Functionalized cis- and trans-fused bicyclic α-amino acids via stereoselective double annulation and dequaternization reactions

Article abstract of DOI:10.1021/jo026643+

Fused bicyclic α-amino acids can be prepared by a double Michael reaction of p-anisyl ethynyl ketone and a tethered diacid, cyclization via hydrogenation or hydration of a CN group, and oxidation of the p-anisyl group. The substitution level of the α-amino acids can be adjusted by decyanation or decarboethoxylation of the intermediates. Bicyclic α-amino acids prepared in this way include cis- and trans-perhydroisoquinoline-3-carboxylic acids and cis-perhydro-2-pyrindine-3-carboxylic acids of various substitutions and oxidation levels. The bicyclic α-amino acids may be regarded as functionalized and conformationally restricted analogues of proline, pipecolic acid, 2-aminoadipic acid, or glutamic acid.

Full text of DOI:10.1021/jo026643+

F u n ction a lized Cis- a n d Tr a n s-F u sed Bicyclic r-Am in o Acid s via
Ster eoselective Dou ble An n u la tion a n d Dequ a ter n iza tion
Rea ction s
Kazuyuki Hattori and Robert B. Grossman*
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055
rbgros1@uky.edu
Received November 1, 2002
Fused bicyclic R-amino acids can be prepared by a double Michael reaction of p-anisyl ethynyl
ketone and a tethered diacid, cyclization via hydrogenation or hydration of a CN group, and oxidation
of the p-anisyl group. The substitution level of the R-amino acids can be adjusted by decyanation
or decarboethoxylation of the intermediates. Bicyclic R-amino acids prepared in this way include
cis- and trans-perhydroisoquinoline-3-carboxylic acids and cis-perhydro-2-pyrindine-3-carboxylic
acids of various substitutions and oxidation levels. The bicyclic R-amino acids may be regarded as
functionalized and conformationally restricted analogues of proline, pipecolic acid, 2-aminoadipic
acid, or glutamic acid.
The synthesis of unusual R-amino acids (that is, R-ami-
no acids that are not coded by DNA) has recently become
an area of intense study. Many unnatural R-amino acids
display desirable pharmacological properties, and they
can confer conformational rigidity and stability to enzy-
matic degradation on peptides into which they are in-
corporated.1 Rigidified analogues of natural amino acids
have been of particular interest. One common strategy
for rigidification has been to incorporate one or two
rings into the R-amino acid. Some examples of bio-
logically significant bicyclic R-amino acids are shown in
Figure 1.2
Over the past few years we have described a suite of
reactions, “double annulation”, that provides access to
highly substituted and functionalized fused carbobicyclic
F IGURE 1. Some biologically significant bicyclic R-amino
acids.
and azabicyclic compounds in stereoselective fashion
(Scheme 1).3 A “tethered diacid”, which consists of two
SCHEME 1
carbon acids connected by a tether, is allowed to undergo
a double Michael reaction with 3-butyn-2-one to give a
new cyclic compound with moderate to high stereoselec-
tivity. If the double Michael adduct contains an equa-
torial CN group, hydrogenation affords a trans-fused
bicyclic piperidine; if it contains an equatorial NO2 group,
hydrogenation affords a trans-fused bicyclic pyrroline or
pyrrolidine; and if it contains only an axial CN group,
treatment with strong acid affords a cis-fused bicyclic 3,4-
dihydro-2-pyridone.
* To whom correspondence should be addressed.
(1) Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789. Gibson, S. E.; Guillo, N.; Tozer,
M. J . Tetrahedron 1999, 55, 585.
(2) Brion, F.; Marie, C.; Mackiewicz, P.; Roul, J . M.; Buendia, J .
Tetrahedron Lett. 1992, 33, 4889. Trova, M. P.; McGee, K. F., J r.
Tetrahedron 1995, 51, 5951. Hansen, M. M.; Bertsch, C. F.; Harkness,
A. R.; Huff, B. E.; Hutchison, D. R.; Khau, V. V.; LeTourneau, M. E.;
Martinelli, M. J .; Misner, J . W.; Peterson, B. C.; Rieck, J . A.; Sullivan,
K. A.; Wright, I. G. J . Org. Chem. 1998, 63, 775. Valls, N.; Lo´pez-
Canet, M.; Vallribera, M.; Bonjoch, J . Chem.sEur. J . 2001, 7, 3446.
Because the double annulation provided access to novel
azabicyclic compounds, we decided to develop it into a
route to bicyclic analogues of the R-amino acids proline
and pipecolic acid.4 This application required that 3-bu-
tyn-2-one be replaced in the double Michael reaction with
(3) Grossman, R. B. Synlett 2001, 13.
an ester of 2-oxo-3-butynoic acid (in Scheme 1, Me re-
10.1021/jo026643+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
J . Org. Chem. 2003, 68, 1409-1417 1409

Hattori and Grossman
SCHEME 2
SCHEME 3
placed with CO2R). The electron-withdrawing CO2R
group, though, was expected to render this ethynyl ke-
tone exceedingly unstable. We chose to mask the CO2R
group as a p-methoxyphenyl (p-anisyl, An) group for
three reasons: (1) p-anisyl ethynyl ketone (1) was known
and stable,5 (2) the An group was expected to be stable
to catalytic hydrogenation and to strong acid, our two
methods for azacyclization, and (3) the An group could
be converted to a CO2H group under conditions (excess
NaIO4, catalytic RuCl3‚H2O) that did not generally affect
amides, esters, nitriles, or unfunctionalized C-C and
C-H σ bonds.6,7
SCHEME 4
Resu lts a n d Discu ssion
Tethered diacid 2, prepared by a modification of our
previously published procedures,8 underwent a double
Michael reaction with alkynone 1 catalyzed by NaH in
THF to provide adduct 3a in 73% yield (Scheme 2).
Hydrogenation of 3a over Pd/C in AcOH then afforded
trans-perhydroisoquinoline 4 in 90% yield. (All stereo-
chemical assignments were made by 1H NMR; the
reasoning is enumerated in the Supporting Information.)
Hydrogenolysis of the new benzylic C-N bond was
apparently not a problem under these reaction conditions.
As expected from our previous observations, only the
equatorial CN group of 3a underwent reduction, and the
two new stereocenters in 4 were formed with complete
fidelity.9,10 Protection of 4 with 2,2,2-trichloroethyl chlo-
roformate (TrocCl) proceeded quantitatively, and oxida-
tion of the An group with excess NaIO4 and catalytic
RuCl3‚H2O afforded trans-perhydroisoquinoline-3-car-
boxylic acid 5 in 79% yield. Similar results were obtained
with the methyl carbamate of 4, but neither the tert-butyl
carbamate nor the trifluoroacetamide gave satisfactory
results in the oxidation.11 We did not try to deprotect 5,
but others have successfully deprotected N-Troc-R-amino
acids.11,12
Although we considered it a strength of our method
that two quaternary centers with rigidly disposed func-
tional groups were installed in bicyclic R-amino acids 5,
we thought that the route would be more widely ap-
plicable if methods for producing less highly substituted
analogues could be developed. Krapcho decarboxylations
of 3a and 5 did not proceed well, but the same reaction
of 4 provided 41% and 29% yields of two separable
monoesters, 6a and 6b, respectively (Scheme 3).13 Ap-
parently the CN group sterically inhibited protonation
of the enolate or enol intermediate from the thermody-
namically preferred direction, affording the more con-
gested, higher energy isomer 6a with slight selectivity,
as has been observed in other systems.14 A 1.1:1 mixture
of 6a and 6b could be converted to a 3:1 mixture in favor
of 6b with catalytic t-BuOK in t-BuOH. In addition, both
6a and 6b could be carried on to trans-perhydroisoquino-
line-3-carboxylic acids 7a and 7b stereospecifically and
in very good yields.
To prepare a bicyclic R-amino acid that lacked a
quaternary center at the ring junction, double Michael
adduct 3b (the methyl ester analogue of 3a ) was treated
with Bu3SnH to afford a mononitrile in 59% yield and as
a 5:1 mixture of diastereomers (Scheme 4).15 The major
diastereomer 8 was separated by crystallization. The
reaction of the intermediate decyanated radical with
Bu3SnH apparently occurred predominantly from the less
hindered face to give the higher energy, cis isomer of the
product. Hydrogenation of 8 gave poor yields, but treat-
ment with 80% H2SO4 in EtOH caused it to rearrange to
(4) Couty, F. Amino Acids 1999, 16, 297. Hughes, F., J r.; Grossman,
R. B. Org. Lett. 2001, 3, 2911.
(5) Irving, F.; J ohnson, A. W. J . Chem. Soc. 1948, 2037.
(6) Ayres, D. C. J . Chem. Soc., Perkin Trans. 1 1978, 585. Carlsen,
P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J . Org. Chem.
1981, 46, 3936. Tverezovsky, V. V.; Baird, M. S.; Bolesov, I. G.
Tetrahedron 1997, 53, 14773. Badorrey, R.; Cativiela, C.; Diaz-de-
Villegas, M. D.; Galvez, J . A. Tetrahedron 1999, 55, 14145. Hasegawa,
M.; Taniyama, D.; Tomioka, K. Tetrahedron 2000, 56, 10153.
(7) Mart´ın-Mart´ınez, M.; Herranz, R.; Garc´ıa-Lo´pez, M. T.; Gonza´lez-
Mun˜iz, R. Tetrahedron 1996, 52, 13991.
(8) Grossman, R. B.; Varner, M. A. J . Org. Chem. 1997, 62, 5235.
The Knoevenagel adduct of 3-pentanone and either malononitrile or
ethyl cyanoacetate was alkylated with an R,ω-dibromide in DMF
(instead of DMPU), the remaining Br was displaced with diethyl
malonate (instead of diethyl isopentylidenemalonate), and the product
was ozonolyzed and then refluxed in acidic EtOH.
(11) Walker, J . R.; Curley, R. W., J r. Tetrahedron 2001, 57, 6695.
