Synthesis of optically active (+)-2-benzyl-, (+)-2-octyl-, and (+)-2-tetradec-5′-enylcyclobutanones via metallated chiral imines or hydrazones

Article abstract of DOI:10.1016/j.tetasy.2005.04.012

A practical asymmetric synthesis of (R)-2-benzyl-, (S)-2-octyl-, and (S)-2-tetradec-5′-enylcyclobutanones was investigated using enantiopure (S)-α-methylbenzylamine, (R)-methoxymethylbenzylamine, or hydrazine (RAMP). These amines were treated with cyclobutanone to afford the corresponding imines or hydrazones, respectively. Metallation of these imine derivatives followed by alkylation with n-octylbromide, benzylbromide, or tetradec-5-enylbromide gave, after hydrolysis, (S)-2-octylcyclobutanone and for the first time optically active (R)-2-benzylcyclobutanone and (S)-2-tetradec-5′-enylcyclobutanone (TECB) with 67-87% ee. The absolute configuration was also established.

Full text of DOI:10.1016/j.tetasy.2005.04.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2067–2070
Synthesis of optically active (+)-2-benzyl-, (+)-2-octyl-, and
(+)-2-tetradec-50-enylcyclobutanones via metallated
chiral imines or hydrazones
Damien Hazelard and Antoine Fadel*
´ ´
Laboratoire des Carbocycles (Associe au CNRS), Institut de Chimie Moleculaire et des Materiaux d’Orsay Bat. 420,
Universite Paris-Sud, 91405 Orsay, France
´
ˆ
´
Received 14 April 2005; accepted 19 April 2005
Available online 31 May 2005
Abstract—A practical asymmetric synthesis of (R)-2-benzyl-, (S)-2-octyl-, and (S)-2-tetradec-50-enylcyclobutanones was investigated
using enantiopure (S)-a-methylbenzylamine, (R)-methoxymethylbenzylamine, or hydrazine (RAMP). These amines were treated
with cyclobutanone to afford the corresponding imines or hydrazones, respectively. Metallation of these imine derivatives followed
by alkylation with n-octylbromide, benzylbromide, or tetradec-5-enylbromide gave, after hydrolysis, (S)-2-octylcyclobutanone and
for the first time optically active (R)-2-benzylcyclobutanone and (S)-2-tetradec-50-enylcyclobutanone (TECB) with 67–87% ee. The
absolute configuration was also established.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In connection with our ongoing program, we report
herein the asymmetric alkylation of N-cyclobutylidene
amines or hydrazone derivatives 5, an easy to perform
and efficient route to enantiomerically enriched 2-
alkylcyclobutanones 2 via the corresponding imines 6
(Scheme 1). Only very recently a synthesis of racemic
2-alkylated cyclobutanones was published,7 and used
as markers for irradiated foodstuffs.8
The synthesis of optically active a-substituted cyclobuta-
nones via asymmetric reactions has not received much
attention. Only a few methods occurring through a ring
enlargement of hydroxycyclopropylcarbinol1 or spiro-
pentane derivatives2a,b or with chirality transfer.2c Poor
to good enantiomeric excesses were generally obtained.
Over the course of our work on the asymmetric synthe-
sis of cyclic analogues of naturally occurring a-amino
acids,3 we have previously published the aminocyclo-
butanecarboxylic acids 14 prepared from readily avail-
able racemic a-substituted cyclobutanones 2.4,5 We
had already prepared enantiopure a-alkoxycyclobuta-
nones 3 by an enzyme-catalyzed transesterification.6
O
NR*
R
NR*
O
*
2
*
6
R
5
4
Scheme 1.
