Titanium-mediated cyclopropanation on diesters: Mechanistic study on the dramatic effects of selected parameters

Article abstract of DOI:10.1055/s-0029-1220125

Competitive reactions of diisopropyloxy(²-alkene)titanium on N-allyl diesters derived from natural amino acids and performed under varying conditions (temperature, nature, and concentration of Grignard reagents) show different regio- and chemoselectivities. In light of the isolated reaction products, a possible mechanism of the formation of original products is discussed.

Full text of DOI:10.1055/s-0029-1220125

LETTER
1627
Titanium-Mediated Cyclopropanation on Diesters: Mechanistic Study on the
Dramatic Effects of Selected Parameters
Titanium-Mediated
C
y
o
c
lopropanati
u
on on Dieste
h
r
s
amad Jida, Xavier Gaucher, Jean Ollivier*
Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay, Université de
Paris-Sud XI, 91405 Orsay, France
Fax +33(1)69157252; E-mail: jean.ollivier@u-psud.fr
Received 5 April 2010
Dedicated to Professor Henri Kagan on the occasion of his 80th birthday
In the present work, we observed that, under classical cy-
Abstract: Competitive reactions of diisopropyloxy(h2-alkene)tita-
clopropanation conditions [1 equiv of Ti(Oi-Pr)4, 4–5
equiv of C6H11MgCl (2–2.4 M in Et2O), Et2O–THF (1:1),
4 h, 20 °C], the N-allyl dimethyl aspartate derivative 1a
nium on N-allyl diesters derived from natural amino acids and per-
formed under varying conditions (temperature, nature, and
concentration of Grignard reagents) show different regio- and
chemoselectivities. In light of the isolated reaction products, a pos- afforded an inseparable mixture of pyrrolidinones 2a,b
sible mechanism of the formation of original products is discussed.
and a small amount of trans-esterified aspartate derivative
1b. Moreover, from the diesters 1a or 1b, no product re-
sulting from a possible reaction between the excess of
Grignard and the ester or ketone functions of the newly
formed pyrrolidinones 2a or 2b was observed (Scheme 3).
Key words: esters, fused ring systems, heterocycles, regioselectiv-
ity, titanium, Kulninkovich reaction
Recently,1 we have studied the regio- and stereoselectivity
of the Kulinkovich reaction2 performed on aspartic acid
derivative 1, and we observed, under classical experimen-
tal conditions [Ti(Oi-Pr)4, C6H11MgCl], the formation of
only the unexpected pyrrolidinone 2. On the other hand,
Joullié et al.3 obtained the expected azabicyclo[3.1.0]hex-
an-1-ol 3 when performing the same reaction, but with
ClTi(Oi-Pr)3 as catalyst (Scheme 1).
Bn
MeOOC
N
MeOOC
1a
a
Bn
Bn
Bn
i-PrOOC
i-PrOOC
N
N
COOMe
COOi-Pr
N
Bn
N
Bn
N
+
R1OOC
+
R1OOC
HO
O
O
a
b
BnN
O
2a (34%)
(cis/trans = 22:78)
1b (9%)
2b (7%)
(cis/trans = 22:78)
R1 = Me, i-Pr
2 = C5H9, C6H11
R1OOC
COOR1
R
2
1
3
Scheme 3 Reagents and conditions: (a) C6H11MgCl, Ti(Oi-Pr)4,
Et2O–THF, 20 °C.
Scheme 1 Reagents and conditions: (a) R2MgBr, Ti(Oi-Pr)4, Et2O–
THF, 20 °C; (b) R2MgBr, ClTi(Oi-Pr)3, Et2O, THF, 20 °C.
To avoid trans-esterification, all the reactions were thus
performed on isopropyl esters 1b. The reactions were car-
ried out in presence of titanium catalyst by dropwise addi-
tion of four equivalents of cyclohexyl Grignard reagent at
a given temperature over three hours. Then, after an addi-
tional hour at the same temperature, the reaction was
quenched and the products isolated. NMR analysis of the
crude product allowed the determination of the cis/trans
ratios, while yields were calculated after purification by
column chromatography.
It is noteworthy that the same reaction, performed on the
homologous glutamic acid derivative 4, only afforded the
corresponding azabicyclo[3.1.0]hexan-1-ol 5 even in the
presence of the titanium tetraisopropoxide (Scheme 2).4
Bn
i-PrOOC
N
a
BnN
i-PrOOC
HO
Parameters such as temperature and amount of titanium
isopropylate, which are able to affect the sequence of the
reaction, were tested (Table 1).
