Controlled synthesis of cis or trans isomers of 1,3-disubstituted tetrahydroisoquinolines and 2,5-disubstituted pyrrolidines

Article abstract of DOI:10.1021/jo0501543

The stereoselective outcome of Pd(II)- or Ag(I)-catalyzed intramolecular N-alkylation to afford 1,3-disubstituted 1,2,3,4-tetrahydroisoquinolines was examined. In the absence of additional substituents, Pd(II) allows a facile access to the cis isomers, wh

Full text of DOI:10.1021/jo0501543

Controlled Synthesis of Cis or Trans Isomers of 1,3-Disubstituted
Tetrahydroisoquinolines and 2,5-Disubstituted Pyrrolidines
Jacques Eustache,*,† Pierre Van de Weghe,† Didier Le Nouen,† Hiroshi Uyehara,‡
Chizuko Kabuto,‡ and Yoshinori Yamamoto*,‡
Laboratoire de Chimie Organique et Bioorganique associe´ au CNRS, Universite´ de Haute-Alsace, Ecole
Nationale Supe´rieure de Chimie de Mulhouse, 3, rue Alfred Werner, F-68093 Mulhouse Cedex, France,
and Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
jacques.eustache@uha.fr
Received January 25, 2005
The stereoselective outcome of Pd(II)- or Ag(I)-catalyzed intramolecular N-alkylation to afford 1,3-
disubstituted 1,2,3,4-tetrahydroisoquinolines was examined. In the absence of additional substit-
uents, Pd(II) allows a facile access to the cis isomers, while Ag(I) favors formation of the trans
isomers. The same observation was made for the synthesis of 2,5-disubstituted pyrrolidines. Possible
reasons for the observed stereoselectivities are discussed.
Introduction
The 1,2,3,4-tetrahydroisoquinoline moiety is commonly
found in biologically active molecules of either natural1
or synthetic origin. Although several well-established
synthetic procedures (Pomeranz-Fritsch, Bischler-
Napieralsky, and Pictet-Spengler) have long been avail-
able for preparing this heterocyclic system,2 these tra-
ditional methods involve an electrophilic aromatic
substitution as a key step and really work well only with
electron-rich systems. Owing to the importance of the
1,2,3,4-tetrahydroisoquinoline moiety, other methods
have been developed that do not rely on the electronic
characteristics of the aromatic ring. For example, the
intramolecular Heck reaction has successfully been used
FIGURE 1. “Nonclassical” syntheses of 1,2,3,4-tetrahydroiso-
quinolines.
to assemble the tetrahydroisoquinoline skeleton in com-
plex alkaloids (Figure 1).3 Electrophile-induced cycliza-
* Corresponding author. Tel: +33 3 89 33 6858. Fax: +33 3 89 33
6860.
† Universite´ de Haute-Alsace.
‡ Tohoku University.
(1) For a recent review on tetrahydroisoquinoline antibiotics, see:
Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669-1730.
(2) For recent reviews on the synthesis of tetrahydroisoquinolines,
see: (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341-3370. (b) Bracca, A. B. J.; Kaufman, T. S. Tetrahedron 2004,
60, 10575-10610. (c) Felpin, F. X.; Lebreton, J. Curr. Org. Synth. 2004,
1, 83-109. (d) Kirsch, G.; Hess, S.; Comel, A. Curr. Org. Synth. 2004,
1, 47-63. (e) Kaufman, T. S. Synthesis 2005, 339-360.
(3) (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552-6554. For earlier
examples of use of the intramolecular Heck reaction for the synthesis
of tetrahydroisoquinolines see: (b) Burns, B.; Grigg, R.; Santhakumar,
V.; Sridharan, V.; Stevenson, P.; Worakun, T. Tetrahedron 1992, 48,
7297-7320 and references therein. (c) Tietze, L. F.; Burkhardt, O.
Synthesis 1994, 1331-1336. (d) Tietze, L. F.; Burkhardt, O.; Henrich,
M. Liebigs Ann. Chem. 1997, 1407-1414.
10.1021/jo0501543 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/13/2005
J. Org. Chem. 2005, 70, 4043-4053
4043

Eustache et al.
The key reaction in this sequence is the intramolecular
N-alkylation which establishes the relative stereochem-
istry between the substituents at positions 1 and 3 in a
racemic synthesis and the absolute configuration at C-1
in an asymmetric synthesis. There were few reports of
this particular cyclization prior to our work,6 and the only
example somewhat related to ours is the recently re-
ported Hg(II)-promoted cyclization of 1-(2-allylphenyl)-
ethylamines to afford 1,3-disubstituted tetrahydroiso-
quinolines.4a In that case, the trans isomer was the major
product of the reaction. In contrast to tetrahydroiso-
quinolines, intramolecular N-alkylation has been used
in several instances for the preparation of 2,6-disubsti-
tuted piperidines. Various agents can trigger the cycliza-
tion including Pd(0)7 or Pd(II)8-10 complexes and Ag(I)
salts.8 In the representative examples shown in Figure
3 the factors which determine the stereoselectivity are
not obvious.
The conditions used for the cyclization and the substi-
tution patterns of the substrates are different in each
experiment, which renders comparisons difficult, but
certain trends are apparent. In experiments c and d, the
Pd(II)-induced cyclization leads to trans isomers, whereas
a cis isomer is formed preferentially when using a NaH/
Ag(I) or NaH/Pd(0) system. Comparing a and b gives
opposite results. It is well-known that A1,3-pseudoallylic
strain effects11 largely determine the outcome of these
cyclizations. However, other steric effects clearly play a
role in the transition state (compare for example cycliza-
tion a when R ) H or OBn). In our case, the situation is
again different because the presence of an aromatic ring
prevents a chairlike transition state generally used to
explain the observed stereoselectivities (see the Discus-
sion and refs 7-10). Therefore, before embarking on the
synthesis of complex 1,2,3,4-tetrahydroisoquinolines, we
considered it necessary to conduct careful cyclization
studies using simpler models. Our first synthetic study
toward (1-carboxy-3-vinyl)tetrahydroisoquinolines is de-
picted in Scheme 1.
FIGURE 2. Synthesis of 1,3-disubstituted 1,2,3,4-tetrahy-
droisoquinolines by intramolecular N-alkylation.
tion of o-allylbenzylamides has also been employed
(Figure 1).4 The number of recent reviews devoted to
1,2,3,4-tetrahydroisoquinolines1,2 provides evidence for
the considerable interest this class of compounds contin-
ues to attract from synthetic and medicinal chemists and
highlights the need for efficient and selective synthetic
approaches to this heterocyclic system.
For a project underway in our laboratories, we became
interested in 1,3-disubstituted-1,2,3,4-tetrahydroisoquin-
olines, an important subclass of 1,2,3,4-tetrahydroiso-
quinolines commonly found in natural products. A key
issue in the synthesis of these molecules is the control of
the relative and absolute stereochemistries at C-1 and
C-3 (see Figure 1 for numbering). Although some elegant
answers to this problem have been reported,5 to the best
of our knowledge, a generally applicable synthesis of 1,3-
disubstituted-1,2,3,4-tetrahydroisoquinolines does not ex-
ist at present. In the present study, we needed a
convenient access to (3-substituted 1-vinyl)- and (1-
substituted 3-vinyl)tetrahydroisoquinolines that fulfilled
the following requirements: (1) The synthesis should be
applicable to a wide range of aromatic substitutions. (2)
It should afford 1,3-cis-1,2,3,4-tetrahydroisoquinolines
preferentially. (3) An asymmetric version of the synthesis
should be easy to develop.
Our first synthetic target was cis-3-carboxy-1-vinyl-
tetrahydroisoquinolines (A, Figure 2). Inspection of the
literature pertaining to 1,2,3,4-tetrahydroisoquinoline
synthesis did not reveal a simple answer to our problem.
Hence, we developed the approach shown in Figure 2,
which fulfills requirements 2 and 3 listed above and
should fulfill requirement 1 with the possible exception
of cases where the aromatic ring substituents in B are
strongly electron-withdrawing groups. An asymmetric
version of the coupling D + E f C should be no problem
to develop.
Results and Discussion
The synthesis commences with the alkylation of the
enolate derived from N-[bis(methylthio)methylene]gly-
cine methyl ester12 by 2-iodobenzyl bromide to provide
the 2-iodophenylalanine derivative (2). This was con-
verted in two steps into rac-N-(benzyloxycarbonyl)-2-
iodophenylalanine methyl ester (4). Sonogashira reaction
(6) While this work was in progress, the preparation of chiral C-1-
substituted tetrahydroisoquinolines using Pd(0)-catalyzed intra-
molecular asymmetric amination of substituted phenethylamines was
described. Conceivably, a nonenantioselective version of this method
could be applied to the synthesis of 1,3-disubstituted tetrahydro-
isoquinolines: Ito, K.; Akashi, S.; Saito, B.; Katsuki, T. Synlett, 2003,
1809-1812.
(7) Takao, K.-I.; Nigawara, Y.; Nishino, E.; Takagi, I.; Koji, M.;
Tadano, K.-I.; Ogawa, S. Tetrahedron 1994, 50, 5681-5704.
(8) Hirai, Y.; Watanabe, J.; Nozaki, T.; Yokoyama, H.; Yamaguchi,
S. J. Org. Chem. 1997, 62, 776-777.
(9) Yokota, W.; Shindo, M.; Shishido, K. Heterocycles 2001, 54, 871-
885.
(4) (a) De Koning, C. B.; van Otterlo, W. A. L.; Michael, J. P.
Tetrahedron 2003, 59, 8337-8345 and references therein. (b) Clive,
D. L. J.; Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen, S.
M. J. Org. Chem. 1980, 45, 2120-2126.
(5) See, for example, ref 3a and: Magnus, P.; Matthews, K. S.;
Lynch, V. Org. Lett. 2003, 5, 2181-2184.
