Stereocontrolled α-alkylation of oxime ether derived from terpene: Efficient synthesis of new chiral γ- and δ-amino alcohols

Article abstract of DOI:10.1055/s-2008-1078492

The alkylation of (+)-nopinone oxime ether with various electrophiles afforded the corresponding adduct with a total stereo-selectivity. Further reduction of the oxime ether afforded an easily access to new chiral γ-and δ-amino alcohols of high interest for catalysis and asymmetric synthesis. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1078492

LETTER
1669
Stereocontrolled a-Alkylation of Oxime Ether Derived from Terpene:
Efficient Synthesis of New Chiral g- and d-Amino Alcohols
S
a
ynthesis of
Ne
h
w Chiral
g
-
a
o
nd
d
-Amino
m
A
lcohols as Jennequin,a Stéphane Labat,a Loïc Toupet,b Jean-Claude Caille,*c Marc Mauduit*a
‘Sciences Chimiques de Rennes’, UMR 6226 CNRS – Equipe Chimie Organique et Supramoléculaire – Ecole Nationale Supérieure de
Chimie de Rennes, Avenue du Général Leclerc, 35700 Rennes, France
E-mail: marc.mauduit@ensc-rennes.fr
Groupe Matière Condensée et Matériaux, UMR CNRS 6626, Avenue du General Leclerc CS 74205, 35042 Rennes, France
Zambon ZI la Croix-Cadeau, B.P. 10079, 49243 Avrillé, France
E-mail: jean-claude.caille@zambongroup.com
b
c
Received 18 March 2008
Shatzmiller's pioneer works:
Abstract: The alkylation of (+)-nopinone oxime ether with various
electrophiles afforded the corresponding adduct with a total stereo-
selectivity. Further reduction of the oxime ether afforded an easily
access to new chiral g-and d-amino alcohols of high interest for ca-
talysis and asymmetric synthesis.
OR1
OR1
OR1
1. n-BuLi, THF
–65 °C, 5 min
N
N
N
1–2 steps
E
E
2. E+
E
1
2
3
Key words: oxime ether, (+)-nopinone, stereocontrolled alkyla-
tion, amino alcohols
This work:
OR2
N
OR2
N
The oxime ether function represents a great interest in or-
ganic synthesis as it can easily be converted into ketone,1
amine,2 or nitrile3 derivatives. Moreover, this function
shows an interesting reactivity in radical reactions4 and
‘enol-like’ reactions5 or can be used as efficient substrates
in 1,2-addition reactions of organometallics reagents.6
Surprisingly, chiral organometallic additions and stereo-
selective radical cyclization have been fully studied,
whereas no asymmetric ‘enol-like’ reaction has been de-
scribed to date. Pioneers in the area of the ‘enol-like’ re-
action of oxime ether derivatives, Shatzmiller and co-
workers have fully studied the a-alkylation of linear
oxime ether 1 toward several electrophiles using lithiated
strong bases (such as n-BuLi or LDA).5 Products 2, result-
ing from lithiation of the a-carbon syn to the oxime ether,
were obtained in excellent yields (Scheme 1). It is worth
noting that the geometrically directed a-lithiation of the
O-alkyl oxime led to a remarkable control of the regiose-
lectivity during the alkylation, since only one adduct 3
was formed even if a double alkylation process was per-
formed.
1. Base
2. E+
E
controlled ?
chiral terpene
scaffold
chiral terpene
scaffold
Scheme 1 a-Alkylation of oxime ether
1. s-BuLi
THF
MeONH2–HCl
pyridine
–60 °C
10 min
inseparable mixture
of by-products
i-PrOH, reflux
7 h
2. Ph2CO
O
N
quant.
4
MeO
5 (E/Z = 70:30)
Scheme 2 Attempt for alkylation of oxime methyl ether 5 derived
from (+)-camphor
at 80 °C for seven hours in 2-propanol afforded the corre-
sponding oxime methyl ether 5 in quantitative yield with
an E/Z ratio of 70:30. Unfortunately, deprotonation of 5
using s-BuLi at –60 °C in THF followed by the addition
of benzophenone afforded a mixture of inseparable
byproducts (Scheme 2).
The aim of this work is to study an asymmetric version of
the aforementioned oxime ether alkylation using a chiral
scaffold derived from terpenes (Scheme 1). This method
should promote a rapid and efficient access to new chiral
g- and d-amino alcohols, which are components of many
interesting biologically active molecules.
