Amino Zinc Enolate Carbocyclization Reactions. New Access to Polysubstituted Piperidine Derivatives

Article abstract of DOI:10.1021/jo971449m

Various N-pent-4-enylglycine methyl esters have been submitted to carbocyclization of their zinc enolates onto the unactivated double bond. The cyclization to substituted pipecolic esters is highly stereoselective. In most cases, substitution of the pent-4-enyl moiety on various sites leads to a single isomer, hence a way to di-, tri-, tetra-, or pentasubstituted piperidines.

Full text of DOI:10.1021/jo971449m

566
J . Org. Chem. 1998, 63, 566-574
Am in o Zin c En ola te Ca r bocycliza tion Rea ction s. New Access to
P olysu bstitu ted P ip er id in e Der iva tives
Edwige Lorthiois, Ilane Marek,* and J ean F. Normant*
Laboratoire de Chimie des Organoe´le´ments, Universite´ P. et M. Curie, 4 Place J ussieu,
75252 Paris Cedex 05-France
Received August 5, 1997
Various N-pent-4-enylglycine methyl esters have been submitted to carbocyclization of their zinc
enolates onto the unactivated double bond. The cyclization to substituted pipecolic esters is highly
stereoselective. In most cases, substitution of the pent-4-enyl moiety on various sites leads to a
single isomer, hence a way to di-, tri-, tetra-, or pentasubstituted piperidines.
Sch em e 1
In tr od u ction
Despite the extensive investigation of the intramolecu-
lar carbometalation reactions1 of alkenes and alkynes,
there are only few reports on the synthesis of six-
membered rings by this strategy.2 Indeed, the 6-exo-trig6
cyclization of a 6-heptenylmetal to a (cyclohexylmethyl)-
metal is much slower than the analogous 5-exo-trig
carbocyclization.2d Recently, our attention turned to the
carbocyclization of stabilized carbanions, for which only
few reports were also described,3 and we have described
the first diastereoselective and enantioselective amino
zinc enolate carbocyclization to give various polysubsti-
tuted pyrrolidine derivatives,4 known to be conforma-
* Fax: 01 44 27 75 67. E-mail: normant@moka.ccr.jussieu.fr.
(1) (a) Knochel, P. Comprehensive Organic Synthesis; Trost, B.,
Fleming, I., Eds., Pergamon Press, NY, 1991, Vol. 4, pp 865-911. (b)
Marek, I.; Normant, J . F. Cross Coupling Reactions, Diederich, D.,
Stang, P., Eds.; VCH: New York, 1997, in press.
(2) (a) Bailey, W. F.; Ovaska, T. V. J . Am. Chem. Soc. 1993, 115,
3080-3090. (b) Bailey, W. F.; Ovaska, T. V. Tetrahedron Lett. 1990,
31, 627-630. (c) Negishi, E. I.; Takahashi, T. J . Am. Chem. Soc. 1986,
108, 3402-3408. (d) Bailey, W. F.; Nurmi, T. T.; Patricia, J . J .; Wang,
W. J . Am. Chem. Soc. 1987, 109, 9, 2442-2448. (e) Krief, A.; Kenda,
B.; Barbeaux, P.; Guittet, E. Tetrahedron 1994, 50, 7177-7192. (f)
Young, J . R.; Stille, J . R. J . Am. Chem. Soc. 1992, 114, 4936-4937
and references therein. (g) W. H. Pearson, F. E. Lovering, Tetrahedron
Lett. 1994, 35, 9173-9176. (h) W. H. Pearson, M. J . Postich, J . Org.
Chem. 1994, 59, 5662-5671. (i) Pearson, W. H.; Lovering, F. E. J . Am.
Chem. Soc. 1995, 117, 12336-12337.
(3) (a) Funk, R. L.; Botton, G. L.; Brummond, K. M.; Ellestad, K.
E.; Stallman, J . B. J . Am. Chem. Soc. 1995, 115, 7023-7024. (b) Yeh,
M-C. P.; Chuang, L-W.; Ueng, C. H. J . Org. Chem. 1996, 61, 3874-
3877. (c) Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi, D.; Balme,
G. Tetrahedron Lett. 1997, 38, 1763-1766. (d) Inoue, T.; Kitagawa,
O.; Oda, Y.; Taguchi, T. J . Org. Chem. 1996, 61, 8256-8263.
(4) (a) Lorthiois, E.; Marek, I.; Normant, J . F. Tetrahedron Lett.
1997, 38, 89-92. (b) Lorthiois, E.; Marek, I.; Normant, J . F. J . Org.
Chem. 1997, submitted. (c) Karoyan, P.; Chassaing, G. Tetrahedron
Lett. 1997, 38, 85-88. (d) Karoyan, P.; Chassaing, G. Tetrahedron
Asymmetry 1997, 3, 2025-2032.
(5) (a) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.; Potier, P.
J . Org. Chem. 1997, 62, 765-770 and references therein. (b) Carpes,
M. J . S.; Miranda, P. C. M. L.; Correia, C. R. D. Tetrahedron Lett. 1997,
38, 1869-1872. (c) Sabol, J . S.; Flynn, G. A.; Friedrich, D.; Huber, E.
W. Tetrahedron Lett. 1997, 38, 3687-3690.
(6) Nakamura, E.; Kubota, K. J . Org. Chem. 1997, 62, 792-793.
(7) For the synthesis of piperidines via an anionic cyclization, see:
(a) Van Der louw, J .; Van Der Baan, J . L.; Stieltjes, H.; Bickelhaupt,
F.; Klumpp, G. P. Tetrahedron Lett. 1987, 28, 5929-5932. (b) Oppolzer,
W.; Gaudin, J . M.; Bedoya-Zurita, M.; Hueso-Rodriguez, J .; Raynham,
T. M.; Robyr, C. Tetrahedron Lett. 1988, 29, 4709-4712. (c) Oppolzer,
W.; Swenson, R. E.; Gaudin, J . M. Tetrahedron Lett. 1988, 29, 5529-
5532. (d) Shanghnessy, K. H.; Waymouth, R. M. J . Am. Chem. Soc.
1995, 117, 5873-5874. (e) Takacs, J . M.; Weidner, J . J .; Newsone, P.
W.; Takacs, B. E.; Chidambaram, R.; Shonaker, R. J . Org. Chem. 1995,
60, 3473-3486. (f) Sole´, D.; Cancho, Y.; Llebaria, A.; Delgado, J . M. A.
J . Org. Chem. 1996, 61, 5895-5904.
tionally restricted R-amino acids analogues.5 This simple
and straightforward intramolecular carbometalation of
a zinc enolate toward an unfunctionalized double bond
(the intramolecular olefinic aldol reaction6) for the cre-
ation of a five-membered ring led us to consider the
possibility to prepare some polysubstituted piperidines.7
Resu lts a n d Discu ssion
The starting material 1, easily prepared in two steps,8
is metalated with LDA in Et2O9 and transmetalated with
zinc bromide to give the corresponding Z-amino zinc
enolate 2.10 After warming to room temperature and
stirring for 5 h, a 6-exo-trig cyclization occurs to give the
metalated piperidine 3 as described in Scheme 1. Hy-
drolysis of the reaction mixture afforded 4 in 66% yield
as single diastereomer. The cis stereochemistry of the
â-methyl pipecolic derivative 4 was established, first by
1
using standard H, 13C, and COSY NMR techniques and
then differencial nuclear Overhauser effects. Moreover,
treatment of 4 with LDA in THF gives the trans isomer
7.
(8) See experimental procedure.
(9) The lithium enolate is unable to cyclize at room temperature.
(10) Van Der Steen, F. H.; Kleijn, H.; Britovsek, G. J . P; J astrzebski,
J . T. B. H.;Van Koten, G. J . Org. Chem. 1992, 57, 3906-3916.
S0022-3263(97)01449-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Amino Zinc Enolate Carbocyclization Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 567
Sch em e 2
Sch em e 3a
a
(i) 5% Pd(dba)2, dppb, mercaptobenzoic acid, THF, rt. (ii) NaH,
DMF, 0 °C then BrCH2COOMe.
Sch em e 4
The formation of the functionalized organometallic
derivative was also checked by iodinolysis or by reaction
with allyl bromide after transmetalation into an orga-
nocopper derivative11 to give respectively 5 and 6 in good
overall yield as unique diastereomers (Scheme 1). The
cis relative configuration of 4 can be explained by a
chairlike transition state in which the electrophilic double
bond occupies a pseudoaxial position (the Z-R-amino zinc
enolate and the double bond are gauche to each other,
see 2 in Scheme 1).
Sch em e 5
To confirm this chairlike transition state and also since
no stereochemical studies were described in the literature
for the synthesis of six-membered ring by anionic cy-
clization, we have decided to study the stereochemical
influence of substituents on the starting linear substrate.
For the preparation of the several starting materials, we
have used the geminated organodimetallics chemistry,
recently reviewed.12 Indeed, by using the allylmetalation
or crotylmetalation of vinylmetals, we have been able to
obtain the corresponding organogembismetallic deriva-
tives, as described in Scheme 2.
