Synthesis of enantiopure 5-substituted 2,3-methanopyrrolidines by cyclization of enantiopure α-Branched α-N-homoallylamino nitriles

Article abstract of DOI:10.1055/s-0031-1291046

The preparation of 5-substituted 2,3-methanopyrrolidines by the stereoselective cyclization of zincated -amino nitriles derived from enantiopure -branched homoallylamines has been investigated. The formation of trans adducts in excellent diastereoselectiv

Full text of DOI:10.1055/s-0031-1291046

1374▌
LETTER
lSetyternthesis of Enantiopure 5-Substituted 2,3-Methanopyrrolidines by Cycliza-
tion of Enantiopure α-Branched α-N-Homoallylamino Nitriles
Cyclisation of Zincated Enantiopure α-Aminonitriles
Sabrina Ouizem, Fabrice Chemla,* Franck Ferreira,* Alejandro Perez-Luna*
UPMC – Univ Paris 06, Institut Parisien de Chimie Moléculaire (UMR CNRS 7201), Institut de Chimie Moléculaire (FR 2769), Case 183,
4 Place Jussieu 75252 Paris Cedex 05, France
Fax +33(1)44277567; E-mail: fabrice.chemla@upmc.fr; E-mail: franck.ferreira@upmc.fr; E-mail: alejandro.perez_luna@upmc.fr
Received: 13.03.2012; Accepted: 28.03.2012
ic amines.8 First, according to our results with adducts 1,
Abstract: The preparation of 5-substituted 2,3-methanopyrro-
cyclization of 2 should provide stereospecifically enantio-
lidines by the stereoselective cyclization of zincated α-amino ni-
pure 5-substituted N-benzyl-2,3-methanopyrrolidines.
triles derived from enantiopure α-branched homoallylamines has
been investigated. The formation of trans adducts in excellent dia-
Second, according to a recent report,9 removal of the ben-
stereoselectivities (up to >98:2) and good yields (up to 71%) is ob- zyl nitrogen protecting group without altering the 2-aza-
served. The absolute configuration and enantiomeric excess are
dependent on the nitrogen protecting group.
bicyclo[3.1.0]hexane framework should be straight-
forward.
Key words: cyclization, zinc, carbenoids, stereoselective synthe-
We chose to prepare the required substrates by the route
sis, bicyclic compounds
depicted in Scheme 2. Diastereomerically pure sulfin-
amides 3a–d were isolated in good yields (57–92%) from
the reaction of the parent enantiopure tert-
2,3-Methanopyrrolidines {2-azabicyclo[3.1.0]hexane de-
butanesulfinylimines10 and allylmagnesium bromide in
rivatives} are interesting molecules that have attracted in-
CH2Cl2.11 Acidic removal of the sulfinyl auxiliary fol-
terest both for their use as scaffolds in biologically active
lowed by reductive amination of benzaldehyde provided
efficiently secondary N-benzyl α-branched homoallylic
amines 4a–c. In the case of 3d, removal of the auxiliary
with HCl also led to desilylation of the protected alcohol.
An additional silylation step to reinstall the tert-butyldi-
methylsilyl group prior to the reductive amination se-
peptide mimics1,2 and as synthetic intermediates for nitro-
gen-containing compounds.3 In contrast with the prepara-
tion of 2,3-methanopyrrolidines in racemic form,1a,3,4
general synthetic methods for the preparation of enantio-
pure 2,3-methanopyrrolidines are not common.1b–e,5–7
quence was thus required. Compound 4d was nevertheless
R
R
R
∗
obtained from 3d in 50% yield. Finally, α-N-(benzyl)-N-
homoallylamino nitriles 2a–d were obtained in 54–95%
yield by alkylation of 4a–d with bromoacetonitrile in
DMF in the presence of K2CO3.
