Hexahydropyrrolo [2,3-b]indoles: A new class of structurally rigid tricyclic skeleton for oxazaborolidine-catalyzed asymmetric borane reduction

Article abstract of DOI:10.1002/adsc.200900908

A new class of structurally rigid tricyclic chiral ligands based on the hexahydropyrrolo [2,3b]indole skeleton has been rationally designed and the catalytic abilities in asymmetric catalysis have been shown in the enantioselective borane reduction of prochiral ketones to afford the chiral alcohols in excellent yields and high enantioselectivities (up to 97% ee).

Full text of DOI:10.1002/adsc.200900908

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DOI: 10.1002/adsc.200900908
Hexahydropyrrolo[2,3-b]indoles: A New Class of Structurally
G
Rigid Tricyclic Skeleton for Oxazaborolidine-Catalyzed
Asymmetric Borane Reduction
Jian Xiao,a Zhen Zhou Wong,a Yun Peng Lu,a and Teck Peng Loha,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371
Fax : (+65)-6791-1961; e-mail: teckpeng@ntu.edu.sg
Received: December 29, 2009; Revised: April 6, 2010; Published online: April 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900908.
Abstract: A new class of structurally rigid tricyclic
chiral ligands based on the hexahydropyrrolo[2,3-
synthetic challenges, comparatively much less atten-
tion has been given to these unique enantiopure
structures themselves, which can also be used as a
template or redesigned, hence providing opportunities
as chiral skeleton for enantioselective catalysis.[6]
In connection with our interest in exploring new
chiral ligands and catalysts,[7] we focus attention to
using natural product skeletons as new chiral skele-
tons to perform asymmetric catalysis. Herein we in-
troduce a new class of structurally rigid tricyclic chiral
ligands for asymmetric synthesis. The design and syn-
theses of these new chiral ligands and their applica-
tion in the asymmetric reduction of ketones are re-
ported.
AHCTUNGTRENNUNG
b]indole skeleton has been rationally designed and
the catalytic abilities in asymmetric catalysis have
been shown in the enantioselective borane reduc-
tion of prochiral ketones to afford the chiral alco-
hols in excellent yields and high enantioselectivities
(up to 97% ee).
Keywords: asymmetric catalysis; chiral skeleton;
DFT calculations; hexahydropyrrolo
ketone reduction; ligand design
ACHTUNGTREN[NGNU 2,3-b]indoles;
The hexahydropyrrolo
ACHTUNGTNER[NUNG 2,3-b]indole skeleton recur-
rently appears in a large number of indole alkaloids
The pursuit of new effective chiral ligands and cata- as a key structural ingredient (Figure 1).[8] Inspired by
lysts which exhibit high reactivity and enantioselectiv-
ity with novel skeletons has always been a challenging
goal for organic chemists. Looking through reference
works on stereoselective syntheses, we repeatedly en-
counter the same chiral skeletons. Such broadly appli-
cable chiral ligands or catalysts have been recognized
as “privileged structures” which provide efficient
chiral environments for a variety of mechanically un-
related enantioselective reactions.[1] They could be di-
vided into two categories according to their origin: in-
spiration from nature or coming from wisdom of man-
kind. For example, state-of-the-art chiral ligands, such
as bis(oxazoline) ligands,[2] were stimulated by the
ligand scaffold of vitamin B12, whereas BINOL[3] and
BINAP[4] came from the creativity of organic chemists
and a profound understanding of the catalytic process.
Biologically active natural products often possess
particularly intriguing structural features and func-
tionalities pertinent to asymmetric synthesis, which
leads to the development of asymmetric catalysis.[5]
Figure 1. Some natural indole alkaloids possessing
As many chemists are engrossed in overcoming these hexahydropyrrolo[2,3-b]indole skeleton.
a
AHCTUNGTRENNUNG
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Jian Xiao et al.
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its tricyclic and structurally rigid nature, we initiated to play a crucial role in catalytic asymmetric reactions.
our study by focusing on the tryptophan-based Furthermore, two more stereogenic centers were in-
hexahydropyrrolo
ACHTUNGTRENNUNG
chiral backbone to deliver enantiocontrol.
Two possible isomers, endo or exo could be generat- tives in ligand design and lead to a conceptually new
ed in the ring closure of tryptophan. These two iso- family of modular chiral ligands.
mers upon complexation with metal will result in two
possible rigid configurations: bowl- or S-shaped con- benzyloxy-l-tryptophan 1, DCC coupling with metha-
figuration (Scheme 1). nol followed by acid-mediated ring closure provided
Starting from the commercially available Na-carbo-
The highly rigid structure, easy preparation and the hexahydropyrroloACTHNUGTRNEUNG[2,3-b]indole 3 as diastereomers.
