselectivity.However, the amount could not be re-
yield (entries 1, 3, and 5).The reaction time was thus
duced to a catalytic level because the highly basic dia-
prolonged until the N,N-acetal 3 disappeared and a mine 1 coordinated with the Lewis acidic salen-man-
sufficient amount of tricyclic compound 4 was ob- ganese complex.
served on TLC; 4 was then obtained in moderate
In sharp contrast, a chiral base complex may effi-
yield (up to 65%) and with the same enantioselectivi- ciently catalyze the second amide formation step.[4]
ty (up to 49% ee, entries 2, 4, and 6).
Therefore, we next examined a commercially avail-
Unfortunately, these chiral Brønsted acids gave able, La-linked BINOL complex.[11] As expected, the
only low enantioselectivity although they could be reaction could proceed with a catalytic amount of the
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Total Synthesis of Antithrombotic Agents M58163 and M58169
Table 1. The cyclic N,N-acetal formation with chiral Brønsted acids or a chiral salen-Mn complex.
[a]
The % ee was determined by chiral HPLC (Daicel CHIRALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
;
;
hexane/EtOH (diethylamine: 0.1%)=50/50; 10.6 and 16.0 min, respectively.
[b]
The % ee was determined by chiral HPLC (Daicel CHIRALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
hexane/EtOH (diethylamine: 0.1%)=50/50; 20.5 and 46.9 min; the absolute configuration was correlated to M58169, of
which the absolute configuration was determined by X-ray crystallographic analysis (see ref.[5]).
La-linked BINOL complex and the enantioselectivity Dynamic Kinetic Resolution
was increased up to 56% ee [Eq.(1)].Particularly,
the tricyclic compound 4 was obtained in 69% yield The results shown in Eq.(1) suggest the following: 1)
without reducing the enantioselectivity even after Since the N,N-acetal 3 could easily racemize, the N,N-
prolonged reaction time.In this case, the racemic
N,N-acetal 3 was again obtained.
acetal 3 was not obtained enantioselectively.2) Dy-
namic kinetic resolution should take place in the
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second amide formation step.We therefore proved
dynamic kinetic resolution.[12] The yield of 4 exceeded
the racemization of both enantiopure N,N-spiro-ace- 50% and racemic 3 was recovered, and both enantio-
tals, (+)- and (À)-3 which were isolated by a chiral mers of 3 racemized with La-linked BINOL complex
HPLC column chromatography [Daicel CHIRAL- at 08C within 2 days.
CEL OJ-H column at 408C; flow rate: 0.5 mLminÀ1;
Dynamic kinetic resolution in the second amide for-
hexane/EtOH (diethylamine: 0.1%)=50/50; (+)-3: mation step was then confirmed with rac-3 and the
10.6 min and (À)-3: 16.0 min]. Both enantiomers (+)- La-linked BINOL complex.However, the amide
4
and (À)-3 slowly racemized at 08C without catalyst. was obtained in lower yield and % ee (Table 2, en-
Racemization was indeed facilitated with the La- tries 1–3; 4: 10–21% yield, 23–37% ee), even with a
linked BINOL catalyst at 08C (Figure 1).
shortened or prolonged reaction time.The reason for
the lower enantioselectivity is that diamine 1 and/or
keto ester 2 could play a significant role as an addi-
tive to assemble with the La-linked BINOL complex
to give higher enantioselectivity.We thus examined
these starting materials 1 and/or 2 as an additive in
the stepwise reaction from rac-3.Diamine 1 led to
higher enantioselectivity (65% ee) than those in the
one-pot reactions (entry 4).In sharp contrast, keto
ester 2 gave the lowest enantioselectivity (21% ee)
(entry 5).Simultaneous addition of diamine 1 and
keto ester 2 gave almost the same enantioselectivity
as in the one-pot reactions (entries 6 and 7, 56–59%
ee).
These results clearly suggest that diamine 1 with
the La-linked BINOL complex shows a positive effect
and keto ester 2 exhibits a negative effect for this dy-
namic kinetic resolution.Therefore, it can be conclud-
ed that the enantioselectivity (56–59% ee) in the one-
Figure 1. Racemization of (+)-3/(À)-3 with La-linked
BINOL.
On the basis of these results, this asymmetric induc- pot reaction was the result of summation of these pos-
tion in the second amide formation step from the rac- itive (65% ee) and negative (21% ee) effects of di-
emic N,N-acetal 3 can be rationalized as a result of amine 1 and keto ester 2, respectively.
Table 2. Dynamic kinetic resolution in the second amide formation step.
[a]
The % ee was determined by chiral HPLC (Daicel CHIRALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
hexane/EtOH (diethylamine: 0.1%)=50/50; 10.6 and 16.0 min, respectively.
;
;
[b]
The % ee was determined by chiral HPLC (Daicel CHIRALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
hexane/EtOH (diethylamine: 0.1%)=50/50; 20.5 and 46.9 min; The absolute configuration was correlated to M58169, of
which the absolute configuration was determined by X-ray crystallographic analysis (see ref.[5]).
Entry 7 was carried out from diamine 1 and keto ester 2 for reference.