∗
Bn
1. LDA
1. LDA
Ph
N
N
PG N
2. ZnX2
ref. 7
2. ZnX2
NC
NC
this work
1
2
R
R
t-Bu
R
t-Bu
Scheme 1
Bn
Bn
S
a
g
S
b–e
N
N
O
N
O
N
H
H
In this context, we recently reported the diastereoselective
formation of 2,3-methanopyrrolidines from α-N-(1-
phenylethyl)-N-homoallylamino nitriles by treatment
with LDA and transmetalation with a zinc salt (Scheme
1).7 In the case of α-branched substrates 1, the stereo-
chemical outcome of the cyclization was governed by the
homoallylic stereocenter, and a stereospecific inversion
was observed. Unfortunately, difficulties associated both
with the control of the stereoselectivity in preparation of
substrates 1 and with the removal of the 1-phenyl-ethyl
chiral auxiliary made it difficult to use this reaction for a
general approach to 2,3-methanopyrrolidines. We rea-
soned that these drawbacks might be avoided starting
NC
R
3a, R = Et
3b, R = i-Pr
3c, R = Ph
4a–c
2a–c
TBSO
OTBS
TBSO
t-Bu
t-Bu
S
Bn
a
g
b, f, d, e Bn
50%
S
O
N
N
O
N
N
H
H
NC
3d
4d
2d
OTBS
Scheme 2 Reagents and conditions: (a) allylmagnesium bromide,
CH2Cl2, –78 °C to r.t., 57% (3a), 86% (3b), 83% (3c), 92% (3d); (b)
4 M HCl–dioxane solution, 0 °C; (c) aq Na2CO3; (d) benzaldehyde,
CH2Cl2, r.t.; (e) NaBH4, MeOH, 0 °C to r.t., 42% (4a), 41% (4b), 68%
from α-N-(benzyl)-N-homoallylamino nitriles 2 derived (4c) (over four steps); (f) TBSCl, imidazole, CH2Cl2, r.t.; (g) bromo-
acetonitrile, K2CO3, DMF, r.t., 75% (2a), 54% (2b), 95% (2c), 93%
(2d).
from readily available enantiopure α-branched homoallyl-
SYNLETT 2012, 23, 1374–1378
Advanced online publication: 14.05.2012
DOI: 10.1055/s-0031-1291046; Art ID: ST-2012-D0232-L
© Georg Thieme Verlag Stuttgart · New York
We initiated our cyclization studies with prototypical eth-
yl-substituted amino nitrile 2a (Scheme 3, Table 1). As
observed in our previous works,7 full metalation of 2a in
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Cyclisation of Zincated Enantiopure α-Aminonitriles
1375
Et2O required treatment with two equivalents LDA at 0 instead of ZnBr2 led to 5a in slightly improved 41% yield,
°C. As anticipated, addition of ZnBr2 (4 equiv) following but with a lower diastereomeric ratio of 83:17 (Table 1,
lithiation led to the formation of methanopyrrolidine 5a in entry 7). Interestingly, reaction of 2a with zinc diisopro-
40% yield but as a trans/cis mixture (88:12) of diastereo- pylamide [Zn(NiPr2)2] or zinc tetramethylpiperidide
mers. Formation of cis-5a was unexpected as cyclization [Zn(TMP)2] without any additional base also resulted in
of α-branched N-(1-phenyl-ethyl)-amino nitriles had al- the formation of methanopyrrolidine, albeit in lower yield
ways shown an excellent trans selectivity.
(29%) and selectivities (trans/cis = 61:39 and 64:36, re-
spectively; Table 1, entries 8 and 9). Following these ob-
servations, we reasoned that excess LDA would have a
deleterious effect on the reaction outcome when ZnBr2
was used if ligand exchange between diisopropylamide
and bromide occurred. We thus carried out the deproton-
ation of 2a with 1.2 equivalents LDA at –78 °C. Follow-
ing treatment with four equivalents ZnBr2,
methanopyrrolidine 5a was obtained in 46% yield and as
a single trans diastereomer. The relative configuration be-
tween the ethyl group and the cyclopropane ring was as-
signed following transformation of 5a into previously
reported Cbz-protected methanopyrrolidine 6a (Scheme
4).
