Azabicyclo[3.1.0]hexane-1-ols as frameworks for the asymmetric synthesis of biologically active compounds

Article abstract of DOI:10.1016/j.tetlet.2007.10.003

Azabicyclo[3.1.0]hexane-1-ols, easily obtained by Ti(IV)-mediated cyclopropanation of amino acid derivatives, constitute versatile, and unprecedented intermediates for the asymmetric synthesis of pharmacologically active products. Indeed, through selective rearrangement, these compounds undergo unusual ring cleavage to lead to pyrrolidinones. Fe(III)-promoted ring opening followed by basic dehydrohalogenation furnishes optically active dihydropyridinones, while Ce(IV)-promoted ring opening provides chiral tricyclopiperidinones via a radical process.

Full text of DOI:10.1016/j.tetlet.2007.10.003

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Tetrahedron Letters 48 (2007) 8765–8767
Azabicyclo[3.1.0]hexane-1-ols as frameworks for the asymmetric
synthesis of biologically active compounds
*
´
Mouhamad Jida, Regis Guillot and Jean Ollivier
`
´ ´ ´
Laboratoire de Synthese Organique et Methodologie, UMR 8182, Institut de Chimie Moleculaire et des Materiaux d’Orsay,
ˆ
´
Bat 420, Universite de Paris-Sud, 91405 Orsay, France
Received 17 July 2007; revised 26 September 2007; accepted 1 October 2007
Available online 5 October 2007
Abstract—Azabicyclo[3.1.0]hexane-1-ols, easily obtained by Ti(IV)-mediated cyclopropanation of amino acid derivatives, constitute
versatile, and unprecedented intermediates for the asymmetric synthesis of pharmacologically active products. Indeed, through
selective rearrangement, these compounds undergo unusual ring cleavage to lead to pyrrolidinones. Fe(III)-promoted ring opening
followed by basic dehydrohalogenation furnishes optically active dihydropyridinones, while Ce(IV)-promoted ring opening provides
chiral tricyclopiperidinones via a radical process.
Ó 2007 Elsevier Ltd. All rights reserved.
Recently, the titanium(IV)-mediated cyclopropanation
of esters by Grignard reagents (Kulinkovich reaction1)
was extended to the case of x-allyl esters to provide
fused bicyclic cyclopropanols, used in the synthesis of
bioactive natural products.2
However, we found that a similar experiment carried out
on the aspartic acid derivative 1b directly led to the
pyrrolidinone 2b as an inseparable mixture of diastereo-
mers4 through an unconventional ring opening of cyclo-
propanol (Scheme 1). The 2b skeleton can be considered
as a plausible precursor of some active pharmacological
products, such as carbapene 4.5 Here, to prove that the
aspartic acid derivative constitutes an exception in the
cyclopropanation reaction, we have prepared esters
5a0–e0 from the amino acids alanine 5a (R = CH3),
valine 5b (R = CH(CH3)2), leucine 5c (R = i-Bu), isoleu-
cine 5d (R = s-Bu), and phenylglycine 5e (R = Ph). The
Previously, Sato and co-workers3 have also successfully
applied this method to synthesize the azabicyclo[3.1.0]-
hexane-1-ol 2a from the serine derivative 1a. A selective
ring opening of the cyclopropane moiety carried out on
the mixture of 2a diastereomers furnished 3-piperidi-
none 3 with 98% ee.
Bn
Bn
N
N
1) FeCl3, Et2O
2) AcONa, MeOH
OTBS
OTBS
OH
O
a
b
Bn
N
3 (94%)
2a (86%)
CO2R'
R
R"MgBr, Ti(Oi-Pr)4
Et2O, THF
cis
/
trans (25/75)
Bn
N
CO2i-Pr
O
N
1a,b
O
O
N
O
O
O
O
a: R= OTBS, R'= Me, R"=
b: R= CO2i-Pr, R'= -Pr, R"=
i
-Pr
O
H
O
i
c
-C6H11
2b(53%)
4
cis/
trans (20/80)
Scheme 1.
Keywords: Azabicyclo[3.1.0]hexan-1-ol; Pyrrolidinone; Dihydropyridinones; Piperidinones.
*
Corresponding author. Tel.: +1 691 532 37; fax: +1 691 562 78; e-mail: jollivie@icmo.u-psud.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.003