(12) Arakawa, Y.; Yasuda, M.; Ohnishi, M.; Yoshifuji, S. Chem.
Pharm. Bull. 1997, 45, 255.
(9) Grossman, R. B.; Varner, M. A.; Skaggs, A. J . J . Org. Chem.
1999, 64, 340.
(13) Krapcho, A. P. Synthesis 1982, 805.
(10) Grossman, R. B.; Pendharkar, D. S.; Patrick, B. O. J . Org.
Chem. 1999, 64, 7178.
(14) Krapcho, A. P.; Weimaster, J . F. J . Org. Chem. 1980, 45, 4105.
(15) Curran, D. P.; Seong, C. M. Synlett 1991, 107.
1410 J . Org. Chem., Vol. 68, No. 4, 2003

Functionalized Cis- and Trans-Fused R-Amino Acids
SCHEME 5
SCHEME 6
cis-hexahydroisoquinolin-1-one 9 in 87% yield.16 An ad-
ditional 9% of the trans isomer of 9 was also obtained.
Hydrogenation of 9 over Pd/C proceeded on the convex
face to give 10 quantitatively and with complete stereo-
selectivity. The oxidation of the An group of 10 provided
none of the desired acid; instead, an imide was obtained
in only 18% yield. This result was surprising, as 5, 7a ,
and 7b were produced in excellent yield under the same
conditions. An explanation for the different behavior of
10 is offered below. However, reduction of 10 with BH3
gave amine 11 in 73% yield, and protection and oxidation
of 11 afforded cis-perhydroisoquinoline-3-carboxylic acid
12 in 74% overall yield.
We also sought to prepare bicyclic amino acids with a
cis ring fusion and an angular substituent at the ring
junction (Scheme 5). Previously prepared tethered diacid
13a and new tethered diacid 13b were each prepared in
three steps by the modified literature procedure.8,17 These
diacids underwent highly diastereoselective double Michael
reactions with 1 to provide adducts 14a (70% yield) and
14b (71% yield), as expected from our previous work.9
The H2SO4-catalyzed rearrangements of 14a and 14b
afforded cis-hexahydroisoquinolin-1-one 15a in 91% yield
and cis-tetrahydro-2-pyrindin-1-one 15b in 62% yield.
Much to our surprise, hydrogenation of 15a over Pd/C
afforded both 16a and 17a in 49% and 44% isolated
yields, respectively. The catalyst 20% Pd(OH)2/C gave
reversed but equally poor stereoselectivity, and PtO2, 5%
Rh/C, Raney Ni, and (Ph3P)3RhCl failed to catalyze the
hydrogenation at all. By contrast, hydrogenation of 15b
over Pd/C afforded only 17b in 96% isolated yield; no
resonances attributable to its diastereomer 16b were
seen in the 1H NMR spectrum of the crude reaction
mixture.
15a , and 15b can exist in two major conformations, T
and C (Scheme 6). Hydrogenation of conformers T from
the convex face is facile because approach of the catalyst
is unhindered and because the reduction places the
nascent piperidone ring in a half-chair conformation with
an equatorial An group. By contrast, hydrogenation of
conformers C from the convex face requires either that
the nascent piperidone ring assume a half-boat confor-
mation with a severe flagpole interaction or that the An
group experience a severe steric interaction with the
endo-CO2Et group, and as a result, these hydrogenations
are slow. For simple steric reasons, compound 9 resides
primarily in conformation T, as shown by the very small
coupling constant between the olefinic H atom and the
adjacent methine H atom (2.4 Hz), so its hydrogenation
is rapid and stereoselective. Compounds 15a and 15b,
on the other hand, reside primarily in conformation C,
as shown by the larger coupling constants between the
olefinic H atoms and the adjacent methine H atoms (5.9
and 6.2 Hz, respectively). However, the five-membered
ring in 15b may make this compound more conforma-
tionally mobile, and as a result the concentration of
15b-T may be sufficiently high that its hydrogenation
(from the convex face) can proceed stereoselectively and
at a reasonable rate. On the other hand, the concentra-
tion of conformer T of the more rigid 15a may be so low
that the hydrogenation of 15a -C (from the concave face
or from both faces) becomes competitive.
It remains to explain how 15a -C can be hydrogenated
from the concave face, even with the encumbrance of the
endo-CO2Et group. Perhaps the insertion of Pd-H into
the convex face of the CdC π bond of 15a -C is such a
high-energy process, and the approach of Pd-H to the
concave face is so hindered, that the mechanism of
hydrogenation switches to an ionic protonation-hydride-
transfer mechanism (Scheme 7): that is, protonation of
15a by H-Pd(II)-H gives [H-Pd(0)]- and a carbocation
stabilized by the NH and An groups, and hydride trans-
fer then provides the product and regenerates neutral
Pd(0). The hydride-transfer step may be much less
sterically demanding than an insertion, and it would
proceed with a stereoelectronic bias for axial delivery of
H-, providing the unexpected 16a as well as 17a . Others
We have great difficulty explaining why the hydroge-
nation of 15a proceeds with such poor selectivity, whereas
the hydrogenations of 9 and 15b proceed with perfect
selectivity, but our best stab at it follows. Compounds 9,
(16) Grossman, R. B.; Pendharkar, D. S.; Rasne, R. M.; Varner, M.
A. J . Org. Chem. 2000, 65, 3255.
(17) Interestingly, an attempt to prepare diethyl 3,3-dicyanopropyl-
malonate, the analogue of 2 with a two-carbon tether, gave only the
known diethyl 2,5-dicyanoadipate.8 The exchange of the positions of a
CN and a CO2Et group apparently occurred in the second alkylation
step (eq i). We mention this reaction because we believe it makes an
excellent mechanism exercise for students.
J . Org. Chem, Vol. 68, No. 4, 2003 1411

Hattori and Grossman
SCHEME 7
SCHEME 8
F IGURE 2. Hyperconjugation of the N lone pair with the
axial, benzylic C-H bonds is greater in piperidones than in
Troc-piperidines, making the benzylic C-H bonds in the
former more prone to oxidation by RuCl3‚H2O.
SCHEME 9
have noted that the polarity of the Pd-H bond in
homogeneous and heterogeneous hydrogenations depends
on the electronic bias of the alkene.18 In 15a , of course,
the alkene is very strongly polarized by the N and An
groups, so the Pdδ--Hδ+ polarization induced by the
alkene may be so pronounced, and the traditional inser-
tion so disfavored by steric factors, that the mechanism
changes from an organometallic one to an ionic one.
Experiments to test this hypothesis are being designed,
and the results will be reported in due course.
SCHEME 10
Oxidation of the An group of 16a provided cis-perhy-
droisoquinolin-1-one-3-carboxylic acid 18 in 72% yield,
with preservation of stereochemistry adjacent to the
newly introduced CO2H group (Scheme 8). By contrast,
oxidation of 17a provided an inseparable 3:1 mixture of
the desired acid and the corresponding R,â-unsaturated
acid in only 44% yield, and oxidation of 17b provided the
desired acid in only 30% yield. The common feature of
the compounds whose oxidations proceeded in poor yield
or that were overoxidized (10, 17a , and 17b) was an axial,
benzylic C-H bond in a δ-lactam. By contrast, among
the compounds whose oxidations proceeded smoothly
(16a and protected 4, 6a , 6b, and 11), the benzylic C-H
bond was equatorial in the first, and the others were not
lactams. The benzylic C-H bonds in 10, 17a , and 17b
may have been particularly prone to oxidation due to
hyperconjugation of the lone pairs of the lactam N atoms
with these axially oriented bonds (Figure 2); on the other
hand, in the protected 4, 6a , 6b, and 11, hyperconjuga-
tion with the benzylic C-H bonds would have been
reduced because of a slightly different orientation of the
N lone pair (and perhaps also because of the potent
electron-withdrawing ability of the Troc group), and in
16a it would have been nearly absent. This reasoning
led us to reduce the amide moiety of 17a (Scheme 9).
Treatment of 17a with Lawesson’s reagent gave the
thioamide 19 in 94% yield, and reductive desulfurization
of 19 by nickel boride gave amine 20 in 80% yield.7 (One-
step reduction of 17a to 20 with BH3 gave an unsatisfac-
tory yield.) Amine 20 was quantitatively protected with
a Troc group, and oxidation of the An group afforded 21
cleanly and in a much more satisfying 64% yield. The
NMR spectra of both Troc-20 and 21 showed extra
resonances due to restricted rotation.
yield, respectively (Scheme 10). Reduction of 22a with
BH3 in THF provided amino ester 23 in 54% yield along
with 11% recovered 22a . Protection of 23 and oxidation
afforded 24 in 99% and 75% yield, respectively. The NMR
spectra of 24 were complicated by the presence of two
rotamers of approximately equal populations, even at
moderately elevated temperatures.
Con clu sion
We have established that double annulation provides
a versatile and generally stereoselective, albeit not enan-
tioselective, route to cis- and trans-fused bicyclic R-amino
acids of diverse ring sizes and substitution patterns. The
dequaternization reactions described here illustrate a
general and desirable feature of these reactions: they
often provide more congested, higher energy stereoiso-
mers by delivering H to the less hindered face of a fully
substituted reactive intermediate. The poor stereoselec-
tivity of the Krapcho decarboxylation is a clear limitation,
and future work will need to address this problem.
Compounds 5, 7a , 7b, 12, 18, 21, and 24 are rigidified
analogues of pipecolic acid, but they also have a 1,6-
disposition of CO2R groups, and as a result they may also
be regarded as rigidified analogues of 2-aminoadipic acid,
the homologue of glutamic acid. The methods described
in this paper may be useful for the preparation of these
and other bicyclic R-amino acids of biological significance.