By combination of the controlled metalotropic equilib-
rium of the crotylmetal13 (partner B) at low temperature
and the diastereofacial choice of the allylmetalation on
the heterosubstituted chelated vinylmetal14 (partner A),
the creation of one to three stereogenic centers is easily
performed with a very high diastereoselectivity in a
single-pot operation. After deallylation of the nitrogen
atom according to Genet methodology15 and alkylation
with the methyl R-bromoacetate, as described in the
general Scheme 3,8 a detailed study of the stereochemical
outcome in the six-membered ring carbocyclization of
these starting materials was undertaken.
metalation with ZnBr2 cyclization at room temperature
in 5 h), we obtain the corresponding cyclic organozinc
bromide, as a unique isomer,16 and then 22 after hy-
drolysis or 23 after reaction with NBS, as described in
Scheme 4.
The relative configuration of 22 was assigned by NOE’s
and can be explained by a chairlike transition state in
which the methyl substituent preferentially occupies a
pseudoequatorial position (see Scheme 5). It should be
noted that, even when the methyl substituent is far from
the two reacting centers, only one isomer is formed in
this process, to minimize the 1,3-interactions with the
electrophilic double bond which is located in the pseudo-
axial position as well as with the zinc moiety of the amino
zinc enolate.
When the substrate 17 (derived from 12) is submitted
to our cyclization conditions (metalation with LDA trans-
(11) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-2188.
(12) Marek, I.; Normant, J . F. Chem. Rev. 1996, 96, 3241-3267.
(13) Marek, I.; Lefranc¸ois, J -M.; Normant, J . F. J . Org. Chem. 1994,
59, 4154-4161.
(14) Brasseur, D.; Marek, I.; Normant, J . F. Tetrahedron 1996, 52,
7235-7250.
(15) Lemaire-Audoire, S.; Savignac, M.; Dupuis, C.; Genet, J . P. Bull.
Soc. Chim. Fr. 1995, 132, 1157-1166.
Moreover, the bromo derivative 23 can serve as a
source of bicyclo[4.1.0]heptane amino ester 24, which is
(16) As determined by 1H and 13C NMR on the crude reaction
mixture.

568 J . Org. Chem., Vol. 63, No. 3, 1998
Lorthiois et al.
Sch em e 6
Sch em e 8
Sch em e 7
Sch em e 9
also an interesting constrained amino ester, by treatment
with LDA as described in Scheme 4.17
If now we start from 19 (derived from 9), according to
our experimental conditions of metalation-transmeta-
lation, the carbocyclization of the Z-R-amino zinc enolate
across the double bond leads to the tetrasubstituted
piperidine also as single diastereomer16 in 70% yield. The
relative configuration of 25 was established by analyzing
the coupling patterns between each hydrogen and can
be explained by a chairlike transition state in which the
two methyl substituents preferentially occupy a pseu-
doequatorial position (match pair) as described in Scheme
6.
However, if we consider the carbocyclization of the
mismatched pair, namely the carbocyclization of 18
(derived from 8), with a diastereomeric ratio of 91/9 for
18/19, we should be able to determine which substituent
is able to fix the stereochemical outcome of the carbocy-
clization. Then, the substrate 18 was subjected to our
metalation-transmetalation-cyclization procedure, to
give, after hydrolysis, the tetrasubstituted piperidine 26
in 68% yield as two diastereomers in a ratio of 90/10 (see
Scheme 7). As we started from a 91/9 ratio of 18/19, the
carbocyclization is, here again, highly diastereoselec-
tive.16
The stereochemistry of the major isomer was deter-
mined by analyzing the coupling constants of the piperi-
dine protons of 26. The relative configuration of the
minor isomer (10%) is identical with that of 25 (Scheme
6), which means that this other diastereomer results from
the presence of 9% of 19 at the start. The stereochem-
istry of 26 can be explained by a chairlike transition state
of the Z-amino zinc enolate in which the methyl at C4
(see Scheme 8) is preferentially axial and the methyl at
C5 is equatorial, rather than the opposite. Indeed, in the
former case, two axial 1,3-interactions exist with the two
hydrogens (as described in B), whereas in the latter case,
two stronger 1,3-interactions exist, one with the double
bond and the second one with the zinc moiety of the zinc
enolate (as described in A).
We can conclude from these studies (Scheme 8) that
the substituent in the homoallylic position (C5) has a
major impact on the stereochemical outcome of the
carbocyclization. So, we were interested in preparing a
second mismatched pair, still with a substituent in the
homoallylic position (C5) but now with a substituent in
position R to the nitrogen atom (C6, see Scheme 9).
Indeed, during the chairlike transition state of the
carbocyclization step, we will still have one of these two
substituents in an axial position and the other one in an
equatorial position, and it was interesting to see which
one determines the diastereoselectivity of the carbocy-
clization in a six-membered ring synthesis.
Having in our hands the starting material 20, prepared
according to Scheme 3 from 10 (see Scheme 2), we have
submitted it to the carbocyclization condition (metala-
tion-transmetalation-cyclization) to give the corre-
sponding cyclic organozinc bromide 27 as described in
Scheme 9. This can be hydrolyzed and oxidized by slow
introduction of dry air18 to give, respectively, 28 and 29
as single diastereomers.16
Both 28 and 29 have the same stereochemistry as
determined by the analysis of the coupling constants.
This stereochemistry can always be explained by the
(18) (a) Chemla, F.; Normant, J . F. Tetrahedron Lett. 1995, 36,
3157-3160. (b) Klement, I.; Lutjens, H.; Knochel, P. Tetrahedron Lett.
1995, 36, 3161-3163. (c) Klement, I.; Lutjens, H.; Knochel, P.
Tetrahedron 1997, 53, 9135-9144.
(17) (a) Hanessian, S.; Reinhold, U.; Ninkovic, S. Tetrahedron Lett.
1996, 37, 8967-8970. (b) Hanessian, S.; Ninkovic, S.; Reinhold, U.
Tetrahedron Lett. 1996, 37 , 8971-8974.

Amino Zinc Enolate Carbocyclization Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 569
Sch em e 10
Sch em e 12
Sch em e 11
we have in the former case A two 1,3-interactions, one
with the double bond and one with the zinc moiety of
the zinc enolate, whereas in the latter case B, we have
three 1,3-interactions: the major one is an axial interac-
tion between the methyl and the ethyl groups, and the
two others are two alkyl-hydrogen interactions (see
Scheme 12). These two transition states are not different
enough in energy, and the two diastereomers are formed.
Con clu sion
chairlike transition state, and the ethyl substituent in
the R-position to the nitrogen atom (C6) occupies a
pseudoaxial position, whereas the substituent in a ho-
moallylic position (C5) occupies the pseudoequatorial
position (see Scheme 10). Indeed, the 1,3-steric interac-
tions between the ethyl substituent with the two hydro-
gens in B are less destabilizing than the 1,3-steric
interactions between the methyl group at C5 with the
electrophilic double bond and with the zinc moiety of the
zinc enolate as described in A in Scheme 10.
So, here again, the substituent in the C5 position
(homoallylic position) is able to control the stereochemical
outcome of the carbocyclization, regardless of the pres-
ence of a mismatched substituent at C4 (Scheme 8) or C6
(Scheme 10) position.
Finally, we decided to study the combination of these
two substituents (C4 and C6) toward the substituent at
C5 in the stereoselectivity of the carbocyclization. The
amino ester 21 (prepared from 11, see Scheme 2) was
submitted to the metalation-transmetalation-cycliza-
tion conditions to give, after 7 h at room temperature and
hydrolysis, the pentasubstituted piperidine 30A and 30B
in moderate chemical yield19 as a mixture of two diaster-
eomers in a ratio of 62/38 (see Scheme 11).
The relative configurations of these two piperidines
30A and 30B were determined by analyzing the coupling
constants.20 When the effect of the homoallylic substitu-
ent at C5 is opposite to the combined effects of the
substituents at C4 and C6, the diastereoselectivity of the
carbocyclization becomes lower. The former substituent
(C5) is now not able to control totally the stereochemical
outcome of the cyclization reaction. Indeed, if we exam-
ine the two following chairlike transition state A and B,
The zinc enolate cyclization allows the easy and
straightforward preparation of piperidines with excellent
control of the diastereoselectivity. During the synthesis
of tri- to pentasubstituted piperidines, we have been able
to determine, for the first time, that the stereochemical
outcome of this carbocyclization was mainly due to the
presence of a substituent in the homoallylic position (C5).
Extension of this chemistry to the stereocontrolled prepa-
ration of various heterocycles, as well as to the enanti-
oselective synthesis, is currently underway.
Exp er im en ta l Section
N-Ben zyl-N-p en t -4-en yla m in e. A solution of benzyl-
amine (30 mmol, 3.21 g), 5-bromopent-1-ene (39 mmol, 5.8 mL),
sodium iodide (90 mmol, 13.5 g), and K2CO3 (90 mmol, 16.4 g)
in dry DMF (100 mL) was stirred at 100 °C during 20 h. The
reaction mixture was then treated with H2O (40 mL) and
extracted with ether (2 × 100 mL). The combined extracts
were washed with satured NaCl (3 × 50 mL), dried over
MgSO4, and concentrated. The crude material was purified
by chromatography from the dialkylated product (eluent, CH2-
Cl2/MeOH 95/5) to give 1.42 g (27%) of the title compound:
1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.88-5.81
(m, 1H), 5.06-4.96 (m, 2H), 3.61 (s, 2H), 2.48 (t, J ) 7.2 Hz,
2H), 2.13-2.07 (m, 2H), 1.65-1.58 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 140.5, 138.6, 128.5, 128.2, 127.0, 114.8, 53.4,
48.9, 31.7, 29.3.