(10) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27-29.
(11) (a) Johnson, R. A. J. Org. Chem. 1968, 33, 3627-3632. (b)
Harding, K. E.; Marman, T. H. J. Org. Chem. 1984, 49, 2838-2840.
(12) Hoppe, D.; Beckmann, L. Liebigs Ann. Chem. 1979, 2066-2075.
4044 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Cis or Trans Isomers of Tetrahydroisoquinolines
formation and treatment with LiCl afforded a much lower
yield of 7). We found the best conditions for cyclization
to require low-temperature deprotonation of 7 by BuLi,
followed by addition of an excess of freshly recrystallized
AgOTf. Under these conditions, cyclization proceeded
smoothly to afford a 1:3 mixture of 8 and 9.15 The isomers
could be separated by chromatography and converted to
the corresponding carboxylic acids by careful hydrolysis
of the esters (solid LiOH, THF/MeOH/water). Using these
optimized conditions, cis/trans isomerization could be
minimized but not completely avoided. Establishing the
relative stereochemistry between substituents on C-1 and
C-3 in the newly formed ring proved unexpectedly
challenging, and detailed NMR experiments failed to
provide the answer. The stereochemistries were estab-
lished as follows:
(a) The minor component of the tetrahydroisoquinoline
mixture obtained after cyclization was converted to
alcohol 13, whose NMR data were compared with that
of the known authentic trans isomer 1416 and found to
be different (Scheme 2).
(b) The stereochemistry of 8 was subsequently con-
firmed from an X-ray structure of the ammonium salt
12 (Figure 4), clearly showing the cis relationship of the
C-1 and C-3 substituents (Figure 4).
Thus, in our case, AgOTf-induced cyclization afforded
mainly the trans instead of the desired cis isomer. We
next examined whether the course of the cyclization could
be modified by switching to the Pd(II) method as shown
earlier by Hirai in his studies on piperidines.8 We were
pleased to observe that treatment of 6 with PdCl2(PhCN)2
in THF at room temperature proceeded smoothly to
afford almost exclusively the cis isomer 8. The course of
the reaction deserves some comments: upon addition of
the catalyst 6 is rapidly converted to a slightly more polar
compound. Thin layer chromatography (TLC) monitoring
of the reaction indicates that after 2 h the new compound
(assumed to be the trans-allylic alcohol 6′) had consider-
ably increased at the expense of 6.
In the meantime, a less polar weakly UV active spot,
corresponding to the cyclization product, appeared.
Completion of the reaction required 24 h. Although we
cannot exclude that a small amount of tetrahydroiso-
quinoline is formed directly from 6, this appears to be a
minor process as compared to the isomerization 6 f 6′
followed by cyclization of the latter.
Thus, in our case, the results are opposite to that
observed in refs 8 and 9 (Figure 3c,d) and agree with
those reported in refs 7 and 10 (Figure 3a,b). A tentative
explanation is proposed in Figure 5.
Several similar chairlike transition-state models have
been proposed to explain the stereoselective outcome of
intramolecular N-alkylation reactions to afford pip-
eridines (TsA, TsB, TsC, and TsD in Figure 5). Transi-
tion state TsB in which A1,3-pseudoallylic strain is
minimal leads to a cis isomer. In transition state TsA,
repulsion between the trityloxymethyl and π-allyl pal-
FIGURE 3. Literature examples of formation of 2,6-disub-
stituted piperidines by intramolecular N-alkylation. *In c, cis
and trans are defined arbitrarily to facilitate comparison with
experiment d.
with propargyl alcohol13 was followed by treatment with
Lindlar catalyst to yield the cis-allylic alcohol 6. Each
step in the sequence proceeded with good yields. Based
upon the literature precedents shown in Figure 3 (entries
c and d), we first focused on the NaH/AgOTf combination
for inducing the cyclization to the desired 1,3-cis-disub-
stituted tetrahydroisoquinoline 11. Conversion of alcohol
6 to the allylic chloride 7 was effected in high yield by
treatment with triphenylphosphine and N-chlorosuccin-
imide14 (the alternative conversion involving mesylate
(13) During the Sonogashira reaction, highly colored impurities are
formed whose polarity is close to that of propargylic alcohol 5. It is
important to use a long enough silica gel column for removing these
impurities. Failure to do so will render the next (reduction) step very
sluggish. If this is the case, the inactivated Lindlar catalyst should be
filtered off and replaced by a fresh one until hydrogen adsorption
proceeds at a fast rate. Otherwise, slow reaction and over reduction
may result.
(15) Similar results in terms of stereoselectivity were obtained using
NaH (-20 °C to rt) or N-diisopropylethylamine (48 h, rt) as bases.
Yields were lower, however and varied from experiment to experiment.
On TLC (SiO2, ether/hexane, 1:2), 8 and 9 are weakly UV active. 8 is
slightly less polar than 9.
(16) Monsees, A.; Laschat, S.; Dix, I.; Jones, P. G. J. Org. Chem.
1998, 63, 10018-10021.
(14) Sakaitani, M.; Ohfune, Y. J. Am. Chem. Soc. 1990, 112, 1150-
1158.
J. Org. Chem, Vol. 70, No. 10, 2005 4045

Eustache et al.
SCHEME 1a
a Reagents and conditions: (a) t-BuOK (1 equiv), THF, -78 °C, 1 h then 2-iodobenzyl bromide (1 equiv), -78 °C to rt, 2 h; (b) HCl,
THF/H2O, rt, 16 h, 71% (two steps); (c) ZCl (1.2 equiv), NEt3 (2.4 equiv), -20 °C to rt, 1 h, 81%; (d) propargyl alcohol (1 equiv), PdCl2(PPh3)2
(5 mol %), CuI (5 mol %), NEt3 (excess), THF, rt, 4 h, 68%; (e) H2 (1 atm), Lindlar catalyst, MeOH, 83%; (f) PPh3 (2 equiv), NCS (1.7
equiv), CH2Cl2, 0 °C, 15 min, 90%; (g) BuLi, (1 equiv), -78 °C, 15 min then AgOTf (excess), THF, 6.5 h, 18% (8) and 53% (9); (h) LiOH‚H2O
(excess), THF/water, 60 °C, 8 h, 100% (11% cis isomer), (i) PdCl2(PhCN)2 (19 mol %), THF, rt, 24 h, 75%; (j) LiOH‚H2O (excess), THF/
MeOH/water, 60 °C, 16 h, 98% (11% trans isomer), (k) dicyclohexylamine (1.1 equiv), ether, rt.
SCHEME 2a
a Reagents and conditions: (a) (i) H2 (1 atm), Pd/C, MeOH, rt,
2.5 h; (ii) LiAlH4, THF, rt, 16 h, 62%, two steps).
ladium groups is apparently able to overcome minimiza-
tion of A1,3-pseudoallylic strain resulting in the prefer-
ential formation of the trans isomer. In transition states
TsC and TsD, the rigid cyclic carbamate can only occupy
the equatorial position while the allyl alcohol or allylic
chloride occupies an axial or equatorial position respec-
tively due to differing complexation modes with Pd(II)
or Ag(I).
Thus, besides the use of Pd(II) or Ag(I), a crucial factor
for controlling the formation of 2,6-trans- or 2,6-cis-
piperidines by intramolecular cyclizing N-alkylation ap-
pears to be the nature of the starting carbamate (cyclic
or acyclic).17 In our case, by analogy to the above models,
the transition states in the Pd(II)- or Ag(I)-induced
FIGURE 4. Crystal structure of 12 (dicyclohexylamine moiety
omitted for clarity).
cyclization, which could explain our findings may be
represented as shown in Figure 5 (TsE and TsF, respec-
tively).
It should also be noted that an enantioselective version
of these syntheses can be easily derived from the present
results because our key intermediate 3 can easily be
prepared in an optically active form.
(17) We thank one of the reviewers for pointing out the importance
of the nature of the starting carbamate in establishing the stereo-
selectivity of the cyclization.
4046 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Cis or Trans Isomers of Tetrahydroisoquinolines
FIGURE 5. Possible transition-state models for intramolecular cyclizing N-alkylation leading to piperidines or tetrahydroiso-
quinolines. Chairlike transition states: A and B, acyclic carbamates;7,10 C and D, cyclic carbamates;8,9 E and F, this work.
SCHEME 3a
We next examined the applicability of the method to
the enantioselective preparation of our second series of
target molecules, 1-substituted 3-vinyl-1,2,3,4-tetra-
hydroisoquinolines (Scheme 3).
Iodostyrene 1518 was converted in high yield to the diol
derivative 16 (ee > 98%) by Sharpless asymmetric
dihydroxylation using AD-mix-R.19 Conversion to epoxide
17,20 and lithium perchlorate-assisted opening of the
latter with NaN3 provided a mixture of two R-azido
alcohols in which the desired regioisomer (19) predomi-
nated. Protection of the primary alcohol in 19 as a MOM
ether, reduction of the azide,21 and protection of the
resulting amine as the corresponding BOC derivative
afforded the protected amino alcohol 21. Direct conver-
sion of 21 to the required allylic alcohol 23 proved not to
be possible: Stille coupling with tributyl((Z)-4-meth-
oxymethoxybut-2-enyl)stannane was unsuccessful, and
palladium acetate-catalyzed coupling with 2-vinyloxirane
proceeded in low yield and without stereoselectivity.22
The problem was solved by first converting 21 to the
stannyl derivative 22. Coupling with 2-vinyloxirane then
proceeded smoothly in DMF, using the weakly liganded
palladium complex (CH3CN)2PdCl2 to afford allylic alco-
hol 23 in excellent yield as the pure (E)-isomer (within
NMR detection limits).23 Allylic alcohol 23 was submitted
to the cyclization conditions shown earlier to favor the
formation of 1,3-cis-tetrahydroisoquinolines. The reaction
proceeded rapidly to provide 24 in very good yield and
with very high stereoselectivity (cis/trans > 95/5). NMR
studies of the free amine 25 revealed an NOE between
a Reagents and conditions: (a) AD-mix-R, t-BuOH/H2O, 0 °C, 5
h, 91%; (b) MeC(OEt)3, TMSCl, CH2Cl2, 0 °C, 2 h then K2CO3,
MeOH, rt, 2 h, 92%; (c) NaN3, LiClO4, CH3CN, 60 °C, 5 h, 29%
i
(18) and 67% (19); (d) MOMCl, Pr2NEt, CH2Cl2, rt, 3 h, 94%; (e)
(18) Acheson, R. M.; Lee, G. C. J. Chem. Soc., Perkin Trans. 1 1987,
2321-2332.