Et
Et
N
Et
Bn
1. LDA, solvent
N
+
Bn
Bn
N
2. ZnX2, T (°C), 1 h
NC
2a
trans-5a
cis-5a
Scheme 3
Table 1 Optimization of the Diastereoselectivity in the Cyclisation
of 2a
Entry LDA
(equiv)
Solvent ZnX2
(equiv)
Temp Yield of Ratio
(°C) 5a (%)a trans/cisb
1
2
2.4c
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
ZnBr2 (4)
ZnBr2 (4)
ZnBr2 (4)
ZnBr2 (4)
ZnBr2 (1.5)
ZnBr2 (8)
ZnI2 (4)
r.t.
r.t.
40
31
28
88:12
87:13
87:13
n.d.
R
R
2.4d
2.4d
2.4d
2.4d
2.4d
2.4d
a, b, e
3
1
3
1
Bn
Bn
N
CBz
CBz
N
5
5
9–23%
3
0
5a–b
6a–b
4
–20 <5
i-Pr
i-Pr
i-Pr
5
r.t.
r.t.
r.t.
19
<5
41
29
29
46
65:35
n.d.
c–e
c–e
3
2
N
N
N
5
1
4
52%
39%
6
Ph
5b
7
8
7
83:17
61:39
64:36
>98:2
e
Scheme 4 Reagents and conditions: (a) ClCO2CH(Cl)CH3, CH2Cl2,
reflux; (b) MeOH, reflux; (c) H2 (1 atm), Pd(OH)2 on carbon (20%
Pd), MeOH, r.t.; (d) 4 M HCl dioxane solution; (e) ClCO2Bn (CBz-
Cl), Et3N, CH2Cl2, r.t.
8
–
Zn(Ni-Pr2)2 (2) r.t.
f
9
–
Zn(TMP)2 (2) r.t.
10
1.2d
ZnBr2 (4)
r.t.
a Isolated yield after silica gel chromatography.
Adduct 6a allowed for determination of enantiomeric ex-
cess by HPLC.12 It was found that 5a was produced from
2a in 60% ee (Scheme 5, Table 2). The 1R,3R,5R config-
uration of the major enantiomer was assigned by compar-
ison of the HPLC retention times with enantiopure
(1R,3R,5R)-6a.7 Hence, cyclization of 2a occurred with
partial loss of the stereochemical integrity of the homoal-
lylic stereocenter.
b Diastereoselectivity determined by 1H NMR analysis of the crude
reaction mixture.
c Conditions: 0 °C, 1 h.
d Conditions: –80 °C, 1 h.
e Compound 2a was reacted directly with a 2:1 mixture of lithium
diisopropylamide/ZnBr2.
f Compound 2a was reacted directly with a 2:1 mixture of lithium
tetramethylpiperidide/ZnBr2.
The reaction of other substrates was next considered
(Scheme 5, Table 2). Cyclization of amino nitrile 2b hav-
ing a secondary substituent (i-Pr) led to 5b in good 67%
isolated yield, excellent diastereoselectivity and in basi-
cally enantiomerically pure form (97% ee measured after
transformation to 6b13). The 1R,3S,5R configuration was
assigned by transformation into 7 (Scheme 4), the config-
uration of which was determined by comparison of the
HPLC retention times with enantiopure (2S,4R)-714 ob-
tained from known 8.7 The 5-phenyl-substituted methano-
pyrrolidine 5c was obtained from 4c in low 23% yield and
only 88:12 dr. Complete diastereoselectivity but low yield
(34%) was obtained in the cyclization of 4d having a sily-
loxymethyl substituent. Furthermore, we were not able to
Seeking to improve both the yield and the diastereoselec-
tivity, we studied the influence of several reaction condi-
tions (Table 1). Metalation of 2a was achieved in THF
using 2.4 equivalents LDA at –78 °C. However, this sol-
vent change had little impact on the reaction outcome (Ta-
ble 1, entry 2). Conversely, the product yield was found to
be dependent on the reaction temperature (Table 1, entries
3 and 4) and, interestingly, we found that no cyclization
occurred below –20 °C. The same stereoselectivity (dr =
87:13) was, however, obtained at 0 °C and at room tem-
perature. We then investigated the influence of the zinc
salt. It was found that either lower (1.5 equiv, Table 1, en-
try 5) or higher (8 equiv, Table 1, entry 6) amounts of zinc
bromide led to significantly lower yields. The use of ZnI2
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1374–1378

