Coupling reactions of α-(N-Carbamoyl)alkylcuprates with enol triflates derived from cyclic β-keto esters: A facile approach to γ-carbamoyl-α,β-enoates

Article abstract of DOI:10.1021/jo026375f

α-(N-Carbamoylalkyl)cuprates couple with enol triflates derived from carbocyclic and heterocyclic (i.e., piperidinones) β-keto esters. Product yields are higher with the alkyl(cyano)cuprates [i.e., RCu-(CN)Li, 56-93%] than with the dialkylcuprate reagents (i.e., R₂CuLi·LiCN). An enol nonaflate works as well as the corresponding enol triflate. A facile synthetic route to γ-amino α,β-enoates not readily prepared from γ-keto-α,β-enoates is thus established. The γ-amino-α,β-enoates, available via N-Boc deprotection, can be cyclized to annulated pyrrolin-2-ones.

Full text of DOI:10.1021/jo026375f

Cou p lin g Rea ction s of r-(N-Ca r ba m oyl)a lk ylcu p r a tes w ith En ol
Tr ifla tes Der ived fr om Cyclic â-Keto Ester s: A F a cile Ap p r oa ch to
γ-Ca r ba m oyl-r,â-en oa tes
ShengJ ian Li†,‡ and R. Karl Dieter*
Howard L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-0973, and
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New J ersey 07033
dieterr@clemson.edu
Received August 30, 2002
R-(N-Carbamoylalkyl)cuprates couple with enol triflates derived from carbocyclic and heterocyclic
(i.e., piperidinones) â-keto esters. Product yields are higher with the alkyl(cyano)cuprates [i.e., RCu-
(CN)Li, 56-93%] than with the dialkylcuprate reagents (i.e., R2CuLi‚LiCN). An enol nonaflate works
as well as the corresponding enol triflate. A facile synthetic route to γ-amino R,â-enoates not readily
prepared from γ-keto-R,â-enoates is thus established. The γ-amino-R,â-enoates, available via N-Boc
deprotection, can be cyclized to annulated pyrrolin-2-ones.
In tr od u ction
methodology was not extended to cyclic systems which
potentially pose problems of steric congestion about the
reactive centers of either the cuprates or the vinyl iodides.
γ-Amino carbonyl derivatives are an important class
of compounds which have shown unique biological
activities7a and they have also been used as synthons for
the construction of therapeutically interesting agents.7b-e
Numerous synthetic routes have been developed for the
synthesis of this class of compounds which remain
attractive intermediates in organic synthesis.8
Palladium chemistry effects the conversion of â-car-
boalkoxy enol triflates (e.g., 2a ) to γ-N-carbamoyl-R,â-
enoates,9 â-aminomethyl enol triflates to R,â-unsaturated
γ-lactams,10 and â-acyl enol triflates to â-acyl-R,â-en-
amides11 which can also be converted to R,â-unsaturated
γ-lactams. The tandem palladium coupling-isomeriza-
tion sequence of â-carboalkoxy enol triflates with the
N-methyl carbamate of 1,2-dihydropyrrole affords the
γ-amino R,â-enoate with isomerization of the pyrroline
double bond.9 Utilization of a chiral binaphthyl ligand
R-(N-Carbamoyl)alkylcuprates1 undergo conjugate ad-
dition2 and substitution reactions3-5 with a wide range
of electrophiles and their reactivity profile is often
complementary to the corresponding lithium reagents6
from which they are derived. They hold considerable
promise for N-heterocycle synthesis and are enhanced by
the development of configurationally stable scalemic5c
reagents. R-(N-Carbamoyl)alkylcuprates, however, either
fail to undergo conjugate addition reactions with cyclic
R,â-enoates or afford the conjugate adducts in low
yields.2b While they do undergo substitution reactions
with vinyl triflates,5a the reaction is very sensitive to
steric factors in the electrophile. â-Iodo-R,â-enoates ef-
ficiently couple with R-(N-carbamoyl)alkylcuprates ste-
reospecifically providing a solution to stereocontrol not
achievable by coupling with R,â-alkynyl esters.2e This
* Address correspondence to this author at Clemson University.
† Current Address: J ohnson & J ohnson Pharmaceutical Research
Institute, Raritan-Bridgewater, NJ .
‡ Schering-Plough Research Institute.