(i) SnCl2, PhSH, NEt3, THF, rt, 30 min; (ii) BOC2O, NEt3, rt, 3 h,
85%; (f) Bu3SnSnBu3, Pd(tBu3P)2 (10 mol %), DMF, 100 °C, 20 h,
60%; (g) 2-vinyloxirane, PdCl2(CH3CN)2 (10 mol %), DMF/H2O, rt,
10 h, 83%; (h) PdCl2(CH3CN)2 (10 mol %), THF, rt, 2 h; (i) TFA/
H2O (1:1), CH3CN, rt, 48 h, 78% (two steps).
(19) Swindell, C. S.; Fan, W. J. Org. Chem. 1996, 61, 1109-1118.
(20) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-
10530.
(21) Barta, M.; Romea, P.; Urpi, F.; Vilarrassa, J. Tetrahedron 1990,
46, 587-594.
(22) Larock, R. C.; Ding, S. J. Org. Chem. 1993, 58, 804-806.
(23) (a) Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetrahedron
1989, 45, 979-992. (b) Echavarren, A. M.; Tueting, D. R.; Stille, J. K.
J. Am. Chem. Soc. 1988, 110, 4039-4041.
the protons located at positions 1 and 3, thus establishing
the cis relationship of the vinyl group and the protected
J. Org. Chem, Vol. 70, No. 10, 2005 4047

Eustache et al.
SCHEME 4a
FIGURE 6. Crystal structure of 31 (dicyclohexylamine moiety
omitted for clarity).
phosphine)ruthenium] (Grubbs II catalyst), according to
Roy,27 proceeded well to afford precursor 26 which was
submitted to the Ag(I) cyclization conditions described
previously (BuLi, AgOTf) to give a 4:1 mixture of pyrro-
lidines 27 and 28. The 2,5-trans configuration in 27 was
ascertained by conversion of the mixture 27-28 to the
mixture of ethyl esters 27′-28′. NMR data of the major
isomer corresponded to that of the authentic material.28
The Pd(II)-induced cyclization was examined next. To
this effect, the allylic chloride 26 was converted in two
steps to the allylic alcohol 30 which was treated with
PdCl2(CH3CN)2 in THF at room temperature to afford
pyrrolidine 28 as a single isomer. To further support our
stereochemical assignments, 28 was converted in two
steps to the crystalline dicyclohexylamine salt 31 from
which an X-ray structure was obtained showing the cis
relationship between the 2 and 5 substituents (Figure
6).
a Reagents and conditions: (a) CH2dCHCH2Cl (3.5 equiv),
Grubbs II (10 mol %), CH2Cl2, 40 °C, 14 h, 67%; (b) BuLi, (1 equiv),
-78 °C, 15 min then AgOTf (1.7 equiv), THF, rt, 2.5 h, 77% (27/
28 ) 4:1); (c) NaOAc (10 equiv), DMF, 100 °C, 26 h, 70%; (d)
NaOMe (0.1 M), MeOH, rt, 2.5 h, 90%; (e) PdCl2(CH3CN)2 (15 mol
%), THF, rt, 12 h, 77%; (f) NaOEt (0.04M), EtOH, rt; (g) HCl (4 M
in dioxane), 0 °C, 1 h, 58% (two steps); (h) LiOH‚H2O (7 equiv),
THF/H2O, 60 °C, 5 h, 100%; (i) dicyclohexylamine (1 equiv), ether,
rt.
Conclusion
hydroxymethyl side chain. Here again, the model shown
in Figure 5 can be used to explain the observed result.
Our project also required the preparation of cis-2-
carboxy-5-vinylpyrrolidines. The few reported syntheses
of cis-2-carboxy-5-vinylpyrrolidines are poorly stereo-
selective.24 Considering the favorable results we had
obtained in the tetrahydroisoquinoline series, we decided
to examine whether the methodology could be applied to
the preparation of pyrrolidines. Here again, despite
literature precedents, we could not find examples that
would allow us to predict with certainty the stereoselec-
tive outcome of the cyclization.25
We developed the short route shown in Scheme 4. (S)-
2-tert-Butoxycarbonylaminohex-5-enoic acid methyl ester
was prepared from BOC-iodoalanine methyl ester and
allyl chloride.26 Cross-metathesis using excess allyl chlo-
ride and [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazoli-
dinylidene)dichloro(phenylmethylene)(tricyclohexyl-
In conclusion, the Pd(II) and Ag(I) intramolecular
N-alkylation initially developed by Hirai for the synthesis
of piperidines and (in one instance) pyrrolidines has been
applied to the preparation of 1,3-disubstituted 1,2,3,4-
tetrahydroisoquinolines. In the absence of additional
substituents, the Ag(I)/base conditions affords 1,3-cis
isomers, whereas the Pd(II)-catalyzed reaction leads to
the formation of trans isomers. This latter observation
is in line with the results reported by Makabe10 and
contrasts with the findings of Hirai in the piperidine
series. A tentative half-chair transition-state model was
proposed for the reaction pathway giving rise to tetra-
hydroisoquinolines. The same observation (i.e., Pd-
induced intramolecular N-alkylation leads to cis isomers)
was made for 2,5-disubstituted pyrrolidines.
Both cis and trans isomers of chiral 1,3-disubstituted-
1,2,3,4-tetrahydroisoquinolines are found in naturally
occurring, biologically active alkaloids; therefore, the
development of highly stereoselective and enantioselec-
tive methods to each isomer is important. The present
work proposes a simple solution to this problem, and the
new synthetic approaches compare favorably with previ-
ous ones in terms of efficacy and potential scope.
(24) (a) Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D. Tetrahedron
2000, 56, 10113-10125. (b) Beal, L. M.; Moeller, K. D. Tetrahedron
Lett. 1998, 39, 4639-4642. (c) Campbell, J. A.; Rapoport, H. J. Org.
Chem. 1996, 61, 6313-6325. (d) Manfre´, F.; Kern, J.-M.; Biellmann,
J.-F. J. Org. Chem. 1992, 57, 2060-2065.
(25) See, for example: Hirai, Y.; Terada, T.; Amemiya, Y.; Momose,
T. Tetrahedron Lett. 1992, 33, 7893-7894. To the best of our knowl-
edge, this is the only reported example of 2,5-disubstituted pyrrolidine
synthesis via Pd(II)-induced cyclization of 4-((Z)-1-benzoyloxy-5-meth-
oxymethoxypent-3-enyl)oxazolidin-2-one, and only the 2,5-trans isomer
was formed. However, in this case, the benzoyloxy group may play a
key role in determining the stereoselectivity of the reaction as observed
for piperidines (ref 8). Ag(I)-induced cyclization was not studied in that
case.
Experimental Section
General Methods. 1H NMR and 13C NMR spectra were
recorded at 500 or 400 MHz and 125.6 and 100 MHz,
(27) Liu, B. Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723-2726.
(28) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60,
5011-5015.
(26) Rodriguez, A.; Miller, D. D.; Jackson, R. F. W. Org. Biomol.
Chem. 2003, 1, 973-977.
4048 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Cis or Trans Isomers of Tetrahydroisoquinolines
respectively. Melting points are not corrected. When required,
reactions were carried out under argon atmosphere with
standard techniques for the exclusion of air and moisture. All
solvents were dried before use. TLC was performed using
fluorescent 60F254 coated plates.
8, 6 Hz), 5.07 (1 H, d, J ) 12 Hz), 5.11 (1 H, d, J ) 12 Hz),
5.49 (1 H, br d, J ) 8 Hz), 7.03 (1 H, m), 7.19 (2 H, m), 7.28-
7.40 (6 H, m); 13C NMR (toluene-d8, 125.6 MHz) δ (ppm) 30.5,
38.8, 51.35, 51.5, 54.6, 67.3, 83.4, 94.1, 124.0, 127.2, 128.5,
128.6, 129.9, 132.0, 136.8, 138.9, 156, 172.2; HRMS (ESI,
positive mode) calcd for C21H21NO5 + Na+ 390.1317, found
390.1312.
Methyl 2-Amino-3-(2-iodophenyl)propionate Hydro-
chloride (3). To a cold (-78 °C) solution of N-[bis(methylthio)-
methylene]glycine methyl ester 1 (11.40 g, 59.0 mmol) in THF
(120 mL) was added under argon atmosphere powdered
t-BuOK (6.62 g, 59.0 mmol). The mixture was stirred until
t-BuOK was dissolved (ca. 1 h). 1-Bromomethyl-2-iodobenzene
was then added (17.54 g, 59.0 mmol), and the reaction was
stirred for 10 min at -78 °C and then 1 h at rt. The resulting
brown-red solution was diluted with ethyl acetate and ex-
tracted with 1 N HCl and then saturated aqueous NaHCO3.