2. Results and discussion
COOH
NH2
O
O
*
Commercially available cyclobutanone 4 was converted
into N-(cyclobutylidene)-amine or hydrazone 5 by
reaction with (S)-a-methylbenzylamine 7A (1 equiv) or
(R)-7B (Scheme 2) in diethyl ether in the presence of
triethylamine (2.5 equiv) and stoichiometric amounts
of titanium(IV) chloride, while with RAMP-7C,9 simple
heating was enough to give the hydrazone 5C. Without
purification, the cyclobutanone imine derivatives 510
*
*
R
R
*
OR'
1
3
2
*
Corresponding author. Tel.: +33 (1) 6915 7252; fax: +33 (1) 6915
6278; e-mail: antfadel@icmo.u-psud.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.012

2068
D. Hazelard, A. Fadel / Tetrahedron: Asymmetry 16 (2005) 2067–2070
The (S) absolute configuration of (+)-2b was assigned by
O
H2N
Ph
H2N N
comparison of its specific rotation with that of literature
(R)-(ꢀ)-2b.1d,e However, the (R) absolute configuration
of (+)-2a (benzyl group), unknown in enantiomerically
enriched form, was assigned by analogy to the alkyl-
ation product (+)-(S)-2b (octyl group), which must have,
under the same conditions, the same geometry but re-
verse absolute configuration (compare in Table 1, entries
4 and 7). Likewise, the absolute configuration of (+)-2c
must be (S).
H2N
Ph
O
7A
7B
7C (RAMP)
Scheme 2.
were deprotonated with LDA (or NaHMDS) in THF at
ꢀ78 ꢁC and the resulting 1-azaallylic anion intermedi-
ates were reacted with various alkylbromides to afford
the corresponding N-2-alkyl-1-cyclobutylidene amines
6. The later crude imines 6 were hydrolyzed with aque-
ous oxalic acid from ꢀ78 ꢁC to room temperature giving
enantiomerically enriched 2-alkylcyclobutanones 2 in
good yields and high enantiomeric excesses (Table 1).
We therefore observed that the (R)-benzylcyclobuta-
none 2a7b,12 underwent a slow epimerization on stand-
ing at 20 ꢁC for 3 days (from 80% to 15% ee).
However it was stable under acidic conditions (oxalic
acid, 20 ꢁC, 3 days).
First, the asymmetric alkylation11 of imine 5A (prepared
from cyclobutanone 4 and amine 7A) conducted with
LDA at ꢀ78 ꢁC for 1 h, then addition of benzylbromide
at ꢀ78 ꢁC to room temperature, gave 2-benzylcyclobu-
tanone 2a with moderate yield and poor enantiomeric
excess (Table 1, entry 1). Improved results were achieved
by using amines 7B and 7C, which gave 2a with 44% and
76% ee, respectively (Table 1, entries 2 and 3). Further-
more, increasing the reaction time of LDA at ꢀ78 ꢁC
(4 h instead of 1 h) before adding benzylbromide, en-
hanced both the yield and the enantioselectivity of the
resulting 2-benzylcyclobutanone (R)-2a {[a]D = +124 (c
1, CHCl3), 79% ee} (entry 4). However, using NaHMDS
as base does not give a better result (entry 5). On the
other hand, upon treatment with octylbromide or tetra-
dec-5-enylbromide,7c hydrazone 5C gave under the same
conditions 2-octylcyclobutanone (S)-2b or 2-tetradec-50-
enylcyclobutanone (S)-(+)-2c, respectively, with good
yields and high enantiomeric excesses {[a]D = +42.7 (c
1, CHCl3), 88% ee} (Table 1, entries 6 and 7), and
{[a]D = +22.7 (c 0.4, CHCl3), 67% ee} (Table 1, entry 8).
It is noteworthy that the alkylation of 5A at ꢀ78 ꢁC with
LDA, and BnBr followed by treatment in situ of the
resulting 6A.a with LDA (1 equiv), then hydrolysis with
guaiacol13 or oxalic acid does not give the expected (R)-
2a, but benzylcyclobutanone (S)-2a (with 24% ee), thus,
indicating that no deprotonation of 6A.a occurred under
these conditions (Scheme 3).