(7) (a) The R-amino carbonyl subunit is quite commonly found in
antibacterial, antiinflammatory, anxiolytic, and analgesic agents which
have been cited in Comprehensive Medicinal Chemistry of the ISIS
database (http://www.mdl.com/products/isisbase.html). For reviews on
using amino carbonyl derivatives as synthons in heterocyclic synthesis
see: (b) Sardina, F. J .; Rapoport, H. Chem. Rev. 1996, 96, 1825. (c)
Hanessian, S.; Claridge, S.; J ohnstone, S. J . Org. Chem. 2002, 67, 4261.
(d) Xue, C.-B.; He, X.; Roderick, J .; Corbett, R. L.; Decicco, C. P. J .
Org. Chem. 2002, 67, 865. (e) Luker, T.; Hiemstra, H.; Speckamp, W.
N. J . Org. Chem. 1997, 62, 8131 and 3592.
(1) For a review see: Dieter, R. K. Heteroatomcuprates and R-Het-
eroatomalkylcuprates in Organic Synthesis. In Modern Organocopper
Chemistry; Krause, N., Ed.; J ohn Wiley & Sons: New York, 2002; p
79.
(2) (a) Dieter, R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron 2000,
56, 2767. (b) Dieter, R. K.; Lu, K.; Velu, S. E. J . Org. Chem. 2000, 65,
8715. (c) Dieter, R. K.; Topping, C. M.; Nice, L. E. J . Org. Chem. 2001,
66, 2302. (d) Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283. (e) Dieter,
R. K.; Lu, K. J . Org. Chem. 2002, 67, 847.
(3) For acylation reactions see: (a) Dieter, R. K.; Sharma, R. R.;
Ryan, W. Tetrahedron Lett 1997, 38, 783. (b) Reference 2c.
(4) For allylic and propargylic substitutions see: (a) Dieter, R. K.;
Velu, S. E.; Nice, L. E. Synlett 1997, 1114. (b) Dieter, R. K.; Nice, L.
E. Tetrahedron Lett. 1999, 40, 4293. (c) Dieter, R. K.; Yu, H. Org. Lett.
2001, 3, 3855.
(5) For vinyl triflate and vinyl iodide substitutions see: (a) Dieter,
R. K.; Dieter, J . W.; Alexander, C. W.; Bhinderwala, N. S. J . Org. Chem.
1996, 61, 2930. (b) Dieter, R. K.; Sharma, R. R. Tetrahedron Lett 1997,
38, 5937. (c) Dieter, R. K.; Topping, C. M.; Chandupatla, K. R.; Lu, K.
J . Am. Chem. Soc. 2001, 123, 6132. (d) Reference 2c. (e) Reference 2e.
(6) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552 and references therein.
(8) (a) J eong, N.; Seo, S. D.; Shin, J . Y. J . Am. Chem. Soc. 2000,
122, 10220. (b) Pagenkopf, B. L.; Belanger, D. B.; O’Mahony, D. J . R.;
Livinghouse, T. Synthesis 2000, 1009. (c) Krafft, M. E.; Bonaga, L. V.
R. SynLett 2000, 959. (d) Hicks, F. A.; Kabaoui, N. M.; Buchwald, S.
L. J . Am. Chem. Soc. 1999, 121, 5881. (e) Sturla, S.J .; Buchwald, S. L.
J . Org. Chem. 1999, 64, 5547. (f) Alcaide, B.; Polanco, C.; Sierra, M.
A. J . Org. Chem. 1998, 63, 6786. (g) Morimoto, T.; Chatani, N.;
Fukumoto, Y.; Murai, S. J . Org. Chem. 1997, 62, 3762.
(9) Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett 1993, 34,
2505.
(10) Crisp, G. T.; Meyer, A. G. Tetrahedron 1995, 51, 5585.
(11) Hamaoka, S.; Kawaguchi, M.; Mori, M. Heterocycles 1994, 37,
167.
10.1021/jo026375f CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/09/2003
J . Org. Chem. 2003, 68, 969-973
969

Li and Dieter
SCHEME 1
SCHEME 2
affords excellent asymmetric induction, but the reaction
appears limited to pyrroline enecarbamates. In addition,
the enol triflates of 4-tert-butyl- or 4-phenyl-2-formyl-
cyclohexanone react with the sodium ferrate complex,
[Cp(CO)2Fe]Na, to form â-formyl alkenyl iron carbonyl
complexes. These iron carbonyl complexes undergo a
titanium-mediated carbonylative coupling with amines
to afford the lactams.12 All these procedures are signifi-
cantly longer than the current method.