The organic solution was dried over MgSO4, and the solvents
were removed under reduced pressure. Polar, colored impuri-
ties and unreacted 1-bromomethyl-2-iodobenzene were re-
moved by chromatography over a short silica gel column to
afford 21.0 g of crude 2. This was dissolved in THF (120 mL),
and 2 N HCl (60 mL) was added. The turbid mixture was
stirred at rt for 16 h at which time a clear solution was
obtained. The THF was evaporated under reduced pressure,
and the aqueous solution was extracted three times with ether
and concentrated to ca. 20 mL at which time an abundant
crystalline precipitate had formed. Ether (100 mL) was added,
and the crystals were recovered by filtration. The crystalline
residue was dissolved in hot chloroform (500 mL), and the
solution was dried (MgSO4) and concentrated under reduced
pressure to ca. 50 mL. Compound 3 crystallized during the
evaporation. Ether (200 mL) was added, and the crystals were
filtered and dried to afford pure 3 (14.32 g, 71%): mp 183-
2-Benzyloxycarbonylamino-3-[2-((Z)-3-hydroxypro-
penyl)phenyl]propionic Acid Methyl Ester (6). The pro-
pargylic alcohol 5 (6.45 g, 17.5 mmol) was dissolved in
methanol (150 mL). Lindlar catalyst (1 g) was added, and the
adsorption of hydrogen was measured. Vigorous stirring was
maintained until the expected amount of hydrogen had been
adsorbed. Completion of the reaction requires about 30 min
and can be checked by TLC on silica gel (hexane/ether, 1:3).
The catalyst was filtered off, the solvents were evaporated,
and the residue was chromatographed over silica gel (hexane/
ether, 1:3) to afford pure 6 (5.41 g, 83%): 1H NMR (CDCl3,
400 MHz) δ (ppm) 2.45 (1 H, t, J ) 6 Hz), 2.84 (1 H, dd, J )
14, 9 Hz), 3.24 (1 H, dd, J ) 14, 5 Hz), 3.71 (3 H, s), 4.08 (1 H,
m), 4.20 (1 H, m), 4.72 (1 H, td, J ) 9, 5.5 Hz), 4.93 (1 H, d, J
) 12 Hz), 4.99 (1 H, d, J ) 12 Hz), 5.19 (1 H, d, J ) 9 Hz),
6.00 (1 H, ddd, J ) 11.5, 5.5, 4 Hz), 6.67 (1 H, d, J ) 11.5 Hz),
6.9-7.4 (9 H, m); 13C NMR (toluene-d8, 125.6 MHz) δ (ppm)
37.0, 51.8, 54.0, 58.9, 67.0, 126.9, 127.5, 128.0, 128.3, 128.5,
1287, 30.7, 130.8, 134.4, 134.7, 136.6, 136.9, 156.1, 172.3;
HRMS (ESI, positive mode) calcd for C21H23NO5 + Na+
392.1474, found 392.1468.
2-Benzyloxycarbonylamino-3-[2-((Z)-3-chloropropenyl)-
phenyl]propionic Acid Methyl Ester (7). The allylic alcohol
6 (1.787 g, 4. 87 mmol) was dissolved in dry CH2Cl2 (70 mL)
under argon at 0 °C. Triphenylphosphine (2.52 g, 2 equiv) and
N-chlorosuccinimide (1.12 g, 1.7 equiv) were added. The
reaction mixture was stirred at 0 °C for 15 min, the solvents
were evaporated, and the residue was purified by chromatog-
raphy over silica gel (toluene/ethyl acetate, 19:1). Compound
7 (1.685 g, 90%) was obtained as a colorless oil which slowly
solidified upon standing: mp 61-62.5 °C; 1H NMR (CDCl3,
400 MHz) δ (ppm) 2.97 (1 H, dd, J ) 14, 7.5 Hz), 3.24 (1 H,
dd, J ) 14, 6 Hz), 3.67 (3 H, s), 4.04 (2 H, d, J ) 8 Hz), 4.58
(1 H, td, 8, 6.5 Hz), 4.96-5.05 (2 H, m), 5.15 (1 H, d, J ) 8.5
Hz), 5.95 (1 H, dt, J ) 11, 7.5 Hz), 6.72 (1 H, d, J ) 11 Hz),
7.10 (1 H, d, J ) 7 Hz), 7.2-7.35 (8 H, m); 13C NMR (toluene-
d8, 125.6 MHz) δ (ppm) 36.4, 40.8, 51.6, 54.5, 66.9, 127.2, 128.1,
128.15, 128.4, 128.6, 129, 129.6, 130.65, 131.9, 135.2, 135.6,
137.1, 155.5, 172; HRMS (ESI, positive mode) calcd for C21H22-
ClNO4 + Na+ 410.1135, found 410.1130.
1,3-cis-2-Benzyloxycarbonyl-1-vinyl-3,4-dihydro-1H-
isoquinoline-3-carboxylic Acid Methyl Ester (8) and 1,3-
trans-2-Benzyloxycarbonyl-1-vinyl-3,4-dihydro-1H-iso-
quinoline-3-carboxylic Acid Methyl Ester (9). (a) Silver
Triflate Method. To a cold (-78 °C) solution of allylic chloride
7 (1.469 g, 3.79 mmol) in THF (15 mL) was added dropwise,
under argon, a solution of BuLi (1.6 M in hexane, 2.37 mL, 1
equiv). After 15 min, silver triflate (1.3 g, freshly recrystallized
from toluene) was added. The light-brown, clear solution was
allowed to warm to rt over the course of 2 h. The now dark
brown suspension was stirred at rt for 2 h. At this point, TLC
showed ca. 80% conversion of the starting material. More
AgOTf (0.4 g) was added, and the reaction was completed in
30 min. TLC (silica gel, hexane/ether, 3:1, two migrations)
showed the formation of two weakly UV-active, faster migrat-
ing spots. The reaction mixture was diluted with ether, washed
with 2 N aqueous HCl and saturated NaHCO3, dried, and
evaporated to dryness. The residue was chromatographed over
silica gel (hexane/ether, 2:1) to give successively 8 (0.248 g,
18%) and then 9 (0.698 g, 53%).
1
186 °C; H NMR (methanol-d4, 400 MHz) δ (ppm) 3.26 (1 H,
dd, J ) 14, 8 Hz), 3.42 (1 H, dd, J ) 14, 8 Hz), 3.74 (3 H, s),
4.32 (1 H, t, J ) 8 Hz), 7.05 (1 H, td, J ) 7.5, 1.5 Hz), 7.31 (1
H, dd, J ) 8, 1.5 Hz), 7.39 (1 H, td, J ) 7.5, 1 Hz), 7.91 (1 H,
dd, J ) 8, 1 Hz). Anal. Calcd for C10H13ClINO2 (M ) 341.5):
C, 35.16; H, 3.84; N, 4.10. Found: C, 35.21; H, 3.85; N, 4.10.
2-Benzyloxycarbonylamino-3-(2-iodophenyl)propion-
ic Acid Methyl Ester (4). To a suspension of 3 (14.32 g, 41.9
mmol) in THF (200 mL) was added triethylamine (14.0 mL,
2.4 equiv). The mixture was cooled to -20 °C, and Z-chloride
(7.18 mL, 1.2 equiv) was added. The mixture was stirred for
10 min at -20 °C and 1 h at rt. The solvents were evaporated,
and the residue was taken up in ether. The precipitate (amine
salts) was filtered off and the residue chromatographed over
silica gel (hexane/ether, 2:1) to afford pure 4 (14.78 g, 81%) as
a thick syrup which slowly solidified upon standing: mp 64-
1
67 °C; H NMR (CDCl3, 400 MHz) δ (ppm) 3.12 (1 H, dd, J )
14, 8 Hz), 3.29 (1 H, dd, J ) 14, 6 Hz), 3.71 (3 H, s), 4.69 (1 H,
m), 5.28 (1 H, br d, J ) 8 Hz), 6.90 (1 H, t, J ) 7 Hz), 7.16-
7.40 (9 H, m); 13C NMR (toluene-d8, 125.6 MHz) δ (ppm) 43.0,
51.8, 54.5, 66.9, 101.3, 128.1, 128.3, 128.4, 128.5, 128.7, 130.6,
139.9, 140.0, 155.7, 171.8; HRMS (ESI, positive mode) calcd
for C18H18INO4 + Na+ 462.0178, found 462.0173.
2-Benzyloxycarbonylamino-3-[2-(3-hydroxyprop-1-
ynyl)phenyl]propionic Acid Methyl Ester (5). The pro-
tected amino acid 4 (4.39 g, 10 mmol) was dissolved in THF
(40 mL). The solution was degassed and placed under argon
atmosphere. PdCl2(PPh3)2 (0.350 g, 0.5 mmol), CuI (95 mg, 0.5
mmol), and triethylamine (20 mL) were added. The solution
was degassed again and placed under argon atmosphere, and
propargyl alcohol (0.60 mL, 1 equiv) was added under stirring.
The mixture was stirred for 4 h and partitioned between ether
and 2 N aqueous HCl. The organic layer was washed with 2
N aqueous HCl and saturated NaHCO3, dried, and evaporated
to dryness. The residue was chromatographed over silica gel
(hexane/ethyl acetate, 2:1), on a long column, to provide pure
5 as a light yellow syrup (2.495 g, 68%): 1H NMR (CDCl3, 400
MHz) δ (ppm) 3.09 (1 H, dd, J ) 13, 8 Hz), 3.35 (1 H, dd, J )
13, 6 Hz), 3.42 (1 H, t, J ) 6 Hz), 3.58 (3 H, s), 4.43 (1 H, dd,
J ) 16, 6 Hz), 4.48 (1 H, dd, J ) 16, 6 Hz), 4.83 (1 H, dt, J )
8 (colorless oil): 1H NMR (toluene-d8, 500 MHz, 100 °C) δ
(ppm) 2.78 (1 H, dd, J ) 15, 6 Hz), 3.01 (1 H, dd, J ) 15, 10
Hz), 3.36 (3 H, s), 4.57 (1 H, br s), 4.99 (1 H, dt, J ) 10, 1 Hz),
5.04 (1 H, br d, J ) 12 Hz), 5.12 (1 H, d, J ) 12 Hz), 5.17 (1
H, dt, J ) 17, 1 Hz), 5.80 (1 H, br s), 6.14 (1 H, ddd, J ) 17,
J. Org. Chem, Vol. 70, No. 10, 2005 4049

Eustache et al.