N-Allyl-N-ben zyl-N-(3-iod o-p r op -2(Z)-en yl)a m in e. (Z)-
1-Iodo-1-propen-3-ol is obtained in two steps according to the
literature21 method and is further converted into the (Z)-1-
iodo-3-bromo-1-propene.14 N-Allyl-N-benzylamine (7.25 mmol,
1 g), K2CO3 (8.7 mmol, 1.2 g), and (Z)-1-iodo-3-bromo-1-propene
(7.98 mmol, 1.97 g) in dry DMF (25 mL) was stirred at room
temperature during 3 h. The reaction mixture was then
treated with H2O (20 mL) and extracted with ether (2 × 25
mL). The organic layer was washed with saturated NaCl (3
(19) The balance being the starting material.
(20) Although 30B could not be well-separated from 30A and from
the starting material, the characteristic signals for H1,2,3 and H5 (see
experimental part) and their NOE effect could be detected.
(21) Marek, I.; Meyer, C.; Normant, J . F. Org. Synth. 1996, 74, 194-
204.

570 J . Org. Chem., Vol. 63, No. 3, 1998
Lorthiois et al.
× 50 mL), dried over MgSO4, and concentrated to give 1.66 g
(73%) of the title compound which was not further purified:
1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 6.43-6.37
(m, 2H), 5.98-5.88 (m, 1H), 5.26 (d, J ) 17.24 Hz, 1H), 5.22-
5.20 (m, 1H), 3.64 (s, 2H), 3.23 (m, 2H), 3.14 (d, J ) 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 139.2, 138.9, 135.7, 129.05,
128.4, 127.1, 118.0, 83.6, 58.2, 57.6, 57.0.
lithium23 (1.5 M in pentane, 13.6 mmol, 9 mL) was added
dropwise and the mixture was stirred for 2 h at -20 °C. It
was then cooled to -60 °C as allylmagnesium bromide (1.3 M
in ether, 24.3 mmol, 18.7 mL) and zinc bromide (1 M in ether,
34 mmol, 34 mL) were added. The reaction mixture was
allowed to warm to room temperature. After completion, a
solution of NH4Cl/NH4OH (2/1) was added slowly at 0 °C.
Ether was added and the mixture was stirred for at least 3 h
with a few Na2S‚9H2O crystals. The layers were separated,
the aqueous one being extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, and
concentrated. The crude material was purified by chroma-
tography on silica gel (eluent, cyclohexane/ether 50/50) to give
1.53 g (60%) of the title compound: 1H NMR (400 MHz, CDCl3)
δ 7.38-7.28 (m, 5H), 5.88-5.78 (m, 1H), 5.08-5.03 (m, 2H),
3.87 (d, J ) 13.2 Hz, 1H), 3.77 (d, J ) 13.2 Hz, 1H), 2.60 (m,
1H), 2.49 (dd, J ) 11.6, 7.0 Hz, 1H), 2.21 (m, 1H), 1.96 (m,
1H), 1.78 (m, 1H), 0.95 (d, J ) 6.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 140.9, 137.3, 128.5, 128.2, 126.9, 116.0, 55.6,
54.3, 39.6, 33.4, 27.6.
N-Allyl-N-ben zyl-N-(2(S*),3(S*)-d im eth ylp en t-4-en yl)-
a m in e (8). A solution of N-allyl-N-benzyl-N-(3-iodoprop-2(Z)-
enyl)amine (5.29 mmol, 1.65 g) in dry ether (15 mL) was cooled
to -80 °C as tert-butyllithium (1.5 M in pentane, 10.6 mmol,
7 mL) was added dropwise. The resultant mixture was stirred
at -60 °C for 5 min as crotylmagnesium bromide (0.96 M in
ether, 7.93 mmol, 8.3 mL) and zinc bromide (1 M in ether,
7.93 mmol, 7.93 mL) were added. The reaction mixture was
stirred for 3 h at -40 °C. After completion, a solution of NH4-
Cl/NH4OH (2/1) was added slowly at -40 °C. Ether was added
and the mixture was stirred for at least 3 h with a few
Na2S‚9H2O crystals. The layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated to give
1.19 g (93%) of the title compound which was not further
purified (dr ) 91/9): 1H NMR (400 MHz, CDCl3) δ 7.39-7.25
(m, 5H), 5.95-5.88 (m, 1H), 5.74-5.67 (m, 2H), 5.21-5.14 (m,
2H), 4.98-4.92 (m, 2H), 3.62 (d, J ) 13.68 Hz, 1H), 3.54 (d, J
) 13.68 Hz, 1H), 3.12-3.05 (m, 2H), 2.43-2.37 (m, 2H), 2.20
(dd, J ) 12.48, 7.64 Hz, 1H), 1.75-1.70 (m, 1H), 1.02 (d, J )
7.0 Hz, 3H), 0.90 (d, J ) 6.67 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 141.5, 140.1, 136.3, 129.0, 128.2, 126.7, 117.1, 114.1,
58.8, 58.5, 57.2, 39.7, 36.2, 17.85, 14.2.
N-Allyl-N-ben zyl-N-(2(R*),3(S*)-d im eth ylp en t-4-en yl)-
a m in e (9). A solution of N-allyl-N-benzyl-N-(3-iodoprop-2(E)-
enyl)amine (3.91 mmol, 1.226 g) in dry ether (10 mL) was
cooled to -80 °C as tert-butyllithium (1.5 M in pentane, 7.8
mmol, 5.22 mL) was added dropwise. The resultant mixture
was stirred at -60 °C for 5 min as crotylmagnesium bromide
(1.05 M in ether, 7.8 mmol, 7.46 mL) and zinc bromide (1 M
in ether, 7.8 mmol, 7.8 mL) were added. The reaction mixture
was stirred for 5 h at -40 °C. After completion, a solution of
NH4Cl/NH4OH (2/1) was added slowly at -40 °C. Ether was
added and the mixture was stirred for at least 3 h with a few
Na2S‚9H2O crystals. The layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography (eluent, cy-
clohexane/ether 95/5) to give 0.62 g (65%) of the title compound
as a unique isomer: 1H NMR (200 MHz, CDCl3) δ 7.40-7.24
(m, 5H), 5.97-5.71 (m, 2H), 5.24-5.12 (m, 2H), 5.03-4.93 (m,
2H), 3.57 (s, 2H), 3.06 (d, J ) 6.36 Hz, 2H), 2.47-2.30 (m,
2H), 1.22-1.12 (m, 1H), 1.80-1.73 (m, 1H), 0.88 (d, J ) 6.84
Hz, 3H), 0.84 (d, J ) 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 144.2, 140.3, 136.5, 129.1, 128.3, 126.9, 117.2, 113.0, 59.0,
58.35, 57.45, 39.6, 35.9, 14.3 (2C).
N-Allyl-N-ben zyl-N-(3-iod op r op -2(E)-en yl)a m in e. This
compound was prepared according to Lipschutz’s22 methodol-
ogy starting from N-allyl-N-benzyl-N-propargylamine. LiEt3-
BH (“Super hydride”, Aldrich, 1 M in THF, 7.3 mmol, 7.3 mL)
was added dropwise over 5 min at room temperature to a
solution of Cp2ZrCl2 (7.3 mmol, 2.13 g) in dry THF (10 mL).
The solution was stirred, shielded from light, for 1 h at room
temperature. After this time, N-allyl-N-benzyl-N-propargyl-
amine (7.29 mmol, 1.35 g) in THF (5 mL) was slowly added
and the mixture stirred for 10 min to provide a clear, yellow
solution. Iodine (7.3 mmol, 1.85 g) in THF (5 mL) was then
added and the resultant mixture was stirred for 5 min at room
temperature. It was then poured into a solution of NH4Cl/
NH4OH 2/1 and the mixture was filtered off on a pad of Celite.
The layers were separated and the aqueous one was extracted
with ether, washed with brine, dried over MgSO4, and con-
centrated. The crude material was purified by chromatogra-
phy on silica gel (eluent, cyclohexane/ether 95/5) to give 1.22
g (54%) of the title compound: 1H NMR (400 MHz, CDCl3) δ
7.40-7.26 (m, 5H), 6.62 (dt, J ) 14.4, 6.6 Hz, 1H), 6.24 (d, J
) 14.4 Hz, 1H), 5.92-5.85 (m, 1H), 5.25-5.17 (m, 2H), 3.61
(s, 2H), 3.12-3.06 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 143.7,
139.2, 135.8, 129.3, 128.9, 127.2, 117.8, 77.9, 57.8, 57.5, 56.7.
N-Ben zyl-N-(1-eth yl-3-iod op r op -2(Z)-en yl)a m in e. (Z)-
1-Iodo-1-penten-3-ol is obtained in two steps according to the
literature21 method and is further converted into (Z)-1-iodo-
3-bromo-1-pentene.14 A solution of N-benzylamine (13.8 mmol,
1.5 g), K2CO3 (16.56 mmol, 2.28 g), and (Z)-1-iodo-3-bromo-1-
pentene (13.8 mmol, 3.62 g) in dry DMF (30 mL) was stirred
at room-temperature overnight. The reaction mixture was
then treated with H2O (25 mL) and extracted with ether (2 ×
25 mL). The organic layer was washed with saturated NaCl
(3 × 20 mL), dried over MgSO4, and concentrated. The crude
material was purified by chromatography on silica gel (eluent,
cyclohexane/ether 60/40) to give 2.3 g (55%) of the title
compound: 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H),
6.44 (d, J ) 7.5 Hz, 1H), 6.07 (t, J ) 7.5 Hz, 1H), 3.84 (d, J )
13.0 Hz, 1H), 3.74 (d, J ) 13.0 Hz, 1H), 3.51-3.46 (m, 1H),
1.68-1.61 (m, 1H), 1.59-1.51 (m, 1H), 1.37 (m, 1H, NH), 0.98
(t, J ) 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 140.6,
128.5, 128.4, 127.05, 83.4, 63.1, 51.7, 28.05, 10.3.