COOi-Pr
4
5
Scheme 2 Reagents and conditions: (a) C6H11MgCl, Ti(Oi-Pr)4,
Et2O–THF, 20 °C.
Firstly, we noted that the use of either 5 or 6 equivalents
of the Grignard reagent had no significant influence on the
yield or cis/trans product ratio of the reaction. Unsatisfac-
tory yields were observed for the reactions carried out at
low temperatures (entries 1–3) while the best result was
SYNLETT 2010, No. 11, pp 1627–1630
Advanced online publication: 01.06.2010
DOI: 10.1055/s-0029-1220125; Art ID: D08410ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1628
M. Jida et al.
LETTER
0.5 mol L–1 (entry 1), the aspartate derivative only fur-
nished pyrrolidinones 2b with a yield close to that previ-
ously obtained with cyclohexyl magnesium chloride and
similar diastereomeric ratio. However, at concentrations
above 1 mol L–1 at room temperature, a dramatic effect
was observed, and the formation of ketone 6 became pre-
ponderant to exclusive, according to the increasing con-
centration (entries 2–4). On the other hand, lowering the
temperature only affected the yield of the product nega-
tively (entry 5–7).
Table 1 Effects of the Amount of Ti(Oi-Pr)4 and the Temperature
on the Formation of Pyrrolidinone 2b
Bn
N
Bn
N
i-PrOOC
C6H11MgCl (4–5 equiv),
Ti(Oi-Pr)4 (n equiv)
COOi-Pr
Et2O–THF (1:1), T °C
O
i-PrOOC
1b
2b
Entry Ti(Oi-Pr)4·(n) Temp (°C) Yield (%) Ratio (cis/trans)
1
2
3
4
5
6
7
1
–78
–40
0
18
25
34
53
45
20
35
27:73
27:73
24:76
20:80
18:82
22:78
23:77
Although high concentrations promote intermolecular re-
actions, no report of such selectivity in the Kulinkovich
reaction has appeared in the literature.6 As depicted in
Scheme 4, the formation of the ketone 6 can occur
through the incorporation of titanium complex 7 in the es-
ter function of the pyrrolidinone 2b giving the oxatitana-
cyclopentane 8, then the cyclopropanol 9 which, on ring
opening, leads to the ketopyrrolidinone 67 (Scheme 4).
1
1
1
20
50
20
20
1
0.1
2
Bn
N
obtained performing the reaction at room temperature (en-
try 4). At a higher temperature of 50 °C (entry 5) the yield
was lower, but the selectivity was essentially maintained.
However, reducing (entry 6) or increasing (entry 7) the
amounts of the titanium species led to lower yields al-
though the variations of the cis/trans ratios remained al-
most unchanged.
a
1b
O
O
6 (51%)
(cis/trans = 28:72)
Oi-Pr
Bn
N
O
Ti(Oi-Pr)2
O
On the other hand, isopropyl magnesium bromide or
chloride had been initially used by Sato5 as a source of
Grignard reagent in certain intramolecular cyclopropana-
tion reactions; surprisingly, when applied to the aspartate
derivative 1b, the formation of the pyrrolidinone 6 was
observed, and in yields highly dependent upon the con-
centration of the organometallic reagent (Table 2).
i-PrMgBr
8'
Ti(Oi-Pr)4
Oi-Pr
O
HO
Ti(Oi-Pr)2
Bn
Bn
N
N
7
Ti(Oi-Pr)2
2b
O
O
Table 2 Effects of the Concentration of Grignard Reagent on the
Synthesis of Pyrrolidinones 2b and 6
8
9
Scheme 4 Reagents and conditions: (a) Ti(Oi-Pr)4 (1 equiv), 2.4 M
i-PrMgBr (5 equiv), Et2O–THF (1:1), 20 °C.
Ti(Oi-Pr)4 (1 equiv), X mol⋅L–1
Bn
Bn
C3H7
N
N
COOi-Pr
+
i-PrMgBr (5 equiv)
1b
O
Et2O–THF (1:1), T °C
O
O
Compared to the bulky cyclopentyl- or cyclohexylmagne-
sium halide, the incorporation of the titanium complex 7
seems quite conceivable. The hypothesis of a possible co-
ordination between the titanium species and the oxygen of
the ketone function could stabilize the complex form 8¢
sufficiently, such that simple hydrolysis would lead di-
rectly to the ketopyrrolidinone 6. On the other hand, the
ring opening on the side chain could be possible but per-
haps less likely.