10, 4.5 Hz), 6.88-7.21 (9 H, m); 13C NMR (toluene-d8, 125.6
MHz) δ (ppm) 30.8, 30.9, 51.6, 55.9, 56.1, 58.5, 58.6, 67.4, 67.7,
115.4, 115.7, 127.0, 127.2, 127.3, 127.4, 127.6, 127.7, 127.8,
128.0, 128.1, 128.2, 128.25, 128.35, 128.5, 128.6, 133.3, 133.4,
135.9, 136.9, 137.0, 137.3, 138.9, 155.4, 155.7, 172.2, 172.6;
HRMS (ESI, positive mode) calcd for C21H21NO4 + Na+
374.1368, found 374.1361.
9 (colorless oil which solidifies upon standing): 1H NMR
(toluene-d8, 500 MHz, 100 °C) δ(ppm) 2.93 (1 H, dd, J ) 15, 2
Hz), 3.00 (1 H, dd, J ) 15, 6 Hz), 3.14 (3 H, s), 4.85 (1 H, d, J
) 10 Hz), 4.90 (1 H, d, J ) 17 Hz), 4.92 (1 H, br s), 5.06 (1 H,
d, J ) 12.5 Hz), 5.20 (1 H, d, J ) 12.5 Hz), 5.74 (1 H, br s),
5.84 (1 H, m), 6.25-7.25 (9 H, m); 13C NMR (toluene-d8, 125.6
MHz) δ (ppm) 31.3, 31.5, 51.5, 51.6, 56.0, 56.1, 58.9, 59.1, 67.4,
67.6, 113.4, 113.8, 127.4, 127.5, 127.55, 127.7, 127.75, 128.0,
128.05, 128.1, 128.25, 128.3, 128.5, 132.5, 132.6, 136.3, 136.4,
137.3, 139.2, 139.7, 155.5, 156, 171.5, 171.9; HRMS (ESI,
positive mode) calcd for C21H21NO4 + Na+ 374.1368, found
374.1362.
(b) Pd(II) Method. The allylic alcohol 6 (5.41 g, 14.6 mmol)
was dissolved in dry THF (50 mL) under argon. PdCl2(PhCN)2
(843 mg, 15 mol %) was added, and the reaction mixture was
stirred at rt for 8 h. More catalyst (230 mg) was added, and
stirring was continued for 16 h. The mixture was partitioned
between ether and saturated NaHCO3, the organic layer was
dried, and the solvents were evaporated. TLC indicated
formation of 8 as a major isomer. The proportion of 8 and 9 in
the mixture of isomers was established by measuring the
relative intensities of the olefinic protons and found to be
10:1. Careful chromatography as above (hexane/ether, 2:1)
afforded pure 8 (3.88 g, 75%).
h upon which time the dicyclohexylamine salt 12 had crystal-
lized (0.49 g): mp 139-140 °C; 1H NMR (DMSO-d6, 100 MHz,
100 °C) δ(ppm) 1.05-1.30 (8 H, m), 1.55 (2 H, m), 1.67 (4 H,
m), 1.80 (4 H, m), 2.63 (2H, m), 3.02 (1H, dd, J ) 15, 9 Hz),
3.12 (1 H, dd, J ) 15, 6 Hz), 4.42 (1 H, dd, J ) 10, 6 Hz), 5.05
(1 H, dt, J ) 10, 1.5 Hz), 5.10 (1 H, d, J ) 13 Hz), 5.15 (1 H,
d, J ) 13 Hz), 5.19 (1 H, dt, J ) 17, 1.5 Hz), 5.63 (1 H, dt, J
) 5, 1.5 Hz), 6.14 (1H, ddd, J ) 17, 10, 5 Hz), 7.2-7.5 (9 H,
m), 13C NMR (DMSO-d6, 100 MHz, 100 °C) δ (ppm) 23.7, 25.0,
29.8, 32.2, 52.1, 54.9, 57.5, 66.0, 114.4, 125.8, 126.0, 126.55,
126.6, 127.0, 127.15, 127.5, 132.9, 135.5, 136.3, 138.2, 154.6,
172.2; HRMS (ESI, positive mode).
(1R,3R)-3-Ethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)meth-
anol (13). A mixture of 8 (30 mg, 0.085 mmol) and Pd/C (30
mg) in MeOH (2 mL) was vigorously stirred at rt for 2.5 h
under H2 atmosphere. The mixture was filtered through a pad
of Celite, and the filtrate was concentrated. The residue was
dissolved in THF (2 mL), and LiAlH4 (30 mg, 0.8 mmol) was
added. The mixture was stirred overnight at rt, water was
added, and the product was extracted with Et2O (three times).
The combined organic layers were dried over MgSO4, filtered,
and concentrated. The crude product was purified by chroma-
tography on silica gel (chloroform/2-propanol, 10:1), and 13 was
isolated as a pale yellow oil (10 mg, 62%): 1H NMR (400 MHz,
CDCl3) δ (ppm) 0.97 (3 H, t, J ) 7.4 Hz), 1.74 (1 H, m), 2.12 (1
H, m), 2.65 (2 H, m), 3.07 (1 H, m), 3.54 (1 H, dd, J ) 7.8, 10.6
Hz), 3.82 (1 H, dd, J ) 3.7, 10.6 Hz), 4.04 (1 H, m), 7.15 (4 H,
m); 13C NMR (100 MHz, CDCl3) δ (ppm) 9.71, 28.65, 32.25,
54.78, 57.32, 66.03, 125.37, 126.07, 126.12, 129.27, 134.79,
138.63. HRMS calcd for C12H17NO + Na+ 214.1208, found
214.1237 (trans isomer14).
(S)-1-(2-Iodophenyl)ethane-1,2-diol (16). A mixture of
tert-butyl alcohol (150 mL), water (150 mL) and AD-mix-R (30
g), was stirred at 0 °C until two clear phases were produced,
and then a solution of 15 (4.0 g, 17.3 mmol) in tert-butyl alcohol
(10 mL) and water (10 mL) was added. After 5 h at 0 °C, the
reaction mixture was treated with Na2SO3 (35 g) with stirring
at rt for 30 min. The aqueous layer was extracted twice with
CH2Cl2, and the combined organic layers were dried over
MgSO4 and concentrated. After flash chromatography on silica
gel (cyclohexane/ethyl acetate, 1:1), a white solid was obtained
1,3-trans-2-Benzyloxycarbonyl-1-vinyl-3,4-dihydro-1H-
isoquinoline-3-carboxylic Acid (10). The pure trans-methyl
ester 9 (0.717 g, 2.04 mmol) was dissolved in a mixture of THF
(15 mL), methanol (1 mL), and water (0.5 mL). Powdered
LiOH‚H2O (630 mg) was added, and the suspension was stirred
at 60 °C under argon for 12 h and partitioned between ether
and 2 N aqueous HCl. The organic layer was washed with
water until the aqueous extracts were neutral (litmus paper),
dried, and evaporated under reduced pressure to afford 10
containing 11% of the cis isomer 11 (0.685 g, quantitative),
which crystallized upon standing. A small amount was recrys-
tallized (ether/pentane) to afford an analytical sample (<3%
11): 1H NMR (DMSO-d6, 400 MHz, 100 °C) δ (ppm) 3.03 (1
H, dd, J ) 15, 2 Hz), 3.21 (1 H, dd, J ) 15, 6 Hz), 4.85 (1 H,
dd, J ) 6, 2 Hz), 4.96-5.01 (2 H, m), 5.15 (2 H, s), 5.56 (1 H,
d, J ) 5 Hz), 5.89 (1 H, ddd, J ) 17, 10, 5 Hz), 6.9-7.5 (9 H,
m), 12.0 (1 H, br s); 13C NMR (DMSO-d6, 100 MHz, 100 °C) δ
(ppm) 30.2, 54.5, 57.7, 66.1, 112.9, 126.4, 126.45, 126.7, 126.8,
127.15, 127.2, 127.7, 131.75, 135.4, 136.3, 138.7, 154.6, 171.7;
HRMS (ESI, positive mode) calcd for C20H19NO4 + Na+
360.1212, found 360.1206.
1,3-cis-2-Benzyloxycarbonyl-1-vinyl-3,4-dihydro-1H-
isoquinoline-3-carboxylic Acid (11). The pure cis-methyl
ester 8 (3.88 g, 11.0 mmol) was treated as 9 to afford the
corresponding carboxylic acid 11 containing 11% of the trans
isomer 10 (3.649 g, 98%): 1H NMR (DMSO-d6, 400 MHz, 100
°C) δ (ppm) 3.02 (1 H, dd, J ) 15, 10 Hz), 3.15 (1 H, dd, J )
15, 6 Hz), 4.46 (1 H, dd, J ) 10, 6 Hz), 4.97 (1 H, dt, J ) 10,
1.5 Hz), 5.01 (1 H, d, J ) 13 Hz), 5.06 (1 H, d, J ) 13 Hz), 5.07
(1 H, dt, J ) 17, 1.5 Hz), 5.67 (1 H, dt, J ) 5, 1.5 Hz), 6.07
(1H, ddd, J ) 17, 10, 5 Hz), 7.2-7.5 (9 H, m), 12.0 (1 H, br s);
13C NMR (DMSO-d6, 100 MHz, 100 °C) δ (ppm) 29.5, 54.5, 57.4,
66.2, 114.7, 126.0, 126.7, 126.8, 127.0, 127.15, 127.6, 132.3,
135.3, 136.1, 137.8, 154.5, 172.0; HRMS (ESI, positive mode)
calcd for C20H19NO4 + Na+ 360.1212, found 360.1206.