A plausible mechanism can be explained for this asym-
metric alkylation. As shown in Figure 1, deprotonation
of RAMP-hydrazone 5C with lithium diisopropylamide
results in azaenolate 8C, a conformationally rigid and
chelated ECC,ZCN structure.11c Electrophilic attack on
this rigid intermediate proceeding under high diastereo-
facial differentiation, leads to alkylcyclobutanone (R)- or
(S)-2 in high enantiomeric purity. These results are in
agreement with those given by Enders and Eich-
enauer.11d While from enamine 5B, the rigid intermedi-
ate 8B providing favorable re face approach of the
electrophile, gives the antipode (S)- or (R)-(ꢀ)-2 but in
a moderate enantioselectivity.
Table 1. Asymmetric alkylation of imines 5 under various conditions
O
R
N-R*
1) Base, THF, -78 ˚C
and antipodes
(+)-2a: R = Bn (R)
(+)-2b: R = Oct (S)
2) RX, -78 ˚C → –50 ˚C
3) (COOH)2
(+)-2
5
(+)-2c: R = tetradecenyl (S)
Entry
H2NR*
Base
RX
2-Alkylcyclobutanones
2
Yield (%)
[a]D
Abs. conf.
Eea (%)
1
2
3
4
5
6
7
8
(S)-7A
(R)-7B
(R)-7C
(R)-7C
(R)-7C
(R)-7C
(R)-7C
(R)-7C
LDA
LDA
PhCH2–Br
PhCH2–Br
PhCH2–Br
PhCH2–Br
PhCH2–Br
C8H15–Br
C8H15–Br
C14H27–Bre
2a
2a
2a
2a
2a
2b
2b
2c
42
41
25
64
24
50
65
35
ꢀ37.7
ꢀ69
(S)
(S)
24
44
76
79
66
87
79.6
67
LDA
+119
+124
NDd
(R)
(R)
(R)
(S)c
(S)c
(S)
LDAb
NaHMDS
LDA
+42.7
+39.1
+22.7
LDAb
LDAb
a Enantiomeric excesses were measured by GC analysis using chiral column (b-cyclodextrine DM).
b LDA was reacted with imine of cyclobutanone at ꢀ78 ꢁC for 4 h before adding alkylbromide.
c The absolute configuration was assigned by comparison to the known product 2b (Ref. 1d,e).
d ND: not determined.
e Z-Tetradec-5-enylbromide.

D. Hazelard, A. Fadel / Tetrahedron: Asymmetry 16 (2005) 2067–2070
2069
O
1) LDA,
-78 ˚C
1) LDA,
-78 ˚C
N
N
x
Ph
2) Guaiacol
2) Br-Bn,
-78 ˚C
Bn
Bn
(R)-2a
Ph
5A
6A.a
de = 24%
no inversion
Scheme 3. Attempt to improve enantiomeric excess by double LDA treatment.
RX
RX
H
R'
R'
OCH3
Li
O
R
O
R
N
R'
O
O
R'
N
N
H
Li
Z
H
E
Z
E
R'
O
O
R'
OCH3
R'
R'
(+)-2
(–)-2
8C
RX
8B
RX
Figure 1. Proposed mechanism of enamine cyclobutanone alkylation.
6. Hazelard, D.; Fadel, A.; Morgant, G. Tetrahedron:
Asymmetry 2004, 15, 1711.
7. (a) Miesch, M.; Miesch, L.; Horvatovich, P.; Burnouf, D.;
3. Conclusion
We have developed a practical asymmetric alkylation
for the synthesis of (R)-benzyl-, (S)-octyl-, and (S)-tetra-
dec-50-enylcyclobutanones or antipodes with reasonably
good yields and high enantiomeric excesses up to 87%,
thus providing the first preparation of optically active
2-benzyl- and 2-tetradec-50-enylcyclobutanones.14 This
approach should constitute a complementary method
to our enzymatic reaction6 for preparing several opti-
cally active cyclobutanones used in the synthesis of
enantiopure aminocyclobutanecarboxylic acids,4 which
is currently in progress in our laboratory.