[c]
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Chiral Diamine
to potassium reduced the chemical yield and enantio-
selectivity of 4 (entries 1–3; 4: 7–24% yield, 15–21%
Since these results gave us a charge, we next tried to ee).[11] When the central lanthanide metals have been
add other typical chiral diamines as an additive for in- changed to yttrium or gadolinium instead of lantha-
creasing selectivity in the one-pot reaction.These
num, chemical yield and enantioselectivity of 4 slight-
chiral diamines were selected from tetramethylated ly decreased (entries 5 and 6; 4: 38–44% yield, 51-
derivatives[13] which could not react with keto ester 2. 52% ee).However, the ytterbium complex gave a low
The results are summarized in Table 3.In entry 3,
(R)-N,N,N’,N’-tetramethylcyclohexyldiamine gave 11% yield, 40% ee).A non-alkaline metal La-linked
slightly lower selectivity (42% ee).However, other di- BINOL complex gave the best yield and enantioselec-
yield although with moderate selectivity (entry 7; 4:
amines gave almost the same selectivity as in the one- tivity (entry 4; 4: 44% yield, 55% ee).
pot reaction (entries 1–2 and 4–7).
Solvent Effects
Alkaline and Central Lanthanide Metals
Several solvents were then checked.According to Shi-
The alkaline and central lanthanide metals were then basakiꢁs reports,[11] tetrahydrofuran and dimethyl
tuned (Table 4).Changing the alkaline metal in the ether were advantageous to Michael reactions with
La-linked BINOL complex from lithium via sodium the La-linked BINOL complex.However, dichloro-
Table 3. Comparison of chiral diamine effect as an additive in the one-pot reaction.
[a]
The % ee was determined by chiral HPLC (Daicel CHIRALPAKL AD-H column) at 408C; flow rate: 0.5 mLminÀ1
EtOH (diethylamine: 0.1%)=100; 27.7 and 40.2 min, respectively.
Yield of 4 (based on 2) and% ee were determined by chiral HPLC (Daicel CHIRALPAK AD-H column) at 408C; flow
rate: 0.5 mLminÀ1; EtOH (diethylamine: 0.1%)=100; 36.2 and 55.1 min; The absolute configuration was correlated to
M58169, of which the absolute configuration was determined by X-ray crystallographic analysis (see ref.[5]).
;
[b]
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Table 4. Comparison of alkaline metals or of central lanthanide metals.
[a]
Each reaction was carried out at 08C for 14 days.
[b]
See ref.[11]
The % ee was determined by chiral HPLC (Daicel CHIRALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
hexane/EtOH (diethylamine: 0.1%)=50/50; 10.6 and 16.0 min, respectively.
;
[c]
[d]
The % ee was determined by chiral HPLC (Daicel CHIRALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
;
hexane/EtOH (diethylamine: 0.1%)=50/50; 20.5 and 46.9 min; The absolute configuration was correlated to M58169, of
which the absolute configuration was determined by X-ray crystallographic analysis (see ref.[5]).
methane gave the best result in this dynamic kinetic A Possible Mechanism
resolution (Table 5).
A possible mechanism in this dynamic kinetic resolu-
tion can be exemplified as shown below (Figure 2 and
Scheme 3).Shibasaki reported that the central lantha-
num metal plays a role of Lewis acid and a lanthanum
phenoxide (O-La) or an ammonium phenoxide (O<
sup>-</sup>-N+H3) coordinated with lanthanide
metal acts as a Brønsted base (Figure 2).[14] First, rac-
3 was formed with diamine 1 and keto ester 2 through
complexation with Lewis acidic site of the La-linked
BINOL complex.Then coordination of ( +)- and (À)-
3 with the La-linked BINOL complex gave intermedi-
ates (R)- and (S)-5, respectively.The Lewis acid could
activate the ester-carbonyl group and the Brønsted
base part could activate the amino group in the N,N-
acetal.Since these intermediates ( R)- and (S)-5 react-
ed to give the corresponding amides (S)- and (R)-4
with unequal rate constants kS and kR (kS >kR; in this
case), the kinetic resolution could take place.There
was equilibrium between intermediates (R)- and (S)-5
via an imino intermediate 6, and both racemization
Table 5. The solvent effects with La-linked BINOL.
[a]
Each reaction with 20 mol% (aR)-La-linked BINOL was
carried out at 08C for 14 days.
The % ee was determined by chiral HPLC (Daicel
[b]
CHIRALCEL OJ-H column) at 408C; flow rate:
0.5 mLminÀ1; hexane/EtOH (diethylamine: 0.1%)=50/
50; 10.6 and 16.0 min, respectively.
[c]
% ee was determined by chiral HPLC (Daicel CHIR-
ALCEL OJ-H column) at 408C; flow rate: 0.5 mLminÀ1
Hexane/EtOH (diethylamine: 0.1%)=50/50; 20.5 and
;
46.9 min; The absolute configuration was correlated with
M58169, the absolute configuration of which was de-
termined by X-ray crystallographic analysis (see ref.[5]).
The reaction did not proceed.NR. . =no reaction.
[d]
Figure 2.