N -Allyl-N -b e n zyl-N -(1-e t h yl-3-iod op r op -2(Z)-e n yl)-
a m in e. A solution of N-benzyl-N-(1-ethyl-3-iodoprop-2(Z)-
enyl)amine (5.15 mmol, 1.55 g), allyl bromide (7.72 mmol, 0.93
g), and K2CO3 (7.72 mmol, 1.06 g) in dry DMF (30 mL) was
stirred at room temperature for 2 h, treated with a solution of
NH4Cl/NH4OH (2/1) (20 mL), and extracted with ether (2 ×
30 mL). The combined extracts were washed with satured
NaCl (3 × 20 mL), dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 70/30) to give 1.65 g (95%) of the
title compound: 1H NMR (400 MHz, CDCl3) δ 7.43-7.25 (m,
5H), 6.49 (d, J ) 7.5 Hz, 1H), 6.29 (dd, J ) 9.0, 7.5 Hz, 1H),
5.92-5.84 (m, 1H), 5.25 (dt, J ) 18.7, 1.7 Hz, 1H), 5.14 (d, J
) 9.9 Hz, 1H), 3.89 (d, J ) 14.2 Hz, 1H), 3.45 (d, J ) 14.2 Hz,
1H), 3.49-3.44 (m, 1H), 3.32-3.26 (m, 1H), 3.0 (dd, J ) 14.36,
7.56 Hz, 1H), 1.0 (t, J ) 7.44 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 140.6, 140.4, 136.9, 128.7, 128.2, 126.8, 117.0, 84.4,
64.7, 54.1, 53.3, 25.4, 10.9.
N-Allyl-N-b en zyl-N-(1(S*)-et h yl-2(S*)-m et h ylp en t -4-
en yl)a m in e (10). A solution of N-allyl-N-benzyl-N-(1-ethyl-
3-iodoprop-2(Z)-enyl)amine (1.98 mmol, 0.677 g) in dry ether
(10 mL) was cooled to -80 °C as tert-butyllithium (1.5 M in
pentane, 4 mmol, 2.66 mL) was added dropwise. The resultant
5-(Ben zyla m in o)-4-m eth ylp en t-1-en e (12). A solution of
benzyl allylamine (13.6 mmol, 2 g) in dry ether (15 mL) was
cooled to -50 °C as n-butyllithium (1.6 M in hexanes, 16.32
mmol, 10.2 mL) was added dropwise. The resultant mixture
was stirred at -30 °C during 20 min and then tert-butyl-
(22) Lipshutz, B.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990,
31, 7257-7260.
(23) Barluenga, J .; Gonzalez, R.; Fananas, F. J . Tetrahedron Lett.
1992, 33, 7573-7574.

Amino Zinc Enolate Carbocyclization Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 571
mixture was stirred at -60 °C for 5 min as allylmagnesium
bromide (1.38 M in ether, 6 mmol, 4.34 mL) and zinc bromide
(1 M in ether, 6 mmol, 6 mL) were added. The reaction
mixture was stirred for 3 h at -30 °C. After completion, a
solution of NH4Cl/NH4OH (2/1) was added slowly at -30 °C.
Ether was added and the mixture was stirred for at least 3 h
with a few Na2S‚9H2O crystals. The layers were separated,
the aqueous one being extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, and
concentrated. The crude material was purified by chroma-
tography (eluent, cyclohexane/ether 95/5) to give 0.4 g (80%)
of the title compound as a unique isomer: 1H NMR (400 MHz,
CDCl3) δ 7.43-7.25 (m, 5H), 5.93-5.81 (m, 2H), 5.21-5.01 (m,
4H), 3.83 (d, J ) 14.16 Hz, 1H), 3.65 (d, J ) 14.16 Hz, 1H),
3.23 (dd, J ) 14.2, 5.48 Hz, 1H), 3.13 (dd, J ) 14.2, 7.24 Hz,
1H), 2.44 (q, J ) 6.2 Hz, 1H), 2.30-2.26 (m, 1H), 1.94-1.88
(m, 1H), 1.79-1.76 (m, 1H), 1.69-1.62 (m, 1H), 1.55-1.47 (m,
1H), 1.02 (t, J ) 7.52 Hz, 3H), 0.99 (d, J ) 7.0 Hz, 3H); 13C
NMR (50 MHz, CDCl3) δ 143.1, 138.4, 138.2, 128.85, 128.2,
126.7, 116.3, 115.55, 64.1, 54.8, 54.3, 39.0, 35.4, 20.4, 17.2, 13.5.
N-Allyl-N-ben zyl-N-(2(S*),3(S*)-dim eth yl-1S*-eth ylpen t-
4-en yl)a m in e (11). A solution of N-allyl-N-benzyl-N-(1-ethyl-
3-iodoprop-2(Z)-enyl)amine (4.85 mmol, 1.65 g) in dry ether
(10 mL) was cooled to -80 °C as tert-butyllithium (1.5 M in
pentane, 9.7 mmol, 6.5 mL) was added dropwise. The result-
ant mixture was stirred at -60 °C for 5 min as crotylmagne-
sium bromide (1.05 M in ether, 14.5 mmol, 13.8 mL) and zinc
bromide (1 M in ether, 14.5 mmol, 14.5 mL) were added. The
reaction mixture was stirred for 3 h at -30 °C. After
completion, a solution of NH4Cl/NH4OH (2/1) was added slowly
at -30 °C. Ether was added and the mixture was stirred for
at least 3 h with a few Na2S‚9H2O crystals. The layers were
separated, the aqueous one being extracted with ether. The
combined extracts were washed with brine, dried over MgSO4,
and concentrated. The crude material was purified by chro-
matography (eluent, cyclohexane) to give 0.98 g (74%) of the
title compound as a unique isomer: 1H NMR (400 MHz, CDCl3)
δ 7.40-7.25 (m, 5H), 5.87-5.82 (m, 1H), 5.78-5.69 (m, 1H),
5.17-5.06 (m, 2H), 4.99-4.95 (m, 2H), 3.88 (d, J ) 14.2 Hz,
1H), 3.60 (d, J ) 14.2 Hz, 1H), 3.29-3.24 (m, 1H), 3.12 (dd, J
) 14.28, 7.64 Hz, 1H), 2.56-2.53 (m, 1H), 2.44-2.39 (m, 1H),
1.64-1.54 (m, 3H),1.03-0.99 (m, 6H), 0.93 (d, J ) 6.92 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 141.6, 141.4, 138.3, 128.9,
128.2, 126.6, 116.0, 114.1, 62.1, 55.1, 54.5, 41.6, 38.8, 21.2, 19.7,
13.5, 12.7.
Gen er a l P r oced u r e for Gen et Dea llyla tion Meth od ol-
ogy.15 N-Ben zyl-N-(2(S*),3(S*)-d im et h ylp en t -4-en yl)
a m in e (13). A mixture of Pd(dba)2 (0.24 mmol, 0.14 g, 5 mol
%) and 1,4-bis(diphenylphosphino)butane (2.67 mmol, 0.1 g,
5 mol %) in THF (0.5 mL) was stirred at room temperature
under an argon atmosphere, for 10 min. The preformed
catalyst and 2-mercaptobenzoic acid (5.39 mmol, 0.82 g, 1.1
equiv) were added to a solution of N-allyl-N-benzyl-N-(2S*,3S*-
dimethylpent-4-enyl)amine (8) (1.19 g, 4.9 mmol) in THF (10
mL) and the reaction mixture was stirred under an argon
atmosphere at 20 °C. After completion, the mixture was
treated with a solution of HCl 10% and extracted by AcOEt to
eliminate the byproduct and the catalyst in the organic layer.
The aqueous layer containing the protonated amine was
basified with a solution of 1 M NaOH and extracted by AcOEt.
The organic layer was dried over MgSO4 and concentrated.
The crude material was purified by chromatography on silica
gel (eluant: cyclohexane/ether 50/50) to give 0.665 g (67%) of
the title compound: 1H NMR (400 MHz, CDCl3) δ 7.36-7.25
(m, 5H), 5.80-5.72 (m, 1H), 5.02-4.98 (m, 2H), 3.81 (s, 2H),
2.65 (dd, J ) 11.66, 6.08 Hz, 1H), 2.45 (dd, J ) 11.66, 7.36
Hz, 1H), 2.33-2.28 (m, 2H), 1.71-1.65 (m, 1H), 2.20 (dd, J )
12.48, 7.64 Hz, 1H), 1.75-1.70 (m, 1H), 1.03 (d, J ) 6.84 Hz,
3H), 0.91 (d, J ) 6.67 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
141.8, 140.85, 128.5, 128.2, 126.9, 114.1, 54.3, 53.7, 40.45, 38.2,
17.75, 14.6.
above for 13). The crude material was purified by chroma-
tography on silica gel (eluant, cyclohexane/ether 70/30) to give
0.205 g (64%) of the title compound: 1H NMR (400 MHz,
CDCl3) δ 7.36-7.25 (m, 5H), 5.83-5.74 (m, 1H), 5.02-4.97 (m,
2H), 3.83 (d, J ) 16.92 Hz, 1H), 3.78 (d, J ) 16.92 Hz, 1H),
2.68 (dd, J ) 11.64, 5.6 Hz, 1H), 2.45 (dd, J ) 11.64, 7.88 Hz,
1H), 2.26-2.21 (m, 1H), 1.71-1.65 (m, 1H), 1.36 (m, 1H, NH),
0.97 (d, J ) 6.84 Hz, 3H), 0.91 (d, J ) 6.76 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.7, 141.1, 128.5, 128.2, 127.0, 113.4,
54.4, 53.8, 40.6, 38.0, 15.5, 14.8.