2b
6
Entry i-PrMgBr Temp Yield of 2b (%),
Yield of 6 (%), ratio
(cis/trans)
(mol·L–1) (°C)
ratio (cis/trans)
1
2
3
4
5
6
7
0.5
1.2
1.8
2.4
2.4
2.4
2.4
20
20
20
20
0
49 (19:81)
0
28 (22:78)
16 (21:79)
29 (26:74)
51 (28:72)
27 (25:75)
23 (27:73)
13 (23:77)
15 (24:76)
0
0
0
0
This result can be extended to the formation of the mono-
cyclic pyrrolidinone skeleton of ester 2b (vide supra
Scheme 1). Indeed, as represented in Scheme 5, following
formation of titanium species 10, the coordination of the
weak Lewis acid (XMgOi-Pr) from Ti(Oi-Pr)4 between
the ester on the side chain and the Oi-Pr residue of the
oxatitanacyclopentane 11a (path a) does not constitute a
sufficient driving force to achieve the contraction cycle,
thus a subsequent hydrolysis leads to the pyrrolidinone
–40
–78
Indeed, in the presence of five equivalents of isopropyl
magnesium bromide at a concentration of approximately
Synlett 2010, No. 11, 1627–1630 © Thieme Stuttgart · New York

LETTER
Titanium-Mediated Cyclopropanation on Diesters
1629
2b. In support of this theory, performing the reaction in
the presence of trimethylsilyl chloride gives a similar re-
sult. On the other hand, the reaction carried out with
ClTi(Oi-Pr)3 (path b) releases a stronger Lewis acid
(XMgCl) which, on coordination to give the complex 11b,
is capable of inducing formation of the titanium salt 12. In
this case, simple hydrolysis yields the stable azabicyc-
lo[3.1.0]hexanol 3b isolated by Joullié.
Table 3 Effects of the Concentration of Grignard Reagent on the
Synthesis of Cyclopropanols 5, 13, and 147
HO
HO
X mol⋅L–1, i-PrMgCl (5 equiv),
Ti(Oi-Pr)4 (1 equiv)
Bn
N
Bn
N
+
+
4
5
Et2O–THF (1:1), 20 °C
HO
HO
13
14
Further evidence supporting our previous assumption
came to light when extending this experiment to the
glutamate derivative 4 which, as we had reported before,
does not undergo cyclopropyl ring opening under titanium
isopropoxide mediated conditions (vide supra Scheme 2).
Entry
i-PrMgBr
Yield of 5
Yield of 13 Yield of 14
(X mol·L–1) (%), ratio
(%), ratio
(%), ratio
(cis/trans)
(cis/trans)
(cis/trans)
1
2
0.5
2.4
50 (69:31)
0
0
0
26 (60:40)
17 (64:36)
Oi-Pr
Ti(Oi-Pr)4 2 XMgOi-Pr
MgX
(Oi-Pr)2
Ti
Bn
( )n
O
1b
N
Meanwhile, novel mechanisms have been proposed to ex-
plain the formation of primary or secondary unexpected
products.
ligand
exchange
Oi-Pr
( )n
ClTi(Oi-Pr)3
ClMgX
+
O
Ti(Oi-Pr)2
XMgOi-Pr
10
Acknowledgment
Oi-Pr
path b
from
The authors gratefully acknowledge Professor Oleg Kulinkovich,
Belarusian State University of Minsk, for helpful discussions.
Bn
O
X
N
ClTi(Oi-Pr)3
Mg
O
Cl
path a
from
Ti(Oi-Pr)4
O
References and Notes
Ti
(Oi-Pr)2
(1) Garnier, J.-M.; Jida, M.; Ollivier, J. Synlett 2006, 2739.
(2) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
(3) Faler, C. A.; Joullié, M. M. Tetrahedron Lett. 2008, 49,
6512.
11b
Oi-Pr
Bn
N
Bn
N
(4) Jida, M. PhD Thesis; Université de Paris-Sud 11: France,
O
X
Mg
2008.
COOi-Pr
O
Oi-Pr
(5) (a) Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am.
Chem. Soc. 1995, 117, 3881. (b) Nakagawa, T.; Kasatkin,
A.; Sato, F. Tetrahedron Lett. 1995, 36, 3207. (c) Harada,
K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203.