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Scheme 3.
rate constants (kinv) were larger than kS or kR.Thus,
M58163 by a reductive amination to complete the
this dynamic kinetic resolution could be achieved synthesis of M58169.In these reaction sequences, rac-
(Scheme 3).
emization did not take place; M58163 and M58169
could be obtained in 57% ee.[5]
Asymmetric Total Syntheses of M58163 and M58169
with the La-linked BINOL Complex
Conclusions
Finally, the target compounds M58163 and M58169 In summary, we have reported the asymmetric cyclic
were synthesized (Scheme 4).The keto ester 2 was N,N-acetal formation and the following dynamic ki-
prepared from N-benzylglycine ethyl ester 7.Com-
netic resolution in the second amide formation step
pound 7 was allowed to react with glycidyl methyl using an La-linked BINOL complex.The dynamic ki-
ether, and the N-benzyl moiety was deprotected by netic resolution is further clarified by a racemization
catalytic hydrogenation under acidic conditions, then experiment on an enantiopure (+)- or (À)-cyclic N,N-
the deprotected compound was reacted with the cor- acetal 3 and by the enamtiomer-selective amide for-
responding sulfonyl chloride to give the hydroxy ester mation step.Interestingly, diamine 1 plays a key role
8 (80% yield, 3 steps).The hydroxy ester 8 was oxi- not only as a substrate but also as an additive to
dized by the 4-hydroxy-2,2,6,6-tetramethylpiperidine modify the La catalyst.We have thus accomplished
1-oxyl benzoate-NaClO oxidation method[15] to obtain the catalytic asymmetric total synthesis of our anti-
the desired keto ester 2 (89% yield).
thrombotic agents M58163 and M58169.
Since the absolute configuration of M58169 was de-
termined to be R by X-ray crystallographic analysis,[5]
the commercially available (aS)-La-linked-BINOL
complex was used with diamine 1[16] and keto ester 2
to obtain the desired compound 4 [60% yield, 57%
ee (R)].The compound 4 was deprotected by a-chloro-
ethyl chloroformate in the presence of proton
spongeꢂ.[17] The deprotected compound 9 was coupled
with 4-chloropyridine hydrochloride to afford
Experimental Section
General Remarks
Nuclear magnetic resonance (NMR) spectra were taken
with JEOL JNM-LA300 and Varian GEMINI 300 spectrom-
eters, in CDCl3 using tetramethylsilane as the internal refer-
M58163.The
N-methyl moiety was created on ence.High-resolution mass spectra (HR-MS) were obtained
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Scheme 4. Asymmetric synthesis of M58163 and M58169.
using JEOL JMS-GCMATE or BRUKER Auto FLEX
TOF/TOF instruments.Infrared absorption spectra (IR)
were run using a HORIBA FT-720 FT-IR spectrrometer.
High performance liquid chromatography (HPLC) was con-
ducted by using Shimadzu LC-10 A and JASCO PU-980 sys-
tems.Optical rotations were measured with a JASCO DIP-
1000 digital polarimeter.
HPLC [Daicel CHIRALCEL OJ-H column (0.46ꢃ25 cm) at
408C, flow rate: 0.5 mLminÀ1 with hexane/EtOH (contain-
ing 0.1% diethylamine)=50/50, retention times: 3 10.6 min
and 16.0 min, 4 20.5 min (S)-form and 46.9 min (R)-form].
Cyclic N,N-Acetal and Amide Formation with a
Salen-Manganese Complex
Method A: To a suspension of dried MS 4 ꢄ (120 mg) in
CH2Cl2 (1.0 mL) were added a chiral salen-manganese com-
plex (84.3 mg, 0.094 mmol) and a solution of keto ester 2
(30.0 mg, 0.072 mmol) in CH2Cl2 (0.5 mL) at 08C.After stir-
ring for 30 min at 08C, a solution of diamine 1 (15.8 mg,
0.072 mmol) in CH2Cl2 (0.5 mL) was added at 08C to the
above mixture.The reaction mixture was stirred for 5 days
at 08C, then MS 4 ꢄ was filtered off and the filtrate was
concentrated under vacuum.The residue was purified by
silica gel column chromatography (eluant: CH2Cl2/MeOH=
95/5–93/7–90/10–80/20) to afford the N,N-acetal 3 as a color-
less amorphous solid (yield: 19.5 mg, 32%, 0% ee) and the
tricyclic intermediate 4-manganese complex.Then this man-
Cyclic N,N-Acetal Formation with a Chiral Brønsted
Acid
To a solution of keto ester 2 (30 mg, 0.072 mmol) in CH2Cl2
(1.0 mL) was added a chiral Brønsted acid (30 mol%) at
08C.After stirring for 30 min at 0 8C, a solution of diamine
1 (15.8 mg, 0.072 mmol) in CH2Cl2 (1.0 mL) was added to
the above mixture.The reaction mixture was stirred at 0 8C
for 2–19 days, then was purified by silica gel column chro-
matography (eluant: CH2Cl2/MeOH=97/3–95/5–93/7–90/10)
to afford the N,N-acetal 3 in 0–59% yield (0% ee) and the
tricyclic compound 4 in 29–65% yield (7–9% ee), respec-
tively.Enantiomeric excess of 3 and 4 were measured by
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ganese complex was once more purified for isolating 4 by
amino-silica gel column chromatography (Fuji Silysia Chem-
ical Ltd., Chromatorex NHꢂ, eluant: Hex/CH2Cl2 =4/1–1/1)
to afford 4 as a colorless amorphous solid [yield: 4.8 mg,
8%, 48% ee (S)].The enantiomeric excesses of 3 and 4
were measured by HPLC under the above conditions.