1376
S. Ouizem et al.
LETTER
find suitable conditions to determine the enantiomeric ex- ZnBr2 in THF) provided methanopyrrolidine 11 in a very
cess of 5d.
good 78% isolated yield, as a single trans diastereomer
and in ee >94% (Scheme 7).
R
R
Et
1. LDA (1.2 equiv), THF
2. ZnBr2 (4 equiv), r.t., 1 h
Bn
N
Ph
Et
Bn
N
Ph
Ph
11, > 94% ee
1. LDA (1.2 equiv), THF
N
Ph
N
NC
2. ZnBr2 (4 equiv), r.t., 1 h
78%, >98:2 dr
2a–d
5a–d
NC
10
Scheme 5
Scheme 7
Table 2 Cyclization of α-Amino Nitriles 5a–d under the Optimized
Conditions15
Removal of the benzhydryl group could only be achieved
through hydrogenolysis with Pd(OH)2 on carbon, but
opening of the cyclopropane ring was observed. The
enantiomeric excess was therefore measured on 1216
(Scheme 8). The 2R,4R configuration of the enantiomer
produced from 11 was established by comparison of the
HPLC retention times with enantiopure (2R,4R)-12 pre-
pared from known 13.7 Accordingly, the configuration of
methanopyrrolidine 11 was determined to be 1R,3R,5R,
indicating that cyclization of 10 occurs with retention of
configuration of the homoallylic stereocenter.
Entry
R
Product
Yield
(%)a
Ratio
ee
(%)
trans/cisb
1
2
3
4
Et
5a
5b
5c
5d
46
67
23
34
>98:2
98:2
60c
97c
–
i-Pr
Ph
88:12
>98:2
CH2OTBS
n.d.d
a Isolated yield after silica gel chromatography.
b Diastereoselectivity determined by 1H NMR analysis of the crude
reaction mixture.
c The enantiomeric excess was measured by HPLC following trans-
formation to products 6a,b (see text).
Et
N
Et
N
Et
N
Ph
Ph
a–c
a–c
3
1
2
d Suitable conditions for ee measurement could not be found.
5
BzC
4
47%
54%
Ph
11
12
13
While disappointing from a synthetic standpoint, the cy-
clization of α-N-(benzyl)-N-homoallylamino nitriles re-
mains interesting from a mechanistic perspective.
Similarly to the reaction of α-branched α-N-(1-phenyl-
ethyl)-N-homoallylamino nitriles, diastereoselective for-
mation of trans-5-substituted 2,3-methanopyrrolidines is
observed. In sharp contrast, however, retention of the con-
figuration of the homoallylic stereocenter is observed for
the major or exclusive enantiomer formed.
Scheme 8 Reagents and conditions: (a) H2 (1 atm), Pd(OH)2 on car-
bon (20% Pd), MeOH, r.t.; (b) 4 M HCl dioxane solution; (c)
ClCO2Bn (CBzCl), Et3N, CH2Cl2, r.t.