(4.2 g, 91% yield, > 98% ee): mp 65-66 °C; [R]20 +57.1 (c
D
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 3.24 (2 H, br
s), 3.50 (1 H, dd, J ) 11.4, 8.2 Hz), 3.87 (1 H, dd, J ) 11.4, 2.8
Hz), 5.02 (1 H, dd, J ) 8.2, 2.8 Hz), 6.98 (1 H, br t, J ) 8.0
Hz), 7.35 (1 H, br t, J ) 8.0 Hz), 7.51 (1 H, br d, J ) 8.0 Hz),
7.80 (1 H, br d, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ
(ppm) 66.44, 77.98, 97.50, 127.61, 128.57, 129.67, 139.39,
142.28. Anal. Calcd for C8H9IO2 (M ) 164): C, 36.39; H, 3.44.
Found: C, 36.32; H, 3.51.
(S)-2-(2-Iodophenyl)oxirane (17). To a solution of diol 16
(2.10 g, 7.9 mmol) and triethyl orthoacetate (1.8 mL, 9.54
mmol, 1.2 equiv) in CH2Cl2 (10 mL) at 0 °C was added
trimethylsilyl chloride (1.2 mL, 9.54 mmol, 1.2 equiv). The
reaction mixture was stirred for 2 h and evaporated under
reduced pressure. The residue was dissolved in methanol (12
mL), and K2CO3 (2.8 g, 20 mmol, 2.5 equiv) was added. The
suspension was stirred at rt for 2 h, and the solid was filtered
and washed with CH2Cl2. The combined filtrates were evapo-
rated, and the crude product was purified by flash chroma-
tography on silica gel (cyclohexane/ethyl acetate, 8:2) to yield
pure 17 as a colorless oil (1.80 g, 92% yield): [R]20 +62.1 (c
D
1.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 2.62 (1 H,
dd, J ) 5.6, 2.6 Hz), 3.18 (1 H, dd, J ) 5.6, 4.4 Hz), 3.99 (1 H,
m), 7.01 (1 H, br t, J ) 7.6 Hz), 7.20 (1 H, br d, J ) 7.6 Hz),
7.33 (1 H, br t, J ) 7.6 Hz), 7.82 (1 H, br d, J ) 7.6 Hz); 13C
NMR (100 MHz, CDCl3) δ (ppm) 50.88, 56.55, 96.65, 125.96,
128.41, 129.53, 138.71, 140.03; HRMS (EI, positive mode) calcd
for C8H7IO 245.9542, found 245.9536.
1,3-cis-2-Benzyloxycarbonyl-1-vinyl-3,4-dihydro-1H-
isoquinoline-3-carboxylic Acid Dicyclohexylamine Salt
(12). The carboxylic acid 11 (47 mg, 0.139 mmol, containing
11% of the trans isomer 10) was dissolved in ether (0.15 mL).
Dicyclohexylamine (27 mg) dissolved in ether (0.1 mL) was
added, and the clear solution was allowed to stand at rt for 48
(S)-2-Azido-1-(2-iodophenyl)ethanol (18) and (R)-2-
Azido-2-(2-iodophenyl)ethanol (19). Epoxide 17 (0.5 g, 2.03
mmol) was dissolved in acetonitrile (10 mL). NaN3 (0.8 g, 12.2
4050 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Cis or Trans Isomers of Tetrahydroisoquinolines
mmol, 6 equiv) and LiClO4 (3.9 g, 36.5 mmol, 18 equiv) were
added, and the mixture was stirred for 5 h at 60 °C. After the
mixture was cooled to rt, the solids were removed by filtration
through a pad of Celite and the filtrate was concentrated. The
residue was partitioned between water and ether. The aqueous
layer was extracted three times with ether, and the combined
organic layers were washed with NaHCO3 and brine, dried
over MgSO4, and concentrated. After flash chromatography
on silica gel (cyclohexane/ethyl acetate 4:1), the two regio-
isomers were isolated as colorless oils (19: 394 mg, 67% and
18: 170 mg, 29%).
[(R)-2-Methoxymethoxy-1-(2-tributylstannanylphen-
yl)ethyl]carbamic Acid tert-Butyl Ester (22). A solution
of 21 (410 mg, 1 mmol), Pd(P-t-Bu3)2 (50 mg, 0.1 mmol, 10 mol
%) and Bu3SnSnBu3 (760 µL, 1.3 mmol, 1.3 equiv) in DMF (1
mL) was stirred overnight at 100 °C under argon atmosphere.
After being cooled to rt, the reaction mixture was diluted with
water and extracted with ether (three times). The combined
organic layers were dried over MgSO4, filtered through a pad
of Celite, and concentrated. After purification by chromatog-
raphy on silica gel (cyclohexane/ethyl acetate 9:1), the product
22 was isolated as a pale yellow oil (350 mg, 60%): [R]20D -8.7
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 0.85 (9 H,
t, J ) 7.3 Hz), 1.10 (6 H, m), 1.30 (6 H, m), 1.40 (9 H, br s),
1.55 (6 H, m), 3.25 (3 H, s), 3.70 (2 H, m), 4.57 (2 H, s), 4.63 (1
H, br s), 5.00 (1 H, br s), 7.20 (1 H, br t, J ) 7.1 Hz), 7.29 (1
H, br t, J ) 7.1 Hz), 7.40 (2 H, m); 13C NMR (100 MHz, CDCl3)
δ (ppm) 10.57, 13.71, 27.46, 28.37, 29.31, 55.33, 57.51, 70.78,
79.47, 96.54, 125.56, 127.03, 128.48, 137.18, 146.74, 154.93
(Cquat-Sn failed); HRMS (ESI, positive mode) calcd for C27H49-
NO4Sn + Na+ 594.2581, found 594.2576.
19: [R]20D -47.7 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3)
δ (ppm) 2.05 (1 H, br s), 3.62 (1 H, dd, J ) 11.6, 8.3 Hz), 3.84
(1 H, dd, J ) 11.6, 3.8 Hz), 5.05 (1 H, dd, J ) 8.3, 3.8 Hz),
7.03 (1 H, d, J ) 7.8 Hz), 7.41 (2 H, m), 7.85 (1 H, d, J ) 7.8
Hz); 13C NMR (100 MHz, CDCl3) δ 65.67, 71.12, 98.89, 128.09,
128.84, 130.22, 138.71, 139.89. Anal. Calcd for C8H8IN3O (M
) 289): C, 33.24; H, 2.79; N, 14.54. Found: C, 33.90; H, 2.80;
N, 13.78.
18: [R]20 +111.6 (c 1.15, CHCl3); 1H NMR (400 MHz,
D
{(R)-1-[2-((E)-4-Hydroxybut-2-enyl)phenyl]-2-methoxy-
methoxyethyl}carbamic Acid tert-Butyl Ester (23). A
mixture of stannyl derivative 22 (350 mg, 0.61 mmol), buta-
diene monoxide (250 µL, 3.1 mmol, 5 equiv), PdCl2(CH3CN)2
(15 mg), and H2O (550 µL, 50 equiv) in DMF (2 mL) was stirred
at 0 °C and slowly allowed to reach rt overnight. Water was
added, and the mixture was extracted with Et2O (twice). The
combined organic layers were dried over MgSO4 and concen-
trated. The residue was purified by PLC (cyclohexane/ethyl
acetate, 3:2) to furnish alcohol 23, a colorless oil (178 mg, 83%
yield): [R]20D -17.4 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.40 (9 H, br s), 2.65 (1 H, br s), 3.25 (3 H, s), 3.57 (2
H, br s), 3.70 (2 H, m), 4.05 (2 H, br d, J ) 6.0 Hz), 4.60 (2 H,
m), 5.20 (2 H, m), 5.60 (1 H, td, J ) 15.4, 6.0 Hz), 5.85 (1 H,
td, J ) 15.4, 5.8 Hz), 7.20 (4 H, m); 13C NMR (100 MHz, CDCl3)
δ (ppm) 28.39, 36.10, 51.00, 55.38, 63.74, 70.32, 79.86, 96.17,
126.28, 126.83, 127.64, 130.52, 131.04, 131.42, 136.98, 138.59,
155.36; HRMS (ESI, positive mode) calcd for C19H29NO5 + Na+
374.1943, found 374.1938.
(1R,3S)-1-Methoxymethoxymethyl-3-vinyl-3,4-dihydro-
1H-isoquinoline-2-carboxylic Acid tert-Butyl Ester (24).
A solution of allylic alcohol 23 (12 mg, 0.034 mmol) and
PdCl2(CH3CN)2 (1 mg) in THF (0.5 mL) was stirred at rt for 2
h under argon atmosphere. The solvent was evaporated, and
the crude product was purified by PLC (cyclohexane/ethyl
acetate, 1:1) to give 24 as a colorless oil (10 mg, 90%): 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.43 (9 H, br s), 2.95 (2 H, m), 3.27
(3 H, br s), 3.75 (2 H, m), 4.60 (3 H, m), 5.10 (2 H, m), 5.32 (1
H, br s), 5.90 (1 H, m), 7.24 (4 H, m); 13C NMR (100 MHz,
DMSO-d6, 90 °C) δ (ppm) 27.50, 31.96, 45.57, 51.68, 54.08,
69.93, 78.82, 95.39, 113.64, 125.41, 126.25, 126.47, 127.34,
132.66, 134.99, 139.99, 153.85. HRMS calcd for C19H27NO4 +
Na+ 356.1838, found 356.1861.