4.22–4.08 (2H, m), 3.70 (1H, d, J=9.5 Hz), 3.50–3.35 (3H,
m), 3.42 (3H, s), 3.27 (1H, d, J=16.9 Hz), 2.87 (1H, d, J=
11.4 Hz), 2.65–2.05 (5H, m), 2.20 (1H, d, J=11.7 Hz), 1.80–
1.65 (2H, m), 1.40–1.20 (2H, m); 13C NMR (75 MHz,
CDCl3): d=163.19, 138.15, 135.65, 135.38, 132.90, 130.79,
130.45, 129.05 (2C), 128.99, 128.93, 128.90, 128.22 (2C),
127.07, 126.81, 123.56, 77.05, 74.49, 62.94, 59.52, 58.41, 53.09,
51.39, 50.80, 50.52, 47.61, 37.97, 36.72; IR (film): n=1653,
1348, 1167, 698 cmÀ1; [a]2D8:0: +50.78 (c 1.120, MeOH, 56%
ee).
Method B: To a suspension of dried MS 4 ꢄ (120 mg) in
CH2Cl2 (1.0 mL) were added a chiral salen-manganese com-
plex (84.3 mg, 0.094 mmol) and a solution of keto ester 2
(30.0 mg, 0.072 mmol) in CH2Cl2 (0.5 mL) at 08C.After stir-
ring for 30 min at 08C, a solution of diamine 1 (15.8 mg,
0.072 mmol) in CH2Cl2 (0.5 mL) was added at 08C to the
above mixture.The reaction mixture was stirred for 32 days
at 08C until the N,N-acetal 3 had disappeared on TLC.
Then MS 4 ꢄ was filtered off and the filtrate was concen-
trated under vacuum.The residue was purified by silica gel
column chromatography (eluant: CH2Cl2/MeOH=95/5–93/
7–90/10) to afford 4-manganese complex.Then this complex
was dissolved in CH2Cl2 (2.0 mL) and Et3N (0.26 mL,
1.88 mmol) was added into the solution for isolating 4.The
mixture was once more purified by silica gel column chro-
matography (eluant: CH2Cl2/MeOH=97/3–95//5–93/7–90/
10) to afford 4 as a colorless amorphous solid [yield:
18.9 mg, 46%, 49% ee (S)].Enantiomeric excesses of 3 and
4 were measured by HPLC under the above conditions.
Racemization of (+)-/(À)-3
(+)-3 and (À)-3 were isolated by chiral HPLC [Daicel
CHIRALCEL OJ-H column (0.46ꢃ25 cm) at 408C; flow
rate: 0.5 mLminÀ1; hexane/EtOH (diethylamine: 0.1%)=
50/50; (+)-3: 10.6 min and (À)-3: 16.0 min, respectively]. To
both enantiomers (+)-3 and (À)-3 in the above eluent, was
added La-linked BINOL, respectively.These solutions with/
without (aR)-La-linked BINOL were stirred at 08C and a
chiral HPLC time course analysis was carried out.
From rac-3 to Amide 4 with La-Linked BINOL and
Diamine 1 and/or Keto Ester 2
To
a
suspension of (aR)-La-linked-BINOL (8.0 mg,
(2.1 mg,
0.0098 mmol) in CH2Cl2 (0.5 mL), diamine
1
0.0098 mmol) and/or keto ester 2 (4.0 mg, 0.0098 mmol)
were added at 08C.Then the solution of rac-3 (30 mg,
0.049 mmol) in CH2Cl2 (0.5 mL) was added into the reaction
mixture at 08C.The reaction mixture was stirred at 0 8C for
50 days.After the reaction, the mixture was purified by
silica gel column chromatography (eluant: CH2Cl2/MeOH=
100/1–50/1–25/1–20/1) to obtain the amide 4 [yield: 18–99%,
21–59% ee (S)] as a colorless amorphous solid and to recov-
er rac-3 as a colorless amorphous solid (yield: 0–52%, 0%
ee).Enantiomeric excesses of 3 and 4 were measured by
HPLC under the above conditions.
Cyclic N,N-Acetal and Amide Formation with a
Lanthanum-Linked BINOL Complex
To a solution of keto ester 2 (30.0 mg, 0.072 mmol) in
CH2Cl2 (2.0 mL) was added the (aR)-La-linked BINOL
complex (11.8 mg, 0.0014 mmol) at 08C.After stirring for
30 min at 08C,
a
solution of diamine
1
(15.8 mg,
0.072 mmol) in CH2Cl2 (1.0 mL) was added at 08C to the
above mixture and the reaction mixture was stirred for 14–
23 days at 08C.After the reaction, the mixture was purified
by silica gel column chromatography (eluant: CH2Cl2/
MeOH=100/1–50/1–25/1–20/1) to afford 3 as a colorless
amorphous solid (yield: 41–23%, 0% ee) and 4 as a color-
less amorphous solid [yield: 44–69%, 56% ee (S)].Enantio-
meric excesses of 3 and 4 were measured by HPLC under
the above conditions.