(d) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36,
4261.
OTi(Oi-Pr)3
O
x
Ti
(Oi-Pr)2
12
11a
(6) Kulinkovich, O. G.; Kananovich, D. G. Eur. J. Org. Chem.
2007, 2121.
(7) Selected Data
Bn
N
Bn
N
i-PrOOC
HO
3b
i-PrOOC
tert-Butyl 3-{3-Benzyl-1-hydroxy-3-azabicyclo-
[3.1.0]hex-2-yl} Propanoate (5)
O
X = Br or Cl
n = 1 or 2
Colourless liquid. IR (neat): 3333, 3027, 2931, 1740, 1602
cm–1. 1H NMR (360 MHz, CDCl3): d = 7.34–7.24 (m, 10 H,
cis + trans), 5.18–5.01 (m, 2 H, cis + trans), 4.09 (d, J = 13.7
Hz, 1 H, cis), 4.00 (d, J = 13.3 Hz, 1 H, trans), 3.86 (d,
J = 13.7 Hz, 1 H, cis), 3.75 (d, J = 13.3 Hz, 1 H, trans), 3.23
(dd, J = 12.6, 6.1 Hz, 1 H, cis), 3.15 (dd, J = 9.7, 4.7 Hz, 1
H, trans), 2.80 (t, J = 4.5 Hz, 1 H, trans), 2.69 (t, J = 4.5 Hz,
1 H, cis), 2.55 (d, J = 12.6 Hz, 1 H, cis), 2.36 (d, J = 9.7 Hz,
1 H, trans), 2.06–1.90 (m, 4 H, cis + trans), 1.87–1.73 (m, 4
H, cis + trans), 1.60–1.54 (m, 2 H, cis + trans), 1.28–1.23
(m, 2 H, cis + trans), 1.25 (d, J = 6.2 Hz, 3 H, trans), 1.22 (d,
J = 6.9 Hz, 3 H, cis), 1.20 (d, J = 6.9 Hz, 3 H, cis), 1.18 (t,
J = 4.8 Hz, 1 H, trans), 1.15 (d, J = 6.2 Hz, 3 H, trans), 1.11
(dd, J = 9.0, 5.8 Hz, 1 H, cis), 0.87 (dd, J = 10.1, 4.8 Hz, 1
H, trans), 0.46 (t, J = 5.8 Hz, 1 H, cis). 13C NMR (63 MHz,
CDCl3): d = 170.8 (cis), 170.6 (trans), 137.9 (cis), 137.8
(trans), 128.9 (cis), 128.7 (trans), 128.5 (cis), 128.3 (trans),
127.3 (cis), 127.2 (trans), 68.4 (cis), 68.2 (trans), 66.6 (cis),
65.8(trans), 59.4 (cis), 59.1 (trans), 58.3 (cis), 58.1 (trans),
Scheme 5 Reagents and conditions: Ti(Oi-Pr)4 or ClTi(Oi-Pr)3,
C5H9MgBr or C6H11MgCl, Et2O–THF, 20 °C.
Indeed, extending the ester on the side chain does not al-
low the previous coordination and, as expected, a cis/trans
inseparable mixture of azabicyclo[3.1.0]hexanols 13 and
14 resulting from a double Kulinkovich reaction occurred
in the presence of a high concentration of Grignard re-
agent (Table 3).
In conclusion, we have investigated alternative experi-
mental conditions allowing different cyclopropanol deriv-
atives to be obtained. The influence of several parameters
such as temperature, titanium catalyst, nature, and con-
centration of Grignard reagent were studied in order to
optimize reactions which may even be competitive.
Synlett 2010, No. 11, 1627–1630 © Thieme Stuttgart · New York

1630
M. Jida et al.
LETTER
1.54 (m, 2 H, a + b), 1.44–1.39 (m, 2 H, a + b), 1.40 (t,
55.7 (trans), 54.9 (cis), 36.8 (cis), 35.9 (trans), 25.8 (cis),
24.5 (trans), 21.7 (cis), 21.1 (trans), 20.9 (cis), 20.2 (trans),
15.8 (cis), 15.6 (trans). MS (EI, trans isomer): m/z
(%) = 303(9) [M+], 160 (48), 96 (27), 91 (100). MS (EI, cis
isomer): m/z (%) = 303(6) [M+], 234 (45), 188 (42), 91
(100). HRMS (ES): m/z calcd for C18H26NO3 [M + H]+:
304.19070; found: 304.19057.