(1R,3S)-1-Methoxymethoxymethyl-3-vinyl-1,2,3,4-tet-
rahydroisoquinoline (25). A solution of TFA (50% in H2O,
50 µL), was added to a solution of 24 (8 mg, 0.024 mmol) in
CH3CN (1 mL), and the reaction mixture was stirred at rt for
48 h. After addition of NaOH (2 M, 0.5 mL), the mixture was
extracted with ethyl acetate (twice), and the combined organic
extracts were dried over MgSO4, and concentrated. The crude
product was purified by PLC (cyclohexane/ethyl acetate, 1:1)
to furnish 25, a colorless oil (5 mg, 78% from 23): [R]20D -61.0
(c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 2.37 (1 H,
br s), 2.80 (2 H, m), 3.20 (3 H, s), 3.55 (1 H, br q, J ) 8.0 Hz),
3.75 (1 H, dd, J ) 9.6, 8.0 Hz), 4.15 (1 H, dd, J ) 9.6, 3.2 Hz),
4.36 (1 H, m), 4.70 (2 H, m), 5.30 (2 H, m), 6.00 (1 H, m), 7.17
(4 H, m); 13C NMR (100 MHz, CDCl3) δ (ppm) 35.89, 55.44,
55.73, 56.39, 71.43, 96.81, 115.58, 124.83, 125.93, 126.12,
129.39, 134.62, 135.31, 140.17; HRMS (ESI, positive mode)
calcd for C14H19NO2 + H+ 234.1494, found 234.1489.
CDCl3) δ (ppm) 2.67 (1 H, br s), 3.30 (1 H, dd, J ) 12.6, 8.3
Hz), 3.56 (1 H, dd, J ) 12.6, 2.8 Hz), 5.10 (1 H, dd, J ) 8.3,
2.8 Hz), 7.01 (1 H, br t, J ) 7.8 Hz), 7.42 (1 H, br t, J ) 7.8
Hz), 7.58 (1H, br d, J ) 7.8 Hz), 7.80 (1 H, br d, J ) 7.8 Hz);
13C NMR (100 MHz, CDCl3) δ (ppm) 56.41, 76.73, 97.11,
127.40, 128.72, 130.00, 139.44, 142.14. Anal. Calcd for C8H8-
IN3O (M ) 289): C, 33.24; H, 2.79; N, 14.54. Found: C, 33.35;
H, 2.84; N, 14.02.
1-((R)-1-Azido-2-methoxymethoxyethyl)-2-iodoben-
zene (20). To a solution of 19 (390 mg, 1.35 mmol) in CH2Cl2
i
(5 mL) were successively added Pr2NEt (290 µL, 1.2 equiv,
1.62 mmol) and MOMCl (125 µL, 1.2 equiv, 1.62 mmol) at rt,
and the reaction mixture was stirred for 6 h. The mixture was
diluted with water and extracted with CH2Cl2 (three times),
the combined organic layers were dried over MgSO4, and
concentrated. After flash chromatography on silica gel (cyclo-
hexane/ethyl acetate 4:1) 20 was isolated as a colorless oil (426
mg, 94%): [R]20 -43.7 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ (ppm) 3.40 (3 H, s), 3.58 (1 H, dd, J ) 10.8, 8.6 Hz),
3.82 (1 H, dd, J ) 10.8, 3.2 Hz), 4.70 (2 H, Abq, J ) 6.8 Hz),
5.09 (1 H, dd, J ) 8.6, 3.2 Hz), 7.02 (1 H, br t, J ) 7.8 Hz),
7.41 (2 H, m), 7.86 (1 H, br d, J ) 7.8 Hz); 13C NMR (100
MHz, CDCl3) δ (ppm) 55.49, 68.76, 70.33, 96.50, 98.83,
128.08, 128.75, 130.10, 138.89, 139.75; HRMS (ESI, posi-
tive mode) calcd for C10H12IN3O2 + Na+ 355.9872, found
355.9866.
[(R)-1-(2-Iodophenyl)-2-methoxymethoxyethyl]carbam-
ic Acid tert-Butyl Ester (21). At rt, PhSH (930 µL, 9 mmol,
6.0 equiv) and NEt3 (940 µL, 6.75 mmol, 4.5 equiv) were added
to a suspension of SnCl2 (425 mg, 2.25 mmol, 1.5 equiv) in
THF (5 mL). The azide 20 (0.5 g, 1.5 mmol, 1.0 equiv) dissolved
in THF (5 mL) was then added, and the resulting mixture was
stirred for 30 min at rt. NaOH (2 M, 25 mL) and CH2Cl2 (25
mL) were added, the aqueous layer was extracted with CH2-
Cl2 (three times), and the combined organic layers were dried
(MgSO4) and concentrated. The resulting colorless oil was
dissolved in THF (10 mL), and NEt3 (1.1 mL, 7.5 mmol, 5.0
equiv) and BOC2O (440 mg, 1.3 equiv, 2 mmol) were added.
The reaction mixture was stirred at rt overnight, hydrolyzed,
and extracted with ethyl acetate (3 times). The combined
organic layers were dried over MgSO4 and concentrated. After
chromatography on silica gel (cyclohexane/ethyl acetate 9:1),
21 was isolated as a white solid (520 mg, 85%): mp 81-82
°C; [R]20D +22.1 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3, 50
°C) δ (ppm) 1.39 (9 H, br s), 3.28 (3 H, s), 3.62 (1 H, m), 3.82
(1 H, dd, J ) 10.4, 4.1 Hz), 4.55 (1 H, d, J ) 6.5 Hz), 4.62 (1
H, d, J ) 6.5 Hz), 5.06 (1 H, m), 5.36 (1 H, br s), 6.93 (1 H, br
t, J ) 7.3 Hz), 7.29 (2 H, m), 7.84 (1 H, br d, J ) 7.6 Hz); 13C
NMR (100 MHz, CDCl3) δ (ppm) 28.41, 55.45, 59.07, 69.45,
79.83, 96.82, 98.64, 127.68, 128.22, 129.10, 139.84, 142.87,
155.20. Anal. Calcd for C15H22INO4 (M ) 407): C, 44.24; H,
5.45; N, 3.44. Found: C, 44.81; H, 5.56; N, 3.45.
(E)-(S)-2-tert-Butoxycarbonyloxy-7-chlorohept-5-eno-
ic Acid Methyl Ester (26). To a solution of (S)-2-tert-
J. Org. Chem, Vol. 70, No. 10, 2005 4051

Eustache et al.
butoxycarbonyloxyhex-5-enoic acid methyl ester (325 mg, 1.34
mmol) and allyl chloride (430 µL, 4 equiv) in CH2Cl2 (22 mL)
was added Grubbs catalyst second generation (114 mg, 0.13
mmol). The reaction mixture was refluxed for 14 h, the solvents
were evaporated under reduced pressure, and the residue was
chromatographed on silica gel (hexane/ethyl acetate 10:1) to
afford 26 (261 mg, 67%) as a 86:14 mixture of trans and cis
isomers and recovered starting material (70 mg, 21%): 1H
NMR (400 MHz, CDCl3) δ (ppm) 1.44 (9 H, s), 1.66-1.77 (1 H,
m), 1.96 (1 H, m), 2.09-2.20 (2 H, m), 3.74 (3 H, s), 4.02 (2 H,
d, J ) 6.6 Hz), 4.26-4.35 (1 H, m), 4.96-5.08 (1 H, m), 5.65
(1H, dt, J ) 15.1, 6.6 Hz), 5.75 (1H, dt, J ) 15.1, 6.6 Hz); 13C
NMR (100 MHz, CDCl3) δ (ppm) 27.9, 28.4, 32.1, 45.1, 52.4,
53.0, 80.0, 127.2, 133.8, 161.6, 173.0; HRMS (ESI, positive
mode) calcd for C13H22ClNO4 + Na 314.1135, found 314.1130.
(2S,5S)-N-tert-Butoxycarbonyl)-5-vinylpyrrolidine-2-
carboxylic Acid Methyl Ester (27) and (2S,5R)-N-tert-
Butoxycarbonyl)-5-vinylpyrrolidine-2-carboxylic Acid
Methyl Ester (28). (a) Silver Triflate Method. Under Ar
atmosphere, the protected amino acid 26 (62 mg, 0.21 mmol)
was dissolved in THF (0.8 mL) and the solution was cooled to
-78 °C. A solution of BuLi (1.6 M in hexanes, 130 µL, 1 equiv)
was added dropwise, and the mixture was stirred at -78 °C
for 15 min. AgOTf (87 mg, 1.6 equiv) was added, and the light
brown solution was allowed to warm to rt over the course of
1.5 h and then stirred for a further 1 h. The heterogeneous
reaction mixture was diluted with ether, washed successively
with 2 N HCl, saturated NaHCO3, and brine, dried (MgSO4),
and concentrated under reduced pressure. Chomatography on
silica gel (hexane/ethyl acetate 2:1) afforded a 87:13 mixture
of 27 and 28 (41 mg, 77%) which could not be separated: 1H
NMR (400 MHz, CDCl2-CDCl2, 120 °C) δ (ppm) 1.39 (9 H, s),
1.65-1.68 (1 H, m), 1.82-1.90 (1 H, m), 2.10-2.20 (2 H, m),
3.68 (3 H, s), 4.45 (2 H, br), 5.04 (1 H, dd, J ) 10.5, 1.2 Hz),
5.05 (1 H, dd, J ) 17.1, 1.2 Hz), 5.76 (1H, ddd, J ) 17.1, 10.5,
5.4 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm) 27.4, 27.7, 28.3,
28.35, 29.3, 30.0, 52.0, 52.3, 59.7, 65.8, 79.9, 80.0, 113.8, 114.0,
137.8, 138.3, 153.3, 154.2, 173.1, 173.4; HRMS calcd for C13H21-
NO4Na m/z 278.1368, found m/z 278.1363.
afford a mixture of 27′ and 28′ (25 mg, 58%): 1H NMR (400
MHz, CDCl3) (major isomer) δ (ppm) 1.26 (3 H, t, J ) 7.1 Hz),
1.51-1.59 (1 H, m), 2.08-2.26 (2 H, m), 3.85 (1 H, dd, J )
8.5, 5.6 Hz), 4.16 (2 H, d, J ) 7.1 Hz), 5.00 (1 H, d, J ) 10.1
Hz), 5.15 (1 H, ddd, J ) 17.1, 1.6, 1.1 Hz), 5.77 (1 H, ddd, J )
17.1, 10.1, 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm) 35.89,
55.44, 55.73, 56.39, 71.43, 96.81, 115.58, 124.83, 125.93,
126.12, 129.39, 134.62, 135.31, 140.17; HRMS (ESI, positive
mode) calcd for C9H15NO2 + H 170.1181, found 170.1199.