Despite this result, we then decided to continue our effort
with the (+)-nopinone (6) readily available from b-pinene
terpene. The use of methoxylamine hydrochloride in eth-
anol with pyridine under reflux over one hour afforded the
desired oxime methyl ether 7 in quantitative yield with an
E/Z ratio of 90:10. Unfortunately, separation of isomers
by silica gel chromatography was unsuccessful. And
many attempts to improve the selectivity towards E-iso-
mer using alkoxylamine bearing more bulky groups such
as benzyl or tert-butyldimethylsilyl have failed leading to
lower or similar selectivities. We then investigated the
alkylation of the E/Z mixture of 7 using tert-butylbro-
We started our study with the (+)-camphor (4), which is a
cheap and readily available chiral terpene. Reaction of
methoxylamine hydrochloride in the presence of pyridine
SYNLETT 2008, No. 11, pp 1669–1672
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078492; Art ID: G09808ST
© Georg Thieme Verlag Stuttgart · New York

1670
T. Jennequin et al.
LETTER
H
1. s-BuLi
THF, –80 °C
E
OMe
10 min
(Z)-7
OMe
2. electrophile
N
N
10%
7 (E/Z = 90:10)
(E)-8b–j
Ph
Ph Ph
OH
OMe
E:
Ph
Ph
(E)-8b 79% (E)-8c 80%
(E)-8d 56% (E)-8e 60% (E)-8f 78%
O
Me Me
CO2Me
CN
OEt
(E)-8h 89%
OH
(E)-8g 75%
(E)-8i 87%
(E)-8j 67%
Scheme 4 Scope of alkylation of oxime methyl ether 7
A wide range of electrophiles bearing different functions
such as ketone, ester, nitrile, allyl, and ether were also
used furnishing the corresponding single adducts 8b–j in
56–89% of yields after purification by chromatography
(Scheme 4).
In order to prepare several functionalized chiral scaffolds
of high interest in synthesis and catalysis, we then focused
on the reduction of the oxime ether fragment. The usual
procedure using lithium and aluminum hydrides only af-
forded byproducts resulting from the degradation of the
nopinone scaffold. The hydrogenation was also investi-
gated; however, no reaction occurred even under drastic
conditions (PtO2, H2, 50 bar, 12 h). Finally, the use of
BH3·THF complex in THF at reflux condition appeared
more suitable to reduce the oxime ether functionality
(Scheme 5). Starting with 8c–g, the corresponding amines
10c–d, or g-amino alcohols 10f–g were isolated in moder-
ate to good yields after chromatographic purification.
Moreover, the X-ray analysis of the nosylamide 117 de-
rived from 10c allowed us to determine the absolute con-
figuration of the new stereogenic center bearing the amine
function, which is in anti position with respect to the alky-
lated group (Scheme 5).
Scheme 3 Stereoselective a-alkylation of (+)-nopinone oxime
methyl ether 7
moacetate as electrophile. The deprotonation step using s-
BuLi was performed at –80 °C in order to avoid the for-
mation of byproducts. Remarkably, the reaction occurred
on the E/Z mixture of isomers and only one adduct 8a was
observed by NMR in the presence of an unreactive oxime
methyl ether (Z)-7. Taking into consideration, Shatzmiller
results,5a we supposed that only the E-isomer of 7 is able
to react through a syn-alkylation process. This reactivity
can be explained by a possible stabilization of the carb-
anion intermediate with the oxygen lone pair of the oxime
methyl ether function (Scheme 3). The initial 10% of (Z)-
7 can be separated after a silica gel chromatography and
then adduct (E)-8a was isolated in 88% yield. The stereo-
chemistry of the alkylated product was determined by
usual NMR spectroscopical studies (COSY and NOESY)
showing that the approach of the carbanion to the electro-
phile occurs from the opposite side of the gem-dimethyl
bridge, as expected. The X-ray crystal structure analysis
of acid 9a,7 resulting from the saponification of the tert-
butylester 8a, allowed us to confirm both the absolute
configuration of the new chiral center and the E-configu-
ration of the oxime ether functionality. Therefore, we
clearly established the geometrically directed a-lithiation
of oxime ether as previously proposed by Shatzmiller
leading to the unique reactivity of the E-isomer towards
the alkylation.
