α-(N-carbamoyl)alkylcuprate chemistry in the synthesis of nitrogen heterocycles

Article abstract of DOI:10.1021/jo016053w

The conjugate adducts obtained via coupling of α-(N-carbamoyl)alkylcuprates with α,β-ynoates, α-allenyl esters, or α,β-enoates or enimides undergo N-Boc deprotection and cyclization onto the ester functionality upon treatment with PhOH/TMSCl, catecholboron bromide, or trimethylsilyl triflate. This two-pot sequence provides synthetic routes to 4-alkylidinepyrrolidine-2-ones, 4-alkylidinepyrrolizidin-2-ones, and 4-alkylidineindolizidin-2-ones via allenyl esters; pyrrolin-2-ones, tetrahydropyrrolizin-2-ones, and tetrahydroindolizin-2-ones via α,β-ynoates; pyrrolidin-2-ones, pyrrolizidin-2-ones, and indolizidin-2-ones via α,β-enoates or α,β-enimides. The reluctance of γ-carbamoyl-α,β-enoates to undergo E/Z isomerization requires the use of (Z)-β-iodo-α,β-enoates readily prepared by the addition of HI to the alkynyl esters for the efficient preparation of pyrrolinones, tetrahydropyrrolizinones, and tetrahydroindolizinones. Utilization of ω-functionalized α,β-ynoates or β-iodo-α,β-enoates allows for cyclization onto the ω-functionality providing for a synthetic route to quinolizidines.

Full text of DOI:10.1021/jo016053w

J . Org. Chem. 2002, 67, 847-855
847
r-(N-Ca r ba m oyl)a lk ylcu p r a te Ch em istr y in th e Syn th esis of
Nitr ogen Heter ocycles
R. Karl Dieter* and Kai Lu
Howard L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-0973.
dieterr@clemson.edu
Received August 23, 2001
The conjugate adducts obtained via coupling of R-(N-carbamoyl)alkylcuprates with R,â-ynoates,
R-allenyl esters, or R,â-enoates or enimides undergo N-Boc deprotection and cyclization onto the
ester functionality upon treatment with PhOH/TMSCl, catecholboron bromide, or trimethylsilyl
triflate. This two-pot sequence provides synthetic routes to 4-alkylidinepyrrolidine-2-ones, 4-alkyl-
idinepyrrolizidin-2-ones, and 4-alkylidineindolizidin-2-ones via allenyl esters; pyrrolin-2-ones,
tetrahydropyrrolizin-2-ones, and tetrahydroindolizin-2-ones via R,â-ynoates; pyrrolidin-2-ones,
pyrrolizidin-2-ones, and indolizidin-2-ones via R,â-enoates or R,â-enimides. The reluctance of
γ-carbamoyl-R,â-enoates to undergo E/Z isomerization requires the use of (Z)-â-iodo-R,â-enoates
readily prepared by the addition of HI to the alkynyl esters for the efficient preparation of
pyrrolinones, tetrahydropyrrolizinones, and tetrahydroindolizinones. Utilization of ω-functionalized
R,â-ynoates or â-iodo-R,â-enoates allows for cyclization onto the ω-functionality providing for a
synthetic route to quinolizidines.
In tr od u ction
cell-cell interactions (e.g., aggregation, differentiation,
and fusion, cellular transport, tumorigenesis, metastasis,
inflammation, and blood clotting).7 Many synthetic routes
to these compounds introduce the nitrogen heteroatom
into a carbon framework via azide, cyanide, or ammonia
substitution reactions or via reduction of imine deriva-
tives. The development of R-aminoalkylcarbanion meth-
odologies has begun to provide alternative strategies for
the synthesis of nitrogen heterocycles offering advantages
in connectivity patterns and in asymmetric synthesis.
R-Lithio carbamates have been exploited in the synthesis
of pyrrolidines8a,b and piperidines,8b-d while benzotriazole
stabilized carbanion chemistry has been exploited in the
synthesis of pyrroles,9a-c imidazolidin-2-ones,9d oxazolidi-
nones,9d and pyrrolidines.9e The participation of N-
protected R-aminoalkylcuprates (i.e., R-cuprio forma-
midines, carbamates, and azo compounds) in conjugate
addition reactions10 and of R-(N-carbamoyl)alkylcuprates
in substitution reactions with vinyl triflates,11a vinyl
Pyrrolidine and piperidine heterocycles and their fused
analogues are ubiquitous in nature and display a wide
range of biological activities.1-5 Numerous synthetic
routes to naturally occurring pyrrolidines,2 piperidines,3
pyrrolizidines,4 indolizidines,5 and quinolizidines5 are
detailed in several monographs and review articles.
Scalemic 3-pyrrolin-2-ones are important synthetic in-
termediates, and the structural unit is found in natural
products displaying pharmacological activity (e.g., anti-
tumor, inhibition of platelet aggregation, and psycho-
tropic properties).6 Polyhydroxylated pyrrolidines and
indolizidines (i.e., aza sugars) are glycosidase inhibitors,
and oligosaccharide synthesis and degradation is impor-
tant in a wide variety of biological phenomena involving
(1) For reviews on amphibian alkaloids, see: Daly, J . W.; Spande,
T. F. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Wiley: New York, 1986; Vol. 4, Chapter 1, p 1. (b) Daly, J .
W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids: Chemistry and
Pharmacology; Cordell, G. A., Ed.; Academic Press: San Diego, 1993;
Vol. 43, Chapter 3, p 185.
(2) Massiot, G.; Delaude, C. In The Alkaloids: Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: San Diego, 1986; Vol.
27, Chapter 3, p 269 and references therein.
(7) Fellows, L. E.; Kite, G. C.; Nash, R. J .; Simmonds, M. S. J .;
Scofield, A. M. Recent Adv. Phytochem. 1989, 23, 395.
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(b) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J . Org. Chem.
1999, 64, 1160. (c) J ohnson, T. A.; Curtis, M. D., Beak, P. J . Am. Chem.
Soc. 2001, 123, 1004. (d) Wilkinson, T. J .; Stehle, N. W.; Beak, P. Org.
Lett. 2000, 2, 155.
(3) Strunz, G. M.; Findlay, J . A. In The Alkaloids: Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: San Diego, 1985; Vol.
26, Chapter 3, p 89 and references therein.
(4) Wro´bel, J . T. In The Alkaloids: Chemistry and Pharmacology;
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p 327 and references therein.
(9) (a) Katritzky, A. R.; Wang, X.; Denisenko, A. J . Org. Chem. 2001,
66, 2850. (b) Katritzky, A. R.; Zhang, L.; Yao, J .; Denisko, O. V. J .
Org. Chem. 2000, 65, 8074. (c) Katritzky, A. R.; Huang, T.-B.;
Voronkov, M. V.; Wang, M.; Kolb, H. J . Org. Chem. 2000, 65, 8819.
(d) Katritzky, A. R.; Luo, Z.; Fang, Y.; Steel, P. J . J . Org. Chem. 2001,
66, 2858. (e) Katritzky, A. R.; Luo, Z.; Fang, Y. Tetrahedron Lett. 2000,
41, 9691.
(10) For conjugate additions to unsaturated ketones and aldehydes,
see: (a) Dieter, R. K.; Alexander, C. W. Tetrahedron Lett. 1992, 33,
5693. (b) Dieter, R. K.; Alexander, C. W. Synlett 1993, 407. (c)
Alexander, C. W.; Lin, S.-Y.; Dieter, R. K. J . Organomet. Chem. 1995,
503, 213. (d) Dieter, R. K.; Alexander, C. W.; Nice, L. E. Tetrahedron
2000, 56, 2767. For conjugate additions to R,â-unsaturated carboxylic
acid derivatives, see: (e) Dieter, R. K.; Velu, S. E. J . Org. Chem. 1997,
62, 3798. (f) Dieter, R. K.; Lu, K. Tetrahedron Lett. 1999, 40, 4011. (g)
Dieter, R. K.; Lu, K.; Velu, S. E. J . Org. Chem. 2000, 65, 8715.