The stereochemical outcomes observed for the differently
protected α-branched α-N-homoallylamino nitriles cannot
be explained by a single mechanistic rationale. In the case
of (1-phenyl-ethyl)-protected α-amino nitriles, the pro-
posed mechanism involved the formation of zincioimini-
um ions 14 from zincated α-amino nitriles, followed by an
aza-Cope rearrangement (Scheme 9, path a) providing
configurationally stable (2-azoniaallyl)zinc 15 that then
undergoes 6-endo cyclization to afford 16 that annulates
to the trans-5-substituted 2,3-methanopyrrolidines.7 Di-
rect insertion of the zincioiminium ions 1417 (Scheme 9,
path b) was ruled out because it did not account for the ste-
reospecific inversion of the homoallylic stereocenter.
Intrigued by the difference of behavior with respect to the
nitrogen protecting group, we decided to study the cycli-
zation of 10 having a bulkier, still achiral, benzhydryl pro-
tecting group. Enantiopure α-branched N-benzhydryl
homoallylic secondary amine 9 was prepared in 48% yield
from 3a in a sequence involving reductive amination of
benzophenone. Alkylation with bromoacetonitrile provid-
ed 10 in 57% yield (Scheme 6).
t-Bu Et
Ph
Et
Ph
Et
R
R
a–c
d
S
N
H
PG
insertion
(path b)
O
Ph
N
Ph
N
H
N
PG N
trans
annulation
48%
57%
NC
BrZn
3a
9
10
14
(path a) aza-Cope
Scheme 6 Reagents and conditions: (a) 4 M HCl dioxane solution,
0 °C; (b) benzophenone, TiCl4, Et3N, CH2Cl2, r.t.; (c) NaBH4, MeOH,
0 °C to r.t., 48% (over 3 steps); (d) bromoacetonitrile, K2CO3, DMF,
r.t., 57%.
R
R
6-endo
PG
PG
N
N
BrZn
BrZn
15
16
Reaction of enantiopure N-(benzhydryl)amino nitrile 10
under our optimized conditions (1.2 equiv LDA, 4 equiv
Scheme 9
Synlett 2012, 23, 1374–1378
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cyclisation of Zincated Enantiopure α-Aminonitriles
1377
The stereoselective formation of product 11 from 10 is
consistent with the same mechanistic picture (Scheme
10). Formation of zincioiminium ion (E)-17 should be ste-
reoselective as a result of the presence of the bulky benz-
hydryl group.18 Aza-Cope rearrangement through TS1
wherein the ethyl substituent occupies an equatorial posi-
tion would afford 18. The 6-endo cyclization should occur
through TS2 in which the C–Zn bond is parallel to the π-
system of the C=N bond to stabilize the adjacent cationic
center by hypercongugative effects (Linderman’s mod-
el).19 Finally, from intermediate 19 thus formed, annula-
tion through a W-conformation20 would afford 11.
R
N
N
BrZn
ZnBr
cis-5
trans-5
H
H
Bn
Bn
H
R
H
TS3
TS4
Scheme 11
results can be obtained for specific substrates, the ap-
proach remains rather narrow in terms of synthetic scope.
Importantly, however, we have observed a remarkable de-
pendence of the stereochemical outcome of the cycliza-
tion on the nitrogen protecting group, indicative of a
mechanistic difference between on the one hand 1-
phenylethyl- and benzhydryl-protected substrates and on
the other hand benzyl-protected ones.
ZnBr
Ph
Et
H
H
ZnBr
H
Ph
N
N
11
Et
N
TS2
TS1
Et
H
Ph
Acknowledgment
ZnBr
Ph
Ph
Ph
19
18
(E)-17
S.O. thanks MESR for a PhD grant.
H
ZnBr
ZnBr
Ph
H
N
H
References and Notes
Et
N
Ph
(1) (a) Switzer, F. L.; Van Halbeek, H.; Holt, E. M.; Stammer,
C. H. Tetrahedron 1989, 45, 6091. (b) Hanessian, S.;
Reinhold, U.; Gentile, G. Angew. Chem., Int. Ed. Engl. 1997,
36, 1881. (c) Hanessian, S.; Reinhold, U.; Saulnier, M.;
Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8, 2123.