N -Be n zyl-N -(1(S *)-e t h yl-2(S *)-m e t h ylp e n t -4-e n yl)-
a m in e (15). N-Allyl-N-benzyl-N-(1(S*),(2S*)-dimethylpent-
4-enyl)amine (10) (0.4 g, 1.55 mmol) was treated according to
the general procedure for Genet deallylation methodology15
(see above for 13). The crude material was purified by
chromatography on silica gel (eluant, cyclohexane/ether 70/
30) to give 0.15 g of the title compound: 1H NMR (400 MHz,
CDCl3) δ 7.35-7.18 (m, 5H), 5.86-5.65 (m, 1H), 5.03-4.93 (m,
2H, H1), 3.81 (d, J ) 13 Hz, 1H), 3.71 (d, J ) 13 Hz, 1H), 2.35
(td, J ) 6.37, 3.72 Hz, 1H), 2.27-2.20 (m, 1H), 1.90-1.83 (m,
1H), 1.78-1.70 (m, 1H), 1.50-1.36 (m, 2H), 1.13 (m, 1H, NH),
0.89 (t, J ) 7.33 Hz, 3H), 0.85 (d, J ) 6.75 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 141.6, 138.5, 128.5, 128.4, 127.0, 115.6,
62.6, 52.4, 37.8, 35.0, 24.0, 14.9, 11.3.
N-Ben zyl-N-(2(S*),3(S*)-d im et h yl-1(S*)-et h ylp en t -4-
en yl)a m in e (16). N-Allyl-N-benzyl-N-(2(S*),3(S*)-dimethyl-
1(S*)-ethylpent-4-enyl)amine (11) (0.768 g, 2.84 mmol) was
treated according to the general procedure for Genet deally-
lation methodology15 (see above for 13); 0.445 g (68%) of the
title compound was thus obtained: 1H NMR (400 MHz, CDCl3)
δ 7.40-7.27 (m, 5H), 5.81-5.72 (m, 1H), 5.04-4.96 (m, 1H),
3.90 (d, J ) 12.84 Hz, 1H), 3.70 (d, J ) 12.84 Hz, 1H), 2.55-
2.51 (m, 1H), 2.35-2.27 (m, 1H), 1.72-1.65 (m, 1H), 1.51-
1.43 (m, 2H), 1.15 (m, 1H, NH), 0.99 (d, J ) 6.72 Hz, 3H),
0.93 (t, J ) 7.44 Hz, 3H), 0.88 (d, J ) 7.04 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.4, 141.4, 128.4 (4C), 126.9, 113.7, 60.3,
52.25, 40.75, 39.9, 24.4, 19.4, 11.2, 10.8.
N-Ben zyl-N-p en t-4-en yl glycin a te Meth yl Ester (1). To
a solution of N-benzyl-N-pent-4-enylamine (8.11 mmol, 1.42
g) in dry DMSO (200 mL) were added methyl R-bromo acetate
(9.73 mmol, 1.49 g) and triethylamine (9.73 mmol, 0.98 g). The
resultant mixture was stirred for 5 h at room temperature and
then treated with a solution of NH4Cl/NH4OH 2/1 (50 mL),
extracted with ether (2 × 100 mL). The combined extracts
were washed with satured NaCl (3 × 50 mL), dried over
MgSO4, and concentrated. The crude material was purified
by chromatography on silica gel (eluent, cyclohexane/ether 70/
30) to give 1.6 g (80%) of the title compound: 1H NMR (400
MHz, CDCl3) δ 7.39-7.27 (m, 5H), 5.86-5.79 (m, 1H), 5.05-
4.95 (m, 2H), 3.81 (s, 2H), 3.70 (s, 3H), 3.35 (s, 2H), 2.68 (t, J
) 7.3 Hz, 2H), 2.14-2.08 (m, 2H), 1.66-1.59 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 172.0, 139.2, 138.6, 129.0, 128.4, 127.2,
114.7, 58.3, 54.1, 53.5, 51.35, 31.4, 26.9.
Gen er a l P r oced u r e for th e Alk yla tion of Secon d a r y
Am in es w ith Meth yl r-Br om oa ceta te. N-Ben zyl-N-(2-
m eth ylp en t-4-en yl)glycin a te Meth yl Ester (17). To a
solution of NaH (50% in grease, 6.3 mmol, 0.3 g) in dry DMF
(20 mL) was added 5-(benzylamino)-4-methylpent-1-ene 12
(0.99 g, 5.24 mmol) at 0 °C. The reaction mixture was stirred
at 0 °C during 10 min, and methyl R-bromoacetate (6.3 mmol,
0.96 g) was added. The reaction mixture was stirred for 6 h
and treated with a solution of NH4Cl/NH4OH (2/1). Ether was
added, and the layers were separated, the aqueous one being
extracted with ether. The combined extracts were washed
with brine, dried over MgSO4, and concentrated. The crude
material was purified by chromatography on silica gel (eluent,
cyclohexane/ether 97/3) to give 0.93 g (68%) of the title
compound: 1H NMR (400 MHz, CDCl3) δ 7.4-7.27 (m, 5H),
5.86-5.75 (m, 1H), 5.06-5.00 (m, 2H), 3.82 (s, 2H), 3.72 (s,
3H), 3.33 (s, 2H), 2.56 (dd, J ) 12.7, 7.16 Hz, 1H), 2.46 (dd, J
) 12.7, 7.24 Hz, 1H), 2.32-2.27 (m, 1H), 1.88-1.83 (m, 1H),
1.79-1.75 (m, 1H), 0.93 (d, J ) 6.56 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 172.8, 139.5, 135.5, 129.0, 128.4, 127.1, 115.9,
60.5, 58.5, 54.4, 51.3, 39.2, 31.6, 17.85.
N-Ben zyl-N-(2(R*),3(S*)-d im et h ylp en t -4-en yl)a m in e
(14). N-Allyl-N-benzyl-N-(2(R*),3(S*)-dimethylpent-4-enyl)-
amine (9) (0.387 g, 1.59 mmol) was treated according to the
general procedure for Genet deallylation methodology15 (see

572 J . Org. Chem., Vol. 63, No. 3, 1998
Lorthiois et al.
N -Be n zyl-N -(2(S *),3(S *)-d im e t h ylp e n t -4-e n yl)glyci-
n a te Meth yl Ester (18). A solution of N-allyl-N-benzyl-N-
(2(S*),3(S*)-dimethylpent-4-enyl)amine (13) (0.665 g, 3.27
mmol) was treated following the general procedure for the
alkylation of secondary amines with methyl R-bromoacetate.
The crude material was purified by chromatography on silica
gel (eluent, cyclohexane/ether 97/3) to give 0.83 g (92%) of the
title compound: 1H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m,
5H), 5.75-5.66 (m, 1H), 4.99-4.93 (m, 2H), 3.83 (d, J ) 13.64
Hz, 1H), 3.78 (d, J ) 13.64 Hz, 1H), 3.70 (s, 3H), 3.32 (s, 2H),
2.63 (dd, J ) 12.7, 7.04 Hz, 1H), 2.44-2.38 (m, 2H), 1.72-
1.66 (m, 1H),1.02 (d, J ) 7.0 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.25, 141.3, 139.5, 129.0,
128.4, 127.1, 114.4, 59.0, 58.4, 54.2, 51.3, 39.6, 36.5, 18.0, 13.9.
N -Be n zyl-N -(2(R*),3(S*)-d im e t h ylp e n t -4-e n yl)glyci-
n a te Meth yl Ester (19). A solution of N-allyl-N-benzyl-N-
(2(R*),(3S*)-dimethylpent-4-enyl)amine (14) (0.205 g, 1 mmol)
was treated following the general procedure for the alkylation
of secondary amines with methyl R-bromoacetate. The crude
material was purified by chromatography on silica gel (eluent,
cyclohexane/ether 70/30) to give 0.163 g (59%) of the title com-
pound: 1H NMR (400 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 5.84-
5.74 (m, 1H), 5.0-4.96 (m, 2H), 3.82 (d, J ) 13.92 Hz, 1H),
3.78 (d, J ) 13.92 Hz, 1H), 3.71 (s, 3H), 3.32 (s, 2H), 2.67 (dd,
J ) 12.8, 6.84 Hz, 1H), 2.40 (dd, J ) 12.8, 7.88 Hz, 1H), 2.36-
2.31 (m, 1H), 1.77-1.70 (m, 1H), 0.89 (d, J ) 6.84 Hz, 3H),
0.86 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2,
144.0, 139.5, 129.1, 128.4, 127.2, 113.2, 58.6, 58.55, 54.4, 51.3,
39.4, 35.9, 14.3, 14.0.