Previous efforts to couple R-(N-carbamoyl)alkylcu-
prates with the enol triflates of â-keto esters were limited
to the dialkylcuprate derived from N-Boc-N,N-dimethyl-
amine and the enol triflate of methyl 3-oxopentanoate
(67%).13 We now report effective procedures for the facile
coupling of R-(N-carbamoyl)alkylcuprates with enol tri-
flates derived from cyclic â-keto esters leading to γ-N-
carbamoyl-R,â-enoates in good to excellent yields even
when considerable steric congestion is present in the
coupling components.
nylcuprates derived from 3a and vinyl triflate 2a (Scheme
2, Table 1, entries 1-6). The lithium dialkylcuprate
prepared from CuCN, CuI,17 or CuCl uniformly gave
lower yields (entries 2 vs 1, 4 vs 3, and 6 vs 5) of coupled
products than the corresponding alkylcyanocuprate or
alkylhalocuprate [i.e., RCu(X)Li, X ) CN, I, or Cl]
reagents. The alkylcyanocuprate and alkylhalocuprate
reagents gave comparable yields of coupled product, but
did show a small diminution of product yield across the
series CuCN > CuI > CuCl (entries 1, 3, and 5) whereas
the dialkylcuprate reagent gave higher yields when
prepared from CuI and significantly lower yields when
prepared from CuCl (entries 4 vs 6). Since the alkyl-
cyanocuprate reagent gave the highest product yields and
was also efficient in R-(N-carbamoyl)alkyl ligand, this
reagent was employed in an examination of the scope of
the reaction.
Resu lts a n d Discu ssion
The enol triflates14 or nonaflates15 were readily pre-
pared by modification of literature procedures in good to
excellent yields (Scheme 1).
The reactions of cuprates derived from 3a with enol
triflates prepared from N-benzyl piperidinones were
examined to probe the sensitivity of the reaction to steric
factors in the substrate. These substrates would also
provide a synthetic entry to substituted piperidines, a
structural feature in many pharmaceuticals and biologi-
cally active nitrogen heterocycles. The effect of topological
and conformational effects in the R-(N-carbamoyl)alkyl
ligands was probed by an examination of cuprates
derived from N-Boc-piperidine (3b), N-Boc-perhydroaza-
pine (3c), and N-Boc-dimethylamine (3d ).
Coupling of the alkyl(cyano)cuprate reagent derived
from N-Boc pyrrolidine (3a ) with the enol triflates of
N-benzyl-3-carboethoxy-4-piperidinone (2b), N-benzyl-4-
carboethoxy-3-piperidinone (2c), or N-Boc-3-carboethoxy-
2-piperidinone (2d ) proceeded uneventfully in good to
excellent yield (Table 1, entries 7-9). The significant
number of heteroatoms in these triflates had no negative
effect upon the coupling reaction and good yields were
obtained with triflate 2d possessing significant steric
congestion about the reactive site. Although deprotona-
tion of N-Boc-piperidine 3b is more difficult than the
pyrrolidine analogue, good yields of cuprate formation
and coupling product were achieved (entry 10) as were
slightly higher yields for the N-Boc-perhydroazapine
derived cuprate and coupling product (entry 11). The
cuprate derived from N-Boc-N,N-dimethylamine gave
The cuprate reagents were prepared by sequential
deprotonation of the carbamates according to the Beak
protocol16 followed by treatment of the in situ generated
organolithium reagents with THF soluble Cu(I) salts
solubilized by LiCl.2c Although it was not necessary to
raise the temperature to guarantee complete cuprate
formation, the THF solution of CuX‚2LiCl was added to
the R-lithiocarbamate at -78 °C, stirred at this temper-
ature for a few minutes, and then stirred at -30 °C for
0.5 h before recooling to -78 °C. Addition to the colorless
to clear yellowish cuprate THF solution of a THF solution
of the enol triflate at -78 °C resulted in a yellowish-dark
brown solution that was stirred at -78 °C for 1-2 h and
-40 °C for 1-3 h and then briefly warmed to room
temperature for 15 min (solution became dark to dark
brown) before quenching the reaction with 1.0 N HCl at
-78 °C. In preliminary experiments, several Cu(I) salts
and cuprate reagents were examined by using pyrrolidi-
(12) Mikulas, M.; Rust, S.; Schollmeyer, D.; Ruck-Braun, K. Synlett
2000, 185.