´
Delincee, H.; Hartwig, A.; Raul, F.; Werner, D.; Marchi-
oni, E. Radiat. Phys. Chem. 2002, 65, 233; (b) Nordvik, T.;
Brinker, U. H. J. Org. Chem. 2003, 68, 9394; (c) Verniest,
G.; Boterberg, S.; Colpaert, J.; Van Thienen, T.; Stevens,
C. V.; De Kimpe, N. Synlett 2004, 1273.
8. (a) Ndiaye, B.; Jamet, G.; Miesch, M.; Hasselmann, C.;
Marchioni, E. Radiat. Phys. Chem. 1999, 55, 437; (b) Le
Tellier, P. R.; Nawar, W. W. Lipids 1972, 7, 75.
9. (a) Commercially available or prepared following Enders,
D.; Eichenauer, H.; Pieter, R. Chem. Ber. 1979, 112, 3703;
(b) Enders, D.; Eichenauer, H.; Bauss, U.; Schubert, H.;
Kremer, K. A. M. Tetrahedron 1984, 40, 1345.
10. (a) Data for crude 5A: 1H NMR (CDCl3): d 1.47 (d,
J = 6.5 Hz, 3H), 1.80–2.10 (m, 2H), 2.75–3.15 (m, 4H),
4.42 (q, J = 6.5 Hz, 1H), 7.13–7.46 (m, 5H); 13C NMR
(CDCl3): d 13.1 (C3), 24.3 (CH3), 34.6 (C4), 37.9 (C2), 60.2
References
0
1. For optically active cyclobutanones, see (a) Fitjer, L.
Cyclobutanes. In Synthesis: by Ring Enlargement In
Houben-Weyl (Methods of Organic Chemistry); de Mei-
jere, A., Ed.; Thieme: Stuttgart, 1997; Vol. E 17e, p 251;
(b) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103,
1449; (c) Nemoto, H.; Miyata, J.; Hakamara, H.; Fukum-
oto, K. Tetrahedron Lett. 1995, 36, 1055; (d) Nemoto, H.;
Miyata, J.; Hakamara, H.; Nagamochi, M.; Fukumoto,
K. Tetrahedron 1995, 51, 5511, and references cited
therein; (e) Krief, A.; Ronvaux, A.; Arounarith, T.
Tetrahedron 1998, 54, 6903; (f) Cho, S. Y.; Cha, J. K.
Org. Lett. 2000, 2, 1337.
(C1 ), [6 arom. C: 126.6 (2C), 126.7 (1C), 128.3 (2C), 145.2
(1C)], 170.9 (C@N).
(b) Data for crude 5B: 1H NMR (CDCl3): d 1.82–2.08 (m,
2H), 2.66–2.86 (m, 1H), 2.86–3.20 (m, 3H), 3.37 (s, 3H),
3.60 (dd, J = 4.5, 9.3 Hz, 1H), 3.70 (dd, J = 8.3, 9.3 Hz,
1H), 4.465 (dd, J = 4.5, 8.3 Hz, 1H), 7.20–7.45 (m, 5H);
13C NMR (CDCl3): d 13.0 (C3), 35.2 (C4), 38.0 (C2), 59.0
(CH3), 65.0 (CH–N), 78.0 (CH2–O), [6 arom. C: 127.1
(1C), 127.3 (2C), 128.3 (2C), 140.9 (1C)], 173.9 (C@N).
(c) Data for crude 5C: 1H NMR (CDCl3): d 1.55–1.74 (m,
1H), 1.74–2.10 (m, 5H), 2.42–2.74 (m, 1H), 2.80–3.21 (m,
4H), 3.22–3.40 (m, 3H), 3.38 (s, 3H, CH3), 3.54 (dd,
J = 3.7, 9.3 Hz, 1H, CH2O); 13C NMR (CDCl3): d 14.0
(C3), 22.3 (t), 25.9 (t), 35.1 (C4), 36.0 (C2), 53.4 (t), 59.1 (q),
65.7 (d), 75.1 (t), 154.9 (C1).
