Stereoselective synthesis of 4-substituted-cyclic sulfamidate-5-carboxylates by asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution and applications to concise stereoselective syntheses of (-)-epi-cytoxazone and the taxotere side-c

Article abstract of DOI:10.1039/c4cc06395c

Dynamic kinetic resolution driven, asymmetric transfer hydrogenation reactions of cyclic sulfamidate imine-5-carboxylate esters were developed. Applications of the new methodology to stereoselective syntheses of the taxotere side-chain and (-)-epi-cytoxaz

Full text of DOI:10.1039/c4cc06395c

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Stereoselective synthesis of 4-substituted-cyclic
sulfamidate-5-carboxylates by asymmetric
transfer hydrogenation accompanied by dynamic
kinetic resolution and applications to concise
stereoselective syntheses of (À)-epi-cytoxazone
and the taxotere side-chain†
Cite this: Chem. Commun., 2014,
50, 13706
Received 14th August 2014,
Accepted 2nd September 2014
DOI: 10.1039/c4cc06395c
Jin-ah Kim,‡a Yeon Ji Seo,‡ab Soyeong Kang,ab Juae Hanab and Hyeon-Kyu Lee*ab
www.rsc.org/chemcomm
Dynamic kinetic resolution driven, asymmetric transfer hydrogenation
reactions of cyclic sulfamidate imine-5-carboxylate esters were developed.
Applications of the new methodology to stereoselective syntheses of the
taxotere side-chain and (À)-epi-cytoxazone are described.
1,2-Amino alcohol motifs, including those found in b-amino-a-
hydroxy acids, are present in a vast range of natural products and
pharmaceutically related compounds.1 In addition, the relative and
absolute stereochemistry of the 1,2-amino alcohol moiety generally
governs the biological activities of these substances. Therefore, the
development of methods for stereoselective synthesis of members
of this family has received considerable attention.1a,2
Transition metal catalyzed-asymmetric transfer hydrogenation
reactions (ATH)3 of carbonyl compounds containing configurationally
labile stereogenic C–H centers, accompanied by dynamic kinetic
resolution (DKR), have become efficient and powerful techniques
for controlling the stereochemistry at two contiguous stereogenic
centers. Examples of processes of this type include ATH of
a-substituted-b-ketoesters,4 b-ketoamides,5 a-alkoxy-b-keto phos-
Scheme 1
phonates,6 1,2-diketones,7 a-ketoesters,8 and a-ketophosphonates.9 we showed that ATH of 4,5-disubstituted cyclic sulfamidate imines 2,
However, only a few reports exist describing ATH reactions of imines possessing configurationally labile stereogenic centers (C5), is
that are accompanied by DKR.10 In this context, we recently accompanied by DKR. It was also observed that DKR is caused by
described a highly efficient procedure for ATH–DKR of prochiral rapid racemization at the acidic stereogenic C5 position adjacent to
cyclic sulfamidate imines, using HCO2H/Et3N as the hydrogen the imine carbon under the reaction conditions. In fact, introduction
source and chiral Rh-catalysts (Scheme 1).10a,b In this early effort, of an aryl in place of a methyl group at C-5 of 2 leads to drastic
improvement in the stereoselectivity of the ATH reaction (e.g., from
75% ee for 3 to 98% ee for 5), an obvious consequence of the
a Korea Chemical Bank, Korea Research Institute of Chemical Technology,
enhanced acidity of H-5 (Scheme 1).10a
PO Box 107, Yuseong, Daejeon 305-600, Korea. E-mail: leehk@krict.re.kr;
While considering other strategies to improve the stereo-
Fax: +82 42 860-7096; Tel: +82 42 860-7016
b Department of Medicinal and Pharmaceutical Chemistry, University of Science and
Technology, Daejeon 305-333, Korea
selectivity of ATH–DKR reactions of cyclic imine 2, we envisioned
that introduction of a carboxylate group at C-5 would also
enhance the acidity of H-5 and, as a result, would promote high
levels of stereoselectivity in the ATH–DKR reaction.
Below, we describe the results of an investigation exploring
this proposal, which led to the first examples of highly efficient
ATH reactions of cyclic imines 6, which are accompanied by
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data with the copies of 1H-, 13C-NMR spectra, chiral HPLC
chromatograms of all chiral compounds and X-ray crystallography data of (S,S)-7j.