N-Ben zyl-N-(1(S*)-eth yl-2(S*)-m eth ylp en t-4-en yl)gly-
cin a te Meth yl Ester (20). A solution of N-benzyl-N -(1(S*)-
ethyl-2(S*)-methylpent-4-enyl)amine 15 (0.094 g, 0.43 mmol)
was treated following the general procedure for the alkylation
of secondary amines with methyl R-bromoacetate. The crude
material was purified by chromatography on silica gel (eluent,
cyclohexane/ether 70/30) to give 0.062 g (50%) of the title com-
pound: 1H NMR (400 MHz, CDCl3) δ 7.43-7.23 (m, 5H), 5.80-
5.71 (m, 1H), 5.04-4.97 (m, 2H), 3.89 (d, J ) 13.84 Hz, 1H),
3.81 (d, J ) 13.84 Hz, 1H), 3.64 (s, 3H), 3.40 (d, J ) 16.76 Hz,
1H), 3.24 (d, J ) 16.76 Hz, 1H), 2.41 (q, J ) 6.28 Hz, 1H),
2.26-2.20 (m, 1H), 1.92-1.86 (m, 1H), 1.75-1.70 (m, 1H),
1.65-1.60 (m, 1H), 1.57-1.50 (m, 1H), 0.99 (t, J ) 7.36 Hz,
3H), 0.97 (d, J ) 6.76 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
173.25, 140.05, 138.1, 129.2, 128.3, 127.1, 115.8, 66.5, 56.3,
53.0, 51.5, 38.7, 36.0, 21.4, 16.9, 13.2.
N-Ben zyl-N-(2(S*),3(S*)-d im et h yl-1(S*)-et h ylp en t -4-
en yl)glycin a te Meth yl Ester (21). A solution of N-benzyl-
N-(2(S*),3(S*)-dimethyl-1(S*)-ethylpent-4-enyl)amine (16) (0.445
g, 1.92 mmol) was treated following the general procedure for
the alkylation of secondary amines with methyl R-bromoac-
etate. The crude material was purified by chromatography
on silica gel (eluent, cyclohexane/ether 80/20) to give 0.294 g
(51%) of the title compound: 1H NMR (400 MHz, CDCl3) δ
7.43-7.22 (m, 5H), 5.76-5.67 (m, 1H), 4.97 (d, J ) 14.76 Hz,
1H), 4.97 (d, J ) 12.4 Hz, 1H), 3.93 (d, J ) 13.72 Hz, 1H),
3.81 (d, J ) 13.72 Hz, 1H), 3.61 (s, 3H), 3.41 (d, J ) 16.6 Hz,
1H), 3.35 (d, J ) 16.6 Hz, 1H), 2.53-2.47 (m, 1H), 2.45-2.37
(m, 1H), 1.65-1.50 (m, 3H), 1.02 (t, J ) 7.36 Hz, 3H), 1.01 (d,
J ) 6.96 Hz, 3H), 0.95 (d, J ) 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.3, 141.3, 140.0, 129.3, 128.2, 127.0, 114.3, 65.0,
56.85, 53.3, 51.4, 41.8, 38.95, 22.2, 19.7, 13.1, 12.3.
Typ ica l P r oced u r e of th e Cycliza tion Rea ction in th e
Syn th esis of P olysu bstitu ted P ip er id in e Der iva tives. A
solution of N-benzyl-N-(pent-4-enyl)glycinate methyl ester (1)
(1 mmol, 0.25 g) in dry ether (15 mL) was cooled to -20 °C as
LDA (2 M in THF/n-heptane, 2 mmol, 1 mL) was added
dropwise. The reaction mixture was then allowed to warm to
10 °C for 10 min and cooled to -40 °C as zinc bromide (1 M in
ether, 2 mmol, 2 mL) was added dropwise. The reaction
mixture was then allowed to warm to 20 °C. The cyclized
organozinc species 3 is ready for further conversions.
Na2S‚9H2O crystals. The layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 90/10) to give 0.163 g (66%) of the
1
title compound as a unique isomer H NMR (400 MHz, CDCl3)
δ 7.35-7.25 (m, 5H), 3.71 (s, 3H), 3.64 (d, J ) 13.5 Hz, 1H),
3.59 (d, J ) 13.5 Hz, 1H), 3.48 (d, J ) 5.2 Hz, 1H), 3.02-2.96
(m, 1H), 2.55-2.51 (m, 1H), 2.09-1.99 (m, 1H), 1.75-1.68 (m,
1H), 1.62-1.46 (m, 3H), 0.92 (d, J ) 7.04 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.2, 139.1, 128.9, 128.3, 127.1, 66.3,
60.25, 50.55, 47.0, 33.25, 27.9, 25.2, 18.25; IR (neat) 2910, 2820,
1720, 1490, 1420, 1360, 1270, 1190, 1140, 1060, 1000, 740, 690.
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.91; H, 8.56; N, 5.60.
(2S*,3R*)-1-Ben zyl-2-ca r bom eth oxy-3-(iod om eth yl)p i-
p er id in e (5). The cyclized product 3 was cooled to 0 °C as
an excess of solid iodine (3 mmol, 0.76 g) was added. After
stirring for 10 min at room temperature, a solution of NH4-
Cl/NH4OH 2/1 was added slowly. Ether was added, and the
layers were separated, the aqueous one being extracted with
ether. The combined extracts were diluted with saturated
Na2S2O3, washed with brine, and stirred for at least 3 h with
a few Na2S‚9H2O crystals. These were then removed by
filtration and the organic solution was washed with brine,
dried over MgSO4, and concentrated. The crude material was
purified by chromatography on silica gel (eluent, dichlo-
romethane/methanol 95/5) to give 0.303 g (81%) of the title
compound as a unique isomer: 1H NMR (400 MHz, CDCl3) δ
7.36-7.24 (m, 5H), 3.75 (s, 3H), 3.77-3.72 (m, 2H), 3.63 (d, J
) 13.6 Hz, 1H), 3.17 (dd, J ) 10.0, 7.2 Hz, 1H), 3.09 (dd, J )
10.0, 7.3 Hz, 1H), 2.94-2.87 (m, 1H), 2.55-2.51 (m, 1H), 2.26-
2.21 (m, 1H), 1.85-1.81 (m, 1H), 1.72-1.69 (m, 1H), 1.63-
1.58 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.7, 138.9, 128.7,
128.4, 127.2, 64.8, 59.95, 50.9, 46.6, 42.1, 26.5, 25.0, 8.5; IR
(neat) 2920, 2820, 1710, 1490, 1450, 1360, 1240, 1190-1140,
990, 730, 690. Anal. Calcd for C15H20NO2I : C, 48.27; H, 5.4;
N, 3.75. Found: C, 48.47; H, 5.6; N, 3.75.
(2S*,3R*)-1-Ben zyl-2-ca r bom eth oxy-3-bu t-3-en ylp ip e-
r id in e (6). The cyclized product 3 was cooled to -20 °C as
copper cyanide (0.18 g, 2 mmol) in THF (10 mL) was added.
The resultant mixture was slowly allowed to rise to -5 °C and
stirred for 15 min. It was then cooled to -40 °C as allyl
bromide (0.36 g, 3 mmol) was injected into the flask. The
reaction mixture was slowly allowed to warm to room tem-
perature overnight and was subsequently quenched with a
solution of NH4Cl/NH4OH (2/1). The layers were separated
and the aqueous one was extracted with ether. The combined
extracts were washed with brine and stirred for at least 3 h
with a few Na2S‚9H2O crystals. These were then removed by
filtration, and the organic layers were washed with brine, dried
over MgSO4, and concentrated. The crude material was
purified by chromatography on silica gel (eluent, cyclohexane/
ether 90/10) to give 0.186 g (65%) of the title compound as a
1
unique isomer H NMR (400 MHz, CDCl3) δ 7.33-7.24 (m, 5H),
5.84-5.73 (m, 1H), 5.02-4.94 (m, 2H), 3.71 (s, 3H), 3.66 (d, J
) 13.45 Hz, 1H), 3.56 (d, J ) 13.45 Hz, 1H), 3.55 (d, J ) 5.12
Hz, 1H), 2.97 (td, J ) 11.36, 8.4 Hz, 1H), 2.58-2.54 (m, 1H),
2.13-2.08 (m, 2H), 1.88-1.85 (m, 1H), 1.73-1.68 (m, 1H),
1.60-1.51 (m, 3H), 1.39-1.23 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 172.8, 139.15, 138.7, 128.9, 128.4, 127.1, 114.85, 64.9,
60.3, 50.6, 46.6, 38.1, 32.2, 31.4, 25.4, 25.2.