(d) Magnin, D. R.; Robl, J. A.; Sulsky, R. B.; Augeri, D. J.;
Huang, Y.; Simpkins, L. M.; Taunk, P.; Betebenner, D. A.;
Robertson, J. G.; Abboa-Offei, B.; Wang, A.; Cap, M.; Xing,
L.; Tao, L.; Sitkoff, D. F.; Malley, M. F.; Gougoutas, J. Z.;
Khanna, A.; Huang, Q.; Han, S.-P.; Parker, R. A.; Hamann,
L. G. J. Med. Chem. 2004, 47, 2587. (e) Mykhailiuk, P. K.;
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S.; Komarov, I. V. Angew. Chem. Int. Ed. 2008, 47, 5765.
(2) Saxagliptin, a dipeptide-containing a 2,3-methano-
pyrrolidine subunit is currently marketed for treatment of
type 2 diabetes: Augeri, D. J.; Robl, J. A.; Betebenner, D. A.;
Magnin, D. R.; Khanna, A.; Robertson, J. G.; Wang, A.;
Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-
Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G.
E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S.
A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G. J. Med.
Chem. 2005, 48, 5025.
(3) (a) Recent examples: Larquetoux, L.; Kowalska, J. A.; Six,
Y. Eur. J. Org. Chem. 2004, 3517. (b) Larquetoux, L.;
Ouhamou, N.; Chiaroni, A.; Six, Y. Eur. J. Org. Chem.
2005, 4654. (c) Madelaine, C.; Six, Y.; Buriez, O. Angew.
Chem. Int. Ed. 2007, 46, 8046. (d) Madelaine, C.; Ouhamou,
N.; Chiaroni, A.; Vedrenne, E.; Grimaud, L.; Six, Y.
Tetrahedron 2008, 64, 8878. (e) Madelaine, C.; Buriez, O.;
Crousse, B.; Florent, I.; Grellier, P.; Retailleau, P.; Six, Y.
Org. Biomol. Chem. 2010, 8, 5591.
Et
Ph
Ph
TS1
TS2
Scheme 10
Following this model, however, cyclization of amino ni-
triles 2 having a less bulkier benzyl nitrogen protecting
group should involve an initial aza-Cope rearrangement,
as in the case of N-(1-phenyl-ethyl)amino nitriles, where-
in both the homopropargylic substituent and the zinc atom
occupy an equatorial position. Inversion of the configura-
tion of the homoallylic stereocenter should be observed.
Thus, formation of N-(benzyl) 2,3-methanopyrrolidines 5
does not take place predominantly via a mechanism in-
volving an aza-Cope rearrangement.
Given literature precedents on intramolecular cyclopropa-
nation of α-N-(homoallyl)amino carbenes,4a,21 our results
are best explained by a mechanism involving a direct in-
sertion of the zincioiminium ion carbenoid (Scheme 9,
path b). According to this picture, formation of trans-
methanopyrrolidines 5 results from transition state TS3
where the R group occupies an equatorial position to pre-
vent a gauche interaction with the benzyl group on the tet-
rahedral nitrogen (Scheme 11). Note that the formation of
cis-methanopyrrolidines (i.e., cis-5), that was not ob-
served in the cyclization of N-(1-phenylethyl)amino ni-
triles proceeding via an aza-Cope–6-endo-annulation
sequence, can be readily explained by an insertion via
TS4. We cannot, however, provide for the moment a sat-
isfactory explanation for this mechanistic shift and for the
partial inversion observed with ethyl-substituted amino
nitrile 2a.
(4) (a) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem. Int. Ed.
2006, 45, 6726. (b) Couty, S.; Meyer, C.; Cossy, J.
Tetrahedron 2009, 65, 1809. (c) Madelaine, C.; Buzas, A.
