An enantioselective synthesis of cis perhydroisoquinoline LY235959

Article abstract of DOI:10.1021/jo9717649

A novel synthesis of NMDA receptor antagonist LY235959 (1) has been achieved in 13% overall yield and 17 steps from (R)-pantolactone (7). Highlights of the synthesis include (a) use of a chiral auxiliary controlled asymmetric Diels - Alder reaction to provide the desired absolute and relative stereochemistry at C-4a, C-6, and C-8a, (b) an efficient alkylation of hindered iodide 13 using a novel amide benzophenone imine, (c) oxidative ring opening of the [2.2.2] bicyclic system to simultaneously functionalize the molecule for intramolecular cyclization and phosphonate introduction, and (d) an increased understanding of how the C-3 stereochemistry may be controlled by thermodynamic equilibration. Synthesis of epimer 20 in high overall yield makes this synthetic route attractive for future development efforts.

Full text of DOI:10.1021/jo9717649

J . Org. Chem. 1998, 63, 775-785
775
An En a n tioselective Syn th esis of Cis P er h yd r oisoqu in olin e
LY235959
Marvin M. Hansen,* Carl F. Bertsch, Allen R. Harkness, Bret E. Huff, Darrell R. Hutchison,
Vien V. Khau, Michael E. LeTourneau, Michael J . Martinelli, J erry W. Misner,
Barry C. Peterson, J ohn A. Rieck, Kevin A. Sullivan, and Ian G. Wright
Chemical Process Research and Development Division, Lilly Research Laboratories, A Division of Eli Lilly
and Company, Lilly Corporate Center, Indianapolis, Indiana 46285-4813
Received September 22, 1997
A novel synthesis of NMDA receptor antagonist LY235959 (1) has been achieved in 13% overall
yield and 17 steps from (R)-pantolactone (7). Highlights of the synthesis include (a) use of a chiral
auxiliary controlled asymmetric Diels-Alder reaction to provide the desired absolute and relative
stereochemistry at C-4a, C-6, and C-8a, (b) an efficient alkylation of hindered iodide 13 using a
novel amide benzophenone imine, (c) oxidative ring opening of the [2.2.2] bicyclic system to
simultaneously functionalize the molecule for intramolecular cyclization and phosphonate introduc-
tion, and (d) an increased understanding of how the C-3 stereochemistry may be controlled by
thermodynamic equilibration. Synthesis of epimer 20 in high overall yield makes this synthetic
route attractive for future development efforts.
LY235959 (1) is a potent NMDA receptor antagonist
previously under development for the treatment of neuro-
degenerative disorders such as Alzheimer’s disease.1 The
synthesis of material for toxicology and clinical studies
provided a number of strategic challenges. Construction
of the cis-fused perhydroisoquinoline core, stereoselective
installation of the amino acid center at C-3 and introduc-
tion of the axial substituent at C-6 are obvious hurdles.
An initial synthesis of LY235959 (1), which suffered from
a late stage resolution and less than 1% overall yield,
has been reported.1
We envisioned a stereoselective approach to LY235959
(1) which utilized a [2.2.2] bicyclic framework to generate
three of the required stereocenters (Scheme 1). Discon-
nection of 1 via an Arbuzov reaction leads to the precur-
sor halide 2. Halide 2 should be available from cycliza-
tion of a bis-functionalized intermediate 3, wherein
regiocontrolled closure should favor the desired fused ring
system. Recognition that bis-activated intermediate 3
could be derived from ring opening of a [2.2.2] bicyclic
system such as amino ester 4 was a key element of the
synthetic strategy. It was anticipated that an asym-
metric Diels-Alder reaction of cyclohexadiene with an
appropriate acrylate followed by alkylation of intermedi-
ate 5 would provide an expeditious route to amino ester
4. This retrosynthesis did not explicitly account for
stereocontrol at C-3; however, we anticipated that this
center could be controlled by equilibration after closure
to the perhydroisoquinoline ring system.
suitable dienophile (Scheme 2). As described by Helm-
chen and co-workers, Diels-Alder reaction of acrylate 8
with cyclohexadiene provided adduct 9 in 75% yield.4
Diels-Alder adduct 9 was converted to bicyclic iodide 13
in 80% overall yield using the four-step process shown.
Ester hydrolysis using lithium hydroxide in aqueous
tetrahydrofuran afforded acid 10. After extraction of acid
10, (R)-pantolactone (7) could be recovered in >90% yield
by evaporation of the acidic aqueous layer and heating
the residual solid in toluene to reclose the hydroxy-acid.
Acid 10 was reduced to alcohol 11 with Red-Al and the
alcohol was converted to iodide 13 via mesylate 12 under
Finkelstein conditions.5
A variety of methods for attachment of a glycine unit
to scalemic iodide 13 could be considered.6 As the C-3
stereochemistry was to be addressed by equilibration
after closure to the perhydroisoquinoline, a classical
acetamido malonate alkylation was investigated first.7
Iodide 13 reacted with diethyl acetamidomalonate slug-
gishly or not at all under typical reaction conditions (e.g.
(2) For reviews, see: (a) Nogradi, M. Stereoselective Synthesis;
VCH: Weinheim, FRG, 1987; pp 266-274. (b) Helmchen, G.; Karge,
R.; Weetman, J . In Modern Synthetic Methods 1986; Sheffold, R., Ed.;
Springer-Verlag: New York, 1986; Vol. 4, pp 262-306. For recent work,
see: (c) Busacca, C. A.; Meyers, A. I. J . Chem. Soc., Perkin Trans. 1
1991, 2299-2316 and ref 1 therein. (d) Maruoka, K.; Akakura, M.;
Saito, S.; Ooi, T.; Yamamoto, H. J . Am. Chem. Soc. 1994, 116, 6153-
6158.
(3) For reviews, see: (a) Kagan, H. B.; Riant, O. Chem. Rev.
(Washington, D.C.) 1992, 92, 1007-1019. (b) Deloux, L.; Srebnik, M.
Chem. Rev. (Washington, D.C.) 1993, 93, 763-784. (c) Togni, A.;
Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497-526. For
recent work, see: (d) Evans, D. A.; Barnes, D. M. Tetrahedron Lett.
1997, 38, 57-58. (e) Corey, E. J .; Letavic, M. A. J . Am. Chem. Soc.
1995, 117, 9616-9617.
(4) Poll, T.; Abdel Hady, A. F.; Karge, R.; Linz, G.; Weetman, J .;
Helmchen, G. Tetrahedron Lett. 1989, 30, 5595-5598. See Supporting
Information for a detailed procedure.
After surveying the extensive Diels-Alder literature
employing either chiral acrylates2 or chiral Lewis acid
catalysts,3 and performing some initial experiments, (R)-
pantolactone (7)-derived acrylate 8 was chosen as a
(1) (a) Ornstein, P. L.; Arnold, M. B.; Augenstein, N. K.; Paschal, J .
W. J . Org. Chem. 1991, 56, 4388-4392. (b) Ornstein, P. L.; Schoepp,
D. D.; Arnold, M. B.; Augenstein, N. K.; Lodge, D.; Millar, J . D.;
Chambers, J .; Campbell, J .; Paschal, J . W.; Zimmerman, D. M.;
Leander, J . D. J . Med. Chem. 1992, 35, 3547-3560. (c) Ornstein, P.
L.; Arnold, M. B.; Augenstein, N. K.; Deeter, J . B.; Leander, J . D.;
Lodge, D.; Calligaro, D. O.; Schoepp, D. D. Bioorg. Med. Chem. Lett.
1993, 3, 2067-2072.
(5) Finkelstein, H. Ber. 1910, 43, 1528.
(6) (a) Greenstein, J . P.; Winitz, M. Chemistry of the Amino Acids;
Wiley: New York, 1961; Volume 2, pp 697-714. (b) For a review of
asymmetric methods, see: Duthaler, R. O. Tetrahedron 1994, 50,
1539-1650.
(7) (a) See ref 6a, pp 709-712. (b) Albertson, N. F. J . Am. Chem.
Soc. 1946, 68, 450-453.
S0022-3263(97)01764-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

776 J . Org. Chem., Vol. 63, No. 3, 1998
Hansen et al.
Sch em e 1. Retr osyn th esis
Sch em e 2. Syn th esis of LY235959 via Aceta m id om a lon a te Alk yla tion
NaOEt/EtOH, reflux; NaH, toluene, reflux; KOH/K2CO3,
DMF, 55 °C). Successful alkylation was ultimately
achieved in 58% yield using a concentrated solution of 2
equiv of the sodium malonate in dimethylimidazolidinone
(DMI)8 at 90 °C for 21 h. All the iodide 13 was consumed
in the reaction, suggesting that iodide elimination to the
alkene was a competing reaction.
Initial experiments with diol 15 showed that the bis-
iodide could be prepared, albeit in low yield, using
triphenylphosphine, iodine, and imidazole. Bis-mesylate
16 proved to be more robust and was isolated in 91% yield
after treatment with methanesulfonyl chloride and tri-
ethylamine in dichloromethane at 0 °C. Cyclization to
perhydroisoquinoline 17 was best accomplished using
sodium hydride in tetrahydrofuran at reflux. The iso-
lated yield was moderate and somewhat variable, pos-
sibly due to partial ester hydrolysis or mesylate decom-
position by adventitious water. Other cyclization condi-
tions (e.g. sodium or potassium hexamethyldisilazide or
potassium tert-butoxide in tetrahydrofuran) afforded
With malonate 14 in hand, we were prepared to
investigate the oxidative opening of the bicyclic ring
system. Ozonolysis under standard conditions, followed
by addition of solid sodium borohydride and warming to
room temperature, afforded diol 15 in 92% yield. The
yield for this process was somewhat variable, and a
significant byproduct was characterized as acid 21.9 Acid
21 was isolated in 5-15% yield but could be easily
removed by a base wash during the workup. Formation
of acid 21 may be explained by cleavage of the intermedi-
ate alkoxy hydroperoxide to the carboxylic acid or ester.10
(9) A 20:1 mixture of regioisomeric acids was isolated, and the major
regioisomer was assigned as acid 21. The regiochemical assignment
is based on comparison of the 1H NMR spectra of acid 21, diol 15, and
alcohol i.
(8) DMI is a less toxic substitute for HMPA, see: Sakurai, H.; Kondo,
F. J . Organomet. Chem. 1976, 117, 149-155. We thank Dr. Tom
Britton for recommending this solvent.