(2S*,3S*)-1-Ben zyl-2-ca r b om et h oxy-3-m et h ylp ip er i-
d in e (7). A solution of (2S*,3R*)-1-benzyl-2-carbomethoxy-
3-methylpiperidine (4) (0.34 mmol, 0.084 g) in dry ether (15
mL) was cooled to -20 °C as LDA (2 M in THF/n-heptane,
1.35 mmol, 0.68 mL) was added dropwise. The reaction
mixture was allowed to warm to room temperature for 20 min,
it was then cooled to 0 °C as a solution of NH4Cl/NH4OH 2/1
was added slowly. Ether was added and the mixure was
stirred for at least 3 h with a few Na2S‚9H2O crystals. The
layers were separated, the aqueous one being extracted with
ether. The combined extracts were washed with brine, dried
over MgSO4, and concentrated. The crude material was
purified by chromatography on silica gel (eluent, cyclohexane/
(2S*,3R*)-1-Ben zyl-2-ca r b om et h oxy-3-m et h ylp ip er i-
d in e (4). The cyclized product 3 was cooled to 0 °C as a
solution of NH4Cl/NH4OH 2/1 was added slowly. Ether was
added and the mixure was stirred for at least 3 h with a few

Amino Zinc Enolate Carbocyclization Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 573
ether 90/10) to give 0.045 g (55%) of the title compound (cis/
trans 35/65): 1H NMR (400 MHz, CDCl3) of the trans isomer
δ 7.34-7.25 (m, 5H), 3.78 (s, 3H), 3.73 (d, J ) 13.32 Hz, 1H),
3.27 (d, J ) 13.32 Hz, 1H), 2.89 (dt, J ) 11.28, 3.52 Hz, 1H),
2.66 (d, J ) 9.2 Hz, 1H), 1.95-1.88 (m, 2H), 1.77-1.71 (m,
1H), 1.63-1.56 (m, 2H), 1.07-0.99 (m, 1H), 0.92 (d, J ) 6.64
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.35, 137.7, 129.6,
128.3, 127.3, 73.75, 61.2, 51.85, 51.4, 34.4, 32.1, 24.6, 18.9.
(2S*,3R*,5*R)-1-Ben zyl-2-ca r b om et h oxy-3,5-d im et h -
ylp ip er id in e (22). A solution of N-benzyl-N-(2-methylpent-
4-enyl)glycinate methyl ester (17) (0.2 g, 0.77 mmol) was
treated following the typical procedure for the cyclization
reaction (as described for the preparation of 3). The cyclized
product was cooled to 0 °C as a solution of NH4Cl/NH4OH (2/
1) was added slowly. Ether was added and the mixure was
stirred for at least 3 h with a few Na2S‚9H2O crystals. The
layers were separated, the aqueous one being extracted with
ether. The combined extracts were washed with brine, dried
over MgSO4, and concentrated. The crude material was
purified by chromatography on silica gel (eluent, cyclohexane/
ether 90/10) to give 0.123 g (62%) of the title compound as a
140.0, 129.3, 128.3, 127.1, 58.5, 53.5, 52.4, 44.2, 31.2, 25.65,
22.35, 18.8, 18.25; IR (neat) 2970, 2810, 1710, 1490, 1450,
1430, 1350, 1250, 1190, 1160, 1100, 740, 690; MS m/z 260
(MH+).
(2S*,3R*,4R*,5*R)-1-Ben zyl-2-ca r bom et h oxy-3,4,5-t r i-
m eth ylpiper idin e (25). A solution of N-benzyl-N-(2(R*),3(S*)-
dimethylpent-4-enyl)glycinate methyl ester (19) (0.16 g, 0.59
mmol) was treated following the typical procedure for the
cyclization reaction (as described for the preparation of 3). The
cyclized product thus obtained was cooled to 0 °C as a solution
of NH4Cl/NH4OH (2/1) was added slowly. Ether was added
and the mixure was stirred for at least 3 h with a few
Na2S‚9H2O crystals. The layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 80/20) to give 0.113 g (70%) of the
title compound as a unique isomer. The relative configuration
was determined after irradiation of the methyl groups located
on the C3 and C4 positions.
1
unique isomer H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H),
3.77 (d, J ) 13.52 Hz, 1H), 3.75 (s, 3H), 3.35 (d, J ) 13.52 Hz,
1H), 3.22 (d, J ) 4.28 Hz, 1H), 2.95 (dd, J ) 10.84, 3.2 Hz,
1H), 2.28-2.23 (m, 1H), 1.91-1.87 (m, 1H), 1.84-1.79 (m, 1H),
1.71-1.65 (m, 1H), 1.26-1.20 (m, 1H), 1.01 (d, J ) 7.04 Hz,
3H), 0.91 (d, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.8, 138.9, 129.1, 128.25, 127.1, 67.85, 60.35, 57.35, 51.2,
37.9, 30.6, 26.2, 19.2, 16.6; IR (neat) 2940, 2920, 1740, 1720,
1490, 1450, 1380, 1260, 1190, 1170, 1140, 1090, 1070, 1020,
740, 690. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N,
5.36. Found: C, 73.44; H, 8.85; N, 5.41.
1H NMR (400 MHz, CDCl3) δ 7.38-7.24 (m, 5H), 3.95 (d, J
) 13.28 Hz, 1H), 3.77 (s, 3H), 3.14 (d, J ) 13.28 Hz, 1H), 3.12
(d, J ) 3.5 Hz, 1H), 2.77 (dd, J ) 10.7, 3.2 Hz, 1H), 2.02-1.99
(m, 1H), 1.59 (dd, J ) 10.95, 10.7 Hz, 1H), 1.55-1.51 (m, 1H),
1.28-1.23 (m, 1H), 0.94 (d, J ) 6.68 Hz, 3H), 0.93 (d, J ) 6.12
Hz, 3H), 0.74 (d, J ) 6.12 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 173.5, 138.7, 129.4, 128.2, 127.05, 70.7, 61.0, 60.3, 51.7, 41.3,
38.5, 30.75, 17.1, 16.9, 9.0. Anal. Calcd for C17H25NO2: C,
74.1; H, 9.15; N, 5.09. Found: C, 74.1; H, 9.14; N, 5.09.
(2S*,3R*,4S*,5*R)-1-Ben zyl-2-ca r b om et h oxy-3,4,5-t r i-
m eth ylpiper idin e (26). A solution of N-benzyl-N-(2(S*),3(S*)-
dimethylpent-4-enyl)glycinate methyl ester (18) (0.2 g, 0.72
mmol) was treated following the typical procedure for the
cyclization reaction (as described for the preparation of 3). The
cyclized product thus obtained was cooled to 0 °C as a solution
of NH4Cl/NH4OH (2/1) was added slowly. Ether was added
and the mixure was stirred for at least 3 h with a few
Na2S‚9H2O crystals. The layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 90/10) to give 0.136 g (68%) of the
title compound (dr ) 90/10). The coupling constants were
assigned (in C6D6 solvent), after irradiation of the methyl group
located on the C4 and C3 positions.
(2S *,3R *,5*R )-1-B e n zy l-5-(b r o m o m e t h y l)-2-c a r b o -
m eth oxy-3-m eth ylp ip er id in e (23). A solution of N-benzyl-
N-(2-methylpent-4-enyl)glycinate methyl ester (17) (0.33 g,
1.26 mmol) was treated by following the typical procedure for
the cyclization reaction (as described for the preparation of
3). The cyclized product was cooled to -30 °C as an excess of
N-bromosuccinimide (2.52 mmol, 0.45 g) was added. After
stirring for 10 min at room temperature, a solution of NH4-
Cl/NH4OH (2/1) was added slowly. Ether was added, and the
layers were separated, the aqueous one being extracted with
ether. The combined extracts were washed with brine and
stirred for at least 3 h with a few Na2S‚9H2O crystals. These
were then removed by filtration and the organic solution was
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 90/10) to give 0.302 g (56%) of the
1
title compound as a unique isomer H NMR (400 MHz, CDCl3)
δ 7.36-7.26 (m, 5H), 3.78 (s, 3H), 3.73 (d, J ) 13.48 Hz, 1H),
3.53-3.49 (m, 3H), 3.42 (d, J ) 13.48 Hz, 1H), 2.93 (dd, J )
11.12, 3.4 Hz, 1H), 2.52-2.46 (m, 1H), 2.08-2.02 (m, 1H),
1.95-1.90 (m, 1H), 1.89-1.84 (m, 1H), 1.36-1.29 (m, 1H), 0.96
(d, J ) 6.56 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0,
138.7, 128.9, 128.35, 127.2, 66.3, 60.1, 58.2, 51.5, 38.5, 34.6,
33.7, 26.3, 18.9.
N-Ben zyl-2-ca r b om et h oxy-2,3-m et h a n o-5-m et h ylp ip -
er id in e (24). A solution of (2S*,3R*,5*R)-1-benzyl-5-(bro-
momethyl)-2-carbomethoxy-3-methylpiperidine (23) (0.27 g, 0.8
mmol) in dry ether (15 mL) was cooled to -40 °C as LDA (2 M
in THF/n-heptane, 1.6 mmol, 0.8 mL) was added dropwise. The
reaction mixture was then allowed to warm to room temper-
ature for 30 min. After completion, the solution was cooled to
0 °C as a solution of NH4Cl/NH4OH (2/1) was added slowly.