To prepare a bicyclic R-amino acid lacking quaternary
centers, perhydro-2-pyrindine 17b was subjected to
Krapcho decarboxylation to afford the two monoesters
22a and 22b (out of four possible ones) in 36% and 25%
Exp er im en ta l Section
Sta n d a r d P r oced u r e for Ad d ition of a Tr oc Gr ou p . A
suspension of a secondary amine and Na2CO3 (1.2-2.0 equiv)
in THF (2-10 mL) was treated with 2,2,2-trichloroethyl
(18) Yu, J .; Spencer, J . B. J . Am. Chem. Soc. 1997, 119, 5257. Yu,
J .; Spencer, J . B. J . Org. Chem. 1997, 62, 8618.
1412 J . Org. Chem., Vol. 68, No. 4, 2003

Functionalized Cis- and Trans-Fused R-Amino Acids
chloroformate (1.2-2.0 equiv). The reaction mixture was
allowed to stir at rt for 5 h. The reaction mixture was extracted
with ether. The combined organic layers were washed with
brine, dried over MgSO4, and evaporated.
(dm, 13.6 Hz, 1H), 2.42 (m, 1H), 2.21 (tq, J t ) 3.6 Hz, J q )
14.5 Hz, 1H), 2.16 (m, 2H), 2.07 (dm, 13.2 Hz, 1H), 1.84 (d
quintet, J d ) 14.5 Hz, J quintet ) 2.7 Hz, 1H), 1.72 (dt, J d ) 3.8
Hz, J t ) 13.4 Hz, 1H), 1.47 (dt, J d ) 4.2 Hz, J t ) 13.4 Hz, 1H),
1.29 (t, 7.1 Hz, 3H), 1.24 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 170.7, 168.2, 158.8, 154.0, 132.3, 127.0 (×2), 120.6,
113.7 (×2), 95.1, 74.7, 61.4, 61.1, 58.9, 56.0, 54.8, 50.8, 43.2,
40.2, 34.8, 32.7, 31.7, 20.3, 13.5, 13.3. IR (neat): 2232, 1728
cm-1. Anal. Calcd for C26H31Cl3N2O7: C, 52.94; H, 5.30.
Found: C, 52.64; H, 5.41.
Sta n d a r d P r oced u r e for Oxid a tion of th e An Gr ou p .
The amide or carbamate was dissolved in a mixture of EtOAc
(2 mL), CH3CN (1 mL), and H2O (8 mL), and NaIO4 (14.5
equiv) and 30% RuCl3‚H2O (3 mol %) were added. The reaction
mixture was allowed to stir vigorously at rt for 4 h. The
reaction mixture was extracted with EtOAc. Magnesium
sulfate was added to the combined organic layers until the
dark color of Ru disappeared. The resulting mixture was
filtered and evaporated. The residue was dissolved in EtOAc
and extracted with diluted NaHCO3 solution. The aqueous
layer was carefully acidified with 1 N HCl and then extracted
with EtOAc. The combined organic layers were dried over
MgSO4 and evaporated.
(1R*,6R,9R)-8-(2,2,2-Tr ich lor oeth oxycar bon yl)-6-cyan o-
8-a za bicyclo[4.4.0]d eca n e-2,2,9-tr ica r boxylic Acid , 2,2-
Dieth yl Ester (5). The previous compound (540 mg, 0.92
mmol) was subjected to the standard procedure for oxidation
of the An group, except 4 times as much solvent and twice as
much reagent were used. The residue was crystallized from
ether to give 5 (383 mg, 0.73 mmol, 79% yield) as a white solid,
mp 175 °C. 1H NMR (400 MHz, CDCl3, 60 °C): δ 9.90 (br, 1H),
4.88 (d, 12.0 Hz, 1H), 4.65 (d, 12.0 Hz, 1H), 4.25 (m, 5H), 4.10
(d, 14.3 Hz, 1H), 3.54 (br, 1H), 2.59 (dm, 12.8 Hz, 1H), 2.44
(dd, 5.0 Hz, 13.5 Hz, 1H), 2.26 (m, 2H), 2.15 (dd, 1.8 Hz, 12.1
Hz, 1H), 2.05 (dm, 14.1 Hz, 1H), 1.82 (dm, 15.0 Hz, 1H), 1.53
Dieth yl 3,3-Dicya n o-2-[2-(4-m eth oxyp h en yl)-2-oxoeth -
yl]-1,1-cycloh exa n ed ica r boxyla te (3a ). A solution of 2 (1.65
g, 6.20 mmol)8 in THF (10 mL) was added to a stirring solution
of 60% NaH (50 mg, 1.24 mmol) in THF (20 mL) under N2.
The flask was cooled to -78 °C. A solution of p-anisyl ethynyl
ketone5 (1.05 g, 6.50 mmol) in THF (10 mL) was added slowly
to the reaction mixture. The reaction mixture was allowed to
stir at rt for 4 h. The reaction was quenched with saturated
NH4Cl solution and diluted with ether. The resulting mixture
was extracted with ether, washed with water and brine, dried
over MgSO4, and evaporated to give the crude product. Flash
chromatography (15% EtOAc in petroleum ether) gave 3a (1.93
(dt, J d ) 3.8 Hz, J t ) 13.6 Hz, 1H), 1.44 (dt, J d ) 4.0 Hz, J t
)
13.4 Hz, 1H), 1.32 (t, 7.1 Hz, 3H), 1.25 (t, 7.1 Hz, 3H). 13C{H}
NMR (100 MHz, CDCl3, 60 °C): δ 174.3, 171.0, 168.2, 154.0,
119.9, 95.0, 75.7, 62.1, 61.8, 58.5, 56.4, 52.8, 43.9, 39.7, 34.8,
33.4, 27.9, 20.2, 13.9, 13.8. IR (KBr): 3437, 2225, 1728 cm-1
.
Anal. Calcd for C20H25Cl3N2O8: C, 45.51; H, 4.77. Found: C,
45.86; H, 4.74.
1
g, 4.52 mmol, 73% yield) as a white solid, mp 84 °C. H NMR
Eth yl (1R*,2S,6R,9R)- a n d (1R*,2R,6R,9R)-6-Cya n o-9-
(4-m eth oxyp h en yl)-8-a za bicyclo[4.4.0]d eca n e-2-ca r boxy-
la te (6a a n d 6b). A solution of 4 (414 mg, 1.00 mmol), lithium
chloride (64 mg, 1.50 µmol), and water (27 µL, 1.50 mmol) in
DMF (10 mL) was refluxed for 48 h. The reaction mixture was
cooled and poured into ice-water. The resulting mixture was
extracted with EtOAc, washed with water and brine, dried over
MgSO4, and evaporated to give the crude product. Flash
chromatography (15-50% EtOAc in petroleum ether) gave 6a
(140 mg, 0.41 mmol, 41% yield) as a white solid, mp 102 °C,
and 6b (100 mg, 0.29 mmol, 29% yield) as a white solid, mp
(400 MHz, CDCl3): δ 7.99 (d, 8.9 Hz, 2H), 6.96 (d, 8.9 Hz, 2H),
4.33 (∼q, 7.2 Hz, 2H), 4.10 (m, 2H), 3.88 (s, 3H), 3.82 (dd, 2.6
Hz, 6.4 Hz, 1H), 3.78 (dd, 2.6 Hz, 19.0 Hz, 1H), 3.44 (dd, 6.4
Hz, 19.0 Hz, 1H), 2.59 (dm, 13.3 Hz, 1H), 2.51 (dm, 13.2 Hz,
1H), 2.20 (dt, J d ) 4.1 Hz, J t ) 13.2 Hz, 1H), 2.04 (m, 1H),
1.94 (m, 1H), 1.77 (dt, J d ) 3.8 Hz, J t ) 13.3 Hz, 1H), 1.39 (t,
7.2 Hz, 3H), 1.14 (t, 7.2 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 193.2, 169.6, 168.3, 163.7, 130.4 (×2), 129.0, 115.1,
114.2, 113.8 (×2), 62.4, 62.2, 56.7, 55.5, 39.7 (×2), 37.7, 35.6,
31.8, 19.0, 13.8, 13.7. IR (KBr): 2246, 1731, 1683 cm-1. Anal.
Calcd for C23H26N2O6: C, 64.78; H, 6.15. Found: C, 64.76; H,
6.50.