Synthesis of Cis Perhydroisoquinoline LY235959
J . Org. Chem., Vol. 63, No. 3, 1998 777
F igu r e 1. Base Catalyzed Epimerization of C-3 Stereocenter
cyclized material at 25 °C, but multiple byproducts were
formed.
of the incorrect stereochemistry at C-3 can be understood
as arising from protonation of the intermediate enol on
the convex face of the cis-fused ring system.
In preparation for introduction of the phosphonate
group, mesylate 17 was converted to iodide 18 using the
Finkelstein reaction.5 In the Arbuzov reaction, an alkyl
phosphite is used to convert reactive alkyl halides to the
corresponding alkyl phosphonate.11 Iodide 18 was an-
ticipated to undergo an SN2 reaction with alkyl phos-
phites slowly, so triethyl phosphite was employed as the
reaction solvent.12 When iodide 18 was heated at reflux
(156 °C) in 73 volumes of triethyl phosphite for 4 h,
phosphonate 19 was obtained in 96% yield after chro-
matography. A slow stream of nitrogen was passed
through a sparge tube into the hot reaction mixture, and
the triethyl phosphite was slowly distilled to aid in
removal of ethyl iodide as the reaction progressed.
Formation of ethyl iodide is problematic as it is more
reactive than iodide 18 and serves to convert triethyl
phosphite to triethyl phosphonate. Residual triethyl
phosphonate was removed with some difficulty by chro-
matography. Trimethyl phosphite also reacted with
iodide 18 at reflux (111 °C); however, 60 h was required
for complete conversion and competing elimination and
partial exchange to the malonate methyl esters was
observed.
With phosphonate 19 in hand, we were ready to
investigate protecting group removal and decarboxylation
to create the C-3 stereocenter. Treatment of phosphonate
19 with 6 M HCl at reflux for 16 h followed by solvent
removal afforded an inseparable 5:1 mixture of amino
acids 20‚HCl and 1‚HCl in high yield. An analytical
sample was prepared in 72% yield by ion exchange
chromatography. The stereochemistry was assigned by
spectral comparison with authentic LY235959 (1) and its
epimer 20.13 The observed 5:1 preference for formation
The most direct method for epimerizing 20‚HCl to 1
was treatment with 5 M KOH at reflux for 16 h. Similar
treatment with NaOH resulted in no epimerization.14
After acidifying the mixture with HCl, analysis of the
product in deuterium oxide without removal of potassium
chloride indicated that a 10:1 mixture of LY235959 (1)
to amino acid 20 was produced. Equilibration to 1 under
thermodynamic conditions can be understood by looking
at the first equation in Figure 1.15 If one assumes a
chair-chair conformation, amino acid 20 must have one
substituent in an axial position while amino acid 1 can
assume a conformation with all substituents in equatorial
positions.
An optional method of achieving C-3 stereocenter
epimerization is shown in Scheme 3. Treatment of a 5:1
mixture favoring epimer 20‚HCl with trimethyl ortho-
acetate in acetic acid at reflux resulted in esterification16
of all three acid groups and amine acetylation. The
resulting 5:1 product isomer ratio was similar to the
starting material ratio, and it was assumed that no C-3
epimerization had occurred. However, exposure of the
opposite epimer 117 to the same reaction conditions
afforded the same major product 22 with <5% of C-3
epimer 23. The stereochemistry of 22 was assigned by
hydrolysis of the 5:1 mixture of 22 and 23 with 6 M HCl
at reflux to afford a 5:1 mixture of LY235959 (1) and C-3
epimer 20.18 Preferential formation of isomer 22 under
the orthoacetate reaction conditions might be explained
by the equilibrium shown in Scheme 3. If acetylation
precedes carboxyl methylation, the N-acetyl group might
(13) 1H and 13C NMR spectra were comparable to those reported in
ref 1b.
(14) Heating in aqueous barium hydroxide at 180 °C is frequently
used to racemize the natural amino acids, see: Greenstein, J . P.;
Winitz, M. Chemistry of the Amino Acids; Wiley: New York, 1961;
Volume 3.
(15) Conformations shown in Figure 1 have not been minimized but
are useful in rationalizing the observed results.
(16) Zeiss, H. J . Org. Chem. 1991, 56, 1783-1788.
(17) LY235959 (1) containing <1% epimer 20 which was prepared
using a modification of the reported procedure. See ref 1.
(10) For activation of the intermediate alkoxy hydroperoxide by Ac2O
and elimination to the ester using Et3N, see: Schreiber, S. L.; Claus,
R. E.; Reagan, J . Tetrahedron Lett. 1982, 23, 3867-3870.
(11) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. (Washington,
D.C.) 1981, 81, 415-430.
(12) For the Arbuzov reaction on a similar substrate, see ref 1c and
Ornstein, P. L.; Augenstein, N. K.; Arnold, M. B. J . Org. Chem. 1994,
59, 7862-7869.

778 J . Org. Chem., Vol. 63, No. 3, 1998
Hansen et al.
Sch em e 3. Ep im er iza tion by Tr im eth yl
Or th ofor m a te
malonate 14 proceeded in low yield under rather harsh
conditions. The cyclization to mesylate 17 was sensitive
to adventitious moisture or other impurities. Control of
the C-3 stereocenter was delayed until a final base-
catalyzed equilibration step and complete epimerization
to the desired epimer was not achieved. Our efforts to
address these deficiencies are described below.
The approach shown in Scheme 4 presented the op-
portunity to replace the difficult glycine alkylation step
with a condensation reaction. In addition, the op-
portunity to control the C-3 stereochemistry through
stereoselective reduction of an enamide was appealing.
Ozonolysis of protected alcohol 2620 followed by borohy-
dride reduction of the intermediate dialdehyde gave diol
27 in a 93% yield. Tosylation of 27 followed by removal
of the CBZ group, Swern oxidation and condensation of
the aldehyde21 with N-(benzyloxycarbonyl)-R-phosphono-
glycine trimethyl ester22 provided acylenamide 29 in 55%
overall yield from 27. Reduction of the double bond and
cyclization with NaH gave a 1.7:1 mixture of C-3 epimeric
decahydroisoquinolines.23 The major isomer 30 was
isolated by chromatography and converted to iodide 31.
Treatment of 31 with triethyl phosphite provided phos-
phonate ester 32 and deprotection with 6 M HCl gave
the undesired epimer 20‚HCl in 12% overall yield from
intercept an activated carboxyl intermediate to afford the
oxazolidinium species shown.19 Equilibration of the
oxazolidinium ions through C-3 proton loss should be
facile. Attack of methanol on the more stable isomer
would result in formation of the major product observed.
Higher than predicted retention of stereochemistry when
starting from 1 suggests that attack by methanol occurs
prior to complete equilibration to a thermodynamic
mixture of oxazolidinium intermediates.
The isomer ratios shown in Scheme 3 may result from
a thermodynamically controlled equilibration of an in-
termediate, but they do not represent a thermodynamic
product ratio. When the 5:1 mixture of 22 and 23 was
subjected to base-catalyzed epimerization using sodium
methoxide in methanol at reflux, an 11:1 mixture of
products favoring isomer 23 was produced. The stereo-
chemistry of isomer 23 was confirmed by treatment with
6 M HCl at reflux to afford a 10:1 mixture of amino acids
20 and 1.18 Preferential formation of 23 under basic
conditions can be explained by the equilibria shown in
Figure 1.15 Ornstein and co-workers have shown that
the ester group in ketones 24 and 25 prefer an axial
disposition to avoid A1,3 strain with the carbamate. Base-
catalyzed equilibration favors ketone 24 due to a 1,3-
diaxial interaction between the ester group and C-5 in
ketone 25. We believe that the same axial ester prefer-
ence will be present in esters 22 and 23. Isomer 23
should be favored over 22 as the former isomer has the
C-6 substituent in an equatorial position.
1
26. This material was identical by H NMR to product
previously obtained and could be converted to LY235959
(1) by base-promoted equilibration (Scheme 2). Attempts
to invert the diastereoselectivity in the hydrogenation of
29 were unsuccessful since the acylenamide was un-
reactive toward hydrogenation in the presence of homo-
geneous catalysts other than (Ph3P)3RhCl24 and use of
heterogeneous catalysts led to cleavage of the CBZ group.
However, the mixture of diastereomers could be carried
through the synthesis to provide a 2.9:1 mixture of 20:
125 in an improved 22% overall yield from 26. This
mixture could be converted to LY235959 (1) by equilibra-
tion as described above.
The enamide approach shown in Scheme 4 provided
an improved method for attachment of the glycine unit,
but did not solve the C-3 stereocontrol issues and did not
increase the overall yield. An alternate solution to the
poor alkylation yield of iodide 13 was provided by
employment of a benzophenone imine glycine enolate.
O’Donnell pioneered use of ester analogue 33 for glycine
ester alkylation under remarkably mild conditions.26
Subsequently, other workers have employed related
glycine amide benzophenone imines27 or bis(methylthio)-
(20) Prepared from corresponding alcohol in 93% yield.
(21) The aldehyde is sensitive to epimerization and should be kept
cold and used without delay.
(22) Schmidt U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487.
The synthesis of LY235959 (1) shown in Scheme 2
demonstrates the utility of such a Diels-Alder approach
as epimer 20 was prepared in 12 steps and 13.4% overall
yield; however, a number of issues remained to be
addressed. Alkylation of the glycine unit to provide
(23) Product ratio was determined by the ratio of integral areas of
the C-3 protons in the 1H NMR spectrum of the crude product mixture.
(24) For a recent review on the use of homogeneous catalysts in
hydrogenation, see: Burk, M. J .; Gross, M. F.; Harper, T. G. P.;
Kalberg, C. S.; Lee, J . R.; Martinez, J . P. Pure Appl. Chem. 1996, 68
(1), 37. See also: Scott, J . W.; Keith, D. D.; Nix, J r., G.; Parrish, D. R.;
Remington, S.; Roth, G. P.; Townsend, J . M.; Valentine, J r., D., Yang,
R. J . Org. Chem. 1981, 46, 5086.
(18) Such acidic hydrolysis conditions do not epimerize the C-3
stereocenter, see ref 1. Close correspondence of the 1H NMR spectral
data of isomers 27 and 28 with analogous C-3 epimers reported by
Ornstein also supports the stereochemical assignment: 27, C-3 proton
a triplet at 4.70 ppm, J ) 5 Hz; 28, C-3 proton a doublet at 5.21 ppm,
J ) 7 Hz. Compare with compounds 31a and 40 in ref 1b.