K.; Kowalska-Six, J. A.; Six, Y.; Crousse, B. Tetrahedron
Lett. 2009, 50, 5367.
(5) Hercouet, A.; Bessières, B.; Le Corre, M. Tetrahedron:
Asymmetry 1996, 7, 1267.
In conclusion, the formation of trans-5-substituted 2,3-
methanopyrrolidines by cyclization of benzyl- or benz-
hydryl-protected enantiopure α-branched N-homoallyl-
amino nitriles has been investigated. While excellent
(6) Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kwon, C.;
Zhao, G.; Magnin, D. R.; Augeri, D. J.; Gungor, T.; Rotella,
D. P.; Sun, Z.; Liu, Y.; Slusarchyk, W. S.; Marcinkeviciene,
J.; Robertson, J. G.; Wang, A.; Robl, J. A.; Atwal, K. S.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1374–1378

1378
S. Ouizem et al.
LETTER
temperature of the solution reached r.t., the bath was
Zahler, R. L.; Parker, R. A.; Kirby, M. S.; Hamann, L. G.
Bioorg. Med. Chem. Lett. 2007, 17, 6476.
removed, and the mixture was stirred for 2 h. An aq solution
of NH4Cl–NH3 (2:1; 10 mL) and ethanolamine (1 mL) were
added. The biphasic mixture was stirred vigorously during
30 min before the aqueous layer was extracted with EtOAc
(3 × 10 mL). The combined organics were washed with
brine, dried over MgSO4, filtered, and concentrated.
Purification by flash chromatography over silica gel
afforded 5b (144 mg, 67%). [α]D20 +230.5 (c 1.89, CHCl3).
IR (neat): 3029, 2954, 1494, 1453, 1157, 733, 696 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 0.02 (dt, J = 8.1, 5.5 Hz, 1 H),
0.63–0.66 (m, 1 H), 0.91 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 6.8
Hz, 3 H), 1.25–1.35 (m, 1 H), 1.80–1.83 (m, 2 H), 1.90–1.94
(m, 1 H), 2.19–2.25 (m, 1 H), 2.55–2.58 (m, 1 H), 3.23 (d, J
= 12.7 Hz, 1 H), 3.91 (d, J = 12.7 Hz, 1 H), 7.25–7.45 (m, 5
H). 13C NMR (100 MHz, CDCl3): δ = 3.1, 13.5, 15.8, 20.5,
27.8, 28.2, 41.4, 57.0, 64.1, 126.8, 128.3, 129.1, 140.5.
HRMS: m/z [M – H]+ calcd for C15H22N1: 216.17468; found:
216.17453.
(7) Ouizem, S.; Cheramy, S.; Botuha, C.; Chemla, F.; Ferreira,
F.; Perez-Luna, A. Chem. Eur. J. 2010, 16, 12668.
(8) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997,
8, 1895. (b) Bloch, R. Chem. Rev. 1998, 98, 1407. (c) Yus,
M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011,
111, 7774.
(9) Wolan, A.; Soueidan, M.; Chiaroni, A.; Retailleau, P.; Py,
S.; Six, Y. Tetrahedron Lett. 2011, 52, 2501.
(10) (a) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
8869. (b) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W.
Acc. Chem. Res. 2008, 41, 831. (c) Ferreira, F.; Botuha, C.;
Chemla, F.; Pérez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162.
(d) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600.
(11) (a) Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso,
P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 490. (b) Yendapally, R.; Lee, R. E. Bioorg. Med. Chem.
Lett. 2008, 18, 1607.
(12) Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm);
hexane–i-PrOH (95:5), flow rate = 1.0 mL min–1, detection
λ = 220 nm]: tR [(1S,3S,5S)-6a] = 10.4 min; tR [(1R,3R,5R)-
6a] = 11.1 min. Racemic 6a was prepared from racemic 4a
obtained by reaction of allylmagnesium bromide with (E)-N-
benzylpropan-1-imine.