(E)-(S)-7-Acetoxy-2-tert-butoxycarbonyloxyhept-5-eno-
ic Acid Methyl Ester (29). A mixture of protected amino acid
26 (1.0 g, 3.43 mmol) and NaOAc (280 mg, 10 equiv) in DMF
(20 mL), was heated at 100 °C for 23 h. More NaOAc (100
mg) was added, and stirring was continued for 3 h. The
reaction mixture was cooled to rt, diluted with ether, and
washed with saturated NH4Cl. The organic layer was dried
and concentrated under reduced pressure. The residue was
purified by chromatography over silica gel (hexane/ethyl
acetate 4:1) to afford pure 29 (726 mg, 70%) and recovered
starting material (131 mg, 13%): 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.43 (9 H, s), 1.66-1.77 (1 H, m), 1.86-1.97 (1 H, m),
2.06 (3 H, m), 2.08-2.23 (2 H, m), 3.74 (3 H, s), 4.25-4.36 (1
H, m), 4.50 (2 H, d, J ) 6.3 Hz), 4.99-5.10 (1 H, m), 5.55-
5.69 (1 H, m), 5.74 (1H, dt, J ) 15.3, 6.6 Hz); 13C NMR (100
MHz, CDCl3) δ (ppm) 21.2, 28.1, 28.4, 32.1, 52.3 53.0, 64.9,
80.0, 125.1, 134.0, 155.2, 170.6, 172.9; HRMS (ESI, positive
mode) calcd for C15H25NO6 + Na 338.1580, found 338.1574.
(E)-(S)-2-tert-Butoxycarbonyloxy-7-hydroxyhept-5-eno-
ic Acid Methyl Ester (30). The protected amino acid 29 (512
mg, 1.62 mmol) was dissolved in a solution of NaOMe in MeOH
(0.1 M, 16 mL). The mixture was stirred for 2.5 h, and 1 N
aqueous HCl (5 mL) was added, followed by ether. The organic
layer was washed with H2O and brine and then dried, and
the solvent was evaporated under reduced pressure. The
residue was purified by chromatography to afford allylic
alcohol 30 (400 mg, 90%): 1H NMR (400 MHz, CDCl3) δ (ppm)
1.45 (9 H, s), 1.65-1.77 (1 H, m), 1.85-1.97 (1 H, m), 2.09-
2.19 (2 H, m), 3.74 (3 H, s), 4.08 (2 H, t, J ) 4.1 Hz), 4.27-
4.37 (1 H, m), 4.95-5.03 (1 H, m), 5.72-5.60 (2 H, m); 13C NMR
(100 MHz, CDCl3) δ (ppm) 28.0, 28.4, 32.1, 52.3, 52.8, 63.4,
80.0, 130.5, 130.7, 155.2, 173.2; HRMS (ESI, positive mode)
calcd for C13H23NO5 + Na 296.1474, found 296.1468.
(2S,5R)-N-tert-Butoxycarbonyl)-5-vinylpyrrolidine-2-
carboxylic Acid Dicyclohexylamine Salt (31). To stirred
solution of ester 28 (81 mg, 0.32 mmol) in THF (2 mL)
containing H2O (60 µL) and toluene was added LiOH‚H2O (93
mg, 2.2 mmol). The reaction mixture was stirred at 60 °C for
5 h. The mixture was cooled to 20 °C and extracted with ether,
and the organic layer was washed twice with 10% HCl, dried
over Na2SO4, and concentrated to give the corresponding acid
(quantitative). A portion of the acid (32 mg, 0.132 mmol) was
dissolved in ether (100 µL). A solution of dicyclohexylamine
(24 mg, 1 equiv) in ether (100 µL) was added. The mixture
was allowed to stand at rt for 16 h. The crystals were isolated
by filtration (40 mg): HRMS (ESI, negative mode) calcd for
C12H18NO4 m/z ) 240.1236, found m/z ) 240.1241.
(b) Pd(II) Method. Under Ar atmosphere, a solution of 30
(230 mg, 0.84 mmol) and PdCl2(CH3CN)2 (33 mg, 15 mol %) in
THF (17 mL) was stirred at rt for 12 h. The mixture was
partitioned between ethyl acetate and water, and the organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
chomatography over silica gel (hexane/ethyl acetate 4:1) to
afford pure 28 (165 mg, 77%): [R]23D -14.45 (c 1.460, CHCl3);
1H NMR (400 MHz, CDCl2-CDCl2, 120 °C) δ (ppm) 1.40 (9 H,
s), 1.76 (1 H, dt, J ) 10.7, 5.0 Hz), 1.90-2.14 (3 H, m), 3.69 (3
H, s), 4.26-4.32 (2 H, m), 5.05 (1 H, d, J ) 10.2 Hz), 5.25 (1
H, d, J ) 17.3 Hz), 5.88 (1H, ddd, J ) 17.3, 10.2, 6.1 Hz); 13
C
NMR (100 MHz, CDCl3) δ (ppm) 28.1, 28.3, 28.8, 30.9, 31.6,
51.9, 52.0, 59.6, 59.8, 60.2, 60.6, 80.0, 114.7, 115.0, 138.0, 138.8,
153.4, 154.2, 173.3, 173.4; HRMS (ESI, positive mode)calcd
for C13H21NO4 + Na 278.1368, found 278.1363.
Mixture of (2S,5S)-5-Vinylpyrrolidine-2-carboxylic Acid
Ethyl Ester (27′) and (2S,5R)-5-Vinylpyrrolidine-2-car-
boxylic Acid Ethyl Ester (28′). A portion of the mixture of
isomers 27 and 28 (67 mg, 0.26 mmol) prepared by the silver
triflate method was dissolved in a 0.04 M solution of NaOEt
in ethanol (6.6 mL). The solution was stirred for 16 h at rt, at
which time TLC showed a single spot just above that of the
starting material. The solvents were evaporated, and the
residue was partitioned between ether and 1 N HCl. The
organic layer was washed with H2O and brine and dried, and
the solvents were evaporated under reduced pressure. The
residue was dissolved in dioxane (0.8 mL), and anhydrous HCl
(4 M in dioxane) was added. The mixture was stirred for 1 h,
the solution was concentrated in vacuo and dissolved in 1 N
aqueous HCl, and the aqueous layer was washed with ether.
NaOH (1 N) was added, and the aqueous layer was extracted
with ether. The organic extract was dried and evaporated to
X-ray Crystallographic Studies. Crystal data for com-
pound 12: MF ) C34H42N2O4.5; MW ) 550.72, triclinic, P-1
(#2); a ) 10.417(2) Å, b ) 11.773(3) Å, c ) 14.433(4) Å, R )
77.35(2)°, â ) 81.38(2)°, γ ) 69.06(1)°, V ) 1608.0(7) Å3; Z )
2, D(calcd) ) 1.137 g/cm3, a colorless crystal (size ) 0.20 ×
0.15 × 0.15 mm), Mo KR radiation (λ ) 0.71069 Å), a total of
28641 (2θ max ) 55°) measured, 7352 unique (Rint )0.065),
final R1 is 0.055 for reflections of Io > 2σ(Io) and wR2 is 0.158
for all reflections, GOF ) 0.922. Crystal data for compound
31: MF ) C24H42N2O4; MW ) 422.61, monoclinic, P21; a )
12.992(3) Å, b ) 10.203(3) Å, c ) 18.760(5) Å, â ) 100.5181-
(11)°, V ) 2445.0(11) Å3; Z ) 4, D(calcd) ) 1.148 g/cm3, a
colorless crystal (size ) 0.25 × 0.2 × 0.15 mm), Mo KR
radiation (λ ) 0.71069 Å), a total of 35818 (2θ max ) 55°)
measured, 11161 unique (Rint )0.069), final R1 is 0.041 for
4052 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Cis or Trans Isomers of Tetrahydroisoquinolines
reflections of Io > 2σ(Io) and wR2 is 0.057 for all reflections,
GOF ) 1.01.
Promotion of Science (JSPS) for a Long Term Invitation
Fellowship.
Acknowledgment. This project is supported in
France by the Ministe`re de l’Education Nationale, de
l’Enseignement Supe´rieur et de la Recherche, and the
Centre National de la Recherche Scientifique (CNRS).
J.E. gratefully acknowledges the Japan Society for the
Supporting Information Available: X-ray crystallo-
graphic data (CIF) and ORTEP drawings. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0501543
J. Org. Chem, Vol. 70, No. 10, 2005 4053