J = 5.1 Hz, 1 H, a), 1.30–1.24 (m, 2 H, a + b), 1.26 (t, J = 5.8
Hz, 1 H, b), 1.18–1.08 (m, 2 H, a + b), 1.16 (d, J = 6.2 Hz, 3
H, a), 1.07 (d, J = 6.2 Hz, 3 H, b), 0.97–0.87 (m, 4 H, a + b),
0.81 (dd, J = 9.4, 5.1 Hz, 1 H, a), 0.07 (dd, J = 10.2, 5.8 Hz,
1 H, b). 13C NMR (63 MHz, CDCl3): d = 139.7 (b), 137.9
(a), 129.6 (b), 128,7 (a), 128.5 (b), 128.3 (a), 128.2 (b),
127.5 (a), 70.2 (b), 70.1 (a), 65.7 (a), 64.6 (b), 57.8 (b), 57.7
(a), 55.8 (a), 55.7 (b), 54.1 (a), 53.4 (b), 37.3 (a), 31.1 (b),
24.6 (a), 24.5 (b), 22.7 (a), 22.1 (b), 20.2 (a), 18.4 (b), 17.4
(a), 16.5 (b), 14.4 (a), 13.8 (b), 12.4 (b), 11.4 (a). MS (EI,
isomer a): m/z (%) = 287 (5)[M+], 218 (18), 200(20),
188(47), 91(100). MS (EI, isomer b): m/z (%) = 287 (6)
[M+], 218 (17), 200(26), 188 (29), 91(100). HRMS (ES):
m/z calcd for C18H26NO2 [M + H]+: 288.19580; found:
288.19622.
1-Benzyl-4-methyl-2-(2-oxopentyl)-3-pyrrolidinone (6)
Colourless liquid. IR (neat): 3057, 3027, 2955, 1758, 1603
cm–1. 1H NMR (250 MHz, CDCl3): d = 7.36–7.27 (m, 10 H,
cis + trans), 3.88 (d, J = 13.0 Hz, 1 H, cis), 3.85 (d, J = 13.0
Hz, 1 H, trans), 3.48 (d, J = 13.7 Hz, 1 H, cis), 3.46 (d,
J = 13.0 Hz, 1 H, trans), 3.40 (t, J = 8.3 Hz, 1 H, trans), 3.29
(t, J = 5.0 Hz, 1 H, cis), 3.01 (dd, J = 11.2, 9.0 Hz, 1 H,
trans), 2.85 (dd, J = 12.6, 7.2 Hz, 1 H, cis), 2.73 (dd,
J = 12.6, 7.2 Hz, 1 H, cis), 2.68 (dd, J = 11.2, 8.3 Hz, 2 H,
cis), 2.67–2.60 (m, 2 H, cis + trans), 2.63 (dd, J = 10.0, 5.0
Hz, 2 H, trans), 2.27–2.20 (m, 4 H, cis + trans), 2.08 (dd,
J = 11.2, 9.0 Hz, 1 H, trans), 1.60–1.54 (m, 4 H, cis + trans),
1.21 (d, J = 7.6 Hz, 3 H, cis), 1.14 (d, J = 7.2 Hz, 3 H, trans),
1.07 (t, J = 7.6 Hz, 3 H, cis), 1.06 (t, J = 7.6 Hz, 3 H, trans).
13C NMR (63 MHz, CDCl3): d = 217.7 (cis), 217.5 (trans),
208.1 (cis), 207.8 (trans), 138.2 (cis), 138.0 (trans), 128.9
(trans), 128.7 (cis), 128.4 (cis), 128.2 (trans), 127.5 (trans),
127.3 (cis), 66.4 (trans), 66.0 (cis), 59.4 (trans), 58.9 (cis),
57.9 (trans), 56.7 (cis), 45.2 (cis), 43.1 (trans), 41.9 (cis +
trans), 36.2 (cis), 35.3 (trans), 18.0 (cis), 17.1 (cis), 17.0
(trans), 16.0 (cis), 13.7 (trans), 11.9 (trans). MS (EI, trans
isomer): m/z (%) = 273 (5) [M+], 86 (40), 84 (61), 55 (55),
51 (35), 49 (100), 44 (49), 40 (90). MS (EI, cis isomer):
m/z (%) = 273 (4) [M+], 91 (100), 86 (41). HRMS (ES):
m/z calcd for C17H24NO2 [M + H]+: 274.18020; found:
274.18082.