(13) Sharma, R. R. Ph.D. Thesis, Clemson University, 1998, p 72-
74.
(14) (a) Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis
1982, 85. (b) Li, S. Masters of Sciences Thesis, Clemson University,
1996.
(15) Bellina, F.; Ciucci, D.; Rossi, R.; Vergamini, P. Tetrahedron
1999, 55, 2103.
(16) (a) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197. (b)
Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(17) Lipshutz, B. H. In Organometallics in Organic Synthesis:
Manual; Schlosser, M., Ed.; J ohn Wiley & Sons: Chichester, England,
1994; Chapter 4, p 283.
A
970 J . Org. Chem., Vol. 68, No. 3, 2003

Coupling Reactions of R-(N-Carbamoyl)alkylcuprates
TABLE 1. Cou p lin g Rea ction s of r-(N-Ca r ba m oyl)a lk ylcu p r a tes w ith En ol Tr ifla tes Der ived fr om â-Keto Ester s
(Sch em e 2)
a
b
The reactions were performed on a 1-mmol scale unless noted. The lithium R-aminoalkyl carbanions were generated by direct
deprotonation [s-BuLi, THF, TMEDA, -78 °C, 2 h]. c The RCu(X)Li (X ) CN, I, Cl) or R2CuLi‚LiX cuprate reagents were generated based
d
on the molar ratio of RLi/CuX. CuCN and CuCl were obtained from a commercial source and were used as received, CuI was purified
by a literature procedure (ref 17) and dried under vacuum before use. e The enol triflates were made by a modified literature method (refs
14 and 21). f The yields were based on pure products isolated after purification by column chromatography. All new compounds were
characterized by their 1H NMR, 13C NMR, and high-resolution MS/LC-MS/MS. The reaction was performed at several scales [2.0 mmol
g
(86%), 5.0 mmol (82%), 10 mmol (83%)].
SCHEME 3
excellent yields with triflate 2a (entry 12), which is
significant since the diminished reactivity of this primary
alkylcuprate reagent was observed in previous work.2b
Since triflic anhydride is relatively expensive, the use
of cyclic vinyl nonaflates was examined. The enol non-
aflate derived from 1a gave a comparable yield of 4 upon
coupling with the alkyl(chloro)cuprate derived from 3a
and a slightly higher yield with the alkyl(cyano)cuprate
reagent (Scheme 3). These results coupled with the
observation that the alkyl(cyano)cuprate reagents afford
higher yields than the lithium dialkylcuprates suggests
that moderation of cuprate and reagent reactivity is
beneficial, resulting in higher yields.
The coupling reaction could not be extended to aro-
matic triflates. Triflate 2e prepared from ethyl salicylate
(1e) gave the cross-coupling product 12 in very low yield
(<8%, as estimated from LC-MS analysis of the crude
product mixture) affording instead the pyrrolidinyl homo-
coupling product 11 (the dimer of the N-Boc-R-pyrrolidi-
nyl ligand) in 83% yield along with 21% of the recovered
triflate 2e. Similar homocoupling products were also
observed for the other alkyl(cyano)cuprates derived from
carbamates 3b-d . The triflate of phenol was previously
observed to be unreactive5a toward the lithium dialkyl-
cuprate whereas triflate 2e induces a coupling reaction
J . Org. Chem, Vol. 68, No. 3, 2003 971

Li and Dieter
suggestive of SET events. Triflate 2e contains two good
electron-withdrawing groups on the aromatic ring and
is apparently easily reduced by the alkyl(cyano)cuprate
reagent affording an R-carbamoyl radical that combines
to afford the dimer. Dimer 1118 has also been obtained
as a mixture of diastereomers in excellent yields either
by the mild oxidation of the dialkylcuprate reagent (i.e.,
R2CuLi‚2LiCl derived from 3a and the homogeneous THF
solution of purified CuI and LiCl) with oxidants (e.g., I2)
or by bubbling oxygen through a solution of the alkyl-
(cyano)cuprate.19
Two mechanistic pathways can be envisioned for these
coupling reactions. The reaction may, in principle, pro-
ceed by either a conjugate addition-elimination pathway
or a direct oxidative addition-reductive elimination
pathway. Given the reluctance of R,â-enoates to partici-
pate in conjugate addition reactions and the failure of
these cuprate reagents to undergo conjugate addition
reactions to either R,â-enones or enoates in the absence
of TMSCl,2 we favor the latter pathway. This view is
additionally supported by the observation that R-(N-
carbamoyl)alkylcuprates give little to no enantioselec-
tivity in conjugate addition reactions but give excellent
enantioselectivity upon reaction with vinyl iodides ir-
respective of whether the double bond is or is not in
conjugation with an ester functionality.5c
cology. Coupling of the scalemic pyrrolidinylcuprate5c
provides potential opportunities for asymmetric synthetic
applications.