(5) (a) Michael, J . P. In The Alkaloids: Chemistry and Pharmacol-
ogy; Cordell, G. A., Ed.; Academic Press: San Diego, 2001; Vol. 55, p
92 and references therein. (b) Takahata, H.; Momose, T. In The
Alkaloids: Chemistry and Pharmacology; Cordell, G. A., Ed.; Academic
Press: San Diego, 1993; Vol. 44, Chapter 3, p 189 and references
therein. (c) Howard, A. S.; Michael, J . P. In The Alkaloids: Chemistry
and Pharmacology; Brossi, A., Ed.; Academic Press: San Diego, 1986;
Vol. 28, Chapter 3, p 183 and references therein.
(6) (a) Cuiper, A. D.; Brzostowska, M.; Gawronski, J . K.; Smeets,
W. J . J .; Spek, A. L.; Hiemstra, H.; Kellogg, R. M.; Feringa, B. L. J .
Org. Chem. 1999, 64, 2567 and references therein. (b) Dittami, J . P.;
Xu, F.; Qi, H.; Martin, M. W. Tetrahedron Lett. 1995, 36, 4201 and
references therein.
10.1021/jo016053w CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/08/2002

848 J . Org. Chem., Vol. 67, No. 3, 2002
Dieter and Lu
Sch em e 1
Sch em e 2a
a
Key: (a) (i) n-BuSnCu‚SMe2, LiBr, THF, -78 °C (from 4a ,
73%; 4b, 69%), (ii) I2, Et2O, rt, overnight [5a , 82% (I2), 89% (ICI);
5b, 91% (I2), 90% (ICI)]; (b) LiI or NaI, HOAc, 70 °C, 12 h; (c)
NaI, TMSCI, H2O (0.5 equiv), MeCN.
respectively) N-heterocycles with the N-atom at the ring
fusion. Although this strategy is largely limited to
formation of simple and annulated five membered N-
heterocycles, ω-functionalized â-iodo-R,â-enoates or R,â-
ynoates can be exploited in the synthesis of larger ring
systems (e.g., quinolizidines, Scheme 1).
Resu lts a n d Discu ssion
The requisite γ-carbamoyl esters (1), â-alkylidine-γ-
carbamoyl esters (2), and γ-carbamoyl-R,â-enoates (3)
were readily prepared via conjugate addition of R-(N-
carbamoyl)alkylcuprates to R,â-unsaturated carboxylic
acid derivatives, R-allenyl esters, and R,â-ynoates as
previously described.10g (Z)-â-Iodo-R,â-enoates were pre-
pared by the addition of HI to the corresponding R,â-
ynoates. Although the use of LiI/AcOH15 gave excellent
yields of (Z)-isomers 6a ,c,d , the reaction gave many
products with 4b yielding only a trace of 6b (Scheme 2).
Good yields of 6b could be obtained with in situ generated
HI (i.e., Me3SiCl, NaI, 0.5 H2O)16 in contrast to literature
reports that treatment of R,â-ynones with this reagent
system affords geometrical mixtures (i.e., E/Z) of â-iodo-
R,â-enones,17 the (E)-isomer,18 or the deconjugated â-iodo-
â,γ-enones17 when excess TMSCl was employed. These
results reflect, in part, the greater tendency of R,â-enones
to undergo (Z)-(E)-isomerization13 than the correspond-
ing R,â-enoates (vide infra).10g (E)-â-Iodo-R,â-enoates were
prepared via a two-step procedure involving conjugate
addition of tri-n-butylstannylcopper to R,â-ynoates fol-
lowed by iodination of the vinyl stannane.19 Iodine and
iodine monochloride gave comparable results in the
iodination of the vinyl stannane. Although the stereo-
chemistry was not rigorously established, the two pro-
cedures gave different geometrical isomers whose identity
was confirmed in subsequent transformations (vide in-
fra). Consequently, stereoselective routes to both the (Z)-
and (E)-â-iodo-R,â-enoates are readily available for ex-
ploitation in R-(N-carbamoyl)alkylcuprate chemistry.
R-(N-Carbamoyl)alkylcuprates derived from N-Boc-
protected dimethylamine 7a , pyrrolidine 7b, or piperidine
7c underwent high-yield coupling with (E)- or (Z)-â-iodo-
iodides,11b,c and propargyl substrates12 provides oppor-
tunities to exploit these reactions in the synthesis of
nitrogen heterocycles. Conjugate addition reactions of
R-(N-carbamoyl)alkylcuprates have been exploited in the
synthesis of pyrroles13 and 4-alkylidene pyrrolidinones
and pyrrolizidinones.10f In this full account, we describe
the synthesis of pyrrolidinones, pyrrolizidinones, indolizidi-
nones, pyrrolinones, tetrahydropyrrolizinones, tetra-
hydroindolizinones, and quinolizidines via R-(N-carbam-
oyl)alkylcuprate chemistry.
The synthetic route to these N-heterocycles in-
volves initial conjugate addition of R-(N-carbamoyl)-
alkylcuprates to R,â-unsaturated carboxylic acid deriva-
tives, R-allenyl esters, or R,â-ynoates followed by car-
bamate deprotection and cyclization (Scheme 1). â-Iodo-
R,â-enoates can be substituted for R,â-ynoates and offer
an alternative approach to stereocontrol in the formation
of γ-carbamoyl-R,â-enoates and provide opportunities for
asymmetric synthesis.14 Cuprates derived from acyclic
carbamates afford simple five-membered heterocycles
while those derived from N-Boc-protected pyrrolidine or
piperidine afford bicyclic (i.e., [3.3.0] and [4.3.0] systems
(11) (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.;
Nice, L. E. J . Org. Chem. 2001, 66, 2302.
(12) Dieter, R. K.; Nice, L. E. Tetrahedron Lett. 1999, 40, 4293.
(13) Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283.
(15) Ma, S.; Lu, X.; Li, Z. J . Org. Chem. 1992, 57, 709.
(16) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675.
(17) (a) Luo, F.-T.; Kumar, K. A.; Hsieh, L.-C.; Wang, R.-T. Tetra-
hedron Lett. 1994, 35, 2553. (b) Luo, F.-T.; Hsieh, L.-C. Tetrahderon
Lett. 1994, 35, 9585. (c) Luo, F.-T. J . Org. Chem. 1998, 63, 5656.
(18) Parsons, P. J .; Caddick, S. Tetrahedron 1994, 50, 13523.
(19) Piers, E.; Chong, J . M.; Morton, H. E. Tetrahedron 1989, 45,
363.
(14) Dieter, R. K.; Topping, C. M.; Chandupatla, K. R.; Lu, K. J .
Am. Chem. Soc. 2001, 123, 5132.

R-(N-Carbamoyl)alkylcuprate Chemistry
J . Org. Chem., Vol. 67, No. 3, 2002 849
Ta ble 1. Rea ction of r-(N-Ca r ba m oyl)a lk ylcu p r a tes w ith
(E)- or (Z)-â-Iod o-r,â-en oa tes
Ta ble 2. Syn th esis of 4-Alk ylid in e-2-p yr r olid in on es,
2-P yr r olizid in on es, a n d 2-In d olizid in on es fr om
â-Alk ylid in e-γ-N-ca r ba m oyl Ester s
a
The R2CuLi reagent prepared from 2RLi + CuCN‚2LiCl (0.5
equiv) was employed unless otherwise noted. Methyl ester used
b
unless otherwise noted. Yields based upon isolated products
purified by flash column chromatography. c Ethyl ester was
d
employed. RCuCNLi was employed.
R,â-enoates (i.e., 5a ,b and 6a -d , respectively) to afford
γ-carbamoyl-R,â-enoates 8-12 stereospecifically in gen-
erally excellent yields (Table 1). Lower yields were
generally obtained with cuprates derived from 7c (entry
10) than from 7a ,b, although a low yield of vinylation
product was observed with the pyrrolidinyl cuprate and
6b (entry 8). Vinylations of R-(N-carbamoyl)alkylcuprates
are high-yield reliable transformations11c that also afford
high enantioselectivity14 with scalemic N-Boc-pyrroli-
dinylcuprates.