8766
M. Jida et al. / Tetrahedron Letters 48 (2007) 8765–8767
aminoesters 5a0–e0 were N-allylated6 to give amines 6a–
e, which were then N-benzylated7 to afford the corres-
ponding ester derivatives 7a–e (Scheme 2).
More recently, Flower II and co-workers10 showed that
bicyclo[4.1.0]hexanol furnished b-substituted cyclohep-
tanones vꢀia CAN pꢀromoted ring opening in the presence
of N3ꢀ, I , and Br .
All products were then submitted to Ti(IV)-mediated
cyclopropanation, which furnished the azabicyclo[3.1.0]-
hexane-1-ols 8a–e as mixtures of cis and trans diastereo-
mers in good yields (Scheme 3).
Surprisingly, following the same protocol, azabi-
cyclo[3.1.0]hexane-1-ols 8a–e furnished, respectively,
products 10a–e, whatever the nucleophile used
(NaN3, NaI, and KBr). Moreover, as depicted in
Scheme 4, an internal radical process, similar to that
reported by Snider,11 allowed these chiral piperidi-
nones 10a–e to be synthesized. The structure of the tri-
cyclic piperidinone 10e was confirmed by X-ray crystal
structure analyses. The tricyclic skeleton of com-
pound 10e is present in inhibitors of biogenic amine
transporters.12
It was noteworthy that, in contrast with the inseparable
isomeric mixture prepared by Sato from a serine deriva-
tive, azabicyclo[3.1.0]hexane-1-ol stereomers 8a–e were
separated by silica gel chromatography and the relative
cis and trans configurations were determined for each by
NOESY two-dimensional NMR experiments.
Furthermore, even as a diastereomeric mixture, the aza-
bicyclo[3.1.0]hexane-1-ol 8e is a precursor for the syn-
thesis of NK1 antagonists.8 Application of the Saegusa
procedure to cyclopropanols 8a–e yielded dihydropy-
ridinones 9a–e, compounds which present potential
inhibitory activities toward c-secretase.9
In summary, we have shown the high potential of azabi-
cyclo[3.1.0]hexane-1-ols to provide original chiral prod-
ucts, which can be considered as precursors of bioactive
products. Extension of this methodology to other
related compounds is under current investigation.
R
R
R
Allyl bromide, LiOH.H2O
Bn Br, K2CO3
N
COOMe
H2N COOH
N
COOMe
H
DMF, 20 ºC
ms 4Å, DMF, 20 ºC
5a-e
MeOH,
SOCl2
6a-e (%)
7a-e (%)
5a'-e'
Me
a
(72%)
(71%)
(75%)
(68%)
(78%)
(74%)
(69%)
(73%)
(66%)
(76%)
R=
i-Pr
b
c
d
e
i-Bu
s-Bu
Ph
Scheme 2.
1) FeCl3 (2eq), Et2O
0 ºC
2) AcONa (5 eq), MeOH
20 ºC
i-PrMgBr (5 eq.), Ti(Oi-Pr)4 (0.1 eq.)
7a-e
N
R
N
R
O
THF, Et2O, 20 ºC
OH
8a-e (%) (cis/trans)
9a-e (%)
Me
a
b
c
d
e
(64%) (68/32)
(75%) (72/28)
(80%) (64/36)
(79%) (71/29)
(76%) (59/41)
(86%)
(83%)
(88%)
(83%)
(87%)
R=
i-Pr
i-Bu
s-Bu
Ph
Scheme 3.
O
R
N
CAN
CH3CN/H2O: 4/1, 0 ºC
8a-e
N
R
O
N
R
O
10a-e (%)
a
Me
R=
(74%)
(68%)
(88%)
(73%)
(95%)
b
c
d
e
i-Pr
i-Bu
s-Bu
Ph
Scheme 4.