CCDC 1007235. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc06395c
‡ These authors contributed equally.
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Table 2 ATH–DKR of cyclic sulfamidate imine-5-carboxylates 6a
Scheme 2 Synthesis of 4-substituted sulfamidate imine-5-carboxylates 6.
Substrate
R1
Entry
Time
(h)
Conv.b
(%)
eec
(%)
Conf.d
DKR and can be applied in the synthesis of stereochemically
enriched, chiral cyclic sulfamidate-5-carboxylate esters 7.
The racemic cyclic imine-5-carboxylate esters 6, used in this
work, were prepared from a-hydroxy-b-keto ester (B) and sulfamoyl
chloride by modification of a previously described procedure
(Scheme 2).11
6, 7
a
R2
Me
i-Pr
Bn
1
0.5
0.5
0.5
0.5
0.5
499(92)
499(85)
499(87)
98 S,Se
2
b
98 S,S
98 S,S
Racemic 4-phenyl-5-methoxycarbonyl cyclic imine 6a was
selected as the model substrate in initial efforts aimed at the
identification of the most suitable catalyst systems for the ATH
reactions. Reactions of 6a were performed using the known
chiral transition metal catalysts 1a–e (0.5 mol%) and employing
HCO2H/Et3N as the hydrogen source in EtOAc at rt (Table 1).
As the results given in Table 1 show, the efficiencies and
stereochemical outcomes of ATH reactions of 6a are strongly
affected by both the nature of the transition metal and the
diamine ligands. For example, reaction of this substrate using
Ru-catalysts with diamine ligands bearing electron rich or
electron deficient arylsulfonyl groups (1c,3c 1d,12 1e4a) proceed
to very low conversions (Table 1, entries 3–5). However, ATH of 6a
using Ir-catalyst 1b13 reaches completion in 0.5 h (conversion 4
99%) but takes place with a low level enantioselectivity (30% ee).
Finally, the results reveal that ATH–DKR of 6a with Rh-catalyst
(R,R)-1a,14 which possesses TsDPEN and pentamethylcyclopenta-
dienyl ligands, for 0.5 h at rt produces (S,S)-7a in the highest
conversion (499%) and level of stereoselectivity (425 : 1 dr, 98% ee).
The influence of solvent on the ATH reaction of 6a catalyzed
by (R,R)-1a was investigated. In most of the solvents tested
(EtOAc, CH2Cl2, Cl(CH2)2Cl, CHCl3, toluene, DMF, MeOH, THF,
and 2-propanol), ATH of 6a takes place completely to form (S,S)-7a
with high levels of stereoselectivity (425 : 1 dr, 84–99% ee) (see,
Table S2 in ESI†). For the purpose of experimental convenience and
based on optimization of stereoselectivity, further ATH reactions
were carried out in EtOAc as solvent.
3
c
4
d
t-Bu
Me
499(87) 499 S,S
5 f
a
499(94)
98 R,R f
6
e
e
Me
Me
12
20
—
—
7g
12g
499(95)g
92g
—
8
f
Me
Me
Me
Me
Me
Me
Me
0.5
0.5
0.5
0.75
0.5
3.5i
0.5
499(99)
499(99)
499(99)
499(92)
99 S,S
99 S,S
97 S,S
97 S,S
9
g
h
i
10
11
12
13i
14
j
499(99) 499 S,Sh
j
499i
99i S,Sh
97 S,S
99 S,S
k
499(96)
499(88)
Table 1 Optimization of chiral catalysts 1a–e for ATH–DKR of 6aa
15
l
Me
0.5
16
17
18
m
n
Me
Me
Me
0.5
0.5
0.5
499(95)
499(92)
499(91)
96 S,S
97 S,S
97 S,S
Entry
Cat.1
Convnb (%)
dr (syn : anti)
eed (%)
Config.e
1
2
3
4
5
(R,R)-1a
(R,R)-1b
(R,R)-1c
(R,R)-1d
(R,R)-1e
499
499
13
6
17
425 : 1c
425 : 1c
—
—
—
98
30
95
—
83
S,S
S,S
S,S
—
o
S,S
19
20
p
q
Me
Me
1.0
2.0
499(92)
499(94)
95 S,S
99 S,S
a
Reaction conditions: 6a (0.5 mmol), cat-1 (0.5 mol%), HCO2H/Et3N
(5:2, 0.5 mL), EtOAc (5 mL), rt, 0.5 h. b Determined by 1H NMR analysis of
crude products. Only 4,5-cis products were detected by using 1H NMR
c
91j NDk
76 NDk
d
e
21
22
r
s
n-Pr–
Ph(CH2)2–
Me
Me
1.5
12
499(69)
499(54)
analysis of crude product mixtures. Determined by chiral HPLC. See
Scheme S1 in ESI.