(1R,2S)-3-Benzyl-2-[2-(1-hydroxy-2-methylcyclo-
propyl)ethyl]-3-azabicyclo[3.1.0]hexan-1-ol (14)
[Inseparable mixture of undetermined cis and trans
diastereomers (ratio 64:36: major a and minor b) on the
side chain.]
Colourless liquid. IR (neat): 3036, 2929, 2791, 1602 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.34–7.25 (m, 10 H, a + b),
3.84 (d, J = 13.3 Hz, 1 H, a), 3.83 (d, J = 13.3 Hz, 1 H, b),
3.64 (d, J = 13.3 Hz, 1 H, a), 3.63 (d, J = 13.3 Hz, 1 H, b),
3.17 (dd, J = 10.1, 4.7 Hz, 1 H, b), 3.02 (t, J = 4.2 Hz, 1 H,
a), 2.97 (t, J = 4.2 Hz, 1 H, b), 2.34 (d, J = 9.4 Hz, 1 H, a),
2.31 (d, J = 10.1 Hz, 1 H, b), 2.29 (dd, J = 9.4, 4.0 Hz, 1 H,
a), 2.01–1.92 (m, 4 H, a + b), 1.83–1.73 (m, 4 H, a + b),
1.59–1.54 (m, 2 H, a + b), 1.47–1.45 (m, 2 H, a + b), 1.29 (t,
J = 6.7 Hz, 1 H, a), 1.28–1.25 (m, 2 H, a + b), 1.17 (dd,
J = 9.0, 5.4 Hz, 1 H, b), 1.06 (d, J = 6.7 Hz, 3 H, a), 1.04 (d,
J = 6.7 Hz, 3 H, b), 0.93 (dd, J = 9.0, 6.7 Hz, 1 H, a), 0.86–
0.81 (m, 2 H, a + b), 0.76–0.73 (m, 4 H, a + b), 0.02 (t,
J = 10.2 Hz, 1 H, b). 13C NMR (63 MHz, CDCl3): d = 139.2
(b), 137.6 (a), 129.4 (a + b), 128,7 (b), 128.6 (a), 128.3 (b),
127.1 (a), 67.1 (b), 66.3 (a), 63.4 (a), 63.2 (b), 58.7 (a), 58.4
(b), 57.8 (a), 57.4 (b), 54.7 (b), 54.2 (a), 30.8 (a), 30.4 (b),
24.6 (a), 24.4 (b), 21.6 (a), 20.4 (b), 20.2 (a), 20.0 (b), 19.6
(a), 19.1 (b), 15.0 (a), 14.9 (b), 14.6 (b), 14.3 (a). MS (EI,
isomer a): m/z (%) = 287 (9)[M+], 218 (21), 200 (23), 188
(22), 91 (100). MS (EI, isomer b): m/z (%) = 287(6) [M+],
218 (28), 200 (19), 188 (33), 91 (100). HRMS (ES): m/z
calcd for C18H26NO2 [M + H]+: 288.19580; found:
288.19653.
(1S,2S)-3-Benzyl-2-[2-(1-hydroxy-2-methylcyclopropyl)-
ethyl]-3-azabicyclo[3.1.0]hexan-1-ol (13)
[Insepable mixture of undetermined cis and trans
diastereomers (ratio 60:40: major a and minor b) on the side
chain.]
Colorless liquid. IR (neat): 3030, 2929, 2797, 1603 cm–1. 1H
NMR (360 MHz, CDCl3): d = 7.34–7.26 (m, 10 H, a + b),
4.14 (d, J = 14.4 Hz, 1 H, b), 4.08 (d, J = 14.4 Hz, 1 H, b),
3.76 (d, J = 13.7 Hz, 1 H, a), 3.71 (d, J = 13.7 Hz, 1 H, a),
3.23 (dd, J = 12.6, 5.8 Hz, 1 H, b), 3.06 (dd, J = 9.7, 4.3 Hz,
1 H, a), 2.92 (t, J = 4.7 Hz, 1 H, a), 2.65 (t, J = 4.2 Hz, 1 H,
b), 2.53 (d, J = 12.6 Hz, 1 H, b), 2.44 (d, J = 9.7 Hz, 1 H, a),
2.21–2.17 (m, 4 H, a + b), 2.06–1.97 (m, 4 H, a + b), 1.63–
Synlett 2010, No. 11, 1627–1630 © Thieme Stuttgart · New York