The alkylated oximes 8h and 8j required a prior reduction
of the ester functionality by using lithium aluminum hy-
dride at 0 °C (Scheme 6). The corresponding oxime alco-
hols were then reduced in the presence of BH3·THF
complex in THF at reflux condition yielding the desired g-
amino alcohols 10h and d-amino alcohol 10i in good iso-
lated yields. Moreover, the treatment of 10i by Boc2O in
the presence of tetrachlorozirconium lead to the corre-
sponding carbamate 11i in 59% of yield, which is a key in-
termediate in the synthesis of a prostaglandin receptor
antagonist 12.8,9
As reported by Shatzmiller et al., aldehydes are excellent
prochiral electrophiles for the alkylation of oxime alkyl
ether promoting the formation of stereogenic alcohols.5a
To complete our study, we were interested to evaluate the
Synlett 2008, No. 11, 1669–1672 © Thieme Stuttgart · New York

LETTER
Synthesis of New Chiral g- and d-Amino Alcohols
1671
Scheme 5 Stereoselective reduction of the oxime methyl ether
function
H
1. LiAlH4
THF, 0 °C
H
CO2R
n
OH
n
OMe
N
2. BH3·THF
THF, reflux
NH2
H
(E)-8h–i
10h n = 0 81%
10i n = 1 82%
R = Me or Et
H
H
ref. 10
Scheme 7 Stereoselective alkylation of (+)-nopinone oxime methyl
ether 7 with aldehydes; formation of chiral g-amino alcohols
Boc2O
OH
NH2
H
ZrCl4
MeCN, r.t.
NHBoc
11i (59%)
[α]D25 +35.2 (c 1, CHCl3)
{lit.10: [α]D25 +35.5 (c 1, CHCl3)}
H
CO2Et
12
catalysis10 and also as new chiral agents for kinetic reso-
lution.11
Scheme 6 Two-step reduction of the oxime methyl ether 8h and 8i;
creation of a key intermediate of the prostaglandine receptor antago-
nist 12
Experimental Section
(+)-Nopinone Oxime Ether 7
To a solution of methoxylamine hydrochloride (1.1 mmol) in EtOH
(30 mL) were added pyridine (1.1 mmol) and (+)-nopinone (6, 1.0
mmol). The mixture was heated to 80 °C for 1 h. Ethanol was then
removed under vacuum. Aqueous HCl solution (1 N) was added to
the residue and the oxime ether was extracted with Et2O. The com-
bined organic layers were washed with sat. aq NaHCO3 solution and
then with brine. The organic phase was dried on anhyd MgSO4, and
the solvent was carefully removed under vacuum to afford 3 in 90%
yield with an E/Z ratio of 90:10. The E- and Z-isomers are only dif-
ferentiated by the 1H NMR chemical shift of the oxime methyl ether
function.
ability to control another asymmetric center. In this partic-
ular purpose, we performed the alkylation reaction using
five different aldehydes (Scheme 7). Resulting alcohols
8k to 8o were obtained in 65–88% of isolated yields with
a diastereoselectivity ranged between 40% de (8k,l) to
100% de (8m–o) depending on the steric hindrance of the
aldehyde used. The further reduction of the oxime methyl
ether function afforded the corresponding g-amino alco-
hols 10m–o in good yields after silica gel purification.
The absolute configuration of these three new chiral cen-
ters formed were determined by the X-ray crystal struc-
ture analysis of 10o7 showing that the carbanion approach
is preferentially occurred on the Si face of the aldehyde.
1H NMR (400 MHz, CDCl3): d = 4.78 (s, 3 H, NOMe, E-isomer),
4.72 (s, 0.3 H, NOMe, Z-isomer), 2.68 (tt, 1 H, J = 5.5 Hz,), 2.53 (t,
1 H, J = 5.5 Hz), 2.33–2.46 (m, 2 H), 2.03 (m, 1 H), 1.83–1.90 (m,
2 H), 1.32 (d, 1 H, J = 10.2 Hz), 1.24 (s, 3 H), 0.78 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.89, 61.29, 61.15, 48.24,
In summary, we have developed an efficient stereoselec- 41.47, 40.96, 30.06, 27.61, 25.43, 21.50.