M. Jida et al. / Tetrahedron Letters 48 (2007) 8765–8767
8767
Selected data: Compound 8e-cis: (1S,2S,5R)-3-benzyl-2-
1H), 7.06–7.51 (m, 9H); 13C NMR (63 MHz, CDCl3) d
37.6, 46.1, 47.3, 57.5, 76.2, 126.3, 127.1, 127.3, 127.6,
128.5, 128.8, 133.4, 136.0, 138.1, 211.7. FT-IR (NaCl,
cmꢀ1) 3025, 2933, 2253, 1710. MS (EI) m/z (%) 263 (5)
[M+Å], 235 (100), 234 (49), 131 (30), 118 (33), 115 (30),
91 (95), 88 (90). HRMS (ES) m/z calcd for
[C18H17NO+H]+: 264.1383. Found: 264.1390.
20
phenyl-3-azabicyclo[3.1.0]hexan-1-ol: colorless oil. ½aꢁD
1
ꢀ9.3 (c 0.5, CH2Cl2). H NMR (360 MHz, CDCl3) d
0.93 (t, J = 4.7 Hz, 1H), 1.21 (dd, J = 9.0, 4.7 Hz, 1H),
1.28 (br s, 1H), 1.71–1.75 (m, 1H), 2.74 (d, J = 9 Hz,
1H), 3.15 (dd, J = 9.0, 4.0 Hz, 1H), 3.39 (AB system,
dmAB = 39.6 Hz, JAB = 14.0 Hz, 2H), 4.20 (s, 1H),
7.15–7.42 (m, 10H); 13C NMR (63 MHz, CDCl3) d
17.0, 23.9, 52.9, 54.7, 64.7, 69.2, 126.9, 127.7, 128.2,
CCDC 653757 contains the supplementary crystallo-
graphic data for this compound. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
128.4, 128.6, 128.7, 138.4, 139.9. FT-IR (NaCl, cmꢀ1
)
3377, 3028, 2799, 1602. MS (EI) m/z (%) 265 (6)
[M+Å], 237 (19), 194 (24), 92 (25), 91 (100), 65 (16).
HRMS m/z calcd for C18H19NO: 265.1461. Found:
265.1474.
Compound 8e-trans: (1R,2S,5S)-3-benzyl-2-phenyl-3-
Acknowledgments
azabicyclo[3.1.0]hexan-1-ol: white solid. Mp 110 °C.
20
½aꢁD ꢀ50.1 (c 0.5, CH2Cl2). 1H NMR (360 MHz,
This work was financially supported by the CNRS and
the University of Paris-Sud, and a grant to M.J. from
CDCl3) d 0.69 (dd, J = 9.0, 4.7 Hz, 1H), 1.28 (br s,
1H), 1.29 (t, J = 4.7 Hz, 1H), 1.58–1.63 (m, 1H), 2.61
(dd, J = 9.0, 4.0 Hz, 1H), 2.90 (d J = 9.0 Hz, 1H), 3.52
(AB system, dmAB = 219.6 Hz, JAB = 13.3 Hz, 2H), (d,
J = 13.3 Hz, 1H), 3.83 (d, J = 13.3 Hz, 1H), 3.86 (s,
1H), 7.15–7.42 (m, 10H); 13C NMR (63 MHz, CDCl3)
d 17.0, 23.9, 52.9, 54.7, 64.7, 69.2, 126.9, 127.7, 128.2,
´
the Fondation Rene Moawad of Libanon.
References and notes
1. Kulinkovich, O. Russ. Chem. Bull., Int. Ed. 2004, 53,
1065–1086; Kulinkovich, O. Eur. J. Org. Chem. 2004,
4517–4529.
128.4, 128.6, 128.7, 138.4, 139.9. FT-IR (NaCl, cmꢀ1
)
3377, 3028, 2799, 1609. MS (EI) m/z (%) 265 (9)
[M+Å], 237 (22), 194 (13), 118 (35), 116 (37), 91 (100),
64 (15), 41 (53). HRMS m/z calcd for C18H19NO:
265.1461. Found: 265.1451.
´
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2005, 2589–2598.
3. Okamoto, S.; Iwakubo, M.; Kobayashi, K.; Sato, F. J.
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Okamoto, S.; Sato, F. Tetrahedron Lett. 1999, 40, 5331–
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2742.
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Compound 9e: (2S)-1-benzyl-2-phenyl-1,6-dihydro-
20
pyridin-3(2H)-one. Colorless oil. ½aꢁD ꢀ74.2 (c 0.8,
CH2Cl2). 1H NMR (300 MHz, CDCl3) d 3.27 (ddd,
J = 19.5, 3.6, 2.1 Hz, 1H), 3.52 (ddd, J = 19.5, 3.6,
2.1 Hz, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.74 (d,
J = 13.5 Hz, 1H), 4.30 (s, 1H), 6.30 (dt, J = 10.2,
2.0 Hz, 1H), 7.04 (dt, J = 10.2, 3.6 Hz, 1H), 7.27–7.43
(m, 10H); 13C NMR (63 MHz, CDCl3) d 48.6, 58.5,
72.6, 127.4, 128.1, 128.2, 128.5, 128.6, 128.7, 128.9,
136.4, 137.8, 147.8, 196.4. FT-IR (NaCl, cmꢀ1) 3030,
2765, 1682, 1628, 1602. MS (EI) m/z (%) 263 (4)
[M+Å], 196 (75), 194 (36), 172 (100), 92 (15). HRMS
m/z calcd for C18H17NO: 263.1305. Found: 263.1299.
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Yokoshima, S.; Koizumi, H.; Takebe, T.; Kan, T.;
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4786–4788.
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Compound 10e: (1R,10S)-10-phenyl-9-azatricyclo-
[7.3.1.02,7]trideca-2,4,6-trien-11-one: white solid. Mp
20
1
80 °C. ½aꢁD +272 (c 0.5, CH2Cl2). H NMR (360 MHz,
CDCl3) d 2.49 (dd, J = 14.1, 1.8 Hz, 1H), 2.85 (dd,
J = 14.1, 4.2 Hz, 1H), 3.25 (d, J = 13.5 Hz, 1H), 3.27
(m, 1H), 3.60 (d, J = 13.5 Hz, 1H), 4.05 (d,
J = 17.7 Hz, 1H), 4.39 (s, 1H), 4.72 (d, J = 17.7 Hz,