Dieth yl (1R*,6R,9R)-6-Cya n o-9-(4-m eth oxyp h en yl)-8-
a za bicyclo[4.4.0]d eca n e-2,2-d ica r boxyla te (4). Compound
3a (1.88 g, 4.41 mmol) was dissolved in acetic acid (15 mL),
and 5% Pd/C (94 mg, 5 wt %) was added. The mixture was
hydrogenated in a Parr shaker at 56 psi for 55 h. The reaction
mixture was filtered through a Celite pad, and the filtrate was
concentrated. The crude product was purified by flash chro-
matography (15-30% EtOAc in petroleum ether) to give 4
(1.39 g, 3.35 mmol, 76% yield) as a white solid, mp 106 °C. 1H
NMR (400 MHz, CDCl3): δ 7.32 (d, 8.6 Hz, 2H), 6.86 (d, 8.6
Hz, 2H), 4.29 (m, 2H), 4.16 (m, 2H), 3.79 (s, 3H), 3.66 (dd, 2.3
Hz, 10.9 Hz, 1H), 3.34 (d, 12.3 Hz, 1H), 2.76 (d, 12.3 Hz, 1H),
2.54 (dm, 13.2 Hz, 1H), 2.27 (m, 2H), 2.15 (m, 1H), 1.98 (m,
2H), 1.79 (m, 2H), 1.47 (dt, J d ) 3.8 Hz, J t ) 13.3 Hz, 1H),
1.36 (dt, J d ) 3.8 Hz, J t ) 13.5 Hz, 1H), 1.31 (t, 7.0 Hz, 3H),
1.20 (t, 7.0 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 171.0,
168.5, 158.6, 135.6, 127.4 (×2), 120.9, 113.4 (×2), 61.1 (×2),
60.8, 57.5, 56.0, 54.7, 46.1, 39.0, 35.1, 33.3, 32.9, 19.1, 13.4,
13.3. IR (KBr): 3335, 2233, 1723 cm-1. Anal. Calcd for
1
67 °C. The following are data for compound 6a . H NMR (400
MHz, CDCl3): δ 7.32 (d, 8.5 Hz, 2H), 6.87 (d, 8.5 Hz, 2H), 4.26
(dq, J d ) 10.7 Hz, J q ) 7.1 Hz, 1H), 4.17 (dq, J d ) 10.7 Hz, J q
) 7.1 Hz, 1H), 3.80 (s, 3H), 3.63 (dd, 2.6 Hz, 11.1 Hz, 1H),
3.32 (d, 12.5 Hz, 1H), 2.68 (d, 12.5 Hz, 1H), 2.64 (dt, J d ) 1.3
Hz, J t ) 3.5 Hz, 1H), 2.29 (m, 2H), 2.18 (ddd, 11.2 Hz, 12.6
Hz, 13.8 Hz, 1H), 2.00 (dm, J d ) 13.6, 1H), 1.90 (dt, J d ) 13.9
Hz, J t ) 2.7 Hz, 1H), 1.82 (ddd, 3.0 Hz, 5.3 Hz, 12.6 Hz, 1H),
1.72 (m, 2H), 1.44 (tt, J t ) 4.6 Hz, 13.9 Hz, 1H), 1.30 (m, 1H),
1.29 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 172.2,
158.9, 135.7, 127.7 (×2), 121.7, 113.8 (×2), 61.5, 60.5, 57.9,
55.2, 45.0, 42.4, 39.9, 37.3, 33.6, 27.7, 19.3, 14.1. IR (KBr):
3332, 2227, 1714 cm-1. Anal. Calcd for C20H26N2O3: C, 70.15;
H, 7.65. Found: C, 70.24; H, 7.92. The following are data for
1
compound 6b. H NMR (400 MHz, CDCl3): δ 7.31 (d, 8.8 Hz,
2H), 6.85 (d, 8.8 Hz, 2H), 4.11 (dq, J d ) 10.8 Hz, J q ) 7.1 Hz,
1H), 4.07 (dq, J d ) 10.8 Hz, J q ) 7.1 Hz, 1H), 3.79 (s, 3H),
3.68 (dd, 2.9 Hz, 11.0 Hz, 1H), 3.32 (d, 12.1 Hz, 1H), 2.74 (d,
12.1 Hz, 1H), 2.51 (dt, J d ) 3.7 Hz, J t ) 11.7 Hz, 1H), 2.03 (m,
1H), 1.86 (m, 4H), 1.72 (dt, J d ) 13.2 Hz, J t ) 2.9 Hz, 1H),
1.58 (m, 2H), 1.54 (m, 1H), 1.38 (m, 1H), 1.21 (t, 7.1 Hz, 3H).
13C{H} NMR (50 MHz, CDCl3): δ 174.4, 158.9, 135.6, 127.8
(×2), 121.6, 113.8 (×2), 60.7, 60.5, 55.7, 55.2, 46.1, 44.9, 42.0,
C
23H30N2O5: C, 66.65; H, 7.30. Found: C, 66.88; H, 7.70.
Dieth yl (1R*,6R,9R)-8-(2,2,2-Tr ich lor oeth oxycar bon yl)-
36.0, 32.5, 29.5, 21.8, 14.1. IR (KBr): 3341, 2234, 1732 cm-1
.
6-cya n o-9-(4-m eth oxyp h en yl)- 8-a za bicyclo[4.4.0]d eca n e-
2,2-d ica r boxyla te. Compound 4 (1.41 g, 3.40 mmol) was
subjected to the standard procedure for addition of a Troc
group. Flash chromatography (15% EtOAc in petroleum ether)
gave the title compound (2.00 g, 3.39 mmol, 100% yield) as a
Eth yl (1R*,2S,6R,9R)-8-(2,2,2-Tr ich lor oeth oxycar bon yl)-
6-cya n o-9-(4-m eth oxyp h en yl)-8-a za bicyclo[4.4.0]d eca n e-
2-ca r boxyla te. Compound 6a (467 mg, 1.36 mmol) was sub-
jected to the standard procedure for addition of a Troc group.
Flash chromatography (15% EtOAc in petroleum ether) gave
the protected amine (618 mg, 1.19 mmol, 88% yield) as a
colorless gum. 1H NMR (400 MHz, CDCl3, 60 °C): δ 7.26 (d,
8.8 Hz, 2H), 6.87 (d, 8.8 Hz, 2H), 4.95 (dd, 8.1 Hz, 9.9 Hz, 1H),
1
colorless gum. H NMR (400 MHz, CDCl3, 60 °C): δ 7.25 (d,
8.8 Hz, 2H), 6.86 (d, 8.8 Hz, 2H), 5.03 (t, 9.0 Hz, 1H), 4.75 (d,
11.9 Hz, 1H), 4.68 (d, 11.9 Hz, 1H), 4.27 (m, 2H), 4.20 (m, 2H),
4.02 (d, 14.5 Hz, 1H), 3.85 (d, 14.5 Hz, 1H), 3.79 (s, 3H), 2.58
J . Org. Chem, Vol. 68, No. 4, 2003 1413

Hattori and Grossman
4.76 (d, 12.0 Hz, 1H), 4.64 (d, 12.0 Hz, 1H), 4.23 (dq, J d ) 10.1
Hz, J q ) 7.1 Hz, 1H), 4.17 (dq, J d ) 10.1 Hz, J q ) 7.1 Hz, 1H),
3.89 (d, 14.3 Hz, 1H), 3.83 (d, 14.3 Hz, 1H), 3.79 (s, 3H), 2.77
of 10% Pd/C (12 mg, 10 wt %) and 9 (118 mg, 0.32 mmol) in
MeOH (2 mL) was allowed to stir at rt under H2 (balloon) for
20 h. The reaction mixture was filtered through Celite, and
the solvent was evaporated to give 10 (122 mg, 0.32 mmol,
(tm, J t ) 3.9 Hz, 1H), 2.37 (m, 3H), 2.17 (tq, J t ) 3.7 Hz, J q
)
1
14.1 Hz, 1H), 2.09 (dm, J t ) 13.2 Hz, 1H), 1.76 (m, 2H), 1.63
(dt, J d ) 3.7 Hz, J t ) 13.4 Hz, 1H), 1.45 (tt, J t ) 4.6 Hz, 13.6
Hz, 1H), 1.28 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3):
δ 171.2, 158.5, 153.7, 132.4, 126.9 (‚2), 120.6, 113.5 (‚2), 95.0,
74.5, 60.0, 58.7, 54.6, 51.4, 41.7, 41.2, 39.9, 34.7, 33.3, 26.7,
100% yield) as a white solid, mp 214 °C. H NMR (400 MHz,
CDCl3): δ 7.20 (d, 8.7 Hz, 2H), 6.89 (d, 8.7 Hz, 2H), 5.63 (br,
1H), 4.45 (dd, 4.4 Hz, 11.4 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H),
3.71 (s, 3H), 3.04 (dm, 12.8 Hz, 1H), 2.95 (dt, J d ) 13.2 Hz, J t
) 4.7 Hz, 1H), 2.24 (dm, 14.5 Hz, 1H), 2.10 (dm, 12.3 Hz, 1H),
1.82 (m, 3H), 1.58 (dq, J d ) 3.8 Hz, J q ) 13.6 Hz, 1H), 1.41
(dm, 13.4 Hz, 1H), 1.21 (tq, J t ) 3.7 Hz, J q ) 13.6 Hz, 1H).
13C{H} NMR (100 MHz, CDCl3): δ 174.5, 170.7, 170.6, 159.5,
133.8, 127.3 (×2), 114.2 (×2), 57.8, 56.8, 55.3, 52.9, 52.7, 34.0,
35.6, 30.4, 25.9, 25.7, 21.9. IR (KBr): 3424, 3185, 1741, 1725,
1666 cm-1. Anal. Calcd for C20H25NO6: C, 63.99; H, 6.71.
Found: C, 64.53; H, 6.82.
Dim eth yl (1R*,6S,9R)-9-(4-Meth oxyp h en yl)-8-a za bicy-
clo[4.4.0]d eca n e-2,2-d ica r boxyla te (11). A solution of bo-
rane in THF (1 M, 2.1 mL) was added to a suspension of 10
(241 mg, 0.64 mmol) in THF (1 mL) at 0 °C under N2. The
mixture was allowed to stir at rt for 18 h. The solution was
cooled in ice-water, and the reaction was quenched by 6 M
HCl (1 mL). After the mixture was stirred for 2 h at 0 °C,
1 N NaOH was added until the pH was 10. The mixture
was extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and evaporated to give the crude product.
Flash chromatography (2% MeOH in CH2Cl2) gave 11 (169
mg, 0.47 mmol, 73% yield) as a colorless oil. 1H NMR (400
MHz, CDCl3): δ 7.28 (d, 8.8 Hz, 2H), 6.84 (d, 8.8 Hz, 2H),
3.79 (s, 3H), 3.74 (s, 3H), 3.64 (s, 3H), 3.60 (dd, 2.4 Hz, 11.2
Hz, 1H), 3.07 (dd, 3.1 Hz, 11.9 Hz, 1H), 2.97 (dd, 1.8 Hz, 11.9
Hz, 1H), 2.71 (dt, J d ) 13.0 Hz, J t ) 3.9 Hz, 1H), 2.18 (dm,
14.1 Hz, 1H), 2.04 (dm, 12.8 Hz, 1H), 1.95 (m, 2H), 1.79 (dt,
J d ) 13.9 Hz, J t ) 3.0 Hz, 1H), 1.65 (dt, J d ) 11.4 Hz,
J t ) 12.8 Hz, 1H), 1.56 (br, 1H), 1.38 (m, 1H), 1.15 (m, 2H).
13C{H} NMR (50 MHz, CDCl3): δ 171.6, 171.2, 158.8, 136.9,
127.8 (×2), 113.7 (×2), 61.6, 59.1, 55.3, 52.5, 52.5, 52.4, 39.1,
32.6, 31.7, 26.0, 24.3, 22.7. IR (neat): 3335, 1733 cm-1. Anal.