[a]D20 +11.9 (c 0.71, CHCl3).
tive a-alkylation of oxime ether derived from (+)-nopi-
none. This method led us to develop a convenient pathway
in the asymmetric synthesis of a prostaglandin receptor
antagonist. Additionally, a wide range of new chiral g-
and d-amino alcohols have been synthesized, which could
be useful in the design of new ligands for asymmetric
General Procedure for the Alkylation of (+)-Nopinone Oxime
Ether
To a solution of 3 (1.0 mmol) in dry THF (10 mL) was added drop-
wise s-BuLi in a solution of hexane (1.1 mmol) at –80 °C. The mix-
Synlett 2008, No. 11, 1669–1672 © Thieme Stuttgart · New York

1672
T. Jennequin et al.
LETTER
ture was then stirred for 20 min at this temperature. Then the
electrophile (1.0 mmol) was added slowly. The reaction mixture
was stirred at –80 °C for 1–6 h. After the completion of the reaction,
aq sat. NaHCO3 solution was added at –80 °C to the mixture. The
compound was extracted with Et2O. The combined organic layer
were washed with brine and then dried over anhyd MgSO4. The sol-
vent was removed under vacuum to afford the alkylated oxime ether
in moderate to good yield.
Acknowledgment
Research supported by the French Ministry of Industry and the
Zambon company is gratefully acknowledged (CIFRE grant for TJ).
MM thanks the CNRS and the French Ministry of Research for their
financial supports. We are also grateful to Dr. Rudolf Jenny of IO3S
for a generous gift of (+)-nopinone.
References and Notes
tert-Butylacetate (+)-Nopinone Oxime Methyl Ether 8a
1H NMR (400 MHz, CDCl3): d = 3.75 (s, 3 H), 3.26 (tdd, 1 H,
J = 11.9, 9.6, 2.6 Hz), 3.07 (dd, 1 H, J = 9.6, 6.3 Hz), 2.50 (t, 1 H,
J = 5.5 Hz), 2.37 (ddt, 1 H, J = 8.5, 5.5, 2.8 Hz), 2.07–2.16 (m, 2 H),
1.98–2.02 (m, 1 H), 1.75–1.91 (m, 2 H), 1.40 (s, 9 H), 1.32 (d, 1 H,
J = 5.1 Hz), 1.21 (s, 3 H), 0.71 (s, 3 H).
(1) Shue, H.-J.; Chen, X.; Schwerdt, J. H.; Paliwal, S.; Blythin,
D. J.; Lin, L.; Gu, D.; Wang, C.; Reichard, G. A.; Wang, H.;
Piwinski, J. J.; Duffy, R. A.; Lachowicz, J. E.; Coffin, V. L.;
Nomeir, A. A.; Morgan, C. A.; Varty, G. B.; Shih, N.-Y.
Bioorg. Med. Chem. Lett. 2006, 16, 1065.
13C NMR (100 MHz, CDCl3): d = 171.78, 165.14, 80.65, 61.34,
48.31, 41.91, 41.22, 40.92, 30.11, 28.17 (3 C), 28.06, 25.91, 25.40,
21.58.
[a]D20 +8.04 (c 0.26, CHCl3).
(2) (a) Shu, Y.; Liu, D.; Sun, N. J. Org. Chem. 2006, 44, 3998.
(b) Huang, X.; Ortiz-Marciales, M.; Huang, K.; Stepanenko,
V.; Merced, F. G.; Ayala, A. M.; Correa, W.; De Jesús, M.
Org. Lett. 2007, 9, 1793.
(3) (a) Czekelius, C.; Carreira, E. M. Angew. Chem. Int. Ed.
2005, 44, 612. (b) Narsaiah, A. V.; Nagaiah, K. Adv. Synth.
Catal. 2004, 346, 1271. (c) Anand, N.; Owston, N. A.;
Parker, A. J.; Slatford, P. A.; Williams, J. M. J. Tetrahedron
Lett. 2007, 48, 7761.
(4) (a) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J. Am. Chem.
Soc. 1988, 110, 1634. (b) For a review, see: Miyabe, H.;
Ueda, M.; Naito, T. Synlett 2004, 1140.
(5) (a) Shatzmiller, S.; Bahar, E.; Bercovici, S.; Cohen, A.;
Verdoorn, G. Synthesis 1990, 502. (b) Lidor, R.;
Shatzmiller, S. J. Am. Chem. Soc. 1981, 103, 5916.
(c) Shatzmiller, S.; Dolitzki, B.-Z. Liebigs Ann. Chem. 1991,
189. (d) Shatzmiller, S.; Bercovici, S. J. Chem. Soc., Chem.
Commun. 1990, 327.
