Convenient synthesis of stable aldimine - Borane complexes, chiral δ-amino alcohols, and γ-substituted GABA analogues from nitriles

Article abstract of DOI:10.1021/ol0710919

A one-pot synthesis of stable aldimine-trialkylborane adducts, the first synthesis of C- and N-deuterated imine-borane complexes, and their application for a highly enantioselective (84-99% ee) synthesis of δ-amino alcohols and γ-substituted γ-aminobutyri

Full text of DOI:10.1021/ol0710919

ORGANIC
LETTERS
2
007
Vol. 9, No. 16
025-3027
Convenient Synthesis of Stable
Aldimine Borane Complexes, Chiral
-Amino Alcohols, and -Substituted
3
−
δ
γ
GABA Analogues from Nitriles
P. Veeraraghavan Ramachandran* and Debanjan Biswas
Herbert C. Brown Center for Borane Research, Department of Chemistry,
Purdue UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received May 10, 2007
ABSTRACT
A one-pot synthesis of stable aldimine
−trialkylborane adducts, the first synthesis of C- and N-deuterated imine−borane complexes, and their
application for a highly enantioselective (84
−
99% ee) synthesis of -amino alcohols and -substituted -aminobutyric acids, including deuterated
δ
γ
γ
amino acids from nitriles, are described.
γ-Aminobutyric acid (GABA) and GABA-associated recep-
As part of our research involving amino acid synthesis,8
we undertook the synthesis of optically active GABA
analogues. Nucleophilic addition to imine derivatives pro-
tors play a vital role in numerous central nervous system
1
disorders. GABA analogues, such as γ-vinyl-GABA, are
2
9
selective and irreversible inhibitors of GABA-transaminase.
vides a simple route to amino acids. Most of the frequently
3
Several other GABA analogues, such as gabapentin and
used azomethines are substituted with benzyl, sulfinyl,
sulfonyl, trialkylsilyl, or metals on the nitrogen, necessitating
4
pregabalin, are widely used in studies related to CNS
5
10
disorders, such as anxiety, addiction, and neuropathic pain.
their removal. Itsuno and co-workers originally reported
Further development of this primary class of biomolecule
analogues and their isotopomers capable of crossing the
blood-brain barrier is important for structure-activity
the allylboration of silylimines and, subsequently, alumino-
1
1
and borylimines in low yields and variable ee. We have
reported high yields and ee for the asymmetric allylboration
of N-silyl- and N-aluminoimines with allyldiisopinocam-
6,7
relationship (SAR) and pharmacokinetic studies and therapy.
(
1) (a) Lu, H. J.; Silverman, R. B. J. Med. Chem. 2006, 49, 7404. (b)
Chen, G.; Kittler, J. T.; Moss, S. J.; Yan, Z. J. Neurosc. 2006, 26, 2513.
c) Farrant, M.; Nusser, Z. Nature ReV. 2005, 5, 215.
2) (a) Dewey, S. L.; Morgan, A. E.; Ashby, C. A., Jr.; Horan, B.;
(6) For a review on SAR of selective GABA uptake inhibitors, see: Hog,
S.; Greenwood, J. R.; Madsen, K. B.; Larsson, O. M.; Frolund, B.;
Schousboe, A.; Krogsgaard-Larsen, P.; Calusen, R. Curr. Top. Med. Chem.
2006, 6, 1861.
(
(
Kushner, S. A.; Logan, J.; Volkow, N. D.; Fowler, J. S.; Gardner, E. L.;
Brodie, J. D. Synapse 1998, 30, 119. (b) γ-Vinyl GABA is commercialized
as Sabril by Aventis.
(7) Millet, O.; Muhandiram, D. R.; Skrynnikov, N. R.; Kay, L. E. J.
Am. Chem. Soc. 2002, 124, 6439.
(8) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.; O’Donnell, M.
J.; Reddy, M. V. R. J. Am. Chem. Soc. 2005, 127, 13450.
(9) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(10) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org.
Chem. 2005, 9, 1315.
(
(
(
3) Pfizer tradename for gabapentin: Neurontin.
4) Pfizer tradename for pregabalin: Lyrica.
5) Yogeeswari, P.; Ragavendran, J. S.; Sriram, D. Recent Pat. CNS Drug
DiscoVery 2006, 1, 113.
1
0.1021/ol0710919 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/14/2007