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Table 2 (continued)
Substrate
R1
Entry
Time
(h)
Conv.b
(%)
eec
(%)
Conf.d
6, 7
R2
23
24g
a
t
t
Me
Me
24
50
—
NDk
NDk
Scheme 3 Proposed mechanism for DKR in ATH of 6a.
48g
499(67)g 47j
Reaction conditions: 6 (0.5 mmol), (R,R)-1a (0.5 mol%), HCO2H/Et3N
para-positions on the phenyl ring leads to production of the
corresponding sulfamidates in high yields and stereoselectivites.
However, ATH of the cyclic imine 6e possessing an ortho-methyl
substituted phenyl group is sluggish, reaching only 20% conversion
even after 12 h. Based on the results of recent studies which show
that the HCO2H/Et3N (F/T) ratio has a significant effect on both the
ATH rate and the level of enantioselectivity,5b,6,15 we employed the
1 : 1 instead of a 5 : 2 mixture of F/T as the hydrogen source for ATH
of 6e. This reaction proceeds to completion in 12 h and is attended
by a slightly decreased level of stereoselectivity (92% ee) (Table 2,
entries 6 and 7). Cyclic imines containing heteroaromatic moieties
also serve as suitable substrates for the ATH–DKR reaction, as
exemplified by the results of reactions of furan 6p and thiophene
6q (Table 2, entries 19 and 20). Importantly, we also found that the
catalyst loading can be reduced to 0.1 mol% (S/C = 1000) in the
ATH–DKR reaction of 6j without deterioration of optical purity
when the process is carried out using a longer reaction time
(Table 2, entry 13). ATH reaction of 4-alkyl substituted cyclic
sulfamidate imine-5-carboxylates was also explored. The results
show that the efficiencies and stereoselectivities of the processes
are sensitive to the steric bulkiness of the 4-alkyl group. Thus, ATH–
DKR reaction of 4-(n-propyl) cyclic imine 6r is complete in 1.5 h
(91% ee) but that of the 4-phenethyl containing cyclic imine 6s
requires 12 h for completion and occurs with a lower level of
stereoselectivity (76% ee) (Table 2, entries 21 and 22). ATH–DKR
reaction of 4-cyclohexyl-substituted cyclic imine 6t is more sluggish
resulting in only 50% conversion after 24 h. However, by employing
a 1:1 mixture of HCO2H/Et3N as the hydrogen source, reaction of
6t reaches completion in 48 h but it takes place with a lower level of
stereoselectivity (47% ee) (Table 2, entries 23 and 24).
(5 : 2, 0.5 mL), EtOAc (5 mL), rt. Determined by 1H NMR analysis of the
crude product mixtures (isolated yields in parentheses). Determined
b
c
by using chiral HPLC. Only 4,5-cis products were detected by using
d
1H NMR analysis of crude product mixtures. Absolute configuration
e
of 7b–i, 7k–q was determined by analogy to 7a and 7j. See, Scheme S1
f
g
in ESI. (S,S)-1a (0.5 mol%) was used. 1 : 1 mixture of HCO2H/Et3N
h
was used as the hydrogen source. Determined by using X-ray crystal-
lographic analysis (CCDC 1007235). 0.1 mol% of (R,R)-1a (S/C = 1000)
was used. ee of ring-opened derivatives derived from 7r and 7t
respectively (see, Scheme S2 in ESI). Not determined.
i
j
k
The scope and limitations of the ATH–DKR reaction were explored
using a variety of cyclic sulfamidate imine-5-carboxylates (6). All
reactions were carried out in EtOAc (25 1C) under the optimized
reaction conditions employing (R,R)-1a (0.5 mol%) as the catalyst and
a 5:2 mixture of HCO2H/Et3N as the hydrogen source. The results are
summarized in Table 2.