2. (a) Yoshida, M.; Ismail, M. A. H.; Nemoto, H.; Ihara, M.
J. Chem. Soc., Perkin Trans. 1 2000, 2629; (b) Bernard, A.
M.; Frangia, A.; Piras, P. P.; Secci, F. Org. Lett. 2003, 5,
2923; (c) Ollivier, J.; Legros, J.-Y.; Fiaud, J. C.; de
11. Stereoselective alkylation was reported for cyclopenta-
none and cyclohexanone: see (a) Kitamato, M.; Hiroi, K.;
Terashima, S.; Yamada, S. Chem. Pharm. Bull. 1974, 22,
459; (b) Meyers, A. I.; Williams, D. R.; Druelinger, M. J.
Am. Chem. Soc. 1976, 98, 3032; For the SAMP-/RAMP-
hydrazone methodology in asymmetric synthesis: see (c)
Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253; (d) Enders, D.; Eichenauer, H.
Chem. Ber. 1979, 112, 2933.
Meijere, A.; Salaun, J. Tetrahedron Lett. 1990, 31,
4135.
¨
3. (a) Fadel, A.; Khesrani, A. Tetrahedron: Asymmetry 1998,
9, 305; (b) Fadel, A.; Tesson, N. Eur. J. Org. Chem. 2000,
2153; (c) Tesson, N.; Dorigneux, B.; Fadel, A. Tetrahe-
dron: Asymmetry 2002, 13, 2267.
´
4. Truong, M.; Lecornue, F.; Fadel, A. Tetrahedron: Asym-
metry 2003, 14, 1053, and references cited therein.
5. Salaun, J.; Fadel, A.; Conia, J. M. Tetrahedron Lett. 1979,
¨
1429.
12. For the synthesis of racemic 2-benzylcyclobutanone: see
Ref. 7b and (a) Bekolo, H.; Howell, A. R. New. J. Chem.

2070
D. Hazelard, A. Fadel / Tetrahedron: Asymmetry 16 (2005) 2067–2070
2001, 25, 673; (b) Molander, G.; McKie, J. A. J. Org.
Chem. 1993, 58, 7216; (c) Cohen, T.; Yu, L.-C.; Daniew-
ski, W. M. J. Org. Chem. 1985, 50, 4596.
ˆ
JBC = 5.5 Hz, 1Hbenzyl), 3.50–3.71 (m, 1H), 7.10–7.40 (m,
5H); 13C NMR (CDCl3): d 16.6 (C3), 35.1 (C1 ), 44.5 (C4),
61.2 (C2), [6 arom. C: 126.3 (1C), 128.5 (2C), 128.7 (2C),
138.8 (1C)], 211.5 (C1); IR (neat): m 3086 cmꢀ1, 3028, 2923,
1778 (C@O), 1603, 1496, 1454; MS (EI) m/z: 160 (M+, 39),
131 (30), 118 (60), 117 (100), 104 (27), 91 (36).
0
13. Navarre, L.; Darses, S.; Genet, J. P. Angew. Chem., Int.
Ed. 2004, 43, 719.