Exp er im en ta l Section
Gen er a l P r oced u r e: En ol Tr ifla te P r ep a r a tion .21 NaH
[0.240 g, 6.00 mmol, 60% (w/w) mineral oil dispersion] was
washed with hexane (3 × 5.0 mL), the gray solid was flushed
with a nitrogen atmosphere, whereupon CH2Cl2 (20 mL, dried
over molecular sieves) was added and the mixture was cooled
to 0 °C with an ice-water bath. The appropriate â-keto ester
(5.0 mmol) was added dropwise (gray suspension became white
as gas evolution proceeded) and the mixture was stirred at 0
°C for 30 min, and then cooled to -78 °C and stirred for an
additional 10-15 min before triflic anhydride was added. The
mixture was stirred at -78 °C for 30 min and then at 0 °C for
18 h. The reaction mixture was diluted with 50 mL of Et2O,
washed with brine (3 × 15 mL), and dried over Na2SO4.
Concentration in vacuo afforded the enol triflates.
1,1-Dim eth yleth yl 2-(2-Ca r boeth oxy-1-cycloh exen -1-
yl)-1-p yr r olid in eca r boxyla te (4). N-Boc-pyrrolidine (1.7 g,
10 mmol, dried over CaH2) was added into a flame-dried (heat
gun) 100-mL round-bottom flask stoppered with a septum.
TMEDA (3.0 mL, 20 mmol, commercial source, dried over
CaH2) was added via syringe, followed by 20 mL of dry THF
(from a sealed bottle). The clear solution was cooled to -78
°C and stirred for ca. 5 min. sec-BuLi (10 mL, 13 mmol, a newly
opened bottle, 1.3 M in cyclohexane/hexane 92/8, commercial
source) was added via syringe dropwise. The yellowish, almost
clear solution was stirred at -78 °C for an additional 2.5 h.
The greenish-white powdered CuCN (0.90 g, 10 mmol, com-
mercial source) was mixed with the colorless crystalline LiCl
(0.86 g, 20 mmol, commercial source, beads <100 ppm H2O)
in another 50-mL round-bottom flask and the flask was heated
with hot air and then cooled to room temperature under a N2
atmosphere. Dry THF (20 mL) was added to the yellowish
powder and the mixture was stirred at room temperature until
all the solid had dissolved, whereupon the mixture became a
homogeneous greenish solution that was cooled to -78 °C. At
this temperature, the homogeneous Cu(I) salt dry THF solu-
tion was quickly transferred into the N-Boc-R-lithiopyrrolidine
solution via syringe. The mixture was stirred for a few
minutes, then stirred at -30 °C (yellowish clear) for 0.5 h and
recooled to -78 °C (yellowish clear).
Finally, we note that treatment of 4 with either 50%
(v/v) of trifluoroacetic acid in dichloromethane at room
temperature or with 2 equiv of trimethylsilyltriflate
effects N-Boc deprotection and cyclization to afford the
tricyclic pyrroline γ-lactam 1320 in good to excellent yields
(91% and 65%, respectively, eq 1). However, treatment
of 4 with 6 equiv of PhOH and TMSCl in dichloromethane
gave lactam 13 in low yield (28%) after the solution was
stirred overnight.