pheylborane and a proton source, such as water or metha-
nol.12 Herein we report a convenient, room-temperature (rt)
preparation of stable aldimine-borane adducts from nitriles
and their allylboration for a general synthesis of chiral
γ-substituted GABA analogues. A detailed 11B NMR spec-
troscopic study, the first synthesis of C- and N-deuterated
imine-borane complexes, and a one-pot conversion of
nitriles to δ-amino alcohols via these complexes are included.
To achieve a simple and general route to chiral GABA
derivatives from nitriles, we sought a rt preparation of
aldimine-borane adducts. Accordingly, reduction of ben-
Scheme 2. Allylboration of Benzaldimine-Triethylborane
Complex with B-Allyldiisopinocampheylborane
1
3
zonitrile (1a) with Super-Hydride (LiEt
3
BH, 2), at rt,
Initiating the reaction at -100 °C for 6 h and warming to
-78 °C over 16 h provided 92% ee for the homoallylamine,
thus establishing a direct correlation between temperature
and enantioselectivity for the allylboration of 4a. We then
examined using 11B NMR spectroscopy, revealed the quan-
titative formation of lithium B-iminotriethylborate (3a) (δ
-
6 ppm). Addition of 1 equiv of methanol converted the
1
5
covalent N-B bond in 3a to a dative bond in the aldimine-
examined B-allyldiiso-2-caranylborane (8) for the allyl-
11
16
triethylborane complex (4a) ( B NMR, δ -3 ppm), with
the concurrent elimination of LiOMe. Filtration and removal
of solvents provided pure 4a, whose spectral characteristics
were identical to those reported earlier14 (Scheme 1). This
boration of 4a and obtained 85% ee for 7a.
The successful preparation of 7a in high ee prompted us
to investigate a one-pot allylboration of in situ generated 4a
11
as described in Scheme 1. A B NMR spectroscopic study
3
revealed the displacement of Et B by 5 from 4a as the LiOMe
complex (δ 1 ppm, Figure 1) (Scheme 3).
Scheme 1. One-Pot Preparation of
Benzaldimine-Triethylborane Complex
provided the new route for stable aldimine-boranes to
achieve GABA analogue synthesis.
A series of aromatic aldimine-triethylborane complexes
(
(
4a-e) were readily prepared from the corresponding nitriles
1a-e) using our protocol (see the Supporting Information
1
1
1
13
for B, H, and C NMR spectra).
To prepare the GABA derivatives, allylboration of the
imine-boranes was examined (Scheme 2). B-Allyldiisopi-
11
nocampheylborane (5, B NMR δ 79 ppm) competes with
1
1
11
triethylborane ( B NMR δ 86 ppm) on 4a ( B NMR δ -3
ppm) and eventually displaces it by converting the complex
1
1
into an amine ( B NMR δ 47 ppm) via the allyl transfer.
Figure 1. 11B NMR spectra showing the reaction progress:
1
1
The B NMR spectrum revealed the conversion of the
tetracoordinated boron to the tricoordinated species within
reduction of benzonitrile with LiEt
boration.
3
BH, methanolysis, and allyl-
12 h at rt. Oxidation provided 86% yield of 1-phenyl-3-
butenamine (7a) in 76% ee. Decreasing the reaction tem-
perature to -78 °C increased the time to 16 h, with a
corresponding increase in ee to 88%. Further lowering the
temperature to -100 °C resulted in a very slow reaction.
Comparable yield and ee was achieved for 7a, and we
extended this protocol to a series of substituted benzaldi-
mines, including fluorobenzaldimines. The corresponding
1-phenyl-3-butenamines were obtained in 82-89% yield and
1-99% ee (Table 1). Representative imine-borane inter-
8
(11) (a) Itsuno, S.; Watanabe, K.; Ito, K.; El-Shehawy, A. A.; Sarhan,
A. A. Angew. Chem., Int. Ed. Engl. 1997, 36, 109. (b) Watanabe, K.; Kuroda,
S.; Yokoi, A.; Ito, K.; Itsuno, S. J. Organomet. Chem. 1999, 581, 103. (c)
Itsuno, S.; Yokoi, A.; Kuroda, S. Synlett 1999, 1987.
mediates were allylborated in one pot with 8 also to show
the generality of this process (entries 14-17).
(
12) (a) Ramachandran, P. V.; Burghardt, T. E. Chem. Eur. J. 2005, 11,
387. (b) Chen, G. M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem.,
Int. Ed. 1999, 38, 825.
13) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980,
5, 1.
14) Chen, G. M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122, 4217.
4
(15) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla,
U. S. J. Am. Chem. Soc. 1990, 112, 2389.
(16) Comparing this result with the 10% ee reported (ref.11c) for the
allylboration of 3 with 8, we find that there was no reaction of 3 with 5 or
8 as reported, as confirmed by 11B NMR spectroscopy.
(
4
(
3026
Org. Lett., Vol. 9, No. 16, 2007