Calcd for C20H27NO5: C, 66.46; H, 7.53. Found: C, 66.71; H,
7.64.
Dim eth yl (1R*,6S,9R)-8-(2,2,2-Tr ich lor oeth oxyca r bo-
n yl)-9-(4-m eth oxyp h en yl)-8-a za bicyclo[4.4.0]d eca n e-2,2-
d ica r boxyla te. Compound 11 (160 mg, 0.44 mmol) was
subjected to the standard procedure for addition of a Troc
group. Flash chromatography (12% EtOAc in petroleum ether)
gave the protected amine (232 mg, 0.43 mmol, 98% yield) as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.17 (d, 8.7 Hz,
2H), 6.84 (d, 8.7 Hz, 2H), 4.98 (dd, 7.1 Hz, 11.2 Hz, 1H), 4.78
(d, 12.1 Hz, 1H), 4.70 (d, 12.1 Hz, 1H), 4.28 (dd, 7.3 Hz, 14.0
Hz, 1H), 3.78 (s, 3H), 3.73 (s, 6H), 2.85 (dd, 7.9 Hz, 14.0 Hz,
1H), 2.64 (m, 2H), 2.21 (dm, 15.0 Hz, 1H), 1.69 (m, 4H), 1.48
(tq, J t ) 1.7 Hz, J q ) 6.4 Hz, 1H), 1.10 (m, 2H). 13C{H} NMR
(50 MHz, CDCl3): δ 171.4, 171.2, 158.9, 154.4, 133.7, 126.9
(×2), 113.9 (×2), 95.7, 75.0, 58.3, 58.2, 55.2, 52.6, 52.5, 47.1,
35.1, 31.1, 28.4, 26.7, 26.5, 20.7. IR (neat): 1733 cm-1. Anal.
Calcd for C23H28Cl3NO7: C, 51.46; H, 5.26. Found: C, 51.27;
H, 5.38.
19.5, 13.4. IR (neat): 2232, 1724 cm-1. Anal. Calcd for C23H27
Cl3N2O5: C, 53.35; H, 5.26. Found: C, 53.09; H, 5.53.
-
(1R*,2S,6R,9R)-8-(2,2,2-Tr ich lor oeth oxyca r bon yl)-6-cy-
an o-8-azabicyclo[4.4.0]decan e-2,9-dicar boxylic Acid,2-Eth -
yl Ester (7a ). The previous compound (374 mg, 0.72 mmol)
was subjected to the standard procedure for oxidation of the
An group. The residue was crystallized from ether to give 7a
(285 mg, 0.62 mmol, 87% yield) as a white solid, mp 180 °C.
1H NMR (400 MHz, CDCl3, 60 °C): δ 6.00 (br, 1H), 4.90 (d,
12.2 Hz, 1H), 4.64 (d, 12.2 Hz, 1H), 4.22 (m, 3H), 4.14 (d, 13.6
Hz, 1H), 3.36 (d, 13.6 Hz, 1H), 2.74 (m, 1H), 2.45 (dt, J d
)
13.4 Hz, J t ) 12.6 Hz, 1H), 2.33 (m, 2H), 2.20 (m, 1H), 2.07
(dm, J t ) 13.2 Hz, 1H), 1.75 (m, 2H), 1.43 (m, 2H), 1.31 (t, 7.1
Hz, 3H). 13C{H} NMR (100 MHz, CDCl3, 60 °C): δ 173.1, 171.3,
154.2, 120.1, 95.0, 75.8, 61.1, 58.4, 53.4, 42.6, 42.0, 39.6, 35.2,
29.8, 27.6, 19.7, 14.0. IR (KBr): 3430, 2234, 1722 cm-1. Anal.
Calcd for C17H21Cl3N2O6: C, 44.80; H, 4.64. Found: C, 44.82;
H, 4.73.
Dim eth yl (2R*,3R)-3-Cya n o-2-[2-(4-m eth oxyp h en yl)-2-
oxoeth yl]-1,1-cycloh exa n ed ica r boxyla te (8). Tributyltin
hydride (269 µL, 1.00 mmol) was added to a solution of 3b
(398 mg, 1.00 mmol) and AIBN (16 mg, 0.10 mmol) in benzene
(10 mL, 0.1 M). The mixture was refluxed for 1.5 h, and then
additional tributyltin hydride (269 mL, 1.00 mmol) and AIBN
(16 mg, 0.10 mmol) were added. After 5 h, the mixture was
cooled to rt, and DBU (359 µL, 2.40 mmol) was added. The
mixture was diluted with wet ether, filtered through a short
column of silica gel with ether, and concentrated. The crude
product was purified by flash chromatography (20% EtOAc in
petroleum ether) to give a 5:1 mixture of diastereomers (220
mg, 0.59 mmol, 59% yield). Crystallization from ether gave 8
1
as a white solid, mp 114 °C. H NMR (400 MHz, C6D6, 60 °C):
δ 7.98 (d, 9.0 Hz, 2H), 6.63 (d, 9.0 Hz, 2H), 3.59 (s, 3H), 3.52
(m, 2H), 3.46 (m, 1H), 3.26 (s, 3H), 3.25 (s, 3H), 3.13 (q, 4.4
Hz, 1H), 2.32 (dt, J d ) 4.4 Hz, J t ) 13.0 Hz, 1H), 1.90 (m, 1H),
1.48 (m, 2H), 1.20 (m, 2H). 13C{H} NMR (50 MHz, CDCl3): δ
195.7, 171.4, 170.0, 163.7, 130.3 (×2), 129.5, 120.3, 113.7 (×2),
56.5, 55.4, 52.9, 52.6, 38.5, 36.0, 31.3, 30.1, 27.3, 19.8. IR
(KBr): 2240, 1730, 1685 cm-1. Anal. Calcd for C20H23NO6: C,
64.33; H, 6.21. Found: C, 64.13; H, 6.17.
Dim eth yl (1R*,6S)-9-(4-Meth oxyp h en yl)-8-a za bicyclo-
[4.4.0]d ec-9-en -7-on e-2,2-d ica r boxyla te (9). Concentrated
sulfuric acid (4 mL) was slowly added to a solution of 8 (189
mg, 0.51 mmol) in absolute EtOH (1 mL) with constant stirring
at 0 °C. The reaction mixture was then allowed to warm to rt.
After 17 h, the mixture was neutralized with saturated
NaHCO3 solution and extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and evaporated to give
the crude product. Flash chromatography (30% EtOAc in
petroleum ether) gave 9 (165 mg, 0.44 mmol, 87% yield) as a
white solid, mp 183 °C. 1H NMR (400 MHz, CDCl3): δ 7.30
(d, 9.0 Hz, 2H), 7.18 (br, 1H), 6.90 (d, 9.0 Hz, 2H), 4.80 (dt, J d
) 2.4 Hz, J t ) 1.6 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 6H), 3.69 (d,
4.9 Hz, 1H), 2.96 (dt, J d ) 12.6 Hz, J t ) 4.6 Hz, 1H), 2.25 (dm,
14.1 Hz, 1H), 1.90 (dt, J d ) 3.5 Hz, J t ) 13.7 Hz, 1H), 1.74 (m,
(1R *,6S ,9R )-8-(2,2,2-T r ic h lo r o e t h o x y c a r b o n y l)-8-
a za b icyclo[4.4.0]d eca n e-2,2,9-t r ica r b oxylic Acid , 2,2-
Dim eth yl Ester (12). The previous compound (230 mg, 0.43
mmol) was subjected to the standard procedure for oxidation
of the An group. The residue was crystallized from ether to
give 12 (153 mg, 0.32 mmol, 75% yield) as a white solid, mp
135 °C. 1H NMR (400 MHz, CDCl3, 60 °C): δ 6.50 (br, 1H),
4.78 (d, 11.9 Hz, 1H), 4.70 (d, 11.9 Hz, 1H), 4.24 (br, 1H),
3.82 (br, 1H), 3.73 (s, 6H), 3.30 (br, 1H), 2.60 (dm, 13.4 Hz,
1H), 2.41 (m, 1H), 2.21 (dm, 13.6 Hz, 1H), 1.79 (m, 3H),
1.54 (m, 2H), 1.29 (m, 1H), 1.10 (tq, J t ) 3.5 Hz, J q ) 13.6
Hz, 1H). 13C{H} NMR (100 MHz, CDCl3, 60 °C): δ 175.4,
171.2, 171.1, 154.9, 95.5, 75.8, 58.7, 57.8, 52.9, 48.7, 35.8,
2H), 1.56 (dq, J d ) 4.6 Hz, J q ) 13.5 Hz, 1H), 1.20 (tq, J t
)
3.5 Hz, J q ) 13.5 Hz, 1H). 13C{H} NMR (50 MHz, CDCl3): δ
173.9, 171.0, 170.4, 160.3, 136.9, 127.1, 126.3 (×2), 114.3 (×2),
99.6, 56.9, 55.4, 52.8 (×2), 40.3, 36.6, 27.1, 23.2, 20.9. IR
(KBr): 3210, 1733, 1668 cm-1. Anal. Calcd for C20H23NO6: C,
64.33; H, 6.21. Found: C, 64.32; H, 6.46.
Dim eth yl (1R*,6S,9R)-9-(4-Meth oxyp h en yl)-8-a za bicy-
clo[4.4.0]d eca n -7-on e-2,2-d ica r boxyla te (10). A suspension
31.8, 29.9, 26.5, 25.8, 24.2, 21.7. IR (KBr): 3278, 1733 cm-1
17H22Cl3NO8.
.
C
1414 J . Org. Chem., Vol. 68, No. 4, 2003

Functionalized Cis- and Trans-Fused R-Amino Acids
Tr ieth yl (2R*,3S)-3-Cya n o-2-[2-(4-m eth oxyp h en yl)-2-
oxoeth yl]-1,1,3-cycloh exa n etr ica r boxyla te (14a ). Cyano
triester 13a 8 (5.50 g, 17.52 mmol) was added to a stirring
solution of potassium tert-butoxide (393 mg, 3.50 mmol) in
CH2Cl2 (30 mL) under N2. The flask was cooled to -78 °C. A
solution of p-anisyl ethynyl ketone5 (3.36 g, 21.02 mmol) in
THF (15 mL) was added slowly to the reaction mixture. The
reaction mixture was allowed to stir at rt for 22 h. The reaction
was quenched with saturated aq NH4Cl and diluted with ether.