In the initial study, the deprotection of the γ-carbam-
oyl-â-alkylidine esters and subsequent cyclization was
achieved in a single pot using PhOH/TMSCl (Table 2).10f
The carbamate deprotection procedure developed by
Merrifield20 called for the use of large excesses of PhOH
(30 equiv) and TMSCl (10 equiv), which at times posed
problems in the workup procedure. Subsequent experi-
ments revealed that these quantities could be reduced
without diminution of yields. Catecholboron bromide21
and trimethylsilyl triflate22 also effected the sequential
carbamate deprotection and cyclization in generally
somewhat higher yields (entries 2 and 3 vs 1 and 14 vs
a
Carbamate deprotonation (s-BuLi, sparteine or TMEDA, THF,
-78 °C) followed by sequential addition of 1.0 equiv of CuCN‚2LiCl
(-55 °C, 45 min) and allenyl ester [TMSCl (2.5 equiv), -55 °C to
b
rt]. A ) PhOH (15-30 equiv), TMSCl (5-10 equiv), CH2Cl2 (25
°C, 2 h). B ) catecholboron bromide. C ) trimethylsilyl triflate
(TMSOTf, 1-2 equiv). D ) TMSOTf (10 equiv). E ) A and then
Me3Al (2.0 equiv), CH2Cl2 [0-25 °C, 3 h]. c Olefin diastereomeric
ratio (dr) determined by 1H NMR analysis; >95:5 unless noted.
d
Isolated yields based upon products purified by column chroma-
tography. e Dr ) 84:16. f Dr ) 88:12. Dr ) 66:34.
g
13), although similar yields were obtained in pyrroli-
zidinone formation (entries 4 and 5). These protocols
failed to effect cyclization to the indolizidine skeleton and
required modification. Formation of indolizidinone 15
required a two-step procedure involving N-Boc deprotec-
tion (PhOH/TMSCl) of the γ-carbamoyl-â,γ′-enoate fol-
lowed by Me3Al-mediated cyclization23 of the free amine
onto the ester functionality to afford 15 in good yield
(63%).
(20) Kaiser, E., Sr.; Picart, F.; Kubiak, T.; Tam, J . P.; Merrifield, R.
B. J . Org. Chem. 1993, 58, 5167.
(21) Boeckman, R. K., J r.; Potenza, J . C. Tetrahedron Lett. 1985,
26, 1411.
(22) Hamada, Y.; Kato, S.; Shioiri, T. Tetrahedron Lett. 1985, 26,
(23) Takahata, H.; Bandoh, H.; Momose, T. Heterocycles 1996, 42,
3223.
39.

850 J . Org. Chem., Vol. 67, No. 3, 2002
Dieter and Lu
Ta ble 3. Syn th esis of P yr r olin -2-on es,
As previously reported, the conjugate addition of R-(N-
carbamoyl)alkylcuprates to R-allenyl esters afforded
the (E)-olefins diastereoselectively in ratios generally
>95:5.10f This stereoselectivity is a consequence of the
cuprate reagent approaching the 2,3-double bond of the
allenyl ester anti to the more bulky substitutent at C-4.
In two instances, where the â,γ-enoate was generated as
a mixture of (E)- and (Z)-diastereomers (e.g., 86:14 and
91:9), the ratio was maintained during the deprotection
and cyclization events (e.g., 84:16 and 88:12, respectively,
Table 1, entries 1 and 2). Nevertheless, a phenyl-
substituted (E)-olefin was found to undergo significant
E/Z isomerization during the deprotection cyclization
sequence with PhOH/TMSCl (i.e., 66:34 dr, entry 8). This
isomerization occurred in the formation of pyrrolizidinone
17 (entry 8) but not during the formation of pyrrolidinone
16 (entry 7). The origin of this isomerization is curious.
It seems unlikely that it occurs via protonation of the
more strained and therefore more easily protonated olefin
in 17 since this would reasonably be expected to afford
the pyrrolin-2-one with an endocyclic double bond. The
observation of E/Z isomerization in 17 but not 16 sug-
gests that isomerization may be tied to the relative rates
of cyclization. This would be consistent with the slow rate
of HCl formation from PhOH/TMSCl compared to the
rapid rate for carbamate deprotection.20
The resultant 4-alkylidinepyrrolidin-2-ones (i.e., 13, 16,
18, 21), pyrrolizidin-2-ones (14, 17, 19, 22), and indoli-
zidin-2-ones (i.e., 15 and 20) contain a â,γ-unsaturated
lactam functionality that can provide opportunities for
enolate chemistry. Deprotonation of 13 or 14 with lithium
diisopropyl amide (1.5-1.8 equiv, THF, -78 °C) followed
by quenching with dimethyl sulfate (-50 to +25 °C) gave
R-alkylation in good to excellent yields (90% and 70%,
respectively) with no positional or stereoisomerization of
the exocyclic double bond. Alkylation of 14 afforded a 1:1
mixture of diastereomers presumably arising via enol-
ization of the methylation product by the excess base
employed (1.8 equiv). Excess base was employed in these
small scale reactions (<1.0 mmol) to ensure complete
deprotonation.
P yr r olizid in -2-on es, a n d In d olizid in -2-on es fr om
γ-N-ca r ba m oyl-r,â-en oa tes
a
Prepared via the stereoselective vinylation of 7a -c or obtained
via chromatographic separation of the E/Z mixture of diastereo-
b
mers resulting from reaction of 7a -c with 4b. A ) PhOH (15-
30 equiv), TMSCl (5-10 equiv), CH2Cl2 (25 °C, 2 h). B ) A and
then Me3Al, CH2Cl2. c 23 R ) n-Bu; 24 R ) -(CH2)3Cl; 25 R )
Ph; 26 R ) n-Bu, n ) 1; 27 R ) -(CH2)3Cl, n ) 1; 28 R )
d
-(CH2)3Cl, n ) 2; 29 R ) n-Bu, n ) 2. Yields based upon isolated
products purified by column chromatography. e The quinolizidine
34 (Scheme 3) was formed in 56% yield. f Yield estimated from
GC-MS ion-current trace. Uncyclized piperidine was recovered
in 51% yield.
to afford 23 in 59% yield (eq 1). Efforts to reduce the
amount of thiophenol employed gave either lower conver-
sions of the (E)-isomer to 23 or increased amounts of the
thiophenol conjugate adduct (eq 1). This deprotection-
thiophenol protocol did not work for a γ-carbamoyl-R,â-
enoate containing a pyrrolidine [i.e., ethyl (E)-3-(2-
pyrrolidinyl)-2-heptenoate] ring system. To circumvent
these difficulties, the vinylation with stereodefined â-iodo-
R,â-enoates was employed for the preparation of (Z)-γ-
N-carbamoyl-R,â-enoates (vide supra, Table 1).
The conjugate addition of R-(N-carbamoyl)alkyl-
cuprates to R,â-ynoates afforded mixtures of (E)- and (Z)-
R,â-enoates and the stereoselectivity of this reaction could
not be controlled.10g Upon treatment of the E/Z mixture
with the deprotection-cyclization protocols only the (Z)-
diastereomer underwent cyclization and the (E)-isomer
was recovered as unchanged amine. Reaction of the
pyrrolidinyl cuprate derived from 7b with ethyl 2-hep-
tynoate gave 11a and its (E)-isomer as a 57:43 mixture
which upon treatment with PhOH/TMSCl gave 26 (53%)
and the free amine of the (E)-diastereomer (35%) in a
comparable ratio (60:40). This was in marked contrast
to the γ-(N-carbamoyl)-R,â-enones in which both the (E)-
and (Z)-diastereomers gave rise to pyrroles under the
carbamate deprotection procedures,13 illustrating the
reluctance of R,â-enoates to undergo facile E/Z isomer-
ization. Efforts to effect isomerization of the (E)-isomer
to the (Z)-isomer with catalytic amounts of PhSSPh
proved unsuccessful.24a Heating (E)-N-Boc-N-methyl-
aminomethyl-2-heptenoate neat with 2.0 equiv of thio-
phenol24c effected (E)- to (Z)-isomerization and cyclization
Treatment of the (Z)-γ-N-carbamoyl-R,â-enoates with
PhOH/TMSCl effected clean carbamate cleavage and
cyclization for the simple pyrrolin-2-ones (Table 3, entries
1-3) and pyrrolizidin-2-ones (entries 4-5). Indolizidin-
2-ones 28 and 29 (entries 6-7) were not obtained upon
treatment of the γ-(N-carbamoyl)-R,â-enoates with PhOH/
TMSCl or TMSOTf. Although low yields of indolizidin-
2-ones could be achieved by subsequent treatment with
trimethylaluminum,23 the major products were either the
free amine of the (E)-diastereomer (entry 7) or cyclization
onto an ω-functionality (entry 6, 34 Scheme 3).