Procedure for Adding a Chiral Diamine
To
a suspension of (aR)-La-linked BINOL (5.9 mg,
0.0072 mmol) in CH2Cl2 (0.2 mL), a chiral diamine [e.g.,
(aR)-N,N,N’,N’-tetramethyl-(1,1’-binaphthalene)-2,2’-diamine;
2.5 mg, 0.0072 mmol] was added at 08C.Then a solution of
keto ester 2 (15.0 mg, 0.036 mmol) in CH2Cl2 (0.5 mL) and a
solution of diamine 1 (7.9 mg, 0.036 mmol) in CH2Cl2
(0.5 mL) were added at 08C, respectively.The reaction mix-
ture was stirred at 08C for 14 days.
Enantiomeric excesses of 3 and 4 were measured and the
yield of 4 (based on keto ester 2) was calculated by HPLC
analysis [Daicel CHIRALPAK AD-H column (0.46ꢃ25 cm)
at 408C, flow rate : 0.5 mLminÀ1 with EtOH (containing
0.1% diethylamine)=100, retention time: 2 25.2 min; 3
27.7 min, and 40.2 min; 4 36.2 min (S)-form and 55.1 min
(R)-form].
rac-Ethyl N-{[8-phenylmethyl-2-(methoxymethyl)-1,3,8-
triazaspiro[4.5]dec-2-yl]methyl}-N-[(6-chloro-2-naphthalenyl)-
E
1
sulfonyl]glycinate (3): H NMR (300 MHz, CDCl3): d=8.32
(1H, s), 7.95–7.75 (4H, m), 7.54 (1H, dd, J=1.8, 9.0 Hz),
7.35–7.20 (5H, m), 4.62 (1H, d, J=18.5 Hz), 4.55 (1H, d,
J=18.5 Hz), 3.94–3.80 (2H, m), 3.55–3.25 (6H, m), 3.34
(3H, s), 2.82 (1H, d, J=11.7 Hz), 2.73 (1H, d, J=11.7 Hz),
2.65–2.10 (4H, m), 1.75–1.45 (4H, m), 1.05 (3H, t, J=
7.2 Hz); 13C NMR (75 MHz, CDCl3): d=169.12, 136.72,
135.37 (2C), 134.77, 130.69, 130.33, 129.11 (2C), 128.58,
128.49, 128.19 (2C), 126.98, 126.70, 124.16, 81.02, 76.81,
75.13, 63.16, 60.91, 60.77, 59.15, 52.38, 51.45, 51.26, 49.98,
38.13, 37.55, 13.98.
(+)-(8aS)-7-[(6-Chloro-2-naphthalenyl)sulfonyl]tetrahy-
dro-8a-(methoxymethyl)-1’-(phenylmethyl)-spiro
[1,2-a]pyrazine-2(3H),4’-piperidin]-5(1H)-one (4): MALDI-
TOF-HR-MS: m/z=569.1960, (M+H), calcd.for
C
Asymmetric Synthesis of M58163 and M58169
G
U
ACHTREUNG
N-[(6-Chloro-2-naphthalenyl)sulfonyl]-N-(2-hydroxy-3-me-
thoxypropyl)glycine ethyl ester (8) [Step 1]: N-Benzylglycine
A
ethyl ester 7 (35 g, 0.181 mol) and glycidyl methyl ether
(21.1 mL, 0.181 mol) were mixed and the reaction mixture
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www.asc.wiley-vch.de
625

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Fumihiko Saitoh et al.
was stirred at 1208C for 3 h.After cooling, it was concen-
trated under vacuo to afford the crude N-(2-hydroxy-3-me-
thoxypropyl)-N-(phenylmethyl)glycine ethyl ester (47.3 g,
quant.) as a yellow oil.
2.0, 8.8 Hz), 7.56 (1H, dd, J=2.0, 8.8 Hz), 4.43 (2H, s), 4.19
(2H, s), 4.11 (2H, s), 4.04 (2H, q, J=7.2 Hz), 3.41 (3H, s),
1.15 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3): d=
202.85, 168.67, 136.46, 135.48, 134.97, 130.72, 130.28, 128.60,
128.55, 128.47, 126.74, 123.78, 76.42, 61.50, 59.49, 54.00,
48.74, 13.95; IR (film): n=1743, 1338, 1157, 955, 696 cmÀ1.
A
pound (47.3 g) which was obtained in Step 1, 4.6 N HCl-
EtOH (100 mL) and 10% Pd/C (4.37 g) were added under
an argon atmosphere.The atmosphere was changed to hy-
(À)-(8aR)-7-[(6-Chloronaphthalen-2-yl)sulfonyl]-
tetrahydro-8a-(methoxymethyl)-1’-(phenylmethyl)-
drogen gas and the reaction mixture was stirred at room
ꢂ
temperature overnight.Then it was filtered through Celite
pad to remove Pd/C and filtrate was concentrated under re-
duced pressure to afford N-(2-hydroxy-3-methoxypropyl)-
glycine ethyl ester hydrochloride (47.8 g, quant.) as a yellow
oil.
spiro
N
N
5(1H)-one (4)
To a solution of keto ester 2 (125 mg, 0.302 mmol) in
CH2Cl2 (16 mL) was added the (aS)-La-linked BINOL com-
plex (49.7 mg, 0.0604 mmol) at 08C.After stirring for 30 min
at 08C, a solution of diamine 1 (66.2 mg, 0.302 mmol) in
CH2Cl2 (8.0 mL) was added at 08C to the above mixture
and the reaction mixture was stirred for 30 days at 08C.