A 20-mL dry THF solution of the enol triflate of 2-carboet-
hoxy-cyclohexanone (2a , 3.4 g, 2.1 mmol) was precooled to -78
°C, and was quickly taken into a syringe and added to the
above N-Boc-R-pyrrolidinylcyanocuprate solution. The reaction
mixture became deep yellow to orange in color and the solution
was stirred at -78 °C for an additional 1 h (still orange), then
stirred at -40 °C for 2.5 h, whereupon the color changed from
orange-brown to dark brown. After being stirred at room
temperature for 15 min, the dark-brown solution was recooled
to -78 °C, quenched with 10 mL of 1.0 N HCl, and warmed to
room temperature whereupon it was treated with NaHCO3
(sat.) to afford a solution with pH 10-11. The aqueous phase
was separated and extracted with Et2O (3 × 100 mL) and CH2-
Cl2 (3 × 60 mL). The combined extracts were dried over Na2-
Con clu sion s
In summary, R-(N-carbamoyl)alkylcuprates couple with
vinyl triflates derived from cyclic â-keto esters in good
to excellent yields. Higher yields are achieved with the
alkyl(cyano)cuprates which are efficient in R-(N-carbam-
oyl)alkyl ligand. The reaction can be achieved with the
corresponding vinyl nonaflates which are less expensive
to prepare. N-Boc deprotection and cyclization affords
annulated pyrrolinones. The method thus provides for
the rapid coupling of two ring systems with functionality
that can react to afford a third ring system. The present
work illustrates the rapid construction of highly func-
tionalized piperidine ring systems focusing on the im-
portant role that piperidine derivatives play in pharma-
1
SO4. The crude coupling product (4.74 g, H NMR showed it
to be mostly the desired coupling product with minor amounts
of 1-carboethoxy-2-sec-butylcyclohenene) was obtained as a
yellowish oil. The pure coupling product 4 (colorless oil, 2.68
g, 83%) was isolated by flash column chromatography (Biotage
65 M silica gel cartridge, 10% AcOEt/Hexane, v/v, ca. 2 L):
1H NMR (CDCl3, TMS) δ 1.28 (t, J ) 7.2 Hz, 3 H), 1.37 (1.46)
(s, 9 H, rotamer), 1.50-2.25 (m, 9 H), 2.25-2.60 (m, 2 H),
3.18-3.40 (m, 2 H), 3.40-3.90 (m, 1 H), 4.17 (q, J ) 7.2 Hz, 2
H), 4.95 (t, J ) 7.8 Hz), 5.10-5.20 (br s, 1 H, rotamer); 13C
(18) Kotsuki, H.; Kuzume, H.; Goheda, T.; Fukuhara, M.; Ochi, M.;
Oishi, T.; Hirama, M.; Shiro, M. Tetrahedron: Asymmetry 1995, 6,
2227.
(19) (a) Dieter, R. K.; Li, S. Unpublished results. (b) Dieter, R. K.;
Watson, R. Unpublished results.
(20) Morimoto, T.; Chatani, N.; Murai, S. J . Am. Chem. Soc. 1999,
121, 1758.
(21) Khim, H.-O.; Ogbu, C.-O.; Nelson, S.; Kahn, M. Synlett 1998,
1059.
972 J . Org. Chem., Vol. 68, No. 3, 2003

Coupling Reactions of R-(N-Carbamoyl)alkylcuprates
NMR (CDCl3, TMS) δ 14.3, 22.0, 22.3, 24.2, 24.6 (25.0), 25.4
(25.8), 26.4, 28.4, 32.4, 45.6 (45.9), 47.5 (48.0), 59.6 (60.0), 78.9,
124.5, 150.0, 154.5, 168.6 (rotamer); HR MS (FAB, m/z)
324.2177 (MH+) (Calcd for M+ + H, C18H30NO4, 324.2175).