(19) Such intermediates are presumably involved in the racemiza-
tion of L-proline by treatment with acetic anhydride in refluxing acetic
acid, see ref 14, p 2195.
(25) Product was identical with material previously prepared by 1
NMR. Ratio was determined by integral areas of the C-3 protons.
H
(26) O’Donnell, M. J .; Boniece, J . M.; Earp, S. E. Tetrahedron Lett.
1978, 2641-2644. (b) O’Donnell, M. J .; Eckrich, T. M. Tetrahedron
Lett. 1978, 4625-4628. (c) O’Donnell, M. J .; Wu, S. Tetrahedron:
Asymmetry 1992, 3, 591-594.
(27) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 6009-6010.

Synthesis of Cis Perhydroisoquinoline LY235959
J . Org. Chem., Vol. 63, No. 3, 1998 779
Sch em e 4. En a m id e Hyd r ogen a tion Ap p r oa ch
Sch em e 5. O’Don n ell Ester Alk yla tion
methylene imines28 for similar alkylations. We found
attack by hydride or hydroxide derived from adventitious
moisture. These side reactions were observed to a lesser
extent even with the more hindered ester groups in the
corresponding malonate intermediates discussed above.
We anticipated that the ester hydrolysis and reduction
problems described above could be avoided by use of the
known pyrrolidine amide 39.31 The successful synthesis
of LY235959 (1) using amide 39 is shown in Scheme 6.
Treatment of iodide 13 with the potassium enolate of
amide 39 afforded the alkylation product 41 after 3 h at
room temperature. Intermediate 40 was not isolated, but
was hydrolyzed to the amine and then acylated with
benzoyl chloride under Schotten-Baumann conditions to
afford amide 41 in 77% yield for two steps. Ozonolysis
of amide 41 and reduction of the intermediate ozonide
with sodium borohydride afforded the ring-opened diol.
The diol was converted to the bis-mesylate 42 in 90%
overall yield for three steps. Cyclization of bis-mesylate
42 to assemble the perhydroisoquinoline ring occurred
in high yield using excess potassium tert-butoxide in
tetrahydrofuran. The inconsistent reaction rates and
that iodide 13 was smoothly alkylated by the potassium
enolate of ester 33 under a variety of conditions (Scheme
5). The conditions are much milder than those employed
with acetamido malonate (Scheme 2), and only a 10%
excess of enolate was required. The crude product was
susceptible to hydrolysis but could be directly converted
to amide 35 in 78% overall yield by hydrolysis and
acylation with p-nitrobenzoyl chloride under Schotten-
Bauman conditions. Imine 34 could be isolated in 48%
yield by alkylation under the conditions reported by
O’Donnell.29
The resulting 1:1 mixture of isomeric amides 35 was
treated with ozone followed by sodium borohydride under
similar conditions to those discussed above. Poor yields
of diol 36 were realized in this reaction due to formation
of byproducts tentatively identified as the triol resulting
from reduction of the R-amido ester group30 and the
amino acid corresponding to 36. Diol 36 was converted
to the bismesylate and cyclization to mesylate 37 was
achieved in marginal yield using either sodium hydride
in tetrahydrofuran at reflux or potassium tert-butoxide
in tetrahydrofuran at room temperature. We concluded
from these experiments that the ester functionality in
these intermediates is too susceptible to nucleophilic
(31) Amide 39 has been used in aldol addition reactions but has not
been previously employed in glycine enolate alkylations, see: Kane-
masa, S.; Mori, T.; Wada, E.; Tatsukawa, A. Tetrahedron Lett. 1993,
34, 677-680. Amide 39 could be prepared by reaction of ester 33 with
pyrrolidine using the Weinreb procedure (Lipton, M. F.; Basha, A.;
Weinreb, S. M. Organic Syntheses; Vol. VI; Wiley: New York, 1988;
Coll. Vol. VI, pp 492-495) or by treatment of N-(aminoacetyl)-
pyrrolidine (38) with benzophenone imine using the O’Donnell proce-
dure.26 Both methods provided amide 39 which contained minor
amounts of benzophenone; however, benzophenone did not interfere
with the subsequent alkylation reaction and was removed at a later
stage (see Supporting Information).
(28) Ikegami, S.; Uchiyama, H.; Hayama, T.; Katsuki, T.; Yamagu-
chi, M. Tetrahedron 1988, 44, 5333-5342.
(29) O’Donnell, M. J .; Wojciechowski, K. Synthesis 1984, 313-315.
(30) Esters with electron-withdrawing substituents at the R-position
can be reduced using NaBH4, see: (a) Sasaki, N. A.; Hashimoto, C.;
Potier, P. Tetrahedron Lett. 1987, 28, 6069-6072. (b) Levai, L.; Ritvay-
Emandity, K. Ber. Dutsch. Chem. Ges. 1959, 92, 2775.

780 J . Org. Chem., Vol. 63, No. 3, 1998
Hansen et al.
Sch em e 6. Syn th esis via Glycin e Am id e
20 psi air @ 6 SCFH and 80% output. Melting points were
obtained using a Mettler FP62 automatic melting point
apparatus. 1H and 13C NMR spectra were obtained at 300 and
75 MHz, respectively, in CDCl3 unless otherwise noted.
Chemical shifts are in ppm downfield from internal tetra-
methylsilane. 1H NMR data are tabulated in order: multiplic-
ity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet),
number of protons, coupling constant(s) in hertz. Mass
spectral analysis and combustion analysis was performed by
the Eli Lilly and Company Physical Chemistry Department.
(1S,2S,4S)-Bicyclo[2.2.2]oct-5-en -2-ylm eth yl Meth a n e-
su lfon a te (12). To alcohol 11 (0.16 mol) in toluene (125 mL)
were added pyridine (30 mL, 0.37 mol) and CH3SO2Cl (16 mL,
0.21 mol), each washed in with 3 × 5 mL of toluene. The
solution was heated at 65 °C for 16 h and cooled to rt, and 5%
aqueous NaHCO3 (150 mL) was added. The mixture was
stirred for 15 min, and the phases were separated. The
aqueous layer was washed with toluene (2 × 100 mL). The
combined organic layers were washed in turn with H2O (150
mL) and 1 M HCl (2 × 100 mL). The combined organic layers
were concentrated to 125 mL in vacuo, and the mesylate
solution was carried on to the next reaction. In a separate
experiment, the solution was concentrated to afford mesylate
12 as an analytically pure oil in 96% yield. IR: 3100-2860
cm-1; 1H NMR: δ 0.75 (m, 1), 1.18-1.38 (m, 2), 1.43-1.59 (m,
2), 1.73 (m, 1), 2.17 (m, 1), 2.55 (m, 1), 2.64 (m, 1), 2.99 (s, 3),
3.81 (d, 2, J ) 8), 6.12 (t, 1, J ) 7), 6.32 (t, 1, J ) 7). 13C
NMR: δ 24.47, 25.29, 29.40, 29.48, 30.92, 37.23 (2C), 73.47,
131.10, 135.49. MS (FD) m/z 216 (M+). Anal. Calcd for
ester hydrolysis observed previously were completely
circumvented with this amide substrate. The cyclized
mesylate was converted to iodide 43 in 96% overall yield
for two steps. The phosphonate moiety was introduced
as described above using the Arbuzov reaction. The
crude phosphonate was taken directly into an acidic
hydrolysis which removed all the protecting groups to
afford a 1:2 mixture of 1‚HCl to the undesired epimer
20‚HCl. Base-catalyzed epimerization using KOH as
described above (Figure 1) afforded a 10:1 mixture
favoring the desired isomer 1. Crystallization of crude
LY235959 (1) from an aqueous solution at pH 2.6 was
achieved in 32% overall yield for three steps.32 LY235959
(1) was obtained in 94% ee and contained 4.7% of epimer
20.33 Other physical data was in accord with that
reported by Ornstein.34
In summary, a novel synthesis of NMDA receptor
antagonist LY235959 (1) has been achieved in 13%
overall yield and 17 steps from (R)-pantolactone (7).
Highlights of the synthesis include (a) use of a chiral
auxiliary controlled asymmetric Diels-Alder reaction to
provide the desired absolute and relative stereochemistry
at C-4a, C-6, and C-8a, (b) an efficient alkylation of
hindered iodide 13 using a novel amide benzophenone
imine, (c) oxidative ring opening of the [2.2.2] bicyclic
system to simultaneously functionalize the molecule for
intramolecular cyclization and phosphonate introduction,
and (d) an increased understanding of how the C-3
stereochemistry may be controlled by thermodynamic
equilibration. Further development of this synthetic
route is needed to address stereocontrol at C-3. Synthesis
of epimer 20 in high overall yield makes this synthetic
route attractive for future development efforts.
C
10H16O3S: C, 55.53; H, 7.46; S, 14.82. Found: C, 55.79; H,
7.50; S, 14.66.
(1S,2S,4S)-Bicyclo[2.2.2]oct-5-en -2-ylm eth yl Iodide (13).
A solution of mesylate 12 (0.16 mol) in toluene (125 mL) was
added to a slurry of NaI (60 g, 0.4 mol) in dry DMF (100 mL)
and washed in with toluene (4 × 5 mL). The mixture was
heated at 85 °C for 21 h. The mixture was partitioned between
hexane (50 mL) and water (80 mL). The lower aqueous/salt/
DMF layer was washed with hexane (2 × 150 mL). The
organic layers were washed in turn with dilute Na2S2O3
solution (1 g in 150 mL H2O) and H2O (2 × 150 mL). The
organic solution was filtered through a pad of silica gel (15 g,
60-200 mesh), concentrated to an oil, and distilled in vacuo.