The resulting mixture was extracted with ether, washed with
water and brine, dried over MgSO4, and evaporated to give
the crude product. Flash chromatography (10-12% EtOAc in
petroleum ether) gave 14a (5.78 g, 12.20 mmol, 70% yield) as
a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 9.0
Hz, 2H), 6.94 (d, 9.0 Hz, 2H), 4.36 (q, 7.1 Hz, 2H), 4.11 (m,
2H), 4.00 (dq, J d ) 10.7 Hz, J q ) 7.1 Hz, 1H), 3.87 (s, 3H),
3.79 (dq, J d ) 10.7 Hz, J q ) 7.1 Hz, 1H), 3.65 (dd, 7.7 Hz, 6.4
Hz, 1H), 3.63 (d, 1.8 Hz, 1H), 3.47 (d, 17.4 Hz, 1H), 2.60 (dm,
13.4 Hz, 1H), 2.27 (dt, J d ) 13.9 Hz, J t ) 4.0 Hz, 1H), 2.10 (m,
2H), 1.88 (dt, J d ) 14.5 Hz, J t ) 3.3 Hz, 1H), 1.73 (dt, J d ) 3.8
Hz, J t ) 13.4 Hz, 1H), 1.42 (t, 7.1 Hz, 3H), 1.14 (t, 7.1 Hz,
3H), 1.00 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ
194.0, 170.4, 168.6, 167.1, 163.3, 129.9 (×2), 129.0, 117.6, 113.5
(×2), 62.9, 61.7, 61.4, 57.3, 55.1, 49.2, 39.5, 39.1, 33.0, 32.4,
18.8, 13.6, 13.5, 13.0. IR (neat): 2255, 1730, 1601 cm-1. Anal.
Calcd for C25H31NO8: C, 63.41; H, 6.60. Found: C, 63.20; H,
6.92.
CDCl3): δ 7.19 (d, 8.7 Hz, 2H), 6.89 (d, 8.7 Hz, 2H), 5.76 (br,
1H), 4.58 (dd, 3.7 Hz, 11.4 Hz, 1H), 4.33 (dq, J d ) 10.8 Hz, J q
) 7.1 Hz, 1H), 4.16 (m, 5H), 3.81 (s, 3H), 3.58 (dm, 13.4 Hz,
1H), 2.54 (dm, 12.8 Hz, 1H), 2.30 (dm, 7.7 Hz, 1H), 1.79 (m,
4H), 1.61 (m, 2H), 1.34 (t, 7.1 Hz, 3H), 1.22 (t, 7.1 Hz, 3H),
1.22 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 172.4,
172.1, 170.2, 169.6, 159.9, 133.4, 127.4 (×2), 114.6 (×2), 61.7,
61.6, 61.4, 58.4, 56.3, 55.3, 53.4, 38.6, 32.8, 28.4, 25.7, 19.3,
14.0, 13.8 (×2). IR (KBr): 3448, 3183, 1740, 1728, 1657 cm-1
.
Anal. Calcd for C25H33NO8: C, 63.14; H, 6.99. Found: C, 62.80;
H, 7.26.
Tr ieth yl (1R*,4S,6S)-4-(4-Meth oxyph en yl)-3-azabicyclo-
[4.3.0]n on a n -2-on e-1,7,7-tr ica r boxyla te (17b). A suspen-
sion of 10% Pd/C (230 mg, 10 wt %) and 15b (2.30 g, 5.01
mmol) in MeOH (40 mL) was allowed to stir at rt under 1 atm
of H2 for 23 h. The reaction mixture was filtered through
Celite, and the solvent was evaporated to give 17b (2.22 g,
1
4.80 mmol, 96% yield) as a white solid, mp 121 °C. H NMR
(400 MHz, CDCl3): δ 7.21 (d, 8.8 Hz, 2H), 6.90 (d, 8.8 Hz, 2H),
5.88 (br, 1H), 4.57 (dd, 2.1 Hz, 11.5 Hz, 1H), 4.21 (m, 5H), 4.04
(dq, J d ) 10.8 Hz, J q ) 7.1 Hz, 1H), 3.81 (s, 3H), 3.74 (dd, 5.3
Hz, 13.2 Hz, 1H), 2.66 (ddd, 3.1 Hz, 7.7 Hz, 10.3 Hz, 1H), 2.54
(ddd, 3.1 Hz, 8.6 Hz, 10.3 Hz, 1H), 2.32 (m, 2H), 1.88 (ddd, 2.1
Hz, 5.3 Hz, 13.2 Hz, 1H), 1.51 (dt, J d ) 11.5 Hz, J t ) 13.2 Hz,
1H), 1.33 (t, 7.1 Hz, 3H), 1.24 (t, 7.1 Hz, 3H), 1.18 (t, 7.1 Hz,
3H). 13C{H} NMR (50 MHz, CDCl3): δ 171.2, 171.0, 170.8,
169.3, 159.8, 132.7, 127.6 (×2), 114.5 (×2), 64.6, 62.1, 61.8,
61.6, 60.6, 55.7, 55.3, 46.9, 34.6, 31.4, 30.9, 14.0 (×2), 13.9. IR
(neat): 3185, 1734, 1664 cm-1. Anal. Calcd for C24H31NO8: C,
62.46; H, 6.77. Found: C, 62.41; H, 6.93.
(1R*,6S,9S)-8-Aza bicyclo[4.4.0]d eca n -7-on e-2,2,6,9-tet-
r a ca r boxylic Acid , 2,2,6-Tr ieth yl Ester (18). A solution of
16a (85 mg, 0.18 mmol) was subjected to the standard
procedure for oxidation of the An group. The residue was
crystallized from ether to give 18 (55 mg, 0.13 mmol, 72% yield)
as a white solid, mp 228 °C. 1H NMR (400 MHz, CDCl3): δ
9.07 (br, 1H), 4.33 (dq, J d ) 10.6 Hz, J q ) 7.1 Hz, 1H), 4.14
(m, 6H), 3.31 (dm, 12.8 Hz, 1H), 2.38 (dm, 14.1 Hz, 1H), 2.27
(dm, 13.9 Hz, 1H), 2.12 (dt, J d ) 6.1 Hz, J t ) 14.1 Hz, 1H),
1.96 (dm, 13.2 Hz, 1H), 1.85 (m, 1H), 1.73 (m, 2H), 1.54 (m,
1H), 1.34 (t, 7.1 Hz, 3H), 1.21 (t, 7.1 Hz, 3H), 1.20 (t, 7.1 Hz,
3H) (CO2H too broad to be seen). 13C{H} NMR (50 MHz,
CDCl3): δ 175.3, 174.6, 171.4, 169.9, 169.7, 62.2, 61.7, 61.6,
58.0, 53.3, 52.8, 35.1, 27.9, 25.7, 24.1, 19.1, 13.8, 13.7, 13.7.
IR (KBr): 3283, 1734, 1635 cm-1. Anal. Calcd for C19H27NO9:
C, 55.20; H, 6.58. Found: C, 55.23; H, 6.57.
Tr ieth yl (1R*,6S)-9-(4-Meth oxyp h en yl)-8-a za bicyclo-
[4.4.0]d ec-9-en -7-on e-2,2,6-tr ica r boxyla te (15a ). Concen-
trated H2SO4 (4 mL) was slowly added to a stirred solution of
14a (683 mg, 1.44 mmol) in absolute EtOH (1 mL) at 0 °C.
The reaction mixture was then allowed to warm to rt. After
17 h, the mixture was neutralized with saturated aq NaHCO3
and extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and evaporated to give the crude product.
Flash chromatography (25% EtOAc in petroleum ether) gave
15a (619 mg, 1.31 mmol, 91% yield) as a white solid, mp 112
1
°C. H NMR (400 MHz, CDCl3): δ 7.31 (d, 8.8 Hz, 2H), 7.09
(br, 1H), 6.88 (d, 8.8 Hz, 2H), 5.45 (dd, 5.9 Hz, 1.5 Hz, 1H),
4.23 (m, 3H), 4.12 (m, 2H), 3.96 (dq, J d ) 10.8 Hz, J q ) 7.1
Hz, 1H), 3.81 (s, 3H), 3.74 (d, 5.9 Hz, 1H), 2.52 (m, 1H), 2.32
(m, 1H), 2.18 (m, 1H), 1.68 (m, 3H), 1.27 (t, 7.1 Hz, 3H), 1.20
(t, 7.1 Hz, 3H), 1.14 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 172.2, 171.0, 170.2, 170.0, 160.2, 137.2, 127.2, 126.5
(×2), 114.0 (×2), 102.0, 61.5, 61.2, 61.2, 56.4, 55.1, 53.0, 39.1,
31.1, 28.0, 18.3, 13.8 (×2), 13.6. IR (KBr): 3220, 1726, 1686
cm-1. Anal. Calcd for C25H31NO8: C, 63.41; H, 6.60. Found:
C, 63.40; H, 6.77.
Tr ieth yl (1R*,6S,9S)-9-(4-Meth oxyph en yl)-8-azabicyclo-
[4.4.0]d eca n e-7-th ion e-2,2,6-tr ica r boxyla te (19). A solution
of 17a (638 mg, 1.34 mmol) and Lawesson’s reagent (434 mg,
1.07 mmol) in toluene (15 mL) was allowed to reflux for 48 h.