1-P h en ylm eth yl-5-car boeth oxy-4-[1-(1,1-dim eth yleth yl-
oxyca r b on yl)p yr r olid in -2-yl]-1,2,3,6-t e t r a h yd r op yr i-
TMS) δ 1.27 (t, J ) 7.2 Hz, 3 H), 1.35 (s, 9 H), 1.45 (s, 5 H),
1.46-1.62 (m, 3 H), 1.62-1.85 (m, 3 H), 1.85-2.25 (m, 4 H),
2.25-2.55 (m, 1 H), 2.75-2.95 (m, 1 H), 3.34 (dt, J ) 18.9 Hz,
J ) 6.0 Hz, 1 H), 4.00-4.30 (m, 2 H), 5.15.(dd J ) 4.5, J )
12.0 Hz), 5.36 (dd J ) 4.5 Hz, J ) 12.0 Hz, 1 H, rotamer); 13
C
NMR (CDCl3, TMS) δ 14.2, 22.0, 22.2, 24.4 (24.9), 26.7 (27.0),
27.4, 28.3 (28.5), 29.3 (29.4), 30.7 (30.9), 32.5 (32.7), 44.1 (44.9),
46.5 (46.9), (59.1) 59.9, 79.1, 123.4, 152.3, 156.1, 168.1 (rota-
mer); HR MS (FAB, m/z) 352.2491 (MH+) (Calcd for M+ + H,
1
d in e (5). H NMR (CDCl3, TMS) δ 1.25 (t, J ) 6.8 Hz, 3 H),
1.39 (1.48) (s, 9 H, rotamer), 1.55-2.65 (m, 8 H), 3.10-3.40
(m, 3 H), 3.40-3.75 (m, 3 H), 4.15 (q, J ) 6.9 Hz, 2 H), 5.20 (t,
J ) 7.2 Hz), 5.25-5.55 (2 br s, 1 H, rotamer), 7.32 (s, 5 H); 13
C
C
20H34NO4, 352.2488).
NMR (CDCl3, TMS) δ 13.8, 23.8, 24.6, 28.0, 31.7 (32.1), 46.9,
48.3, 52.8, 58.7, 59.6, 61.6, 78.7, 122.3, 126.6, 127.8, 128.3
(128.7), 137.8, 150.8, 153.9, 166.0 (rotamer); HR MS (FAB, m/z)
415.2600 (MH+) (Calcd for M+ + H, C24H35N2O4, 415.2595).
1-P h en ylm eth yl-4-car boeth oxy-3-[1-(1,1-dim eth yleth yl-
oxyca r b on yl)p yr r olid in -2-yl]-1,2,5,6-t e t r a h yd r op yr i-
1,1-Dim eth yleth yl Ester (2-Ca r boeth oxy-1-cycloh exen -
1-ylm et h yl)m et h ylca r b a m ic Acid (10). 1H NMR (CDCl3,
TMS) δ 1.29 (t, J ) 7.2 Hz, 3 H), 1.45 (s, 9 H), 1.50-1.80 (m,
4 H), 2.03 (br s, 2 H), 2.29 (br s, 2 H), 2.74 (br s, 3 H), 4.18 (q,
J ) 7.2 Hz, 4 H); 13C NMR δ (CDCl3, TMS) 14.2, 21.8, 22.1,
26.8, (28.1) 28.4, 32.5, 49.7, 50.7, 60.3, 79.5, 127.8, 143.6, 156.0,
168.8 (rotamer); HR MS (FAB, m/z) 298.2014 (MH+) (Calcd
for M+ + H, C16H28NO4, 298.2018).
1
d in e (6). H NMR (CDCl3, TMS) δ 1.26 (t, J ) 6.9 Hz, 3 H),
1.38 (1.46) (s, 9 H, rotamer), 1.55-2.20 (m, 5 H), 2.20-3.40
(m, 6 H), 3.40-3.80 (m, 3 H), 4.16 (q, J ) 7.2 Hz, 2 H), 5.12 (t,
Bis(1,1-d im eth yleth yl) Ester [2,2′-Bip yr r olid in e]-1,1′-
d ica r boxylic Acid (11). 1H NMR δ (CDCl3 at 7.24 ppm as
internal standard) 1.44 (s, 18 H), 1.53-2.18 (br m, 8 H), 3.08-
J ) 7.4 Hz), 5.20-5.60 (3 br s, 1 H, rotamer), 7.30 (s, 5 H); 13
C
NMR (CDCl3, TMS) δ 14.2, 24.2, 26.7, 28.4, 32.4 (32.6), 47.4,
49.1, 52.4 (53.0), 58.5, 60.1, (62.1) 62.3, 79.3 (81.7), 122.4,
127.1, 128.2, 129.0, 137.8, 149.8, 154.4, 167.2 (rotamer); HR
MS (FAB, m/z) 415.2600 (MH+) (Calcd for M+ + H, C24H35N2O4,
415.2595).