The fraction distilling at 100-105 °C at ∼8 mm amounted to
35.58 g (90% from alcohol 11) of iodide 13. IR: 3048-2868
cm-1; 1H NMR: δ 0.81 (m, 1), 1.20 (m, 1), 1.28 (m, 1), 1.48 (m,
2), 1.80 (m, 1), 2.10 (m, 1), 2.55 (m, 1), 2.69 (m, 1), 2.85 (t, 1,
J ) 7), 2.95 (t, 1, J ) 7), 6.12 (t, 1, J ) 7), 6.31 (t, 1, J ) 7);
13C NMR: δ 15.61, 23.97, 25.94, 30.73, 35.34, 35.75, 41.28,
130.89, 135.46; MS (FD) m/z 248 (M+). Anal. Calcd for
C9H13I: C, 43.57; H, 5.28; I, 51.15. Found: C, 43.28; H, 5.28;
N, 51.40. [R]D ) -24.78 (CH2Cl2, c ) 1.0).
Exp er im en ta l Section
Gen er a l. Reactions involving air or moisture sensitive
reagents were carried out under nitrogen. Tetrahydrofuran
(THF) was distilled from benzophenone ketyl and dimethyl-
formamide (DMF) was dried over 3 Å molecular sieves. Unless
otherwise noted, other reagents and solvents were used as
received from commercial suppliers. Flash chromatography
was performed using Merck silica gel 60 (230-400 mesh).
Ozonolysis was performed using a PCI generator operated at
(32) The low isolated yield of 1 is due to an inefficient crystallization.
(33) The enantiomeric excess of 1 correlates to the diastereomer ratio
of Diels-Alder adduct 9. The enantiomeric excess and diastereomeric
purity were assigned by HPLC.
Dieth yl 2-Aceta m id o-2-[(1R,2R,4S)-bicyclo[2.2.2]oct-5-
en -2-ylm eth yl]m a lon a te (14). Diethyl acetamidomalonate
(15.7 g, 72.5 mmol) was dissolved in 40 mL of DMI (stored

Synthesis of Cis Perhydroisoquinoline LY235959
J . Org. Chem., Vol. 63, No. 3, 1998 781
over 3 Å molecular sieves). The solution was placed in a rt
H2O bath and 2.90 g (72.5 mmol) of NaH (60% in mineral oil)
was added slowly. After 15 min, 8.80 g (35.5 mmol) of iodide
13 was added. The mixture was heated at 90 °C for 21 h. The
brown solution was allowed to cool to rt and was diluted with
120 mL of 3:1 ether/hexanes followed by 60 mL of H2O. The
aqueous layer was adjusted to pH ) 5-7 with 1 M HCl.
Layers were separated, and the aqueous layer was extracted
with 3:1 ether/hexanes (2 × 100 mL). The combined organic
layers were washed with 100 mL of brine and dried (Na2SO4).
The solvent was removed in vacuo to afford 18.18 g of an
orange oil which contained DMI. The crude material was
dissolved in 180 mL of 3:1 ether/hexanes and washed with H2O
(2 × 50 mL) followed by 25 mL of brine. The organic layer
was dried (Na2SO4), and the solvent was removed in vacuo to
leave 12.14 g of yellow solids. The solids were dissolved in 10
mL of EtOAc and 60 mL of hexanes at reflux. The solution
was allowed to cool to rt, and the resulting slurry was stirred
for 2 h in an ice bath. The solid was collected by filtration,
washed with hexanes, and dried to afford 6.98 g (58%) of
diester 14 as white solids. IR: 3416, 3029-2868, 1734, 1679
23.13, 26.67, 31.04, 34.57, 35.57, 37.20, 37.38, 37.62, 62.81,
62.97, 66.03, 67.44, 73.85, 168.02, 168.41, 169.57. MS (FD)
m/z 530 (M+ for C20H35NO11S2).
Dieth yl (4a R,6S,8a R)-6-[(Meth a n esu lfon yl)m eth yl]-2-
a cetyl-1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r oisoqu in olin e-3,3-d i-
ca r boxyla te (17). NaH (0.78 g, 60% dispersion in mineral
oil, 19.5 mmol) was slurried with 16 mL of dry THF. The
solvent was decanted by syringe, and 25 mL of dry THF,
followed by a solution of 5.15 g (9.72 mmol) of dimesylate 16
in 17 mL of dry THF, was added. The tan suspension was
heated at reflux for 17 h. After cooling to rt, excess NaH was
quenched with 10 mL of EtOH. The mixture was diluted with
20 mL of CH2Cl2 and 20 mL of H2O. The aqueous layer was
adjusted to pH ) 1 with HCl, and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 × 25 mL).
The combined organic layers were washed with brine and dried
(Na2SO4). The solvent was removed in vacuo to afford 4.24 g
of an oil. Flash chromatography on 400 g of silica gel using
EtOAc afforded 3.15 g (75%) of 17 as a viscous yellow oil. IR:
3050-2800, 1727, 1662 cm-1; 1H NMR: δ 0.95 (m, 1), 1.08 (m,
1), 1.27 (t, 3), 1.32 (t, 3), 1.50-1.83 (m, 5), 1.95 (m, 1), 2.15
(m, 1), 2.18 (s, 3), 2.32 (dd, 1, J ) 14, 6), 2.47 (dd, 1, J ) 14,
3), 3.00 (s, 3), 3.28 (dd, 1, J ) 13, 13), 3.41 (dd, 1, J ) 13, 5),
3.99 (m, 2), 4.15-4.38 (m, 4). MS (FD) m/z 433 (M+). Anal.
Calcd for C19H31NO8S: C, 52.64; H, 7.21; N, 3.23. Found: C,
52.40; H, 7.31; N, 3.50.
Dieth yl (4a R,6S,8aR)-6-(Iodom eth yl)-2-acetyl-1,2,3,4,4a,
5,6,7,8,8a -d eca h yd r oisoqu in olin e-3,3-d ica r boxyla te (18).
Mesylate 17 (2.30 g, 5.31 mmol) was dissolved in 13 mL of
acetone, and 2.39 g of NaI (15.93 mmol) was added. The
solution was heated at reflux for 4 h. After cooling to rt, 20
mL of H2O and 20 mL of CH2Cl2 were added. Layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with
20 mL of brine and dried (Na2SO4). The solvent was removed
in vacuo to afford 2.24 g (91%) of iodide 18 as a viscous yellow
oil. IR: 3050-2800, 1727, 1661 cm-1; 1H NMR: δ 0.83-1.12
(m, 2), 1.27 (t, 3, J ) 7), 1.34 (t, 3, J ) 7), 1.40 (m, 1), 1.54-
1.75 (m, 4), 1.87-2.10 (m, 2), 2.17 (s, 3), 2.31 (dd, 1, J ) 14,
5), 2.49 (dd, 1, J ) 14, 3), 3.04 (dd, 1, J ) 10, 6), 3.12 (dd, 1,
J ) 10, 5), 3.26 (dd, 1, J ) 13, 13), 3.40 (dd, 1, J ) 13, 5),
4.17-4.35 (m, 4); 13C NMR: δ 13.78, 14.02, 15.03, 22.29, 27.72,
28.19, 32.32, 32.37, 32.49, 37.00, 39.37, 44.02, 61.75, 62.00,
65.65, 168.58, 169.20, 172.82. MS (FD+) m/z 465 (M+). Anal.
Calcd for C18H28NO5: C, 46.46; H, 6.06; N, 3.01. Found: C,
46.21; H, 6.07; N, 2.89.
Dieth yl (4a R,6S,8a R)-6-[(Dieth ylp h osp h on o)m eth yl]-
2-a cetyl-1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r oisoqu in olin e-3,3-
d ica r boxyla te (19). In a flask fitted with a short path
condenser was dissolved 1.50 g (3.19 mmol) of iodide 18 in 110
mL (643 mmol) of (EtO)3P. The solution was sparged with N2
and heated at a mild reflux for 4 h during which time a few
milliliters of EtI and (EtO)3P was distilled off. The heat was
increased to distill off 100 mL of (EtO)3P, and the remaining
solvent was removed in vacuo followed by 5 days under high
vacuum (0.1 mmHg) to afford 2.56 g of a viscous oil. Flash
chromatography on 170 g of silica gel using 5% EtOH in EtOAc
afforded 1.46 g (96%) of phosphonate 19 as a viscous, colorless
oil. IR: 3050-2800, 1727, 1650 cm-1; 1H NMR: δ 0.88-1.10
(m, 2), 1.23-1.42 (m, 12 H), 1.55-1.80 (m, 7), 1.89-2.00 (m,
1), 2.00-2.13 (m, 1), 2.17 (s, 3), 2.28 (dd, 1, J ) 14, 6), 2.45
(dd, 1, J ) 14, 3), 3.28 (dd, 1, J ) 12, 12), 3.39 (dd, 1, J ) 12,
5), 3.98-4.38 (m, 8); 13C NMR: δ 13.58, 13.71, 15.84, 16.12,
16.20, 22.09, 28.20, 28.42, 28.56, 31.79, 31.94, 32.20, 32.45,
32.50, 33.25, 33.39, 33.63, 36.85, 43.90, 61.02, 61.10, 61.49,
61.61, 62.30, 65.47, 168.52, 169.01, 172.60. MS (FD) m/z 475
(M+ for C22H38NO8).
1
cm-1; H NMR: δ 0.74 (m, 1), 1.20 (m, 8), 1.28-1.75 (m, 4),
2.02 (s, 3), 2.08 (dd, 1, J ) 15, 8), 2.29 (m, 2), 2.40 br s, 1),
4.20 (m, 4), 6.05 (t, 1, J ) 8), 6.23 (t, 1, J ) 8), 6.80 (br s, 1);
13C NMR: δ 13.95, 13.98, 23.10, 24.18, 26.44, 30.02, 33.56,
35.24, 35.63, 40.31, 62.39, 62.44, 66.14, 103.94, 131.65, 135.01,
168.67, 168.79. MS (FD) m/z 338 (M+). Anal. Calcd for
C18H27N1O5: C, 64.08; H, 8.07; N, 4.15. Found: C, 63.90; H,
8.01; N, 4.18.
Dieth yl 2-Aceta m id o-2-[(1R,2R,5S)-[1-[2,5-Bis(h yd r oxy-
m eth yl)cycloh exyl]m eth yl]m a lon a te (15). In 35 mL of 3:1
CH2Cl2/EtOH was dissolved 2.53 g (7.51 mmol) of diester 14.