After the reaction, the mixture was purified by silica gel
column chromatography (eluant: CH2Cl2/MeOH=97/3–95/
5–93/7–90/10) to afford 3 as a colorless amorphous solid
(yield: 38.3 mg, 21%, 0% ee) and 4 as a colorless amor-
phous solid [yield: 99.5 mg, 60%, 57% ee, (R)].Enantio-
meric excesses of 3 and of 4 were measured by HPLC under
the above conditions.[ a]2D9:0: À51.58 (c 0.953, MeOH, 57%
ee).
A
(47.8 g) which was obtained in Step 2, 6-chloronapthalene-2-
sulfonyl chloride (47.3 g, 0.181 mol) was added. Then tri-
ethylamine (55.5 mL, 0.398 mol) was slowly added into the
above mixture at 08C.The reaction mixture was stirred at
room temperature for 1 hour.Then water was added into
the reaction mixture at 08C and it was extracted with
CH2Cl2.The organic layer was washed with 1 N aqueous
HCl, H2O, saturated aqueous NaHCO3, and brine, respec-
tively.After drying the organic layer with anhydrous
Na2SO4, the solvent was removed under reduced pressure
and the resulting residue was purified by silica gel flash
column chromatography (eluant: hexane/AcOEt=2/1–4/3)
to obtain compound 8 as a colorless amorphous solid; yield:
80% (3 steps).EI-HR-MS: m/z=415.0858 (M+), calcd.for
(À)-(8aR)-7-[(6-Chloronaphthalen-2-yl)sulfonyl]-
C18H2235ClNO6S: 415.0856; H NMR (300 MHz, CDCl3): d= tetrahydro-8a-(methoxymethyl)-spiro
A
1
8.39 (1H, s), 7.95–7.83 (3H, m), 7.84 (1H, dd, J=1.7,
8.8 Hz), 7.56 (1H, dd, J=2.2, 8.8 Hz), 4.19 (2H, s), 4.07
(2H, q, J=7.2 Hz), 4.05–3.95 (1H, m), 3.48–3.29 (2H, m),
3.44 (2H, d, J=5.1 Hz), 3.35 (3H, s), 1.17 (3H, t, J=
7.2 Hz); 13C NMR (75 MHz, CDCl3): d=169.77, 136.49,
135.47, 134.98, 130.74, 130.36, 128.65, 128.64, 128.51, 126.75,
123.85, 73.89, 69.22, 61.70, 59.24, 52.62, 50.30, 13.99; IR
(KBr): n=3483, 1732, 1344, 1153, 694 cmÀ1.
[1,2-a]pyrazine-2(3H),4’-piperidin]-5(1H)-one (9)
To a solution of 4 (90.0 mg, 0.158 mmol) in CH2Cl2 (1.5 mL)
were added proton spongeꢂ [1,8-bis(N, N-dimethylamino)-
naphthalene, 40.7 mg, 0.19 mmol] and a-chloroethyl chloro-
formate (0.043 mL, 0.395 mmol) at 08C.The reaction mix-
ture was stirred at room temperature for 5 min and then
was refluxed for 2 h.After cooling, the reaction mixture was
concentrated under vacuum.Then MeOH (15.mL) was
added to the residue, and the reaction mixture was refluxed
for 2 h.After cooling, the mixture was concentrated under
vacuum and 1 N HCl was added to the residue and the mix-
ture was washed with Et2O to remove benzyl chloride that
was generated in this reaction.Then 1 N NaOH was added
to the water layer at 08C (pH>11).The water layer was ex-
tracted with CH2Cl2, washed with brine and dried with anhy-
drous Na2SO4.The solvent was removed under reduced
pressure and the residue was purified by amino-silica gel
column chromatography (Moritex Corporation, Purif-pack
N-[(6-Chloronaphthalen-2-yl)sulfonyl]-N-(3-methoxy-
2-oxopropyl)glycine Ethyl Ester (2)
To a solution of compound 8 (60.4 g, 0.145 mol) in CH2Cl2
(560 mL) were added an aqueous solution of potassium bro-
mide (3.46 g, 0.291 mol) in H2O (58.2 mL) and 4-hydroxy-
2,2,6,6-tetramethylpiperidine 1-oxyl benzoate free radical
(0.454 g, 0.291 mol). Then within 58C, an alkaline aqueous
NaClO solution, which was prepared with 5 wt% aqueous
NaClO solution (281 mL, 0.189 mol), water (280 mL) and
sodium hydrogen carbonate (28.1 g, 0.338 mol), was added
dropwise into the above mixture.This oxidation reaction
ended almost as soon as dropping the NaClO solution was
completed.Then the reaction mixture was extracted with
CH2Cl2 and the organic layer was washed with 10% aque-
ous Na2S2O3 solution and brine and was dried with anhy-
drous Na2SO4.The solvent was removed under reduced
pressure and the resulting residue was purified by silica gel
flash column chromatography (eluant: hexane/AcOEt=2/1)
to obtain compound 2 as a pale yellow amorphous solid;
yield: 53.8 g (89%). EI-HR-MS: m/z=413.0701 (M+), calcd.