Ether was added, and the layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 80/20) to give 0.1 g (50%) of the title
compound: 1H NMR (400 MHz, CDCl3) δ 7.51-7.24 (m, 5H),
3.80 (d, J ) 13.48 Hz, 1H), 3.69 (s, 3H), 3.55 (d, J ) 13.48 Hz,
1H), 2.39-2.36 (m, 1H), 2.15 (dd, J ) 13.52, 10.44 Hz, 1H),
2.02-1.92 (m, 2H), 1.56-1.52 (m, 1H), 1.45-1.39 (m, 1H), 1.37
(dd, J ) 9.8, 4.24 Hz, 1H), 1.06 (dd, J ) 7.6, 4.24 Hz, 1H),
0.79 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3,
1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 3.72 (s,
3H), 3.58 (s, 2H), 3.47 (d, J ) 4.76 Hz, 1H), 3.11 (dd, J ) 11.28,
3.4 Hz, 1H), 2.29 (dd, J ) 11.28, 4.12 Hz, 1H), 1.97-1.88 (m,
2H), 1.85-1.81 (m, 1H), 0.95 (d, J ) 7.0 Hz, 3H), 0.92 (d, J )
6.56 Hz, 3H), 0.90 (d, J ) 6.52 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 173.0, 139.4, 128.7, 128.3, 127.0, 66.25, 60.0, 53.5,
50.6, 34.6, 34.2, 33.0, 16.3, 15.9, 13.2.
1H NMR (400 MHz, C6D6) δ 7.37 (d, J ) 7.48 Hz, 2H), 7.19
(t, J ) 7.36 Hz, 2H), 7.09 (t, J ) 7.28 Hz, 1H), 3.59 (d, J )
13.4 Hz, 1H), 3.53 (d, J ) 13.4 Hz, 1H), 3.43 (d, J ) 5.24 Hz,
1H), 3.32 (s, 3H), 3.31-3.27 (m, 1H), 2.23 (dd, J ) 11.2, 3.6
Hz, 1H), 1.98-1.94 (m, 1H), 1.79-1.75 (m, 1H), 1.65-1.61 (m,

574 J . Org. Chem., Vol. 63, No. 3, 1998
Lorthiois et al.
1H), 0.87 (d, J ) 7.0 Hz, 3H), 0.83 (d, J ) 6.92 Hz, 3H), 0.74
(d, J ) 6.92 Hz, 3H); 13C NMR (50 MHz, C6D6) δ 171.9, 139.6,
128.7, 127.2, 127.0, 66.2, 60.1, 53.3, 49.7, 34.2, 34.0, 33.25, 16.2,
15.6, 12.8. Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N,
5.09. Found: C, 74. 13; H, 9.12; N, 5.21.
(d, J ) 7.0 Hz, 1H), 0.89 (t, J ) 7.36 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 176.5, 140.8, 128.5, 126.9, 70.5, 60.8, 59.4, 52.5,
32.1, 31.6, 29.9, 29.4, 12.6, 11.6; MS m/z 274 (MH+).
(2S*,3R*,4S*,5R*,6R*)-1-Ben zyl-2-ca r bom eth oxy-3,4,5-
tr im eth yl-6-eth ylp ip er id in e (30A)/(2S*,3R*,4R*,5S*,6S*)-
1-Ben zyl-2-ca r bom eth oxy-3,4,5-tr im eth yl-6-eth ylp ip er i-
d in e (30B). A solution of N-benzyl-N-(2(S*),3(S*)-dimethyl-
1(S*)-ethylpent-4-enyl)glycinate methyl ester (21) (0.13 g, 0.42
mmol) was treated following the typical procedure for the
cyclization reaction (as described for the preparation of 3). The
cyclized product thus obtained was cooled to 0 °C as a solution
of NH4Cl/NH4OH (2/1) was added slowly. Ether was added
and the mixure was stirred for at least 3 h with a few
Na2S‚9H2O crystals. The layers were separated, the aqueous
one being extracted with ether. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
crude material was purified by chromatography on silica gel
(eluent, cyclohexane/ether 90/10) to give 0.038 g (30%) of 30A
and 0.02 g (15%) of 30B. The coupling constants of 30A were
determined by irradiation of the methyl groups located on the
C3 and C4 positions.
(2S *,3R *,5*R ,6R *)-1-Be n zyl-2-ca r b om e t h oxy-3,5-d i-
m eth yl-6-eth ylp ip er id in e (28). A solution of N-benzyl-N-
(1(S*)-ethyl-2(S*)-methylpent-4-enyl)glycinate methyl ester
(20) (0.032 g, 0.11 mmol) was treated following the typical
procedure for the cyclization reaction (as described for the
preparation of 3). The cyclized product 27 was cooled to 0 °C
as a solution of NH4Cl/NH4OH (2/1) was added slowly. Ether
was added and the mixure was stirred for at least 3 h with a
few Na2S‚9H2O crystals. The layers were separated, the
aqueous one being extracted with ether. The combined
extracts were washed with brine, dried over MgSO4, and
concentrated. The crude material was purified by chroma-
tography on silica gel (eluent, cyclohexane/ether 90/10) to give
0.019 g (60%). The coupling constants were determined by
irradiation of the methyl group located on the C5 position.
1H NMR (400 MHz, CDCl3) δ 7.36-7.21 (m, 5H), 4.07 (d, J
) 14.68 Hz, 1H), 3.68 (s, 3H), 3.44 (d, J ) 5.68 Hz, 1H), 3.35
(d, J ) 14.68 Hz, 1H), 3.34-3.30 (m, 1H), 2.25-2.16 (m, 1H),
2.04-1.96 (m, 1H), 1.79 (td, J ) 12.8, 4.44 Hz, 1H), 1.71-
1.65 (m, 1H), 1.41 (dt, J ) 12.8, 3.72 Hz, 1H), 1.18-1.12 (m,
1H), 1.01 (d, J ) 6.88 Hz, 3H), 0.90 (t, J ) 7.36 Hz, 3H), 0.83
(d, J ) 7.04 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5,
143.3, 128.25, 128.1, 126.7, 65.8, 58.45, 54.5, 50.4, 36.1, 29.4,
27.2, 23.5, 18.45, 12.8, 11.1; IR (neat) 2950, 1730, 1600, 1490,
1450, 1380, 1190, 1140, 1090, 740, 690; MS m/z 290 (MH+).
2-Ben zyl-2-a za -3-et h yl-4-m et h yl-8-oxa b icyclo[4.3.0]-
n on a n -9-on e (29). A solution of N-benzyl-N-(1(S*)-ethyl-
2(S*)-dimethylpent-4-enyl)glycinate methyl ester (20) (0.032
g, 0.11 mmol) was treated following the typical procedure for
the cyclization reaction (as described for the preparation of
3). The cyclized product 27 was oxydized with dry air. After
completion, a solution of NH4Cl/NH4OH (2/1) was added
slowly. Ether was added and the mixure was stirred for at
least 3 h with a few Na2S‚9H2O crystals. The layers were
separated, the aqueous one being extracted with ether. The
combined extracts were washed with brine, dried over MgSO4,
and concentrated. The crude material was purified by chro-
matography on silica gel (eluent, cyclohexane/ether 90/10) to
give 0.022 g (60%) of the title compound. The coupling
constants were determined by irradiation of the hydrogen atom
located on the C5 position.
30A: 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 4.08
(d, J ) 14.64 Hz, 1H), 3.67 (s, 3H), 3.51-3.44 (m, 1H), 3.41 (d,
J ) 5.8 Hz, 1H), 3.30 (d, J ) 14.64 Hz, 1H), 2.22-2.16 (m,
1H), 1.99-1.92 (m, 1H), 1.87-1.82 (m, 2H), 1.21-1.17 (m, 1H),
0.91-0.85 (m, 9H), 0.78 (d, J ) 6.92 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.7, 141.8, 128.3, 128.1, 126.8, 66.5, 60.2,
54.0, 50.3, 36.3, 35.35, 32.3, 24.05, 17.65, 10.9, 15.7, 5.5. Anal.
Calcd for C19H29NO2: C, 75.2; H, 9.63; N, 4.62. Found: C,
74.81; H, 9.66; N, 4.51.
The coupling constants20 of 30B were determined by ir-
radiation of the methyl group located on the C4 position, the
hydrogen atom on the C5 position as well as the CH2 of the
ethyl groups.
30B: 1H NMR (400 MHz, CDCl3) δ 7.48-7.20 (m, 5H), 3.75
(d, J ) 16.36 Hz, 1H), 3.66 (s, 3H), 3.58 (d, J ) 16.36 Hz, 1H),
3.39 (d, J ) 4.0 Hz, 1H), 2.24-2.20 (m, 1H), 2.04-1.98 (m,
1H), 1.84-1.80 (m, 1H), 1.66-1.60 (m, 2H), 1.04 (d, J ) 7.16
Hz, 3H), 0.99 (d, J ) 7.16 Hz, 3H), 0.97-0.92 (m, 1H), 0.88 (d,
J ) 6.84 Hz, 3H), 0.73 (d, J ) 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.9, 142.2, 128.0, 127.8, 126.2, 70.6, 58.1, 51.5, 38.2,
37.6, 34.4, 29.9, 23.6, 17.4, 12.3, 10.6, 9.6.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of starting amines and of compounds 1, 4-11, 13-26,
28, 29, and 30A (67 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1H NMR (400 MHz, CDCl3) δ 7.40-7.23 (m, 5H), 4.21 (d, J
) 14.24 Hz, 1H), 4.17-4.13 (m, 1H), 4.13 (d, J ) 14.24 Hz,
1H), 3.96 (dd, J ) 8.8, 1.88 Hz, 1H), 3.53 (d, J ) 6.32 Hz, 1H),
2.71-2.66 (m, 1H), 2.59-2.54 (m, 1H), 1.97-1.92 (m, 1H),
1.82-1.73 (m, 2H), 1.62-1.57 (m, 1H), 1.29-1.24 (m, 1H), 0.98
J O971449M