The solution was purged with N2 while stirring in an acetone/
dry ice bath. With an N2 blanket over the solution, O3 was
bubbled into the solution through a fritted glass sparger until
the reaction was complete as indicated by Sudan III indicator
(orange-red to colorless). To the solution was added 1.40 g
(37.04 mmol) of NaBH4 in one portion. The cooling bath was
removed after 5 min and after 50 min the solution was diluted
with 10 mL of CH2Cl2 and cooled in an ice bath. The mixture
was treated with 10 mL of saturated aq. NH4Cl slowly over
12 min. After stirring for 1 h, 5 mL of H2O was added. Layers
were separated, and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with brine and dried (Na2SO4). Solvent was removed in vacuo
to afford 2.57 g (92%) of diol 15 as a slightly yellow foam. IR:
3600, 3400, 3050-2800, 1734, 1682 cm-1; 1H NMR: δ 0.74 (m,
1), 1.10 (m, 1), 1.20-1.56 (m, 5), 1.43 (t, 6, J ) 7), 1.72 (br s,
1), 1.90 (br s, 2), 1.97 (br s, 1), 2.03 (s, 3), 2.21 (dd, 1, J ) 15,
6), 2.52 (dd, 1, J ) 15, 5), 3.38 (m, 2), 3.58 (dd, 1, J ) 10, 10),
3.67 (dd, 1, J ) 10, 4), 4.42 (q, 4, J ) 7), 6.95 (br s, 1); 13C
NMR: δ 13.91, 22.94, 22.99, 26.94, 31.76, 35.17, 35.66, 40.48,
40.58, 59.28, 62.59, 66.15, 68.02, 168.32. 168.43, 169.52. MS
(FD) m/z 374 (M+). Anal. Calcd for C18H31NO7: C, 57.89; H,
8.37; N, 3.75. Found: C, 57.79; H, 8.51; N, 3.75.
Dieth yl 2-Aceta m id o-2-[(1R,2R,5S)-[1-[[2,5-bis[(m eth yl-
su lfon yl)oxy]m et h yl]cycloh exyl]m et h yl]m a lon a t e (16).
Diol 15 (4.02 g, 10.78 mmol) was dissolved in 45 mL of CH2Cl2.
The solution was cooled in an ice bath, and 3.06 mL (22.1
mmol) of Et3N was added followed by dropwise addition of 1.72
mL (22.2 mmol) of CH3SO2Cl. After 20 min, 20 mL of H2O
was added, and the aqueous layer was adjusted to pH ) 1 with
1 M HCl. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The organic layers
were washed with 15 mL of saturated aqueous NaHCO3
followed by 15 mL of brine and dried (Na2SO4). The solvent
was removed in vacuo to leave 5.51 g of a viscous oil.
Chromatography on 400 g of flash silica gel using EtOAc
afforded 5.18 g (91%) of 16 as a white foam/oil. IR: 3400,
(3R ,4a R ,6S ,8a R )-6-(P h osp h on om e t h yl)-1,2,3,4,4a ,5,
6,7,8,8a -d eca h yd r o-isoqu in olin e-3-ca r boxylic Acid (20).
To 694 mg (1.46 mmol) of phosphonate 19 was added 18 mL
of 6 M HCl. The solution was heated at reflux for 16 h. The
solvent was removed in vacuo, and H2O was removed twice to
1
3050-2800, 1736, 1681 cm-1; H NMR: δ 0.89 (q, 1, J ) 12),
1.15 (m, 1), 1.25 (m, 6), 1.35-170 (m, 4), 1.81 (m, 1), 1.92-
2.10 (m, 2), 2.07 (s, 3), 2.25 (dd, 1, J ) 15, 6), 2.53 (dd, 1, J )
15, 5), 3.02 (s, 3), 3.06 (s, 3), 3.95 (dd, 1, J ) 9, 8), 4.04 (dd, 1,
J ) 9, 6), 4.25 (m, 6), 5.87 (br s, 1); 13C NMR: δ 13.97, 22.46,
1
provide 514 mg (112%) of tacky, white solids. Analysis by H
NMR indicated that a ratio of 5:1 of amino acids 20:1 as HCl

782 J . Org. Chem., Vol. 63, No. 3, 1998
Hansen et al.
salts was obtained. 20‚HCl: 1H NMR (D2O): δ 0.95-1.20 (m,
3), 1.50-2.40 (m, 10), 3.04 (dd, 1, J ) 4, 12), 3.40 (dd, 1, J )
12, 12), 4.19 (d, 1, J ) 6). Ion exchange chromatography on
7.5 g of BioRad AX1-8, 50-100 mesh, chloride form ion-
exchange resin (load in aqueous NaOH, elute with aqueous
AcOH) afforded 384 mg of a slightly yellow foam. A 198 mg
portion was reslurried twice in 10 mL of boiling acetone to
afford 177 mg (72%) of offwhite solids characterized as a 5:1
ratio of 20:1. The major isomer was identified by 1H NMR
and 13C NMR comparison with the data reported previously.34
20: 1H NMR (D2O, KOD): δ 0.86-1.15 (m, 3), 1.43-2.25 (m,
10), 2.94 (dd, 1, J ) 3, 12), 3.36 (dd, 1, J ) 12, 12), 4.00 (d, 1,
J ) 5). MS (FAB+) m/z 278.2 (MH+ for C11H21NO5P).
Dieth yl 2-Aceta m id o-2-[(1R,2R,5S)-[1-[2-ca r boxy-5-(h y-
d r oxym eth yl)cycloh exyl]m eth yl]m a lon a te (21). The pro-
cedure above for diol 15 was followed starting from 0.99 g of
diester 14. After extraction of the diol from the basic aqueous
layer, addition of HCl (pH 1) and extraction afforded 190 mg
(17%) of acid 21 as a foamy oil. IR: 3650-2500, 3400, 1735,
treated with Sudan III (a dilute solution in EtOAc), and the
pink solution was cooled to -78 °C. O3 was passed through
the solution until the pink color disappeared (∼1.5 h at 25%
output and 2.5% O2 flow). The clear solution was sparged with
N2 for 10 min and then treated with NaBH4 (11.5 g, 305.0
mmol, 5 equiv). The reaction was allowed to warm to 0 °C
and was stirred for 20 min. The mixture was treated with
saturated NH4Cl (600 mL) in a slow stream and stirred at 0
°C for 50 min. The layers were separated, and the organic
phase was dried (Na2SO4) and concentrated in vacuo to provide
27 as a yellow oil which crystallized upon standing (19.7 g,
93%), mp 75.7 °C: IR (CHCl3): 3626, 3453, 3018, 2927, 2869,
1715, 1456, 1401, 1268, 1052, 943 cm-1 1H NMR: δ 7.30-
;
7.50 (5, m,), 5.15 (2, s,), 4.00-4.20 (2, m), 3.55-3.80 (2, m),
3.45 (2, d, J ) 7.3), 1.90-2.10 (3, m), 1.35-1.70 (6, m), 0.80-
1.15 (2, m); 13C NMR: δ 155.1, 135.0, 128.4, 128.2, 71.0, 69.5,
69.4, 67.7, 60.0, 39.8, 38.5, 37.0, 27.1, 27.0, 23.6. MS (FD) m/z
309 (M + 1). Anal. Calcd for C17H24O5: C, 66.21; H, 7.85.
Found: C, 66.44; H, 7.77.
1
1681 cm-1; H NMR: δ 1.00-1.25 (m, 1), 1.25 (m, 6), 1.35-
(1S,2R,5S)-[2,5-Bis[[[(4-m et h ylp h en yl)su lfon yl]oxy]-
m eth yl]cycloh exyl]m eth yl P h en ylm eth yl Car bon ate (28).
A solution of 27 (2.00 g, 6.49 mmol, 1.0 equiv) in pyridine (15
mL) was treated with p-toluenesulfonyl chloride (2.97 g, 15.56
mmol, 2.4 equiv) and stirred at rt overnight. The mixture was
concentrated in vacuo and the residue was dissolved in EtOAc
(40 mL) and washed with 1 M HCl (2 × 15 mL), dried (Na2SO4)
and concentrated in vacuo. The residue was purified by flash
chromatography (gradient of 12.5% to 50% EtOAc in hexane,
30 g of silica) to provide 28 as a colorless oil (3.02 g of 95 wt
%,35 corrected yield 2.86 g, 72%): IR (CHCl3): 3028, 2931,
1.68 (m, 6), 2.05 (s, 3), 2.12 (s, 1), 2.42 (br dd, 1, J ) 15, 3),
2.61 (m, 2), 3.43 (br d, 2, J ) 4), 4.22 (m, 4), 5.8-6.4 (br s, 2),
7.15 (s, 1); 13C NMR: δ 13.88, 22.88, 24.45, 29.12, 31.60, 34.61,
36.49, 40.34, 43.36, 62.56, 62.60, 66.17, 67.83, 168.29, 168.47,
169.84. High-resolution MS (FAB), exact mass calcd for MH+
C18H30NO8: 388.1998. Found: 388.1971.
Meth yl (3S,4a R,6S,8a R)-6-[(Dim eth ylp h osp h on o)m eth -
yl]-2-a cetyl-1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r oisoqu in olin e-
3-ca r boxyla te (22) fr om 1. To 2.0 g (7.2 mmol) of amino acid
1 prepared independently34 were added 110 mL of AcOH and
230 mL of trimethyl orthoacetate. The mixture was heated
at reflux for 2 h, and the solvent was removed in vacuo to
afford ester 22 (<5% 23). The residue was chromatographed
on 400 g of silica gel using 10:1 EtOAc/MeOH to afford 2.26 g
1744, 1711, 1362, 1267, 1189, 1176, 946 cm-1 1H NMR: δ
;
7.70-7.80 (4, m), 7.25-7.45 (9, m), 5.15 (2, s), 3.70-4.05 (6,
m), 2.40-2.45 (6, 2s), 1.30-2.20 (7, m), 0.70-0.95 (2, m); 13C
NMR: δ 154.8, 144.8, 132.6, 129.9, 128.5, 128.3, 127.8, 74.2,
69.7, 37.8, 36.6, 33.6, 26.6, 26.5, 23.0, 21.6, 21.5. MS (FD) m/z
616 (M + 1). Anal. Calcd for C31H36O9S2: C, 60.37; H, 5.88.
Found: C, 60.58; H, 6.05.