NHꢂ,
eluant:
hexane/CH2Cl2 =50/50–CH2Cl2–CH2Cl2/
MeOH=99/1–98/2–97/3) to afford 9 as a colorless amor-
phous solid; yield: 52.7 mg (70%), 57% ee (R).MALDI-
TOF-HR-MS:
m/z=479.1526
(M+H),
calcd.for
C22H2835ClN4O4S: 479.1520. H NMR (300 MHz, CDCl3): d=
8.33 (1H, s), 8.00–7.85 (3H, m), 7.78 (1H, dd, J=1.8,
8.6 Hz), 7.60 (1H, dd, J=1.8, 8.8 Hz), 4.32 (1H, d, J=
16.7 Hz), 4.24–4.10 (2H, m), 3.71 (1H, d, J=9.4 Hz), 3.43
(1H, d, J=9.4 Hz), 3.43 (3H, s), 3.29 (1H, d, J=16.7 Hz),
3.00–2.80 (2H, m), 2.88 (1H, d, J=11.4 Hz), 2.75–2.28 (3H,
m), 2.23 (1H, d, J=11.9 Hz), 1.80–1.60 (2H, m), 1.35–1.15
(2H, m); 13C NMR (75 MHz, CDCl3): d=163.26, 135.66,
135.41, 132.92, 130.81, 130.46, 129.02, 128.94, 128.93, 126.82,
123.56, 77.08, 74.60, 59.52, 58.77, 53.20, 51.47, 47.61, 43.96,
1
for C18H2035ClNO6S: 413.0700; H NMR (300 MHz, CDCl3):
1
d=8.42–8.38 (1H, m), 7.95–7.85 (3H, m), 7.81 (1H, dd, J=
626
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Adv. Synth. Catal. 2007, 349, 617 – 628

DEDICATED CLUSTER
FULL PAPERS
Total Synthesis of Antithrombotic Agents M58163 and M58169
43.50, 38.92, 37.56; IR (film): n=2920, 1655, 1456, 1348,
1167, 698 cmÀ1. [a]2D8:0: À52.38 (c=1.090, MeOH, 57% ee).
zebecher, Thromb. Res. 1999, 93, 203–241; e) J.I.
Weitz, J.Hirsh, Chest. 2001, 119, 95S-107S.
[2] a) H.Van Aken, C.Bode, H.Darius, C.Diehm, A.
Encke, D.C.Gulba, S.Haas, W.Hacke, W.Puhl, M.
Quante, H.Riees, R.Scharf, S.Schellong, K.Schror,
K.-L. Schulte, U. Tebbe, Clinic. Appl. Thromb./Hemost.
2001, 7, 195–204; b) J.J. Sixma, P.G. De Groot,
Thromb. Res. 1992, 68, 507–512.
(À)-(8aR)-7-[(6-Chloronaphthalen-2-yl)sulfonyl]-
tetrahydro-8a-(methoxymethyl)-1’-(4-pyridinyl)-
spiro
N
N
5(1H)-one (M58163)
To the solution of 9 (40 mg, 0.084 mmol) in EtOH (2.0 mL)
was added 4-chloropyridine hydrochloride (18.9 mg,
0.126 mmol) and i-Pr2NEt (0.073 mL, 0.42 mmol). The reac-
tion mixture was heated at 160–1808C in sealed tube for 4 h.
After cooling, the mixture was concentrated under vacuum.
Then the residue was purified by amino-silica gel column
chromatography (Moritex Corporation, Purif-pack NHꢂ,
eluant: CH2Cl2/MeOH=99.5/0.5–99.3/0.7–99/1–98.5/1.5) to
afforded M58163 as a colorless amorphous solid; yield:
30.3 mg (65%), 57% ee (R).[5] The enantiomeric excess of
M58163 was measured by HPLC [Daicel CHIRALCEL AS-
H column (0.46ꢃ25 cm) at 408C, flow rate: 1.0 mLminÀ1
with MeOH (containing 0.1% diethylamine), retention
time: 8.7 min (S)-form, 11.4 min (R)-form].[ a]2D8:6: À59.18 (c
0.580, MeOH, 57% ee) (lit.[ a]2D6: À1118 (c 0.320, MeOH),
98.6% ee).[5]
[3] H.Nishida, T.Mukaihira, F.Saitoh, K.Harada, M.
Fukui, T.Matsusue, A.Okamoto, Y.Hosaka, M.Mat-
sumoto, I.Shiromizu, S.Ohnishi, H.Mochizuki, Chem.
Pharm. Bull. 2004, 52, 406–412, and references cited
therein.
[4] F.Saitoh, H.Nishida, T.Mukaihira, K.Aikawa, K.
Mikami, Eur. J. Org. Chem. 2006, 2269–2272.