ω-Functionalized R,â-ynoates provide potential op-
portunities for cyclization onto the ω-functionality as well
as onto the ester moiety (Scheme 3). This synthetic
strategy was probed employing R-(N-carbamoyl)alkyl-
cuprates derived from N-Boc-protected N,N-dimethyl-
amine (7a ), pyrrolidine (7b), and piperidine (7c) and
methyl 6-chloro-2-ynoate 4b (prepared from 5-chloro-1-
pentyne and methyl chloroformate) or (E)-5b and (Z)-6-
chloro-3-iodo-2-enoate 6b derived from it. The requisite
(24) (a) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T. Synthesis
1990, 1123. (b) Harrowven, D. C.; Hannam, J . C.; Tetrahedron 1999,
55, 9341. (c) Tanikaga, R.; Yamashita, H.; Kaji, A. Synthesis 1986,
416.

R-(N-Carbamoyl)alkylcuprate Chemistry
J . Org. Chem., Vol. 67, No. 3, 2002 851
Ta ble 4. Syn th esis of P yr r olizid in -2-on es a n d
In d olizid in on es fr om γ-N-ca r ba m oyl Ester s
Sch em e 3
a
Diastereomeric ratio (dr) determined from 1H NMR integra-
tions and 13C NMR peak heights. A ) PhOH (30), TMSCl (10),
CH2Cl2. B ) A and then ii. Me3Al, CH2Cl2. C ) A and then
neutralize with solid K2CO3/CH2Cl2. c Yields determined on iso-
b
γ-carbamoyl-R,â-enoates were prepared either as a sepa-
rable mixture of (E)- and (Z)-diastereoisomers via con-
jugate addition of R-(N-carbamoyl)alkylcuprates to R,â-
ynones or stereoselectively via vinylation of R-(N-
carbamoyl)alkylcuprates with either (E)- or (Z)-6-chloro-
3-iodo-2-hexynoate (i.e., 5b or 6b, respectively). Reaction
of E/Z mixtures of γ-carbamoyl-R,â-enoates obtained via
the conjugate addition of 7a or 7b with 4b gave mixtures
of products arising via the two modes of cyclization in
ratios comparable to the original E/Z ratio. The reaction
of 7a with 4b gave an E/Z mixture of diastereomers 8b/
10b (47:53) that upon deprotection-cyclization gave a
49:51 mixture of 31/24. Similarly, reaction of the cuprate
derived from 7b with 4b afforded a 64:36 mixture of 11b
and its (E)-diastereomer 9, which upon treatment with
PhOH/TMSCl gave a 74:26 ratio of 27/32.
These observations were confirmed by utilization of the
pure (E)- or (Z)-diastereomers obtained either by chro-
matographic separation or stereospecifically from the
respective (E)- or (Z)-6-chloro-3-iodo-2-enoates 5b and 6b,
respectively. Upon treatment with PhOH/TMSCl, the (E)-
diasteromer 8b, 9, or 30c underwent N-Boc deprotection
and cyclization onto the alkyl chloride in good to excellent
yields to afford the piperidine 31, indolizidine 32, and
quinolizidine 33, respectively. Similar treatment of the
(Z)-diastereomers 10b or 11b afforded the pyrolin-2-one
24 or pyrrolizin-2-one 27, respectively, in good yields.
Reaction of the (Z)-diastereomer of 30c, however, afforded
quinolizidine 34 rather than the indolizin-2-one 28 (Table
3, entry 6) reflecting again the difficulty of forming
indolizin-2-ones via these cyclizations. Quinolizidines 33
and 34 are diastereomeric about the carbon-carbon
double bond.
d
lated products purified by column chromatography. Dr deter-
mined from HPLC, GC-MS, 1H NMR integrations, and 13C NMR
peak heights. e Conjugate addition was performed in ether. Con-
f
jugate addition was performed in THF. Determined by 1H NMR
g
integration on the spectrum of the HCl salt of the free amine.
methyl acrylate followed by deprotection and cyclization
with PhOH/TMSCl afforded both the pyrrolizidin-2-one
37a and indolizidin-2-one 37b in excellent to good yields
(entries 1 and 2). PhOH/TMSCl effected N-Boc deprotec-
tion of 35d but failed to effect cyclization to 37d , which
could be achieved in good yield by subsequent treatment
with Me3Al (entry 4). The methyl absorptions for 37d in
the 1H NMR spectrum permitted assignment of the major
[(1R*,9S*), δ 1.19 (lit.25 δ 1.08-1.14)] and minor [(1S*,9S*),
δ ) 1.08 (lit.25 δ 0.96-1.04)] diastereomers by comparison
with previous assignments.
Utilization of methyl crotonate also afforded a mixture
of diastereomeric conjugate adducts (entry 3). Deprotec-
tion and cyclization of 35c gave a mixture of diastereo-
meric pyrrolizidin-2-ones 37c in roughly the same ratio
as the starting γ-carbamoyl esters (entry 3), while
cyclization of 35d gave a slightly enhanced dr of indol-
izidin-2-ones 37d (entry 4) suggesting a differential
cyclization efficiency for the two diastereomeric conju-
gate adducts. The major [(1R*,8S*), δ 1.12 (lit.26a,b
δ
1.00-1.15)] and minor [(1S*,8S*), δ ) 0.95 (lit.26b δ 0.98)]
diastereomers of pyrrolizidin-2-one 37c could also be
assigned by comparison with a literature report. The 13C
absorptions for 37c matched those reported for the
(1R*,8S*) diastereomer.26a Utilization of enantiopure
oxazolidinone 36c derived from crotonic acid afforded an
undetermined mixture of diastereomeric conjugate ad-
Conjugate addition of pyrrolidinyl- (from 7b) or piperi-
dinylcuprates (from 7c) to R,â-unsaturated esters10g
followed by N-Boc deprotection and cyclization affords
the fully saturated pyrrolizidin-2-ones and indolizidin-
2-ones, respectively (Table 4). Conjugate addition to
(25) Das, S.; Kumar, J . S. D.; Shivaramayya, K.; George, M. V.
Tetrahedron 1996, 52, 3425.
(26) (a) Das, S.; Kumar, J . S. D.; Shivaramayya, K.; George, M. V.
J . Chem. Soc., Perkin Trans. 1 1995, 1797. (b) Mori, M.; Kanda, N.;
Oda, I.; Ban, Y. Tetrahedron 1985, 41, 5465.

852 J . Org. Chem., Vol. 67, No. 3, 2002
Dieter and Lu
ducts in Et2O and a 76:24 ratio in THF (entries 5 and 6).
The diastereomer ratio for the 1,4-adducts obtained in
THF was determined from the H NMR spectrum of the
acid derivatives followed by N-Boc-deprotection and
cyclization affords efficient synthetic routes to a diverse
range of simple and fused nitrogen heterocycles. These
include 4-alkylidine pyrrolidine-2-ones, 4-alkylidine pyr-
rolizidin-2-ones, and 4-alkylidine indolizidin-2-ones via
allenyl esters; pyrrolin-2-ones, tetrahydropyrrolizin-2-
ones, and tetrahydroindolizin-2-ones via R,â-ynoates and
pyrrolidin-2-ones; and pyrrolizidin-2-ones and indolizidin-
2-ones via R,â-enoates. Incorporation of an additional
functional group in the R,â-unsaturated system provides
opportunities for the synthesis of addition ring systems
(e.g., quinolizidines) via cyclization onto this additional
functionality. This strategy provides a rapid entry to the
piperidinyl acetic acid 31, which in principle, can be
converted via lithium diethyl cuprate conjugate addition
to 3,3-dialkylpiperidines of the type employed in a
number of synthetic approaches to quebrachamine and
the aspidospermidine family of alkaloids.29 The two pot
sequence of conjugate addition followed by N-Boc-depro-
tection and cyclization is efficient for the synthesis of all
the ring systems examined with the exception of tetra-
hydroindolizin-2-ones which were formed in low yields.
Utilization of chiral oxazolidinones allows for modest to
excellent diastereoselectivity in both a relative and
absolute sense for the synthesis of the fully saturated
rings systems. Asymmetric vinylation of R-(N-carbamoyl)-
alkylcuprates provides opportunities for the synthesis of
scalemic pyrrolin-2-ones and tetrahydropyrrolizin-2-ones,
which are richly functionalized for further synthetic
elaboration.