ATH of 6a with (R,R)-1a under the optimized reaction conditions
produces a mixture of stereoisomeric 4,5-cis sulfamidates, in which
the (4S,5S)-7a isomer predominates (98% ee, 92% yield, Table 2,
entry 1). None of the 4,5-trans sulfamidates are detected in the crude
product mixture by using 1H-NMR spectroscopic analysis. These
results show that hydrogen addition to 6a occurs exclusively from the
less hindered face of the cyclic imine moiety.10a In addition, ATH–
DKR reactions of 4-phenyl-cyclic imine-5-carboxylates containing
different ester moieties, such as isopropyl (6b) and benzyl (6c), also
produce the corresponding cyclic sulfamidates (7b, 7c) with excellent
efficiencies and stereoselectivities. Moreover, ATH–DKR of the t-butyl
ester 6d forms nearly a single stereoisomer of the corresponding
cyclic sulfamidate 7d.
ATH reaction of 6a under the optimized conditions, except in
this case using the (S,S)-1a as catalyst, produces the antipodal
sulfamidate (R,R)-7a with efficiency and stereoselectivity (98% ee,
94% yield) that match those of accompanying reaction using (R,R)-1a
(Table 2, entry 5). These observations demonstrate that the
source of dynamic kinetic resolution in this process is the
configurational ability of the C-5 stereogenic center in 6a caused
by rapid racemization under the reaction conditions10a (Scheme 3).
As a result, the absolute stereochemistry of the major reduction
product depends on the enantiomer of the Rh-catalyst employed in
a manner such that (5S)-6a is preferentially reduced with (R,R)-1a to
form sulfamidate (S,S)-7a and (5R)-6a is preferentially reduced with
(S,S)-1a to give sulfamidate (R,R)-7a.
The cyclic sulfamidates 7 produced in these reactions are
valuable intermediates for the synthesis of various chiral b-amino-a-
hydroxy carboxylic acids or 1,2-functionalized amines16 such as those
present in the side chain of the anticancer drug taxotere (10)17 and
the potent cytokine modulator (À)-epi-cytoxazone (12)2b,18 (Fig. 1).
ATH–DKR of cyclic sulfamidate imines possessing either
electron-withdrawing or -donating groups at the meta- or
Fig. 1 Examples of biologically important 1,2-amino alcohol compounds.
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Notes and references
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Scheme 4 Reaction conditions: (a) (Boc)2O, Et3N, cat. DMAP, CH2Cl2,
100%; (b) (i) PhCO2NH4, DMF, 55 1C, 12 h; (ii) 1N HCl, CH2Cl2, 6 h, rt, 82%;
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Scheme 5 Reaction conditions: (a) (Boc)2O, Et3N, cat. DMAP, CH2Cl2, 94%;
(b) (i) PhCO2NH4, DMF, 55 1C, 12 h; (ii) 1N HCl, CH2Cl2, 6 h, rt, 100%; (c) KCN,
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In order to demonstrate the utility of the methodology
developed in this effort, we employed it in the synthesis of
the taxotere side-chain 1017 (Scheme 4).
Accordingly, (S,S)-7a formed by ATH–DKR reaction of 6a is
converted to its N-Boc derivative, which upon treatment with
PhCO2NH4 undergoes ring opening10a,19 to form (2R,3S)-8a.
Selective removal of the O-benzoyl group in 8a using KCN11
in MeOH and subsequent hydrolysis of methyl ester 9a produce
the taxotere side-chain 1017 (ca. 61% overall yield over 4 steps
from (S,S)-7a).
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over 5 steps from (S,S)-7j).
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In summary, a convenient and highly stereoselective method for
the preparation of 4-substituted cyclic sulfamidate-5-carboxylate
esters 7 was developed in this investigation. The process, involving
asymmetric transfer hydrogenation accompanied by dynamic kinetic
resolution (ATH–DKR), uses HCO2H/Et3N as the hydrogen source
and chiral Rh catalysts (S,S)- or (R,R)-Cp*RhCl(TsDPEN). Most of the
ATH–DKR reactions probed in this study occur rapidly (30 min) and
highly stereoselectively under mild and experimentally convenient
conditions (rt, without the need for solvent degassing or an inert
atmosphere). The utility of this methodology was demonstrated by
its application to stereoselective syntheses of the taxotere side-chain
and (À)-epi-cytoxazone.
This research was financially supported by grants from the
National Research Foundation of Korea (2008-2004732) and
Korea Research Institute of Chemical Technology (SI-1405).
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