2-Acetic Acid Nopinone Oxime Methyl Ether 9a
To 8a (1.0 mmol) in dry CH2Cl2 (5 mL) was added TFA (5 mL)
dropwise at r.t. The mixture was then stirred for 2 h at this temper-
ature. The reaction mixture was quenched with aq sat. NaHCO3 so-
lution followed by the extraction of the acid with CH2Cl2. The
combined organic layers were washed with brine and dried over an-
hyd MgSO4. The solvent was then removed under vacuum to afford
9a in 57% yield.
1H NMR (400 MHz, CDCl3): d = 3.76 (s, 3 H), 3.38 (m, 1 H), 3.07
(dd, 1 H, J = 9.6, 6.7 Hz), 2.53 (t, 1 H, J = 5.5 Hz), 2.37–2.44 (m, 1
H), 2.16–2.31 (m, 2 H), 2.00–2.05 (m, 1 H), 1.51–1.57 (m, 2 H),
1.31 (d, 1 H, J = 5.3 Hz), 1.22 (s, 3 H), 0.72 (s, 3 H).
(6) (a) Gallagher, P. T.; Hunt, J. C. A.; Lightfoot, A. P.; Moody,
C. J. J. Chem. Soc., Perkin Trans. 1 1997, 2633. (b)Hunt, J.
C. A.; Laurent, P.; Moody, C. J. J. Chem. Soc., Perkin Trans.
1 2002, 2378.
13C NMR (100 MHz, CDCl3): d = 177.92, 164.72, 61.39, 48.20,
41.24, 40.81, 30.35, 27.59, 25.95, 25.37, 21.63.
[a]D20 +53 (c 0.05, CHCl3).
(7) Crystallographic data for the structural have been deposited
with the Cambridge Crystallographic Data Centre, CCDC
No. 665258, 298980, and 653068 for compounds 9a, 11c,
and 10o, respectively. Copies of this information may be
obtained free of charge from The Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033; e-
mail: deposit@ccdc.cam.ac.uk or www: http://
General Procedure for the Reduction of the Oxime Ether
Group
To the oxime ether (1.0 mmol) was added BH3·THF solution (1 M)
in THF (3.0 mmol). The mixture was stirred under reflux (80 °C)
overnight. The mixture was quenched with aq NaOH solution (1 M)
and the product was extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhyd MgSO4, and con-
centrated under vacuum to afford the corresponding compound in
moderate to good yields.
www.ccdc.cam.ac.uk].
(8) Campos, K. R.; Journet, M.; Cai, D.; Kowal, J. J.; Lee, S.;
Larsen, R. D.; Reider, P. J. J. Org. Chem. 2003, 68, 2338.
(9) (a) Tsuri, T.; Honma, T.; Hiramatsu, Y.; Mitsumori, S.;
Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino,
J.; Ohtani, M. J. Med. Chem. 1997, 40, 3504. (b) Seno, K.;
Hagashita, S. Chem. Pharm. Bull. 1989, 37, 1524.
(10) Lait, S. M.; Rankic, D. A.; Keavy, B. A. Chem. Rev. 2007,
107, 767.
(1R)-1-{(2S,3S)-2-amino-6,6-dimethylbicyclo[3.1.1]heptan-3-
yl}-2-methylpropan-1-ol (10o)
1H NMR (400 MHz, CDCl3): d = 3.32 (m, 1 H), 3.04 (dd, 1 H,
J = 7.5, 1.8 Hz), 2.23–2.27 (m, 1 H), 2.15 (m, 2 H), 1.85–1.95 (m,
2 H), 1.67–1.82 (m, 3 H), 1.17 (s, 3 H), 1.06 (s, 3 H), 0.96 (d, 3 H,
J = 6.7 Hz), 0.79 (d, 3 H, J = 6.7 Hz), 0.64 (d, 1 H, J = 9.8 Hz).
(11) Cordova, A.; Sunden, H.; Xu, Y.; Ibrahem, I.; Zou, W.;
Engqvist, M. Chem. Eur. J. 2006, 12, 5446.
13C NMR (100 MHz, CDCl3): d = 83.07, 59.15, 49.72, 40.31, 37.19,
31.98, 28.48, 28.15, 27.185, 21.54, 19.36, 12.96.
[a]D20 +51.6 (c 0.62, CHCl3).
Synlett 2008, No. 11, 1669–1672 © Thieme Stuttgart · New York