1
HCl salt of the free amine obtained via N-Boc-deprotec-
tion. The reaction of the pyrrolidinyl cuprate with enan-
tiopure oxazolidine 36c can afford four diastereomers
which upon N-Boc-deprotection and cyclization with
concomitant removal of the chiral auxiliary reduces to
two diastereomers readily discernible in the 1H and
13NMR spectra of 37c. The sample of pyrrolizidin-2-one
37c obtained via deprotonation of 7b in Et2O, cuprate
formation, conjugate addition, and cyclization was ana-
lyzed by chiral-phase HPLC, which displayed three
separable components X, Y, Z (17.5:3.5:79.9 ratios, re-
spectively). A dr of 95:5 observed in the 1H NMR
spectrum requires that the minor enantiomer of the
minor diastereomer lie under either peak X or peak Z
and the major enantiomer of the minor diastereomer be
identified with peak Y. Even without knowing which
peak conceals the minor enantiomer of the minor dia-
stereomer, an enantiomeric excess of the major dia-
stereomer can be placed in the range of 64-66% (i.e.,
82:18-83:17 er) and approximately 40% ee for the minor
diastereomer.27a The latter figure is extremely sensitive
to errors in 1H integration values. Chiral phase HPLC
analysis thus confirms the diastereoselectivity (95:5) and
establishes an upper limit for the enantioselectivity (66%,
er ) 83:17) of the major diastereomeric conjugate adduct.
This is consistent with differential rates of reaction for
a matched and mismatched pair of chiral reactants27b
(i.e., 36c and the chiral cuprate containing a stereogenic
center bound to copper) resulting in a dynamic kinetic
resolution of the racemic cuprate reagent. This interpre-
tation is supported by the observation that reaction of
the pyrrolidinylcuprate gave no enantioselectivity in
conjugate addition reactions with benzyl acrylate14 con-
sistent with kinetic resolution of the chiral pyrrolidinyl-
cuprate by the scalemic oxazolindinone. The excellent
diastereoselectivity and good enantioselectivity under
dynamic kinetic resolution suggests that the procedure
may be synthetically useful. Finally, conjugate addition
of the cuprate reagent derived from N-Boc-2-methyl-
pyrrolidine gave an 80:20 dr of conjugate adducts from
which a single diastereomeric pyrrolizidin-2-one 37e was
isolated from the deprotection cyclization sequence. The
diastereomeric product obtained from 35e could be as-
signed as (5S*,8S) 37e [δ ) 3.43 H5 (lit.28 δ ) 3.55), δ )
3.94 H8 (lit.28 δ ) 3.95) rather than the (5R*,8S*)
diastereomer [lit.28 δ ) 4.16-3.55] by comparison with
literature data. These results indicate that modest to
excellent diastereoselectivity can be achieved depending
upon the substitution pattern of the R-(N-carbamoyl)-
alkylcuprate and the carboxylic acid derivative employed.
The use of scalemic oxazolidinones as a chiral auxiliary
holds some promise for control of both relative and abso-
lute stereochemistry in this approach to fused hetero-
cyclic ring systems.
Exp er im en ta l Section
Ma ter ia ls. R,â-Alkynyl esters were commercially available
(i.e., 4a , 4d ) or readily prepared (i.e., 4a -c) by an established
procedure.10g γ-Carbamoyl-R,â-enoates 8a /10a , 8b/10b, 9, 10c,
and 11a ,b were previously prepared as mixtures of (E)- and
(Z)-diastereomers10g while 11d was previously prepared enan-
tioselectively.14 The ethyl ester analogue of 12 was previously
prepared.10g The known â-iodo enoates 5a ,30 6a ,30 and 6c31 and
the commercially available 6d , along with 5b and 6b, were
prepared by the stereoselective addition of HI to the corre-
sponding R,â-alkynyl esters15,16 or by reaction of vinylstan-
nanes with I2. The â-alkylidine-γ-N-carbamoyl esters (Table
2) were prepared as previously described.10g Heterocycles 22,33
23,32 25,34 31,35 37a ,36 37b,37 37c,26 37d ,25 and 37e28have been
reported in the literature.
General conditions for GC-MS analysis involved utilization
of an Alltech EC-1 column [100% dimethylpolysiloxane, 30 m,
0.25 i.d., 0.25 µm coating, 60/350 °C] with an initial oven
temperature of 60 °C, a final temperature of 280 °C, and a
heating rate of 10 °C/minute. Deuteriochloroform (CDCl3) was
employed as solvent for 1H and 13C NMR measurements.
(29) (a) Wenkert, E.; Hudlicky, T. J . Org. Chem. 1988, 53, 1953. (b)
Temme, O.; Taj, S.-A.; Andersson, P. G. J . Org. Chem. 1998, 63, 6007.
(c) Herrmann, J . L.; Cregge, R. J .; Richman, J . E.; Kieczykowski, G.
R.; Normandin, S. N.; Quesada, M. L.; Semmelhack, C. L.; Poss, A. J .;
Schlessinger, R. H. J . Am. Chem. Soc. 1979, 101, 1540.
(30) Li, A.-R.; Chen, Q.-Y. Synthesis 1997, 1481.
(31) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(32) Doyle, M. P.; Kalinin, A. V. J . Org. Chem. 1996, 61, 2179.
(33) Marson, C. M.; Pink, J . H.; Smith, C.; Hursthouse, M. B.; Malik,
K. M. A. Tetrahedron Lett. 2000, 41, 127.
(34) Wijnberg, J . B. P. A.; Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1978, 34, 179.
(35) Wenkert, E.; Dave, K. G.; Haglid, F.; Lewis, R. G.; Oishi, T.;
Stevens, R. V.; Terashima, M. J . Org. Chem. 1968, 33, 747.
(36) Mori, M.; Hashimoto, A.; Shibasaki, M. J . Org. Chem. 1993,
58, 6503.
Su m m a r y
In summary, conjugate addition of R-(N-carbamoyl)-
alkylcuprates to a variety of R,â-unsaturated carboxylic
(27) (a) By assuming the minor enantiomer represents a peak area
W contributing to peak X or Z, there is a unique value of W that
reproduces the NMR diastereomeric ratio (X + Z - W)/(Y + W) ) 95/
5. (b) Masamune, S.; Choy, W.; Peterson, J . S.; Sita, L. R. Angew.
Chem., Int. Ed, Engl. 1985, 24, 1.
(37) (a) Sanchez-Sancho, F.; Herradon, B. Tetrahedron: Asymmetry
1998, 9, 1951. (b) Waldmann, H.; Braun, M. J . Org. Chem. 1992, 57,
4444.
(28) Takahashi, K.; Brossi, A. Heterocycles 1988, 27, 2475.

R-(N-Carbamoyl)alkylcuprate Chemistry
J . Org. Chem., Vol. 67, No. 3, 2002 853
Meth yl 6-Ch lor o-2-h exyn oa te (4b). To a solution of
5-chloropentyne (2.05 g, 20 mmol) in diethyl ethyl (50 mL) at
-30 °C was added a solution of n-BuLi in hexane (1.5 N, 13.3
mL) dropwise via syringe. The reaction mixture was stirred
at -30 °C for 30 min and warmed to 0 °C for 30 min. Then
the resulting white turbid mixture was cooled to -30 °C, and
a solution of methyl chloroformate (1.89 g, 20 mmol) in 10 mL
of ether was added dropwise via syringe. As the addition
proceeded a white solid was formed. The reaction mixture was
stirred at -30 °C for 20 min and warmed to room temperature
during a period of 1 h. The solid LiCl was filtered, and the
filtrate was washed with brine and dried over MgSO4. Removal
of the solvent in vacuo afforded crude alkynyl ester. Kugelrohr
distillation gave pure alkynyl ester 4b as a colorless oil (3.11
g, 97%): 1H NMR (CDCl3) δ 2.00-2.14 (m, 2H), 2.59 (t, J )
6.9 Hz, 2H), 3.69 (t, J ) 6.6 Hz, 2H), 3.73 (m, 3H); 13C NMR
δ 15.9, 30.1, 43.1, 52.5, 73.4, 87.3, 153.8.