(13) Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm);
hexane–i-PrOH (95:5), flow rate = 0.8 mL min–1, detection
λ = 220 nm]: tR [(1S,3R,5S)-6b] = 13.9 min; tR [(1R,3S,5R)-
6b] = 15.0 min. Racemic 6b was prepared from racemic 4b
obtained by reaction of allylmagnesium bromide with (E)-N-
benzyl-2-methylpropan-1-imine.
(16) Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm);
hexane–i-PrOH = 98:2, flow rate = 0.8 mL min–1, detection
λ = 220 nm]: tR [(2S,4S)-12] = 13.5 min; tR [(2R,4R)-12] =
14.5 min. Racemic 12 was prepared from racemic 9 obtained
by reaction of allylmagnesium bromide with (E)-N-benz-
hydrylpropan-1-imine.
(17) (a) Bégis, G.; Cladingboel, D. E.; Motherwell, W. B. Chem.
Commun. 2003, 2656. (b) Bégis, G.; Cladingboel, D. E.;
Motherwell, W. B.; Sheppard, T. D.; Tocher, D. A. Synthesis
2005, 3186. (c) Motherwell, W. B.; Bégis, G.; Cladingboel,
D. E.; Jerome, L.; Sheppard, T. D. Tetrahedron 2007, 63,
6462. (d) Bégis, G.; Cladingboel, D. E.; Jerome, L.;
Motherwell, W. B.; Sheppard, T. D. Eur. J. Org. Chem.
2009, 1532. (e) Jerome, L.; Sheppard, T. D.; Aliev, A. E.;
Motherwell, W. B. Tetrahedron Lett. 2009, 50, 3709.
(18) Johnson, B. F.; Marrero, E. L.; Turley, W. A.; Lindsay, H. A.
Synlett 2007, 893.
(14) Daicel Chiralpak AD column [(4.6 mm × 250 mm, 5 μm);
hexane–i-PrOH (98:2), flow rate = 0.4 mL min–1, detection
λ = 220 nm]: tR [(2R,4S)-7] = 52.4 min; tR [(2S,4R)-7] = 53.2
min. Racemic 7 was prepared from racemic 4b obtained by
reaction of allylmagnesium bromide with (E)-N-benzyl-2-
methylpropan-1-imine.
(19) Linderman, R. J.; Anklekar, T. V. J. Org. Chem. 1992, 57,
5078.
(15) Procedure for the Preparation of 5a–d (Table 2) and 11 –
Preparation of 5b is Representative
(20) Beruben, D.; Marek, I.; Normant, J. F.; Platzer, N. J. Org.
Chem. 1995, 60, 2488.
Diisopropylamine (0.17 mL, 1.2 mmol) was added at r.t. to
n-BuLi (2.4 M in hexane, 0.50 mL, 1.2 mmol). Once the
gummy mixture formed, dry THF (1.5 mL) was added, and
the solution was cooled to –80 °C. A solution of α-amino
nitrile (2b, 243 mg, 1 mmol) in dry THF (1.5 mL) was added
dropwise. After 1 h of stirring at –80 °C, ZnBr2 (1.0 M in dry
THF, 4.0 mL, 4.0 mmol) was added at once, and the cooling
bath was removed and replaced by a water bath. Once the
(21) (a) Casey, C. P.; Vollendorf, N. W.; Haller, K. J. J. Am.
Chem. Soc. 1984, 106, 3754. (b) Soderberg, B. C.; Hegedus,
L. S. Organometallics 1990, 9, 3113. (c) Ogawa, A.;
Takami, N.; Sekigushi, M.; Ryu, I.; Kambe, N.; Sonoda, N.
J. Am. Chem. Soc. 1992, 114, 8729. (d) Barluenga, J.;
Aznar, F.; Gutierrez, I.; Llorca-Baragano, M. A. Org. Lett.
2002, 4, 4273.
Synlett 2012, 23, 1374–1378
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