δ-amino alcohols in ∼75% yields was then achieved,
avoiding the protection-deprotection steps, from the nitriles
wherein the intermediates 6a-k were hydroborated with
Scheme 3. One-Pot Allylboration of Aldimine-Triethylborane
Complex with (-)-B-Allyldiisopinocampheylborane
1
8
BH
3
·SMe
2
2 2
and oxidized with alkaline H O . Attempted
oxidation of the hydroboration product directly to the GABA
derivatives with PDC resulted in a mixture of products.
Therefore, representative examples of the BOC-protected
δ-amino alcohols (9) were oxidized to the corresponding
GABA derivatives (10) in 70-72% yields by utilizing PDC
(Scheme 4).
Contrary to the reported lack of reduction of aliphatic
1
3
nitriles with 2, we also achieved the reduction of repre-
sentative aliphatic nitriles, cyclohexanecarbonitrile (4f) and
isobutyronitrile (4g), as evidenced by the preparation of the
corresponding homoallylic amines in 42% and 40% yields
and 84% and 80% ee, respectively.17 We are currently
investigating procedures to improve the yields.
Scheme 4. One-Pot Conversion of Benzonitriles to δ-Amino
Alcohols and γ-Substituted GABA
Initially, the N-protected γ-substituted GABA derivatives
were synthesized in 72% yields from these homoallylic
amines without any loss of optical activity using three
steps: (i) protecting them as the BOC derivative, followed
by (ii) hydroboration using dicyclohexylborane and (iii)
oxidation with PDC. A successful one-pot synthesis of the
Extending this protocol, the C-deuterated, N-deuterated,
or C- and N-dideuterated benzaldimine-triethylborane com-
plexes were prepared from benzonitrile using Super-Deu-
teride and CH
combination of Super-Deuteride and CD
Scheme 1). The C-deuterated homoallylic amine provided
3
OH or Super-Hydride and CD
3
OD, or a
3
OD, respectively
Table 1. Allylboration of Aldimine-Borane Complexes
(
imine-BEt3
entry no.
homoallylamine
the corresponding γ-deuterated γ-phenyl GABA.
a
b
R
reagent T, °C no. yield, % ee, %
In conclusion, we have achieved an efficient highly
enantioselective synthesis of γ-substituted GABA derivatives
via a one-pot preparation of a variety of δ-amino alcohols
from nitriles using a sequential reduction with trialkylboro-
hydrides, methanolysis, allylboration, hydroboration, and
oxidation. We are further examining the applications of the
imine-borane complexes in organic synthesis.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
4a Ph
4a Ph
4a Ph
4b 4-Tol
4c 4-MeOC6H4
4d 4-NO2C6H4
4e 2-Thioph
4f Chx
5
5
5
5
5
5
5
5
5
5
5
5
5
8
8
8
8
25 7a
-78 7a
-100 7a
-100 7b
-100 7c
-78 7d
-100 7e
-78 7f
-78 7g
-60 7h
-60 7i
-60 7j
-60 7k
25 7a
86
80
79
86
90
64
82
42
40
63
69
57
60
71
62
61
70
76
88
92
94
94
81
99
84
80
91
90
93
90
76
85
88
84
Acknowledgment. Financial support from the Herbert C.
Brown Center for Borane Research is gratefully acknowl-
edged.
4g i-Bu
1
1
1
1
1
1
1
1
4h 3-FC6H4
4i 4-FC6H4
4j 2,6-F2C6H3
4k 3,4-F2C6H3
4a Ph
4a Ph
4b 4-Tol
4c 4-MeOC6H4
Supporting Information Available: Experimental details
and spectral data of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
-60 7a
-60 7b
-60 7c
OL0710919
a
Isolated yield after chromatography. b Determined by 19F NMR of
(17) The 11B NMR spectrum reveals the formation of the imine-borane
complex.
Mosher amides.
(18) Hydroboration with 9-BBN and Chx2BH gave complex mixtures.
Org. Lett., Vol. 9, No. 16, 2007
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