modification are the most important features of privi- In agreement with a literature precedent,[8] after pro-
leged chiral ligands. Based on the rigid tricyclic scaf- tection with various carbamates, the thermodynami-
fold of the hexahydropyrroloACHTNUTRGNE[NUG 2,3-b]indole skeleton cally stable endo isomer 4 was obtained. Initial at-
and promising generality, we designed a series of new tempts to perform a direct Grignard addition to 4
chiral ligands as shown in Scheme 2. This diversified were unsuccessful, with no reaction observed. This
ligand scaffold offers remarkably high tunability in was probably due to the highly crowded nature of the
both steric and electronic properties by judicious se- structure. To remove the steric effect, we decided to
lection of the substituent R group at the amine N remove the protecting group first, followed by
atom and R’ group on the tertiary alcohol. Their Grignard addition. This strategy proved successful
unique rigidity and fine-tuning capability are expected and a series of chiral ligands 7a–f was obtained in var-
ious yields (Scheme 3). The crystal structure of 7a fur-
ther demonstrated the fascinating rigid, tricyclic ring
system (Figure 2).[9]
With these chiral ligands in hand, we proceeded to
investigate their application for asymmetric catalysis.
The asymmetric reduction of ketones was selected as
model reaction to test our new chiral ligand.[10] The
initial study was conducted using chiral ligand 7a with
BACTHUNTRGENNG(U OMe)3 to generate a borane complex in situ for the
asymmetric reduction of 2-acetonaphthone at room
temperature. Unfortunately, the desired product was
obtained in only 37% ee (Table 1, entry 1). When this
reaction was carried out under reflux conditions, the
enantioselectivity was increased to 85% ee (Table 1,
entry 2). Direct refluxing with borane gave a better
enantioselectivity (89% ee) (Table 1, entry 3). Screen-
ing the different substituting groups showed that the
ethyl carbamate-protected ligand 7a is the best ligand
for this reaction and THF is the best solvent (Table 1,
entries 3–10). It is notable that good enantioselectivity
could be obtained by varying the ligand structure
(Table 1, entries 3–8). For example, ligand 7b without
Scheme 1. Two different configurations of the metal com-
plexes.
Scheme 2. Design of a new class of structurally rigid chiral ligands.
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HexahydropyrroloACHTUNGTRENNUNG[2,3-b]indoles: A New Class of Structurally Rigid Tricyclic Skeleton
Scheme 3. Syntheses of chiral ligands 7a–f.
Figure 2. The X-ray structure of 7a.
a phenyl substituent still furnished 85% ee in the re- tably, chiral ligand 7a could be salvaged with 90% re-
duction of 2-acetonaphthone (Table 1, entry 4). How- covery and reused for 3 times without loss of activity
ever, in the case of the prolinol ligand, only 44% ee and enantioselectivity for the asymmetric reduction of
was obtained in the reduction of acetophenone.[11] No- 2-acetonaphthone (Table 1, entries 11–13).
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Jian Xiao et al.
Table 2. Catalytic asymmetric reduction of ketones.[a]
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Table 1. Optimizations for enantioselective borane reduction
of acetonaphthone.[a]
Entry
Ligand
Sovlent
Yield [%][b]
ee [%][c]
Entry Product
1
Yield [%][b] ee [%][c]
1[d]
2[e]
3
4
5
6
7
8
9
10
11
12
13
7a
7a
7a
7b
7c
7d
7e
7f
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
CH2Cl2
THF
THF
THF
96
99
99
96
98
97
96
96
95
92
98
96
92
37
85
89
85
85
81
60
75
36
59
89
89
86
9a 98
81
92
2
3
9b 95
9c 99
89
70
7a
7a
7a[f]
7a[g]
7a[h]
4
9d 92
[a]
Reactions were performed with 0.5 mmol acetonaph-
thone, 0.6 mmol borane, 10 mol% ligand in 2 mL of sol-
vent with heating at reflux.
Isolated yield by column chromatography.
The ee values were determined by HPLC analysis using a
Daicel Chiralcel AS-H column.
Catalyst prepared from 0.1 equiv. of ligand and
0.12 equiv. of BACTHNUTRGNEUNG(OMe)3 at room temperature and the
ketone was added at room temperature.
Catalyst prepared from 0.1 equiv. of ligand and
5
6
7
9e 93
9f 96
9g 99
86
92
95
[b]
[c]
[d]
[e]
0.12 equiv. of BACHTUNGTRENNUNG(OMe)3 under reflux conditions and the
ketone was added at reflux.
Ligand was recycled once.
Ligand was recycled twice.
Ligand was recycled a third time.
[f]
8
9h 99
95
97
93
[g]
[h]
9
9i
99
Under the optimized reaction conditions, ligand 7a
was employed in the asymmetric borane reduction of
a variety of aromatic ketones (Table 2). As summar-
ized in Table 2, high yields and enantioselectivities
were obtained for different prochiral ketones. For
electron-rich ketones, a slightly decreased ee was ob-
served (Table 2, entries 3 and 4). In comparison, the
electron-deficient ketones showed good or excellent
enantioselectivities (Table 2, entries 5–11). Especially
noteworthy was that (R)-3,5-bistrifluoromethylphenyl-
10
9j 98
9k 97
11
86
50
12
9l
92
ACHTUNGTRENNUNGethanol (BTMP), which is an interesting chiral build-
ing block for a number of pharmaceutically interest-
ing targets such as an Nk-1 receptor antagonist, could
be obtained in 98% yield and 93% ee (Table 2,
entry 10).[12] For aliphatic ketones, moderate enantio-
selectivity was observed (Table 2, entry 12).