3.41 (m, 4 H), 3.41-3.61 (br s, 1 H), 3.61-3.95 (br s, 1 H); 13
C
NMR δ (CDCl3 at 77.0 ppm as internal standard) 22.7, 23.4,
28.5, 46.6 (45.9, rotamer), 59.7, 79.5 (78.5, rotamer), 155.2; HR
MS (FAB, m/z) 341.2441 (MH+) (Calcd for M+ + H, C18H33N2O4,
341.2440).
1,1-Dim et h ylet h yl 3-Ca r b oet h oxy-2-[1-(1,1-d im et h yl-
ethyloxycarbonyl)pyrrolidin-2-yl]-1,4,5,6-tetrahydropyridine-
1,2,3,6,7,8,9,9b-Octa h yd r o-5H-p yr r olo[2,1-a ]isoin d ole-
5-on e (13). 1H NMR δ (CDCl3, TMS) 1.00-1.20 (m, 1 H), 1.50-
1.80 (m, 4 H), 1.95-2.10 (m, 1 H), 2.10-2.20 (m, 3 H), 2.20-
2.40 (m, 3 H), 3.15-3.30 (m, 1 H), 3.30-3.50 (m, 1 H), 3.95-
4.05 (m, 1H); 13C NMR δ (CDCl3, TMS) 20.7, 22.3, 22.5, 24.4,
28.9, 29.7, 42.4, 68.1, 132.5, 157.4, 177.3; HR MS (FAB, m/z)
178.1233 (MH+) (Calcd for M+ + H, C11H16NO, 178.1232).
1
1-ca r boxyla te (7). H NMR (CDCl3, TMS) δ 1.25 (t, J ) 7.1
Hz, 3 H), 1.43 (s, 9 H), 1.47 (s, 9 H), 1.60-2.05 (m, 5 H), 2.05-
2.70 (m, 4 H), 2.95-3.15 (m, 1 H), 3.15-4.00 (m, 2 H), 4.15 (q,
J ) 7.2 Hz, 2 H), 5.22 (t, J ) 8.6 Hz, 1 H); 13C NMR (CDCl3,
TMS) δ 14.2, (23.8) 24.3, 24.8, 28.3, 28.5, 31.1, 32.5, 45.1, 45.8,
47.9 (48.0), 59.6 (60.1), 78.6 (78.9), 80.9 (81.2), 118.0, 153.3,
153.7, (154.4) 154.9, 167.1 (rotamer); LC-MS (EI, m/z) 6.01
min, 425.1 (M+ + 1, 30%), 369.1 (20%), 325.1 (60%), 269.1
(100%), 225.1 (70%), 179.1 (90%).
Ack n ow led gm en t. S. Li gratefully acknowledges
Schering-Plough Research Institute (SPRI) and its
employee education assistance program. The guidance
of Drs. William J . Greenlee, Michael Czarniecki, and
J ohn W. Clader at Schering-Plough Research Institute
is gratefully appreciated.
1,1-Dim eth yleth yl 2-(2-Ca r boeth oxy-1-cycloh exen -1-
1
yl)-1-p ip er id in eca r boxyla te (8). H NMR (CDCl3, TMS) δ
1.26 (t, J ) 6.9 Hz, 3 H), 1.38 (s, 9 H,), 1.40-1.75 (m, 9 H),
1.75-1.85 (m, 1 H), 2.00-2.30 (m, 3 H), 2.30-2.50 (m, 1 H),
3.00 (m, 1 H), 3.96 (dd, J ) 6.3 Hz, J ) 12.0 Hz, 1 H), 4.13 (q,
J ) 6.6 Hz, 2 H), 5.07 (t, J ) 5.1 Hz, 1 H); 13C NMR (CDCl3,
TMS) δ 14.2, 19.2, 22.1, 22.2, 22.8, 25.6, 26.7, 27.3, 28.3, 39.7,
55.3, 59.9, 79.2, 123.8, 151.5, 155.8, 168.5; HR MS (FAB, m/z)
338.2330 (MH+) (Calcd for M+ + H, C19H32NO4, 338.2331).
1,1-Dim eth yleth yl 2-(2-Ca r boeth oxy-1-cycloh exen -1-
yl)h exa h yd r o-a zep in e-1-ca r boxyla te (9). 1H NMR (CDCl3,
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 4-11 and 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O026375F
J . Org. Chem, Vol. 68, No. 3, 2003 973