(87%) of ester 22 as a viscous oil. IR: 1738, 1640 cm-1 1H
;
NMR: δ 1.25 (m, 2), 1.45-2.30 (m, 11), 2.12 (s, 3), 3.40 (m, 2),
3.71 (s, 3), 3.72 (s, 3), 3.74 (s, 3), 4.70 (br t, 1, J ) 5). 13C
NMR: δ 21.56, 25.78, 28.81, 28.94, 30.18, 30.23, 30.55, 30.64,
30.95, 32.16, 32.39, 35.16, 35.30, 46.38, 51.33, 52.02, 52.11,
171.19, 172.30. MS (FD) m/z 361 (M+).
(1S(Z),2R,5S)-3-[2,5-Bis[[[(4-m et h ylp h en yl)su lfon yl]-
oxy]m eth yl]cycloh exyl]-2-[[(p h en ylm eth oxy)ca r bon yl]-
a m in o]-2-p r op en oic Acid Meth yl Ester (29). A solution
of 28 (9.60 g, 15.6 mmol, 1.0 equiv) in CH2Cl2 (40 mL) was
treated with 10% Pd/C (1.50 g) and stirred at rt under an
atmosphere of H2 for 5 h. The mixture was filtered through
Hyflo, and the filtrate was used directly in the next step. A
solution of oxalyl chloride (1.63 mL, 18.7 mmol, 1.2 equiv) in
CH2Cl2 (35 mL) was cooled to -78 °C and treated dropwise
with DMSO (2.65 mL, 37.4 mmol, 2.4 equiv). After 15 min at
-78 °C, the solution prepared above was added by cannulation,
and the mixture was stirred at -78 °C for 10 min and at -20
°C for 30 min. The mixture was treated with diisopropylethyl-
amine (13.0 mL, 74.7 mmol, 4.8 equiv) and washed with 1 M
HCl (2 × 90 mL) and dried (Na2SO4) and the solution was used
directly in the next step. A solution of N-(benzyloxycarbonyl)-
R-phosphinoglycine trimethyl ester (5.42 g, 16.3 mmol, 1.05
equiv) in CH2Cl2 (70 mL) was cooled to -78 °C and treated
with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.44 mL, 16.3 mmol,
1.05 equiv). The reaction was stirred at -78 °C for 15 min
and then treated with the solution prepared above. The
mixture was stirred at -78 °C for 1 h and at -30 °C for 30
min. The mixture was warmed to 0 °C and washed with 1 M
HCl (2 × 50 mL). The organic phase was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash
chromatography (gradient of 12.5% to 50% EtOAc in hexane,
75 g of silica) and further purified by flash chromatography
(gradient of 2.5% to 5% EtOAc in CH2Cl2, 75 g of silica) to
provide 29 as a white foam (8.10 g, 76%): 1H NMR: δ 7.70-
7.80 (4, m), 7.30-7.40 (9, m), 6.35 (1, d, J ) 9.7), 6.20 (1, br s),
5.10 (2, s), 4.05 (2, d, J ) 7.3), 3.70-3.80 (5, m), 2.65-2.80 (1,
m), 2.40-2.45 (6, 2s), 2.10-2.25 (1, m), 1.25-1.85 (5, m), 0.80-
1.05 (2, m); 13C NMR: δ 164.6, 154.1, 144.9, 144.8, 144.7, 137.2,
135.7, 132.7, 132.6, 132.5, 129.8, 128.4, 128.2, 128.0, 127.8,
Ester 22 fr om 20. To 1.17 g (3.73 mmol) of 20‚HCl were
added 12 mL of AcOH and 24 mL of trimethyl orthoacetate.
The mixture was heated at reflux for 3 h. The solvent was
removed in vacuo, and CHCl3 was removed three times to
afford 1.45 g (95%) of a viscous golden oil. Analysis by 1H
NMR indicated a 5:1 ratio of methyl esters 22 and 23.
Meth yl (3R,4aR,6S,8aR)-6-[(Dim eth ylph osph on o)m eth -
yl]-2-a cetyl-1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r oisoqu in olin e-
3-ca r boxyla te (23). To 1.17 g (3.23 mmol) of ester 22 were
added 25 mL of MeOH and 0.33 mL (1.6 mmol) of a 28%
solution of NaOMe in MeOH. The mixture was heated at
reflux for 20 h and then partitioned between 150 mL of CH2Cl2,
150 mL of water, and 5 mL of 1 M HCl. The layers were
agitated and separated, and the aqueous layer was washed
with 20 mL of CH2Cl2. The organic layers were dried, and
the solvent was removed in vacuo to afford an 11:1 mixture of
esters 23 and 22. The residue was chromatographed on 150
g of silica gel using 6:1 EtOAc/MeOH to afford 0.96 g (82%) of
ester 23 (23:22 ) 16:1) as mixture of rotomers. 1H NMR data
is for the major rotomer only and 13C NMR data is for both
rotomers. IR: 1732, 1638 cm-1 1H NMR: δ 0.90-1.15 (m,
;
2), 1.50-2.35 (m, 11), 2.16 (s, 3), 3.35 (dd, 1, J ) 4.3, 13), 3.51
(dd, 1, J ) 13, 13), 3.70 (s, 3), 3.72 (s, 3), 3.74 (s, 3), 5.23 (d, 1,
J ) 7.0). 13C NMR: δ 21.39, 21.51, 28.56, 28.70, 28.79, 30.81,
31.44, 32.44, 32.57, 32.65, 32.74, 32.79, 32.89, 33.04, 33.15,
33.28, 33.51, 37.64, 43.06, 48.45, 52.01, 52.38, 53.79, 170.56,
170.64, 172.45, 172.90. MS (FD) m/z 361 (M+). Anal. Calcd
for C16H28NO6P: C, 53.18; H, 7.81; N, 3.88. Found: C, 53.44;
H, 7.66; N, 3.97.
(1S,2R,5S)-[2,5-Bis(h yd r oxym et h yl)cycloh exyl]m et h -
yl P h en ylm eth yl Ca r bon a te (27). A solution of 26 (18.8 g,
69.0 mmol, 1.0 equiv) in 3:1 CH2Cl2:MeOH (380 mL) was
(35) Yield correction was based on residual EtOAc on sample as
determined by integral area in the 1H NMR. An analytical sample was
prepared by drying at 60 °C under high vacuum.
(34) See ref 1b.

Synthesis of Cis Perhydroisoquinoline LY235959
J . Org. Chem., Vol. 63, No. 3, 1998 783
125.3, 74.0, 68.2, 67.3, 52.4, 37.2, 36.2, 35.2, 29.0, 25.9, 22.3,
21.5. MS (FD) m/z 685 (M+). Anal. Calcd for C34H39NO10S2:
C, 59.55; H, 5.73; N, 2.04. Found: C, 59.62; H, 5.76; N, 1.84.
(125.7 MHz): δ 173.7, 157.0, 156.5, 137.1, 128.9, 128.8, 128.4,
128.2, 128.1, 67.7, 67.6, 61.8, 61.7, 61.6, 52.0, 51.7, 41.0, 40.8,
34.1, 33.8, 33.7, 33.6, 33.4, 33.2, 33.0, 32.4, 32.2, 29.4, 29.3,
29.2, 16.9, 16.8. MS (FD) m/z 481 (M+). Anal. Calcd for
Meth yl(3R,4a R,6S,8a R)-6-[[[(4-Meth ylp h en yl)su lfon yl]-
oxy]m e t h yl]-2-(ca r b ob e n zyloxy)-1,2,3,4,4a ,5,6,7,8,8a -
d eca h yd r oisoqu in olin e-3-ca r boxyla te (30). A solution of
29 (1.90 g, 2.77 mmol, 1.0 equiv) in 2.5:1 MeOH:toluene (40
mL) was treated with (Ph3P)3RhCl (769 mg, 0.83 mmol, 0.3
equiv) and shaken on a Parr apparatus at 50 psi H2 for 22 h.
The mixture was concentrated in vacuo, and the residue was
treated with silica gel (3.5 g) and 50:50 EtOAc:hexane (100
mL). The mixture was stirred at rt for 15 min and then
filtered, and the filter-cake was washed with 50:50 EtOAc:
hexane. The filtrate was concentrated in vacuo, and the
residue was dissolved in toluene (35 mL) and treated with NaH
(166 mg of 60% in mineral oil, 4.16 mmol, 1.5 equiv). The
mixture was heated at 95 °C for 1 h, cooled, washed with 50%
saturated NaCl solution (15 mL), dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash chroma-
tography (gradient of 12.5% to 25% EtOAc in hexane, 60 g of
silica) to provide 30 as a colorless film (472 mg of 95 wt %36 or
447 mg corrected, 31%): 1H NMR (500 MHz): δ 7.78-7.81 (2,
m), 7.28-7.39 (7, m), 5.11-5.22 (2, m), 4.70 and 4.81 (1, d, J
) 6.9), 3.67-3.81 (6, m), 3.14 and 3.24 (1, t, 13.7), 2.47 (3, s),
2.00-2.25 (2, m), 1.35-1.92 (7, m), 0.88-1.05 (2, m); 13C NMR
(125.7 MHz): δ 173.5, 156.9, 156.5, 145.1, 137.0, 133.5, 130.3,
128.9, 128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 75.0, 67.8, 67.7,
51.9, 51.6, 41.0, 40.7, 38.2, 38.1, 33.7, 33.4, 33.3, 33.1, 32.4,
32.1, 28.6, 28.5, 28.3, 24.1, 24.0, 22.0. MS (FD) m/z 515 (M+).
Anal. Calcd for C27H33NO7S: C, 62.89; H, 6.45; N, 2.72.
Found: C, 62.82; H, 6.53; N, 2.66. Further elution of the
column provided a mixture of 30 (116 mg, 8% and the other
C-3 epimer (288 mg, 20%) (total yield of 851 mg, 59%).37
C
24H36NO7P: C, 59.87; H, 7.54; N, 2.91. Found: C, 59.73; H,
7.46; N, 3.18.
Com p ou n d 20‚HCl fr om 32. A solution of 32 (49 mg, 0.10
mmol) in CH2Cl2 (0.1 mL) was treated with 6 M HCl (1.5 mL),
and the mixture was heated at reflux (110 °C) for 22 h. The
mixture was cooled and washed several times with CH2Cl2.