(E)-Meth yl 6-Ch lor o-3-iod o-2-h ep ten oa te (5b). To a
solution of diisopropylamine (0.28 mL, 2 mmol) in dry THF (2
mL) at -78 °C under nitrogen was added a solution of n-BuLi
in hexane (1.4 mL, 1.6 N, 2.1 mmol), and the resulting solution
was stirred for 20 min at -78 °C. Tri-n-butyltin hydride
(Bu3SnH) (0.52 mL, 2 mmol) was added to the above solution
by syringe, and the mixture was stirred for 1 h. Then the
complex Me2S‚CuBr (0.41 g, 2 mmol) was added quickly as a
solid, and the resulant dark red solution was stirred for
another 20 min at -78 °C until the cuprate was formed. A
solution of R,â-ynoates (1.54 mmol) in THF (1 mL) was added
to the cuprate solution, and the reaction mixture was stirred
at -78 °C for 3 h before 0.5 mL of methanol was added,
followed by a solution of NH3/NH4Cl (pH ) 8). The organic
layer was separated, and the aqueous layer was extracted with
ether (3 × 10 mL). The combined organic solution was washed
with brine and dried with MgSO4. Removal of solvent in vacuo
gave crude stannane, which was purified by chromatography
(silica gel, 100% petroleum ether followed by petroleum ether/
ether (98:2). The resultant vinyl tin compound was added to a
solution of iodine or monochloroiodide (1.5 equiv. in 10 mL
ether) and the reaction solution was stirred overnight at room
temperature. The reaction solution was then diluted with 30
mL of ether and washed with Na2S2O3 (5%) until the color of
iodine disappeared and then with brine. The organic phase
was dried over MgSO4. Removal of the solvent in vacuo gave
crude product which was purified by chromatography (silica
gel, 98:2/petroleum ether:ether, v/v) affording 5b in 60% overall
yield for the two steps as a colorless oil: 1H NMR δ 1.99-2.19
(m, 2H), 3.27 (t, J ) 7.2 Hz, 2H), 3.57 (t, J ) 6.6 Hz, 2H), 3.70
(s, 3H), 6.69 (s, 1H); 13C NMR δ 32.3, 38.9, 43.3, 51.6, 126.9,
131.9, 164.3.
(Z)-Meth yl 6-Ch lor o-2-h exyn oa te (6b). To 10 mL of dry
CH3CN in a 50 mL round-bottomed flask at room temperature
under nitrogen was added dry NaI (1.80 g, 12 mmol), and the
mixture was stirred for several minutes until NaI was dis-
solved. TMSCl (1.54 mL, 12 mmol) was added to the solution
by syringe, and the resultant solution was stirred for 15 min
followed by the addition of water (95 mg). The mixture was
stirred for 30 min, and a solution of methyl 6-chlorohexynoate
(1.61 g, 10 mmol) was added by syringe. After being stirred
for 2-3 h at room temperature, the reaction was quenched
with H2O (1-2 mL). The mixture was diluted with ether (30
mL), washed with Na2S2O3 (5%) and brine, and dried with
MgSO4. Removal of solvent afforded crude product, which was
almost pure vinyl iodide. Further purification by Kugelrohr
distillation gave 1.95 g of 6b as a colorless oil (68%) (0.05
mmHg, 75-80 °C oven temperature): 1H NMR (CDCl3) δ
1.99-2.12 (m, 2H), 2.88 (t, J ) 7.2 Hz, 2H), 3.53 (t, J ) 6.3
Hz, 2H), 3.75 (s, 3H), 6.43 (s, 1H); 13C NMR δ 31.4, 42.8, 44.3,
51.6, 119.1, 125.9, 164.7; mass spectrum, m/z (relative inten-
sity) EI 290 (M+ + 2, isotope peak, 06), 288 (M+, 19), 257 (16),
161 (M+ - I, 48), 129 (19), 93 (25), 59 (100).
via syringe, and this mixture was allowed to stir at -78 °C
for 1 h.38 A solution of the complex CuCN‚2LiCl in THF
(prepared by dissolving 0.5 mmol of CuCN and 1 mmol of LiCl
in 2 mL of THF) was added via syringe to the 2-lithio-N-Boc
carbamate, and the solution was warmed from -78 to -55 °C
over a period of 60 min to generate the cuprate reagent. A
solution of (E)- or (Z)-â-iodo-R,â-enoate (0.5 mmol) in THF (1
mL) was added to the cuprate reagent, and the reaction
mixture was stirred at -55 °C for 0.5 h followed by warming
to room temperature over 3-4 h. The reaction mixture was
quenched with saturated aqueous NH4Cl (5 mL), filtered
through Celite, extracted with ether (3 × 10 mL), and washed
with saturated NH4Cl (2 × 5 mL) and brine (5 mL). The extract
was dried (MgSO4), filtered, and concentrated in vacuo to
afford the crude product, which was purified by chromatog-
raphy.
(E)-Meth yl 3-[[(1,1-Dim eth yleth oxyca r bon yl)m eth yl-
a m in o]m eth yl]-6-ch lor o-2-h exen oa te (8b). Employing the
general procedure and 7a (1 mmol) afforded after purification
by chromatography [silica gel, ether/petroleum ether, 10:90,
v/v] pure 8b as a colorless oil (145 mg, 95%): IR (neat) 2979
(m), 2944 (m), 2936 (m), 1720 (s), 1700 (s) cm-1 1H NMR
;
(CDCl3) δ 1.43 (1.46) (s, 9H), 1.87-2.08 (m, 2H), 2.63 (t, J )
7.5 Hz, 2H), (2.79) 2.83 (s, 3H), 3.57 (t, J ) 6.6 Hz, 2H), 3.69
(s, 3H), 3.87 (3.92) (s, 2H), 5.65 (s, 1H); 13C NMR δ 27.6, 28.3,
31.4, 34.4, 44.7, 51.1, (54.1) 54.7, 80.1, 115.2, 155.4 (155.9),
157.4, 166.3 (rotamer); mass spectrum, m/z (relative intensity)
EI 249 (M+ - C4H8, 02), 232 (03), 205 (M+ - CO2, 28), 190
(11), 174 (16), 142 (27), 57 (100).
(E)-Meth yl 3-[[(1,1-Dim eth yleth oxy)ca r bon yl]-2-p yr -
r olid in yl]-6-ch lor o-2-h exen oa te (9). Employing the general
procedure and 7b (171 mg, 1 mmol) afforded after purification
by chromatography [silica gel, ether/petroleum ether, 20:80,
v/v] pure 9 as a colorless oil (117 mg, 71%): IR (neat) 2975
(s), 2956 (s), 2884 (m), 1725 (s), 1702 (s), 1659 (s), 1394 (s),
1169 (s) cm-1 1H NMR (CDCl3) δ 1.38 (1.44) (s, 9H), 1.15-
;
1.85 (m, 3H), 1.85-2.35 (m, 4H), 2.90-3.20 (m, 1H), 3.25-
3.55 (m, 2H), 3.50-3.65 (m, 2H) 3.67 (s, 3H), 4.20-4.45 (m,
1H), 5.65 (s, 1H) (rotamer); 13C NMR δ 23.3, 28.0, 28.4, 31.4,
31.8, 45.0, 46.9, 51.0, 62.1, 79.9, 113.5, 154.1, 162.7, 166.7;
mass spectrum, m/z (relative intensity) EI 331 (M+, 01), 275
(M+ - C4H8, 06), 258 (14), 231 (275 - CO2, 24), 216 (17), 196
(48), 168 (100), 70 (48), 57 (C4H9, 88).
(Z)-Meth yl 3-[[(1,1-Dim eth yleth oxyca r bon yl)m eth yl-
a m in o]m eth yl]-6-ch lor o-2-h exen oa te (10b). Employing the
general procedure and 7a (1 mmol) afforded after purification
by chromatography [silica gel, ether/petroleum ether, 10:90,
v/v] pure 10b as a colorless oil (81-88%): IR (neat) 2979 (m),
2948 (m), 2936 (m), 1720 (s), 1700 (s), 1149 (s) cm-1; 1H NMR
(CDCl3) δ 1.44 (s, 9H), 1.87-2.09 (m, 2H), 2.17-2.42 (m, 2H),
(2.74) 2.77 (s, 3H), 3.52 (t, J ) 6.6 Hz, 2H), 3.69 (s, 3H), (4.52)
4.55 (s, 2H), (5.81) 5.83 (s, 1H) (rotamers); 13C NMR δ 28.3,
(29.8) 30.3, (31.7) 31.9, 35.9, 43.9 (44.1), (46.5) 48.0, 51.2, 80.0
(80.5), (119.3) 119.5, 156.0 (156.9), (158.2) 158.3, 166.7 (rota-
mer); mass spectrum, m/z (relative intensity) EI 249 (M+
-
C4H8, 02), 232 (06), 205 (M+ - CO2, 43), 190 (28), 172 (31),
142 (41), 110 (44), 57 (100).