The solvent was evaporated. Flash chromatography (10-25%
EtOAc in petroleum ether) gave 19 (622 mg, 1.27 mmol, 94%
yield) as a white solid, mp 199 °C. 1H NMR (400 MHz,
CDCl3): δ 8.09 (br, 1H), 7.18 (d, 8.7 Hz, 2H), 6.91 (d, 8.7 Hz,
2H), 4.57 (dd, 3.9 Hz, 11.5 Hz, 1H), 4.33 (dq, J d ) 10.8 Hz, J q
) 7.1 Hz, 1H), 4.16 (m, 5H), 3.82 (s, 3H), 3.61 (dm, 11.2 Hz,
1H), 2.88 (dm, 13.9 Hz, 1H), 2.52 (dm, 15.0 Hz, 1H), 1.75 (m,
6H), 1.33 (t, 7.1 Hz, 3H), 1.23 (t, 7.1 Hz, 3H), 1.22 (t, 7.1 Hz,
3H). 13C{H} NMR (50 MHz, CDCl3): δ 205.7, 171.9, 170.4,
169.5, 160.5, 132.0, 127.9 (×2), 115.0 (×2), 62.0, 61.9, 61.8,
59.8, 59.2, 58.0, 55.6, 38.9, 33.2, 31.6, 25.7, 19.9, 14.2, 14.0,
Tr ieth yl (1R*,6S,9S)- a n d (1R*,6S,9R)-9-(4-Meth oxy-
p h en yl)-8-a za bicyclo[4.4.0]d eca n -7-on e-2,2,6-tr ica r boxy-
la te (16a a n d 17a ). A suspension of 10% Pd/C (380 mg, 10
wt %) and 15a (3.80 g, 8.03 mmol) in MeOH (40 mL) was
allowed to stir at rt under 1 atm of H2 for 18 h. The reaction
mixture was filtered through Celite, and the solvent was
evaporated to give the crude product. Flash chromatography
(25-50% EtOAc in petroleum ether) gave 16a (1.69 g, 3.56
mmol, 44% yield) as a white solid, mp 193 °C, and 17a (1.89
g, 3.97 mmol, 49% yield) as a white solid, mp 199 °C. The
following are data for compound 16a . 1H NMR (400 MHz,
CDCl3): δ 7.37 (d, 8.7 Hz, 2H), 6.89 (d, 8.7 Hz, 2H), 6.10 (br,
1H), 4.72 (m, 1H), 4.34 (dq, J d ) 10.8 Hz, J q ) 7.1 Hz, 1H),
4.22 (dq, J d ) 10.8 Hz, J q ) 7.1 Hz, 1H), 4.07 (m, 2H), 3.89 (q,
7.1 Hz, 1H), 3.88 (q, 7.1 Hz, 1H), 3.82 (s, 3H), 3.38 (dm, 11.5
13.7. IR (KBr): 3133, 1727, 1249 cm-1. Anal. Calcd for C25H33
NO7S: C, 61.08; H, 6.77. Found: C, 60.94; H, 6.71.
-
Hz, 1H), 2.51 (dm, 14.3 Hz, 1H), 2.34 (dt, J d ) 5.5 Hz, J t
)
Tr ieth yl (1R*,6S,9R)-9-(4-Meth oxyph en yl)-8-azabicyclo-
[4.4.0]d eca n e-2,2,6-tr ica r boxyla te (20). A solution of 19
(405 mg, 0.82 mmol) and nickel chloride hexahydrate (1.63 g,
6.84 mmol) in MeOH (8 mL) and THF (8 mL) was treated with
NaBH4 (776 mg, 20.5 mmol) at 0 °C. After being stirred at rt
for 3 h, the reaction mixture was filtered through Celite,
rinsing with CH2Cl2. The resulting solution was washed with
diluted aq NaHCO3. The organic layer was dried over MgSO4
and evaporated. Flash chromatography (20% EtOAc in petro-
13.6 Hz, 1H), 2.23 (dm, 13.7 Hz, 1H), 1.77 (m, 3H), 1.56 (m,
1H), 1.43 (t, 7.1 Hz, 3H), 1.41 (m, 1H), 1.15 (t, 7.1 Hz, 3H),
0.85 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 172.7,
171.8, 170.0, 169.5, 159.1, 133.4, 127.6 (×2), 113.8 (×2), 61.5,
61.4 (×2), 58.0, 55.3, 53.8, 53.7, 32.5, 30.1, 28.0, 25.8, 19.2,
13.9 (×2), 13.6. IR (KBr): 3439, 1734, 1666 cm-1. Anal. Calcd
for C25H33NO8: C, 63.14; H, 6.99. Found: C, 63.17; H, 7.04.
The following are data for compound 17a . 1H NMR (400 MHz,
J . Org. Chem, Vol. 68, No. 4, 2003 1415

Hattori and Grossman
leum ether) gave 20 (304 mg, 0.66 mmol, 80% yield) as a white
solid, mp 105 °C. H NMR (400 MHz, CDCl3): δ 7.27 (d, 8.7
38.5, 29.8, 29.0, 14.4. IR (neat): 3185, 1720, 1648 cm-1. Anal.
Calcd for C18H23NO4: C, 68.12; H, 7.30. Found: C, 67.87; H,
7.00. The following are data for compound 22b. H NMR (400
1
1
Hz, 2H), 6.85 (d, 8.7 Hz, 2H), 4.24 (dq, J d ) 10.8 Hz, J q ) 7.1
Hz, 1H), 4.11 (m, 5H), 3.80 (s, 3H), 3.72 (dd, 3.3 Hz, 11.1 Hz,
1H), 3.33 (d, 12.3 Hz, 1H), 3.25 (dd, 5.0 Hz, 12.5 Hz, 1H), 2.83
(d, 12.3 Hz, 1H), 2.19 (m, 1H), 2.03 (m, 1H), 1.91 (m, 2H), 1.80
(m, 1H), 1.70 (m, 1H), 1.54 (m, 2H), 1.31 (t, 7.1 Hz, 3H), 1.26
(br, 1H),1.22 (t, 7.1 Hz, 3H), 1.19 (t, 7.1 Hz, 3H). 13C{H} NMR
(50 MHz, CDCl3): δ 176.0, 170.5, 170.2, 158.8, 136.5, 127.5
(×2), 113.8 (×2), 61.3, 60.6, 60.5, 58.8, 56.7, 55.3, 45.4, 39.5,
32.4, 29.7, 25.3, 25.2, 19.6, 14.1, 14.0, 13.9. IR (neat): 3331,
1733, 1514 cm-1. Anal. Calcd for C25H35NO7: C, 65.06; H, 7.64.
Found: C, 65.30; H, 7.87.
MHz, CDCl3): δ 7.20 (d, 8.7 Hz, 2H), 6.89 (d, 8.7 Hz, 2H), 5.71
(br, 1H), 4.40 (dd, 3.2 Hz, 11.4 Hz, 1H), 4.11 (m, 2H), 3.81 (s,
3H), 3.01 (dt, J d ) 6.8 Hz, J t ) 9.5 Hz, 1H), 2.82 (m, 2H), 2.31
(m, 1H), 2.08 (m, 2H), 1.91 (m, 1H), 1.72 (dt, J d ) 13.2 Hz, J t
) 3.3 Hz, 1H), 1.46 (dt, J d ) 11.7 Hz, J t ) 13.1 Hz, 1H), 1.23
(t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 174.5, 173.2,
160.0, 133.9, 127.7 (×2), 114.7 (×2), 60.7, 57.1, 55.6, 48.7, 44.3,
40.4, 32.1, 28.4, 24.5, 14.4. IR (neat): 3179, 1729, 1653 cm-1
.
Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30. Found: C, 68.12;
H, 7.08.
Eth yl (1R*,4R,6R,7R)-4-(4-Meth oxyph en yl)-3-azabicyclo-
[4.3.0]n on a n e-7-ca r boxyla te (23). A solution of BH3 in THF
(1 M, 1.1 mL) was added to a suspension of 22a (159 mg, 0.50
mmol) in THF (1 mL) at 0 °C under N2. The mixture was
allowed to stir at rt for 24 h. The solution was cooled in ice-
water, and the reaction was quenched by 6 M HCl (1 mL).
After the mixture was stirred for for 2 h at 0 °C, 1 N NaOH
was added until the pH was 10. The mixture was extracted
with CH2Cl2. The combined organic layers were dried over
MgSO4 and evaporated to give the crude product. Flash
chromatography (3% MeOH in CH2Cl2) gave 23 (82 mg, 0.27
mmol, 54% yield) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 7.28 (d, 8.8 Hz, 2H), 6.85 (d, 8.8 Hz, 2H), 4.12 (q,
7.1 Hz, 2H), 3.79 (s, 3H), 3.51 (dd, 2.4 Hz, 11.5 Hz, 1H), 3.14
(dd, 2.3 Hz, 12.5 Hz, 1H), 3.10 (dd, 3.6 Hz, 12.3 Hz, 1H), 2.50
(m, 1H), 2.38 (dt, J d ) 12.5 Hz, J t ) 6.0 Hz, 1H), 2.07 (m, 4H),
1.73 (m, 3H), 1.35 (q, 12.4 Hz, 1H), 1.26 (t, 7.1 Hz, 3H). 13C-
{H} NMR (50 MHz, CDCl3): δ 176.8, 158.9, 137.4, 127.8 (×2),
114.0 (×2), 60.6, 60.5, 55.5, 50.2, 47.4, 42.9, 37.8, 37.7, 27.1,
26.4, 14.5. IR (neat): 3333, 1729, 1648 cm-1. Anal. Calcd for
Tr ieth yl (1R*,6S,9R)-8-(2,2,2-Tr ich lor oeth oxycar bon yl)-
9-(4-m eth oxyp h en yl)-8-a za bicyclo[4.4.0]d eca n e-2,2,6-tr i-
ca r boxyla te. Compound 20 (29 mg, 0.063 mmol) was sub-
jected to the standard procedure for addition of a Troc group.