The aqueous portion was concentrated in vacuo to provide
20‚HCl as a colorless foam (30 mg, 96%): 1H NMR (500 MHz,
D2O): δ 4.18 (1, d, J ) 6.0), 3.40 (1, t, J ) 13.0), 3.03 (1, dd,
J ) 13, 3.7), 2.11-2.29 (2, m), 2.00-2.10 (1, m), 1.89-1.99 (1,
m), 1.53-1.80 (7, m), 0.96-1.15 (2, m); 13C NMR (125.7 MHz,
D2O): δ 172.8, 51.8, 41.2, 34.4, 33.6, 33.5, 33.4, 32.8, 32.1, 31.2,
29.6, 28.3, 28.2, 27.7. MS (FD) m/z 278 (M + 1). Anal. Calcd
for
C11H21ClNO5P‚1.25 H2O: C, 39.29; H, 7.04; N, 4.17.
Found: C, 39.42; H, 7.02; N, 3.99.
N-[1-[(1R(RS*),2R,4S)-Bicyclo[2.2.2]oct-5-en -2-ylm eth yl]-
2-oxo-2-(1-p yr r olid in yl)eth yl]ben za m id e (41). Imine 39
(37.3 g, assumed 85% pure, 0.11 mol) was dissolved in a
mixture of dry DMF (100 mL) and dry toluene (50 mL). Solid
KOBut (14.7 g, 95%, 0.12 mol) was added to the reaction
mixture, and the addition funnel was washed down with
DMF-toluene (25 mL each). The solution became dark, and
an orange precipitate began to form after 10 min. After 15
min, a solution of iodide 13 (20.0 g, 0.081 mol) in DMF-toluene
(25 mL each) was added over 1.6 h. After 18 h (reaction
complete in 2-3 h), the mixture was partitioned between
toluene (150 mL) and H2O (100 mL). The layers were
separated, and the aqueous layer was extracted with toluene
(2 × 150 mL). The combined toluene layers were washed with
100 mL each of H2O, 0.2 M HCl, and 1% NaHCO3 and brine
(25 mL). The solvent was removed in vacuo to afford 42.8 g
of an oil which was dissolved in 75 mL of EtOAc and stirred
with 330 mL of 1 M HCl for 2 h. The mixture was extracted
with toluene (3 × 100 mL), and the organic layers were washed
with 0.2 M HCl (2 × 25 mL). The combined aqueous layers
were cooled in an ice bath, and 100 mL of CH2Cl2, followed by
92 mL of 5 M NaOH, was added (pH 10). The aqueous layer
was washed with CH2Cl2 (3 × 50 mL). The combined organic
layers were layered with H2O (50 mL), and 9.4 mL (0.081 mol)
of PhCOCl followed by 14.5 mL of 5 M NaOH was added. The
addition of NaOH was stopped when the pH was stable at
9-10. After stirring for 1 h, the layers were separated, and
the aqueous layer was washed with CH2Cl2 (2 × 50 mL). The
combined organic layers were dried (Na2SO4 and Darco) and
concentrated. Recrystallization from EtOAc afforded 21.9 g
(2 crops, 77%) of amide 41 as a 1:1 mixture of diastereomers.
Meth yl (3S,4a R,6S,8a R)-6-(Iod om eth yl)-2-(ca r boben z-
yloxy)-1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r oisoqu in olin e-3-ca r -
boxyla te (31). A solution of 30 (1.15 g, 2.23 mmol, 1.0 equiv)
in 2-butanone (20 mL) was treated with NaI (6.7 g, 44.6 mmol,
20 equiv) and stirred at 60 °C for 1.5 h. The mixture was
cooled, concentrated to ∼10 mL, and partitioned between
EtOAc and H2O. The organic phase was washed with 50%
brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash chromatography (gradient of 10% to 20%
EtOAc in hexane, 20 g of silica) to provide 31 as a light tan oil
(910 mg of 96 wt %37 or 876 mg corrected, 83%): IR (CHCl3):
1
3013, 2928, 1739, 1693, 1426, 1142, 1020 cm-1; H NMR: δ
7.25-7.40 (5, m), 5.10-5.30 (2, m), 4.70-4.90 (1, m), 3.70-
3.90 (4, m), 3.00-3.35 (3, m), 2.20-2.30 (1, m), 2.00-2.10 (1,
m), 0.95-1.95 (9, m); 13C NMR: δ 173.0, 172.9, 156.4, 155.9,
136.5, 128.3, 128.2, 127.8, 127.7, 67.2, 67.1, 52.3, 51.4, 51.0,
40.4, 40.2, 39.5, 39.4, 33.0, 32.8, 32.7, 32.1, 32.0, 31.9, 31.6,
28.4, 28.3, 27.7, 27.6, 15.9, 15.7. MS (FD) m/z 471 (M+). Anal.
Calcd for C20H26INO4: C, 50.95; H, 5.56; N, 2.97. Found: C,
51.09; H, 5.62; N, 2.97.
IR: 1633 cm-1 1H NMR: δ 0.74-0.98 (m, 1), 1.10-2.06 (m,
.
12), 2.33 (m, 0.5), 2.48 (m, 1), 2.67 (m, 0.5), 3.34-3.57 (m, 3),
3.66-3.83 (m, 1), 4.88-5.08 (m, 1) 6.07-6.18 (m, 1), 6.23-
6.34 (m, 1), 7.10-7.21 (m, 1), 7.36-7.53 (m, 3), 7.79-7.88 (m,
2). 13C NMR: δ 24.15, 24.17, 24.52, 26.05, 26.33, 30.05, 30.18,
33.62, 34.08, 34.35, 34.66, 35.63, 40.81, 41.29, 46.02, 46.09,
46.44, 49.05, 49.45, 127.19, 128.47, 131.52, 131.59, 132.02,
134.19, 134.21, 134.85, 135.20, 166.91, 170.93, 171.15. MS
(FAB) m/z 353 (MH+). Anal. Calcd for C22H28N2O2: C, 74.97;
Meth yl (3S,4aR,6S,8aR)-6-[(Dieth ylph osph on o)m eth yl]-
2-(c a r b o b e n zy lo x y )-1,2,3,4,4a ,5,6,7,8,8a -d e c a h y d r o -
isoqu in olin e-3-ca r boxyla te (32). A solution of 31 (143 mg,
0.303 mmol) in 5.0 mL of (EtO)3P was heated at 148 °C with
a gentle stream of N2 passing through the solution for 28 h.
The mixture was cooled, and solvent was removed by evapora-
tion under a stream of N2. The residue was purified by flash
chromatography (gradient of 2.5% to 5% EtOH in EtOAc, 4.5
H, 8.01; N, 7.95. Found: C, 74.75; H, 7.94; N, 8.16. [R]D
-6.32 (CH2Cl2, c ) 1.0).
)
N-[1-[(1R(RS*),2R,5S)-[1-[[2,5-Bis[[(m et h ylsu lfon yl)-
oxy]m eth yl]cycloh exyl]m eth yl]-2-oxo-2-(1-p yr r olid in yl)-
eth yl]]]ben za m id e (42). A solution of amide 41 (20.7 g, 0.059
mol) in a mixture of CH2Cl2 (150 mL) and EtOH (100 mL) was
stirred under N2 at -45 °C. Sudan III (20 drops of a 0.1%
solution in EtOAc) was added as an indicator, and O3 was
added through a subsurface glass frit until the indicator color
faded (25 min). The mixture was purged with N2. A NaBH4
(4.44 g, 0.118 mol) solution was prepared in ice cold H2O (55
mL). The NaBH4 solution was stirred vigorously at -5 °C
while the cold (-45 °C) ozonolysis mixture was added over 20
min. When the exotherm subsided (10 min), the mixture was
allowed to warm to rt. After ∼3 h, the mixture was cooled in
g of silica) to provide 32 as a colorless film (143 mg of 97 wt
%
7.38 (5, m), 5.13-5.19 (2, m), 4.69 and 4.81 (1, d, J ) 7.0),
4.05-4.12 (4, m), 3.65-3.88 (4, m), 3.19 and 3.30 (1, t, J )
13.7), 2.12-2.25 (1, m), 1.96-2.07 (1, m), 1.80-1.95 (2, m),
1.48-1.79 (7, m), 1.25-1.40 (6, m), 0.95-1.03 (2, m); 13C NMR
37
or 139 mg corrected, 95%): 1H NMR (500 MHz): δ 7.28-
(36) Product was concentrated in vacuo from dichloromethane, and
yield correction was based on residual solvent as determined by
integral area in the 1H NMR. An analytical sample was prepared by
drying at 60 °C under high vacuum.
(37) Yields were determined by integral areas of the C-3 protons in
the 1H NMR after subtracting for residual solvent.

784 J . Org. Chem., Vol. 63, No. 3, 1998
Hansen et al.
ice and quenched by cautious addition of 2 M HCl. The
mixture was acidified to pH 2 and stripped in vacuo to remove
the organic solvents. The residual aqueous solution was
extracted with EtOAc (3 × 200 mL) and 1:1 toluene/EtOAc (3
× 200 mL). The organic extracts were washed with a mixture
of brine and 10% aqueous NaHCO3 (50 mL each). The organic
solution was dried (Na2SO4) and concentrated in vacuo to
afford 23.9 g of the diol corresponding to dimesylate 42.
Spectral data was obtained on this crude material before
thus obtained was a 5-10:1 mixture of isomers and was
suitable for use in the next reaction. IR: 1623, 1650 cm-1. 1H
NMR: δ 0.84-1.06 (m, 1), 1.33-2.06 (m, 13), 2.06-2.21 and
2.39-2.49 (m, 1), 3.06 (d, 2, J ) 7), 3.22-3.81 (m, 5), 4.01 (t,
1, J ) 13), 4.19 and 4.41 and 4.76 (m, 3), 5.32 and 5.56 (d, 1,
J ) 8), 7.30-7.50 (m, 5). 13C NMR: δ 14.69, 23.93, 26.45,
28.05, 28.69, 30.97, 32.56, 33.82, 34.12, 40.80, 45.44, 46.31,
46.73, 48.80, 125.90, 128.38, 128.46, 129.47, 136.29, 171.62,
171.85. MS (FD) m/z 480 (M+). [R]D ) -79.05 (CH2Cl2, c )
1.0).
carrying it directly into the next reaction IR: 1631 cm-1 1H
.