(Z)-Met h yl 3-[[(1,1-Dim et h ylet h oxy)ca r bon yl]-2-p yr -
r olid in yl]-6-ch lor o-2-h exen oa te (11b). Employing the gen-
eral procedure and 7b (171 mg, 1 mmol) afforded after
purification by chromatography [silica gel, ether/petroleum
ether, 20:80, v/v] pure 11b as a colorless oil (84 mg, 51%): IR
(neat) 2976 (s), 2880 (s), 1720 (s), 1692 (s), 1460 (s), 1169 (s)
cm-1; 1H NMR (CDCl3) δ 1.35 (1.42) (s, 9H), 1.45-1.65 (m, 1H),
1.65-2.05 (m, 4H), 2.05-2.50 (m, 3H), 3.20-3.40 (m, 1H), 3.54
(t, J ) 6.3 Hz, 2H), 3.67 (3.65) (s, 3H), 3.50-3.80 (m, 1H), 5.54
(t, J ) 7.5 Hz, 1H), 5.64 (s, 1H) (rotamer); 13C NMR δ 24.3
(24.7), 28.2, 28.4, (30.4) 30.7, 32.4, 44.2 (44.3), 47.6 (47.8), 51.0,
58.1 (58.3), 79.6, 114.5 (117.7), 154.6, 163.9, 166.3 (rotamer);
mass spectrum, m/z (relative intensity) EI 331 (M+, 01), 274
(M+ - C4H9, 05), 258 (14), 230 (274 - CO2, 83), 216 (12), 198
(76), 168 (100).
Gen er a l P r oced u r e for Rea ction of r-(N-Ca r ba m oyl)-
a lk ylcu p r a tes w ith â-Iod o-r,â-en oa tes. A solution of N-Boc-
protected amine (i.e., 7a -c, 1 mmol) and (-)-sparteine (1.3
mmol) in 3 mL of THF under an Ar or N2 atmosphere was
cooled to -78 °C. s-BuLi (in cyclohexane, 1.2 mmol) was added
(38) (a) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197. (b)
Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.

854 J . Org. Chem., Vol. 67, No. 3, 2002
Dieter and Lu
(Z)-Meth yl 3-[[(1,1-Dim eth yleth oxy)ca r bon yl]-2-p ip er i-
d in yl]-2-h ep ten oa te (12). Employing the general procedure
and 7c (185 mg, 1 mmol) afforded after purification by
chromatography [silica gel, ether/petroleum ether, 10:90, v/v]
pure 12 as a colorless oil (106 mg, 65%): IR (neat) 2953 (s),
sity) 125 (M+, 100), 110 (M+ - CH3, 51), 96 (13), 82 (33), 67
(88), 53 (33).
(E)-1-Eth ylid en eh exa h yd r o-3H-p yr r olizin -3-on e (14).
Employing general procedure A, the 1,4-adduct (90 mg, 0.3
mmol) was treated with phenol (0.74 g, 7.9 mmol) and TMSCl
(2.6 mmol, 0.34 mL) in 5 mL of CH2Cl2 to afford pure 14 (28
mg, 60%) as a colorless oil after purification by chromatogra-
phy. Employing general procedure C, the 1,4-adduct (24 mg,
0.1 mmol) was treated with TMSOTf (0.15 mL) at -30 to +25
°C for 3 h, giving 14 as colorless oil (8 mg, 61%): IR (neat)
2928 (s), 2868 (m), 1720 (s), 1695 (s), 1404 (s), 1155 (s) cm-1
;
1H NMR (CDCl3) δ 0.85 (t, J ) 7.2 Hz, 3H), 1.30 (s, 9H), 1.23-
1.44 (m, 5H), 1.44-1.72 (m, 4H), 1.74-1.86 (m, 1H), 2.00-
2.14 (m, 2H), 2.97-3.07 (m, 1H), 3.61 (s, 3H), 3.86-3.97 (m,
1H), 5.49-5.55 (m, 1H), 5.54 (s, 1H); 13C NMR δ 14.0, 19.3,
22.7, 22.9, 27.8, 28.3, 29.9, 32.1, 39.9, 51.0, 54.1, 79.9, 113.3,
155.9, 166.5, 167.5; mass spectrum, m/z (relative intensity) EI
268 (M+ - C4H9, 66), 252 (07), 224 (268 - CO2, 93), 210 (19),
192 (49), 182 (100), 166 (33), 150 (55), 57 (C4H9, 70).
1
2970 (m), 2927 (m), 1702 (s), 1677 (s) cm-1; H NMR (CDCl3)
δ 1.25-1.45 (m, 1H), 1.55-1.75 (m, 3H), 1.90-2.15 (m, 3H),
3.00-3.15 (m, 1H), 3.15 (AB quartet, δA ) 3.34, δB ) 2.96, J AB
) 21.0 Hz, 2H), 3.55-3.75 (m, 1H), 4.25-4.40 (m, 1H), 5.40-
5.50 (m, 1H); 13C NMR (CDCl3) δ 14.6, 24.2, 31.2, 37.3, 41.8,
66.2, 118.8, 134.2, 174.2; mass spectrum, m/z (relative inten-
sity) 151 (M+, 100), 136 (M+ - CH3, 79), 123 (77), 108 (23), 94
(58), 80 (98), 67 (33); high-resolution mass spectrum m/z
151.0993 (M+) (calcd for C9H13NO 151.0997).
Gen er a l P r oced u r e A for N-Boc Dep r otection a n d
La cta m F or m a tion . To a solution of PhOH (2.82 g, 30 mmol)
and TMSCl (1.28 mL, 10 mmol) in 10 mL of CH2Cl2 at room
temperature was added 1 mmol of the conjugate addition
product in 2 mL of CH2Cl2. The mixture was stirred for 60
min and then diluted with 50 mL of ether. The solution was
washed three times with 10% NaOH (20, 10, 5 mL) and one
time with brine (5 mL) and then dried over MgSO4. Removal
of solvent gave crude product that was purified by chroma-
tography [silica gel, ether/petroleum ether (1:1), or pure ether].
Gen er a l P r oced u r e B for N-Boc Dep r otection a n d
La cta m F or m a tion . A solution of the conjugate addition
product (0.5 mmol) in dry CH2Cl2 (2 mL) was treated dropwise
with catecholboron bromide (0.2 M in CH2Cl2, 5 mL) at room
temperature. After being stirred at room temperature for 1 h,
the reaction mixture was quenched with 2 mL of H2O, stirred
for 20 min, and then diluted with an additional 30 mL of
CH2Cl2 whereupon it was washed with 10% NaOH solution
(2 × 15 mL) and brine. The organic phase was dried over
MgSO4. Removal of solvent gave crude product that was
purified by chromatography [silica gel, ether/petroleum ether
(1:1), or pure ether).
Gen er a l P r oced u r e C for N-Boc Dep r otection a n d
La cta m F or m a tion . A solution of the conjugate addition
product (0.5 mmol) in 5 mL of dry CH2Cl2 was treated with
TMSOTf (1-10 equiv) at -30 °C, followed by warming the
solution to room temperature over a period of 2-3 h. The
reaction mixture was then diluted with 30 mL of CH2Cl2 and
washed with NaHCO3 (saturated), and the solution was dried
over MgSO4. Removal of solvent gave crude product that was
purified by chromatography [silica gel, ether/petroleum ether
(1:1), or pure ether].
Gen er a l P r oced u r e D for N-Boc Dep r otection a n d
La cta m F or m a tion . Crude product (0.5 mmol) from general
procedure A was dissolved in CH2Cl2, and the solution was
cooled to 0 °C. A solution of Me3Al in toluene (2 M, 0.5 mL,
2.0 equiv) was added dropwise to the reaction mixture via
syringe. The reaction mixture was then warmed to 25 °C,
stirred for 5-6 h, quenched by addition of water, and diluted
with CH2Cl2. The organic phase was washed with aqueous HCl
(5%) and dried over MgSO4. Removal of the solvent in vacuo
afforded crude material that was purified by column chroma-
tography.