To fully understand this new finding, DFT calcula-
tions were carried out with the Gaussian 03 package
(see Supporting Information). Initially, we investigat-
[a]
Reactions were performed with 0.7 mmol ketone,
0.87 mmol borane, 10 mol% ligand in 2 mL THF under
reflux.
Isolated yield by column chromatography.
The ee values were determined by HPLC analysis using a
Daicel Chiralcel chiral column.
[b]
[c]
ed the two possible catalyst-borane complexes: the plex according to the coordination manner of BH3
trans catalyst-BH3 complex and cis catalyst-BH3 com- relative to the hydrogen on the carbon of the ring
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HexahydropyrroloACHTUNGTRENNUNG[2,3-b]indoles: A New Class of Structurally Rigid Tricyclic Skeleton
Figure 4. The lowest transition state by DFT calculation.
Figure 3. The trans catalyst-BH3 complex and cis catalyst-
BH3 complex.
enantioselectivity by varying the ligand substituent,
whereas for the CBS ligand, the phenyl substituent is
À À À
fusion (Figure 3). In both cases, the N B H B ring is critical for good enantioselectivity. Secondly, in the
closed. The cis complex is more stable as its energy is model reaction, while the enantioselectivity is compa-
35.3 kJmolÀ1 lower than that of the trans complex rable to that of the CBS catalyst, this skeleton could
which adopts a high energy twisted conformation and be further modified to provide a diversity-oriented
leads to the opposite enantiomer. Next, several possi- ligand library for other asymmetric reactions while
ble catalyst-borane-acetophenone complexes were in- the CBS ligand offers little room for modification.
vestigated: (1) exo/anti; (2) skew/anti; (3) endo/anti; The rigid backbone and easy modification of these li-
(4) exo/syn (5) skew/syn.[13] The calculation results gands skeleton, as well as their recoverability make
show that the endo/anti form is the most stable com- them promising ligands for asymmetric catalysis. In
plex as it has the lowest energy as compared to the combination with the previously successful design of a
others (see Supporting Information). The correspond- new type of organocatalyst based on the
ing transition state was proposed after DFT calcula- hexahydropyrrolo
ACHTUNGTRENNUNG
tions (Figure 4). In this transition state, the si face was now identified the hexahydropyrroloACHTUNGTRENNNUG
exposed for hydride attack which leads to the R prod- skeleton as a privileged chiral skeleton for asymmet-
uct which is preferentially formed in the experiment. ric catalysis. The successful natural product skeleton-
In summary, a new class of structurally rigid, tricy- based design will lead to a conceptually new family of
clic chiral ligands based on the hexahydropyrroloACTHNUTRGNEU[GN 2,3- modular chiral ligands or chiral catalysts. Further
b]indole skeleton has been rationally designed and design of other novel chiral ligands based on this skel-
conveniently synthesized from commercially available eton as well as applications to other asymmetric reac-
l-tryptophan derivative in five steps. Their catalytic tions are underway.
abilities have been shown in the enantioselective
borane reduction of prochiral ketones to afford the
desired product in excellent yields and high enantio-
Experimental Section
selectivities (up to 97% ee). The fused tricyclic rigid
ring system behaves in a significantly different fashion
as compared to the CBS ligand skeleton derived from
the pyrrolidine ring of proline in view of the following
reasons. Firstly, the bowl-shaped hexahydropyrrolo-
General Procedure for the Enantioselective Ketone
Reductions
To an oven-dried 10-mL round-bottom flask equipped with
a magnetic stirring bar was added the new chiral ligand 7a
ACHTUNGTRENNUNG[2,3-b]indole skeleton provides a well-organized chiral
induction environment, allowing achievement of good (0.07 mmol, 0.10 equiv.). The ligand was azeotropically dried
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Jian Xiao et al.
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´
with anhydrous THF (2 mLꢁ2) before the addition of
1.5 mL of THF. Then BH3·Me2S (0.87 mmol, 10 mol/L) was
added under nitrogen at room temperature and the mixture
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was stirred at reflux for 3 h.
A solution of ketone
(0.7 mmol) in dry THF (0.5 mL) was added dropwise by sy-
ringe pump over a period of 1 h at reflux temperature. Then
the reaction mixture was cooled down and quenched by
dropwise addition of methanol (5 mL). After the solvent
had been removed, the product was purified by column
chromatography on silica gel (hexane/ethyl acetate 5:1) to
afford the corresponding secondary alcohol. The enantio-
meric excess was determined by chiral HPLC analysis em-
ploying a Daicel Chiracel column.
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can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. See Supporting Information for de-
tails.
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Acknowledgements
We thank Dr Yong-Xin Li (Nanyang Technological Universi-
ty) for X-ray analyses. We gratefully acknowledge Nanyang
Technological University and Ministry of Education Academ-
ic Research Fund Tier 2 (No. T207B1220RS) for the funding
of this research.
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