[5] F.Saitoh, T.Mukaihira, H.Nishida, T.Satoh, A.
Okano, Y.Yumiya, M.Ohkouchi, R.Johka, T.Matsu-
sue, I.Shiromizu, Y.Hosaka, M.Matsumoto, S.Oh-
nishi, Chem. Pharm. Bull. 2006, 54, 1535–1544, and ref-
erences cited therein.
[6] a) A.J.Moreno-Vargas, P.Vogel,
Tetrahedron: Asym-
metry 2003, 14, 3173–3176; b) R.Deprez-Poulain, N.
Willand, C.Boutillon, G.Nowogrocki, N.Azaroual, B.
Deprez, Tetrahedron Lett. 2004, 45, 5287–5290; c) P.
Boffelli, A.Brouillard, C.Colladant, S.Droux, M.
Elter, D.Ferroud, G.Lemaitre, J.Paladino, World
Patent WO2003/054001 A3, 2003.
(À)-(8aR)-[(6-Chloronaphthalen-2-ylyl)sulfonyl]-
tetrahydro-8a-(methoxymethyl)-1-methyl-1’-
(4-pyridinyl)-spiro
N
N
[7] a) W.T. Green, P.G. Wuts,
ganic Synthesis, 3rd.edn,. Wiley, New York,
b) H.Sharghi, N.M.Ali, Phosphorus, Sulfur and Sili-
con and the Related Elements 2003, 178, 1353–1359.
Protecting Groups in Or-
4’-piperidin]-5(1H)-one (M58169)
1999;
To the solution of M58163 (25 mg, 0.045 mmol) in CH2Cl2
(1 mL) were added paraformaldehyde (8.1 mg, 0.27 mmol)
[8] a) S.M.Sondhi, N.Singh, M.Johar, A.Kumar,
Bioorg.
and NaBH(OAc)3 (28.6 mg, 0.135 mmol). The reaction mix-
N
Med. Chem. 2005, 13, 6158–6166; b) G.Claudon, N.
ture was refluxed for 10 h.After cooling, 10% HCl-MeOH
(1 mL) was added into the reaction mixture.Then the mix-
ture was refluxed again for 1 hour to degrade the product-
borane complex.At the end of reaction, saturated aqueous
NaHCO3 solution was added into the mixture to adjust the
Le Bris, H.Bernard, H.Handel,
Eur. J. Org. Chem.
2004, 5027–5030; c) F.Chanteau, B.Didier, B.Dondy,
P.Doussot, R.Plantier-Royon, C.Portella, Eur. J. Org.
Chem. 2004, 1444–1454; d) P.Sohar, A.Csampai, G.
Magyarfalvi, A.E. Szabo, G. Stajer, Monatsh. Chem.
2004, 135, 1519–1527; e) F.Miklos, A.Hetenyi, P.
Sohar, G.Stajer, Montsh. Chem. 2004, 135, 839–847;
f) Y.V. Sosnovskikh, A.M. Barabanov, I.B. Usachev,
Russian Chem. Bull. 2003, 52, 1758–1767; g) E.Mala-
midou-Xenikaki, J. Chem. Soc., Perkin Trans. 1 1996,
2523–2529.
pH to more than 11.The mixture was extracted with CH Cl2
2
and the organic solvent was washed with brine and dried
with anhydrous Na2SO4.The solvent was removed under re-
duced pressure and the resulting residue was purified by
amino-silica gel column chromatography (Moritex Corpora-
tion, Purif-pack NHꢂ, eluant: hexane/AcOEt=50/50–0/100)
to afford M58169 as a colorless amorphous solid; yield:
18.0 mg (70%), 57% ee, (R)-form).[5] The enantiomeric
excess of M58169 was measured by HPLC [Daicel CHIR-
ALCEL AS-H column (0.46ꢃ25 cm) at 408C, flow rate:
1.0 mLminÀ1 with MeOH (containing 0.1% diethylamine),
retention time: 11.9 min (R)-form, 17.8 min (S)-form].
[a]2D7:3: À79.78 (c 0.455, MeOH, 57% ee) (lit.[ a]2D9: À1298 (c
0.560, MeOH),>99% ee).[5]
[9] a) A.J.Moreno-Vargas, I.Robina, E.Petricci, P.Vogel,
J. Org. Chem. 2004, 69, 4487–4491; b) G.Verardo, P.
Geatti, M.Merli, E.E.Castellarin,
2004, 2833–2939; c) F.Miklos, I, Kanizsai, S.Thomas,
E.Kleinpeter, R.Sllianpaeae, G.Stajer, Heterocycles
Eur. J. Org. Chem.
2004, 63, 63–74; d) D.Tepfenhart, L.Moisan, PI..
Dalko, J.Cossy, Tetrahedron Lett. 2004, 45, 1781–1784;
e) A.J.Moreno-Vargas, P.Vogel,
Tetrahedron: Asym-
metry 2003, 14, 3173–3176; f) N.Halland, R.G.Hazell,
K.A. Jorgensen, J. Org. Chem. 2002, 67, 8331–8338;
g) A.Forster, T.Kovac, H.Mosimann, P.Renaud, P.
Vogel, Tetrahedron: Asymmetry 1999, 10, 567–572;
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 617 – 628