NMR: δ 0.80-1.13 (m, 2), 1.21-2.16 (m, 14), 3.30-3.65 (m,
7), 3.68-3.88 (m, 2), 4.95 and 5.18 (m,1), 7.30-7.55 (m, 4),
7.78-7.92 (m, 2). 13C NMR: δ 23.80, 23.93, 24.16, 26.02, 28.08,
28.15, 30.81, 31.82, 35.80, 36.41, 36.66, 37.40, 38.44, 40.37,
40.43, 40.51, 40.77, 46.26, 46.75, 46.84, 49.36, 50.16, 60.41,
60.69, 68.06, 68.08, 125.32, 127.35, 127.39, 128.24, 128.45,
128.50, 129.05, 131.62, 131.69, 133.79, 133.84, 167.25, 167.39,
171.42, 171.47. MS (FD+) m/z 389 (MH+). The crude diol was
dissolved in 150 mL of toluene and 100 mL of THF, and 22
mL of pyridine (0.27 mol) and 15 mL of CH3SO2Cl (0.19 mol)
were added. The mixture was heated at 70 °C for 5 h and
stirred for 70 h at rt. Aqueous NaHCO3 (100 mL, 10%) was
added with stirring (to pH 6). The pH was brought to 7.5 by
addition of saturated aqueous Na2CO3 (70 mL) and held for
20 min to allow hydrolysis of excess CH3SO2Cl. The mixture
was extracted with EtOAc (3 × 200 mL), and the combined
organic layers were washed in turn with 10% NaHCO3 (200
mL), 1 M HCl (2 × 150 mL), and brine (100 mL). The organic
layer was dried (MgSO4 and Darco) and concentrated in vacuo
to afford 28.9 g (90.1%) of dimesylate 42 as a 1:1 mixture of
(3S ,4a R ,6S ,8a R )-6-(P h osp h on om e t h yl)-1,2,3,4,4a ,5,
6,7,8,8a -d eca h yd r o-isoqu in olin e-3-ca r boxylic Acid (1).
Iodide 43 (22.7 g, 0.047 mol) was dissolved in (EtO)3P (690
mL, 4 mol) in a flask equipped with a subsurface frit for
nitrogen purging and a 25 in. Vigreaux distillation column.
The solution was heated with heating rate and an N2 flow
balanced to keep the pot temperature at 138-146 °C and the
distillation head temperature at 40-60 °C with slow distilla-
tion to remove EtI. After 22 h (115 mL distillate collected),
the solution was cooled to <60 °C, tetraethylene glycol di-
methyl ether (100 mL) was added as a scavenger solvent (bp
275 °C), and the excess (EtO)3P was removed by distillation
in vacuo. When the pot temperature reached 155 °C, the heat
was removed. The pot residue was taken up in toluene (250
mL) and washed with H2O (3 × 200 mL). The aqueous layers
were back-washed with toluene (3 × 200 mL). The combined
toluene layers were concentrated in vacuo to 200 mL and
passed through a short column of silica gel (340 g, EM Grade
62, 60-200 mesh), eluting initially with toluene and then
EtOH in EtOAc (15%, then 30%) to afford 19.3 g of the diethyl
phosphonate. Spectral data was obtained on the mixture of
diethyl phosphonate isomers before carrying it on directly into
diastereomers. IR: 1634 cm-1 1H NMR: δ 0.83-1.31 (m, 2),
.
1.40-2.08 (m, 12), 2.13 and 2.45 (m, 1), 2.97 and 3.04 and 3.05
(s, 6), 3.35-3.65 (m, 3), 3.69-3.86 (m, 1), 3.94-4.14 (m, 2),
4.16-4.40 (m, 2), 4.96-5.19 (m, 1), 7.33-7.56 (m, 4), 7.77-
7.88 (m, 2). 13C NMR: δ 23.04, 24.14, 26.01, 26.78, 27.22,
29.63, 31.09, 34.96, 35.08, 35.24, 36.32, 37.21, 37.24, 37.28,
37.39, 37.53, 37.59, 46.34, 46.48, 46.69, 47.00, 49.08, 49.12,
67.53, 67.91, 73.90, 74.07, 127.25, 128.54, 128.59, 131.76,
131.83, 133.70, 167.10, 167.37, 170.46, 170.57. MS (FAB+)
m/z 545 (MH+). [R]D ) -16.06 (CH2Cl2, c ) 1.0).
the next reaction. IR: 1623, 1650 cm-1
.
1H NMR: δ 0.94-
1.12 (m, 1), 1.31 (t, 6, J ) 8), 1.31-2.07 (m, 13), 2.07-2.21
(m, 1), 3.25-3.86 (m, 5), 3.96-4.14 (m, 7), 5.24-5.36 (m, 1),
7.31-7.49 (m, 5). 13C NMR: δ 16.41, 16.49, 23.93, 26.45, 28.86,
29.02, 31.07, 31.85, 32.93, 32.98, 33.41, 33.55, 33.68, 33.83,
33.87, 45.52, 46.26, 46.72, 48.80, 61.24, 61.32, 125.90, 127.02,
128.37, 128.45, 129.43, 136.37, 171.78, 171.88. MS (FD) m/z
490 (M+). [R]D ) -77.23 (CH2Cl2, c ) 1.0). To a solution of
the diethyl phosphonate (18.9 g, 0.039 mol) in CH2Cl2 was
added 6 M HCl (220 mL, 1.32 mol). The mixture was heated
at reflux for 16 h and then cooled and extracted with CH2Cl2
(3 × 200 mL) to remove benzoic acid. The organic extract was
back-washed with 1 M HCl (40 mL). The aqueous layers were
concentrated in vacuo to afford 16.7 g of amine hydrochloride
salts. The mixture of pyrrolidine and product HCl salts was
dissolved in H2O (100 mL) and cooled while KOH pellets (89.9
g, 1.36 mol) were added slowly, with stirring (washed in with
85 mL of H2O). The solution was heated at reflux with a
nitrogen purge to sweep out pyrrolidine). After 23 h, the
solution was cooled, 135 mL of 12 M HCl was added, and the
solvent was removed in vacuo. The solid was extracted
repeatedly with 1:1 MeOH/CH2Cl2, and the organic extracts
were stripped in vacuo to yield 12.6 g of a glassy foam. 1H
NMR and FAB-MS showed this material to be a mixture
consisting of ∼40% of the methyl esters. The material was
taken up in H2O (50 mL), heated at reflux 1 h, and then
distilled until the volume was reduced to about half. The
solution was cooled to rt and the pH adjusted from 0.7 to 2.6
by addition of 5 M NaOH (8 mL). The solution was seeded
with an authentic sample of 1.34 After standing at rt overnight
and in an ice bath for 4 h, the resulting precipitate was filtered,
washed with cold H2O (4 × 4 mL) and acetone, and air-dried,
yielding 4.18 g (33%) of a white solid. LY235959 (1) was
obtained in 94% ee and contained 4.7% of epimer 20 as
determined by HPLC. This material was characterized by MS,
1H NMR, IR, and by HPLC comparison with authentic mate-
rial prepared independently.34 IR (KBr): cm-1, 1736. 1H NMR
(D2O/DCl): δ 0.98-1.22 (1, m), 1.35-1.58 (1, m), 1.58-1.95
(7, m), 1.95-2.26 (4, m), 3.09-3.40 (2, m), 4.11 (1, dd, J ∼ 14,
4). MS (FD+) m/z 278 (MH+).
(3R,4a R,6S,8a R)- a n d (3S,4a R,6S,8a R)-6-(iod om eth yl)-
2-ben zoyl-3-(N-p yr r olid in ylca r bon yl)-1,2,3,4,4a ,5,6,7,8,8a -
d eca h yd r oisoqu in olin e (43). The 28.9 g (0.053 mol) of
dimesylate 42 was dissolved in toluene (200 mL), and the
volume was reduced in vacuo to 150 mL. The solution was
diluted with dry THF (100 mL), and a 1 M solution of KOBut
in HOBut (133 mL, 0.133 mol) was added over 3 h. After 21
h, a solution of AcOH (14.3 mL, 0.25 mol) in toluene (25 mL)
was added, and the mixture was concentrated in vacuo to a
thick slurry (150 mL). The mixture was transferred to a
separatory funnel with EtOAc (150 mL) and washed with 125
mL of 10% NaHCO3. The aqueous layer was washed with
EtOAc (2 × 150 mL). The organic layers were washed in turn
with 10% NaHCO3 (50 mL), 0.2 M HCl (50 mL), and brine (25
mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo to 22.7 g of the mesylate corresponding
to iodide 43. Spectral data was obtained on this crude material
(5-10:1 mixture of isomers) before carrying it on directly to
the iodide. 1H NMR: δ 0.90-1.10 (m, 1), 1.30-2.07 (m, 13),
2.08-2.22 and 2.38-2.49 (m, 1), 2.99, 3.00 (s, 3), 3.26-3.86
(m, 5), 3.91-4.12 (m, 3), 4.18, 4.42, 4.78 (m, 3), 5.32 and 5.56
(d, 1, J ∼ 8), 7.31-7.51 (m, 5). 13C NMR: δ 23.65, 23.83, 23.91,
24.12, 26.24, 26.43, 28.11, 28.16, 31.05, 33.21, 33.57, 34.16,
37.20, 37.88, 45.37, 46.09, 46.19, 46.29, 46.73, 48.73, 74.37,
125.89, 127.80, 128.23, 128.40, 128.48, 129.51, 136.24, 171.74,
171.86. MS (FD) m/z 448 (M+). The mesylate (22.3 g) was
dissolved in methyl ethyl ketone (255 mL), and 22.5 g of NaI
(0.15 mol) was added. After heating for 5 h at reflux, the
mixture was concentrated in vacuo to a thick slurry. EtOAc
(200 mL) and dilute aqueous Na2S2O3 (100 mL) were added,
and the layers were separated. The aqueous layer was washed
with EtOAc (3 × 150 mL). The organic layers were washed
with brine (2 × 75 mL), dried (MgSO4), filtered, and concen-
trated in vacuo to a yellow foam (22.9 g, 95.9%). Iodide 43

Synthesis of Cis Perhydroisoquinoline LY235959
J . Org. Chem., Vol. 63, No. 3, 1998 785
38, and 39; 1H NMR spectra for compounds 16, 19, 21, 22, 42,
and 43 (12 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and may be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. We thank the Molecular Struc-
ture Division of Eli Lilly and Company for spectral data
and J oseph Kennedy for HPLC analysis of compound
1.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of compounds 8, 9, 10, 11, 34, 35,
J O9717649