14. General asymmetric alkylation procedure: To a cooled
solution (ꢀ78 ꢁC) of crude imine or hydrazone 5 [1 mmol,
prepared from cyclobutanone 4 (1.2 mmol) and amines or
hydrazine 7 (1 mmol)] in THF (3 mL), was added drop-
wise a solution of LDA (2.2 mmol). The mixture was
stirred at ꢀ78 ꢁC for 4 h, then alkylbromide (2 mmol) was
added at ꢀ78 ꢁC, stirred at ꢀ78 ꢁC (3 h), warmed up to
ꢀ50 ꢁC (3 h), and recooled at ꢀ78 ꢁC (14 h). The cold
resulting mixture (ꢀ78 ꢁC) was hydrolyzed with an aque-
ous saturated solution of oxalic acid (3 mL) and ether
(3 mL), with stirring at ꢀ78 ꢁC (5 min) then at room
temperature for 24 h. The mixture was extracted with
ether (3 · 30 mL), and the organic layer was dried
(MgSO4), filtered, and then concentrated under partial
vacuum (30 ꢁC, P > 200 mmHg). The residue was purified
by chromatography on silica gel column (eluent, ether–
pentane, 5/95 ! 1/9) to give pure 2-alkylcyclobutanone 2
(as noted in Table 1).
(b) Data for (S)-(+)-2-octylcyclobutanone (S)-2b: [a]D
=
+39.1 (c 1, CHCl3) (79.6% ee) {lit. for (R)-2b: [a]D = ꢀ32
(c 0.56, CHCl3) 64% ee},1e Rf = 0.57 (ether–pentane,1/9),
tR(S)) = 72.11 min; tR(R) = 71.02 min (cyclodextrine DM,
1
125 ꢁC, 0.5 bar); H NMR (CDCl3): d 0.87 (t, J = 6.6 Hz,
3H), 1.10–1.55 (m, 14H), 1.55–1.80 (m, 1H–C3), 2.05–2.29
(m, 1H–C3), 2.79–3.15 (m, 2H–C4), 3.15–3.88 (m, 1H–C2);
13C NMR (CDCl3): d 14.1 (CH3), 16.9 (C3), 22.6, 27.0,
29.2, 29.4, 29.45, 29.5, 31.8, 44.4 (C4), 60.6 (C2), 212.6
(C1); IR (neat): m 2926 cmꢀ1, 1782 (C@O), 1466; MS (EI)
m/z: 182 (M+, 1), 164 (3), 112 (20), 98 (100), 84 (31), 83
(27).
(c) Data for (S)-(+)-2-(tetradec-5-enyl)-cyclobutanone (S)-
2c: [a]D = +22.7 (c 0.4, CHCl3) (67% ee) Rf = 0.58 (ether–
pentane, 2/8), tR(S)) = 267.54 min; tR(R) = 264.39 min
1
(cyclodextrine DM, 145 ꢁC, 1 bar); H NMR (CDCl3): d
0.88 (t, J = 6.6 Hz, 3H), 1.16–1.56 (m, 17H), 1.56–1.84 (m,
2H), 1.84–2.09 (m, 4H), 2.09–2.30 (m, 1H–C3), 2.77–3.13
(m, 2H–C4), 3.15–3.88 (m, 1H–C2), 5.20–5.36 (m, 2Holefin);
13C NMR (CDCl3): d 14.1 (CH3), 16.9 (C3), 22.7,
26.7, 27.0, 27.2, 29.3 (2C), 29.4, 29.5 (2C), 29.7,
31.9, 44.4 (C4), 60.6 (C2), 129.3 (C@C), 130.2 (C@C),
212.2 (C1); IR (neat): m 2926 cmꢀ1, 1782 (C@O), 1645
(C@C), 1463.
(a) Data for (R)-(+)-2-benzylcyclobutanone (R)-2a:
[a]D = +119 (c 0.6, CHCl3) (76% ee), Rf = 0.50 (ether–
pentane, 2/8), tR(R) = 38.48 min; tR(S) = 37.66 min (cyclo-
dextrine DM, 145 ꢁC, 0.5 bar); 1H NMR (CDCl3): d 1.50–
1.95 (m, 1H), 2.09–2.30 (m, 1H), 2.54–3.18 (m, 2H), 2.84
(A part of ABC system, JAB = 14.5 Hz, JAC = 9.1 Hz,
1Hbenzyl), 3.06 (B part of ABC system, JAB = 14.5 Hz,