Flash chromatography (15% EtOAc in petroleum ether) gave
the protected amine (40 mg, 0.063 mmol, 100% yield) as a
1
white solid, mp 87 °C. H NMR (400 MHz, CDCl3, 60 °C): δ
7.10 (d, 8.7 Hz, 2H), 6.82 (d, 8.7 Hz, 2H), 4.98 (dd, 6.4 Hz,
11.7 Hz, 1H), 4.75 (d, 11.0 Hz, 1H), 4.52 (d, 12.3 Hz, 1H), 4.34
(d, 14.5 Hz, 1H), 4.19 (m, 6H), 3.77 (s, 3H), 3.25 (dm, 10.4 Hz,
1H), 3.11 (d, 14.5 Hz, 1H), 2.19 (m, 2H), 1.76 (m, 2H), 1.60
(m, 4H), 1.29 (t, 7.1 Hz, 3H), 1.27 (t, 7.1 Hz, 3H), 1.20 (t, 7.1
Hz, 3H). 13C{H} NMR (50 MHz, CDCl3, 60 °C): δ 175.5, 170.7,
170.6, 159.1, 153.9, 134.8, 126.4 (×2), 114.2 (×2), 95.5, 75.4,
61.5, 61.4, 61.1, 58.8 and 58.8, 58.0, 55.4 and 55.3, 50.9, 45.5,
37.7, 31.6, 28.7, 26.6, 18.3, 14.1, 14.0, 13.9 (a resonance at δ
29.7 is attributed to grease19). IR (neat): 1729, 1514 cm-1
28H36Cl3NO9.
(1R *,6S ,9R )-8-(2,2,2-T r ic h lo r o e t h o x y c a r b o n y l)-8-
.
C
azabicyclo[4.4.0]decan e-2,2,6,9-tetr acar boxylic Acid, 2,2,6-
Tr ieth yl Ester (21). The previous compound (392 mg, 0.62
mmol) was subjected to the standard procedure for oxidation
of the An group to give 21 (227 mg, 0.40 mmol, 64% yield) as
C
18H25NO3: C, 71.26; H, 8.31. Found: C, 71.23; H, 8.58.
Eth yl (1R*,4R,6R,7R)-3-(2,2,2-Tr ich lor oeth oxyca r bo-
n yl)-4-(4-m et h oxyp h en yl)-3-a za b icyclo[4.3.0]n on a n e-7-
ca r boxyla te. Compound 23 (58 mg, 0.19 mmol) was subjected
to the standard procedure for addition of a Troc group. Flash
chromatography (10% EtOAc in petroleum ether) gave the
protected amine (90 mg, 0.19 mmol, 99% yield) as a colorless
1
a white solid, mp 151 °C. H NMR (400 MHz, CDCl3): δ 5.20
(br, 1H), 5.00 (d, 11.9 Hz, 0.5H), 4.85 (d, 11.9 Hz, 0.5H), 4.64
(d, 11.9 Hz, 0.5H), 4.56 (dd, 10.0 Hz, 19.0 Hz, 1H), 4.50 (d,
11.9 Hz, 0.5H), 4.18 (m, 7H), 3.12 (dd, 7.8 Hz, 15.1 Hz, 1H),
3.03 (d, 11.9 Hz, 0.5H), 2.94 (d, 14.7 Hz, 0.5H), 2.21 (m, 1H),
2.13 (dm, 14.1 Hz, 1H), 1.79 (m, 3H), 1.63 (dt, J d ) 14.1 Hz, J t
) 4.2 Hz, 1H), 1.48 (m, 1H), 1.27 (t, 7.1 Hz, 6H), 1.26 (m, 1H),
1.21 (t, 7.0 Hz, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 176.3,
175.5, 175.3, 170.5 and 170.3, 153.2, 95.1, 75.5 and 75.2, 61.8,
61.2, 57.8, 56.7 and 56.6, 50.1 and 49.8, 44.9 and 44.7, 37.0
and 36.7, 29.7, 28.5, 26.4, 25.3, 24.8, 18.1, 14.0, 13.9. IR
(neat): 3209, 1733 cm-1. Anal. Calcd for C22H30Cl3NO10: C,
45.97; H, 5.26. Found: C, 46.24; H, 5.60.
1
oil. H NMR (400 MHz, CDCl3, 60 °C): δ 7.18 (d, 8.7 Hz, 2H),
6.83 (d, 8.7 Hz, 2H), 4.78 (dd, 5.5 Hz, 11.9 Hz, 1H), 4.69 (d,
11.9 Hz, 2H), 4.61 (br, 1H), 4.33 (dd, 6.1 Hz, 13.6 Hz, 1H),
4.14 (q, 7.1 Hz, 2H), 3.77 (s, 3H), 2.98 (dd, 11.4 Hz, 13.4 Hz,
1H), 2.44 (m, 3H), 2.16 (dt, J d ) 13.6 Hz, J t ) 5.0 Hz, 1H),
1.99 (m, 2H), 1.79 (m, 1H), 1.65 (dt, J d ) 13.9 Hz, J t ) 12.0
Hz, 1H), 1.25 (t, 7.1 Hz, 3H). 13C{H} NMR (100 MHz, CDCl3,
60 °C): δ 175.1, 159.1, 154.3, 136.1, 126.6 (×2), 114.3 (×2),
96.0, 75.4, 60.6, 57.1, 55.5, 51.6, 44.4, 40.0, 38.7, 36.4, 30.2,
30.0, 14.5. IR (neat): 1717 cm-1. Anal. Calcd for C21H26Cl3-
NO5: C, 52.68; H, 5.47. Found: C, 52.75; H, 5.71.
Eth yl (1R*,4R,6R,7R)- a n d (1R*,4R,6R,7S)-4-(4-Meth -
oxyp h en yl)-3-a za b icyclo[4.3.0]n on a n -2-on e-7-ca r b oxy-
la te (22a a n d 22b). A solution of 17b (2.58 g, 5.59 mmol),
LiCl (711 mg, 16.77 mmol), and H2O (302 µL, 16.77 mmol) in
DMF (50 mL) was allowed to reflux for 18 h. The reaction
mixture was cooled and poured into ice-water. The resulting
mixture was extracted with EtOAc, washed with water and
brine, dried over MgSO4, and evaporated to give the crude
product. Flash chromatography (50-65% EtOAc in petroleum
ether) gave 22a (645 mg, 2.03 mmol, 36% yield) as a white
solid, mp 124 °C, and 22b (440 mg, 1.39 mmol, 25% yield) as
a white solid, mp 199 °C. The following are data for compound
(1R*,4R,6R,7R)-3-(2,2,2-Tr ich lor oet h oxyca r b on yl)-3-
a za b icyclo[4.3.0]n on a n e-4,7-d ica r b oxylic Acid , 7-E t h yl
Ester (24). The previous compound (74 mg, 0.15 mmol) was
subjected to the standard procedure for oxidation of the An
group to give 24 (47 mg, 0.11 mmol, 75% yield) as a colorless
1
oil. H NMR (400 MHz, CDCl3): δ 8.36 (br, 1H), 4.82 (d, 11.9
Hz, 0.5H), 4.82 (d, 11.9 Hz, 0.5H), 4.75 (d, 11.9 Hz, 0.5H), 4.68
(d, 11.9 Hz, 0.5H), 4.41 (dd, 5.4 Hz, 11.3 Hz, 0.5H), 4.39 (dd,
5.4 Hz, 11.3 Hz, 0.5H), 4.18 (m, 1H), 4.16 (q, 7.1 Hz, 2H), 2.92
(dd, 11.6 Hz, 13.6 Hz, 0.5H), 2.88 (dd, 11.6 Hz, 13.6 Hz, 0.5H),
2.40 (m, 4H), 2.01 (m, 2H), 1.79 (m, 2H), 1.28 (m, 1H), 1.27 (t,
7.1 Hz, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 178.0 and
177.3, 175.0 and 175.0, 154.4 and 153.8, 95.6 and 95.4, 75.4
and 75.4, 60.9, 55.1, 50.8 and 50.2, 43.4 and 43.3, 39.2 and
39.1, 38.4 and 38.2, 29.9 and 29.8, 29.7 and 29.6, 29.6 and 28.9,
14.5. IR (neat): 3230, 1725 cm-1. Anal. Calcd for C15H20Cl3-
NO6: C, 43.24; H, 4.84. Found: C, 43.42; H, 5.18.
1
22a . H NMR (400 MHz, CDCl3): δ 7.21 (d, 8.7 Hz, 2H), 6.89
(d, 8.7 Hz, 2H), 5.77 (br, 1H), 4.42 (dd, 2.6 Hz, 11.4 Hz, 1H),
4.14 (∼q, 7.1 Hz, 2H), 3.81 (s, 3H), 2.92 (dt, J d ) 8.4 Hz, J t
)
9.5 Hz, 1H), 2.78 (ddd, 5.2 Hz, 10.2 Hz, 14.6 Hz, 1H), 2.58 (dt,
J d ) 5.1 Hz, J t ) 7.9 Hz, 1H), 2.36 (m, 1H), 2.10 (m, 2H), 1.82
(m, 2H), 1.48 (dt, J d ) 11.7 Hz, J t ) 12.8 Hz, 1H), 1.26 (t, 7.1
Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 175.2, 174.7, 160.0,
133.7, 127.6 (‚2), 114.7 (×2), 60.8, 56.8, 55.5, 51.6, 43.9, 40.4,
Ack n ow led gm en t . We thank the NIH (Grant
GM1002-01A1) for its support of this work. NMR instru-
ments used in this research were obtained with funds
(19) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J . Org. Chem. 1997,
62, 7512.
1416 J . Org. Chem., Vol. 68, No. 4, 2003

Functionalized Cis- and Trans-Fused R-Amino Acids
characterization of 3b, 7b, 13b, 14b, and 15b, and spectra of
6b, 7b, 12, and Troc-20, for which satisfactory elemental
analyses were not obtained. This material is available free of
charge via the Internet at http://pubs.acs.org.
from NSF’s CRIF program (Grant CHE-997841) and the
University of Kentucky’s Research Challenge Trust
Fund. We also thank Reuben K. Maggard for executing
the initial exploratory studies.
Su ppor tin g In for m ation Available: Evidence with which
stereochemical assignments were made, preparation and
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