(E)-1-Eth yliden eh exah ydr o-2H-in dolizin -3-on e (15). Em-
ploying general procedure D, the 1,4-adduct (187 mg, 0.6
mmol) was treated with phenol (0.85 g, 9.0 mmol) and TMSCl
(3.0 mmol, 0.39 mL) in 4 mL of CH2Cl2, followed by addition
of Me3Al solution (2 N, 0.5 mL) at 0 °C and then warming to
room temperature over 5 h. Pure 15 (62 mg) was obtained as
a white solid after chromatography: 1H NMR (CDCl3) δ 1.06-
1.18 (m, 1H), 1.18-1.33 (m, 1H), 1.33-1.48 (m, 1H), 1.57 (d,
J ) 4.5 Hz, 3H), 1.55-1.68 (m, 1H), 1.77-1.92 (m, 2H), 2.51-
2.62 (m, 1H), 2.93 (s, 2H), 3.76-3.84 (m, 1H), 4.08-4.18 (m,
1H), 5.31-5.41 (m, 1H); 13C NMR (CDCl3) δ 14.6, 23.6, 24.6,
32.6, 34.3, 39.7, 61.2, 117.9, 133.8, 170.9; mass spectrum, m/z
(relative intensity) 165 (M+, 49), 150 (M+ - CH3, 100), 136
(17), 122 (19), 108 (14), 94 (19), 80 (19). Anal. Calcd for C10H15
-
NO: C, 72.70; H, 9.20; N, 8.50. Found: C, 72.48; H, 9.18; N,
8.69.
(E)-Hexa h yd r o-1-(p h en ylm eth ylid en e)-3H-p yr r olizin -
3-on e (17). Employing general procedure A, the 1,4-adduct
(90 mg, 0.3 mmol) was treated with phenol (0.60 g, 6.4 mmol)
and TMSCl (2.1 mmol, 0.27 mL) in 5 mL of CH2Cl2 affording
pure 17 (49 mg, 92%) as a colorless oil after purification by
chromatography [silica gel, ether/petroleum ether, v/v 1:1]: IR
(neat) 3060 (m), 3030 (m), 2970 (s), 2894 (s), 1690 (s), 1404 (s)
cm-1 1H NMR (CDCl3) δ 1.05-1.25 (m, 1H), 1.87-2.05 (m,
;
1H), 2.10-2.45 (m, 2H), 3.20-3.40 (m, 1H), 3.42-3.60 (m, 1H),
3.72 (s, 2H), 4.10-4.21(m, 1H), 5.75 (s, 1H), 7.15-7.55 (m, 5H);
13C NMR (CDCl3) δ 28.8, 29.2, 36.2, 42.0, 68.6, 123.0, 126.9,
128.6, 128.8, 136.7, 164.8, 176.5; mass spectrum, m/z (relative
intensity) 213 (M+, 100), 185 (30), 170 (22), 156 (37), 122 (56),
91 (PhCH2+, 04)
(E)-Hexah ydr o-1-(2-m eth ylpr opyliden e)-3H-pyr r olizin -
3-on e (19). Employing general procedure A, the 1,4-adduct
(150 mg, 0.46 mmol) was treated with phenol (1.20 g, 12.8
mmol) and TMSCl (6.3 mmol, 0.80 mL) in 5 mL of CH2Cl2
affording pure 19 (55 mg, 67%) as a colorless oil after
purification by chromatography [silica gel, ether/petroleum
ether, v/v 1:1]: IR (neat) 2962 (s), 2928 (s), 2868 (m), 1711 (s),
1685 (s) cm-1 1H NMR (CDCl3) δ 0.93 (d, J ) 3.6 Hz, 3H),
;
0.95(d, J ) 3.6 Hz, 3H), 1.25-1.45 (m, 1H), 1.90-2.15 (m, 3H),
2.15-2.35 (m, 1H), 2.98-3.10 (m, 1H), 3.16 (AB quartet, δA )
3.36, δB ) 2.96, J AB ) 19.5 Hz, 2H), 3.55-3.70 (m, 1H), 4.20-
4.30 (m, 1H), 5.60-5.75 (m, 1H); 13C NMR (CDCl3) δ 22.3, 22.5,
26.1, 28.8, 31.2, 37.2, 41.7, 66.1, 131.1, 131.7, 174.1.
(E)-4-Eth ylid en e-1-m eth yl-2-p yr r olid in on e (13). Em-
ploying general procedure A, ethyl 3-[[[(1,1-dimethylethoxy)-
carbonyl]methylamino]methyl]-3-pentenoate (40 mg, 0.13 mmol)
was treated with phenol (0.367 g, 3.9 mmol) and TMSCl (1.3
mmol, 0.17 mL) in 3 mL of CH2Cl2 to afford pure 13 (12 mg,
65%) as a colorless oil after purification by chromatography.
Employing general procedure B, ethyl 3-[[[(1,1-dimethyl-
ethoxy)carbonyl]methylamino]methyl]-3-pentenoate (120 mg,
0.39 mmol) was treated with catechol boron bromide (0.2 M
in CH2Cl2, 2 mL) to afford 13 as a colorless oil (46 mg, 83%).
Employing general procedure C, the 1,4-adduct (60 mg, 0.20
mmol) was treated with TMSOTf (0.05 mL) at -40 to -20 °C
for 3 h in 2 mL of CH2Cl2 to afford 13 (24 mg, 85%): IR (neat)
(E)-Hexa h yd r o-1-(2-m eth ylp r op ylid en e)-2H-in d olizin -
3-on e (20). Employing general procedure C, the 1,4-adduct
(26 mg, 0.1 mmol) was treated with TMSOTf (0.15 mL) at -30
to 25 °C for 3 h in 2 mL of CH2Cl2 affording pure 20 (14 mg,
91%) as a colorless oil after purification by chromatography
[silica gel, ether/petroleum ether, v/v 1:1]: 1H NMR (CDCl3) δ
0.96 (d, J ) 6.6 Hz, 6H), 1.11-1.57 (m, 3H), 1.61-1.72 (m,
1H), 1.81-2.06 (m, 2H), 2.24-2.45 (m, 1H), 2.63-2.75 (m, 1H),
3.02 (d, J ) 1.2 Hz, 2H), 3.86 (d, J ) 11.1 Hz, 1H), 4.21 (dd,
J ) 4.8 Hz, J ) 12.6 Hz, 1H), 5.12-5.26 (m, 1H); 13C NMR
(CDCl3) δ 22.4, 22.5, 23.6, 24.5, 28.9, 32.6, 34.1, 39.7, 61.0,
130.7, 130.9, 170.8; mass spectrum, m/z (relative intensity) 193
2919 (s), 2868 (s), 1685 (s) cm-1 1H NMR (CDCl3) δ 1.55-
;
1.65 (m, 3H), 2.85 (2.88) (s, 3H), 2.98 (3.04) (s, 2H), 3.94 (s,
2H), 5.36-5.52 (m, 1H); 13C NMR (CDCl3) δ 14.4, 29.2, 34.3,
54.7, 118.7, 127.6, 172.9; mass spectrum, m/z (relative inten-
(M+, 05), 192 (M+ - 1, 06), 178 (M+ - CH3, 16), 150 (M+
-

R-(N-Carbamoyl)alkylcuprate Chemistry
J . Org. Chem., Vol. 67, No. 3, 2002 855
C3H7, 100), 136 (04), 122 (08); high-resolution mass spectrum
m/z 193.1469 (M+) (calcd for C12H19NO 193.1467).
(M+, 09), 178 (M+ - Cl, 28), 150 (100), 136 (22), 122 (14), 108
(13); mass spectrum m/z 213.0918 (M+) (calcd for C11H16ClNO
213.0920).
(E)-1-Met h yl-4-(1-m et h ylet h ylid en e)-2-p yr r olid in on e
(21). Employing general procedure A, the 1,4-adduct (90 mg,
0.3 mmol) was treated with phenol (0.71 g, 7.4 mmol) and
TMSCl (2.6 mmol, 0.34 mL) in 5 mL of CH2Cl2 affording pure
21 (27 mg, 62%) as a colorless oil after purification by
chromatography [silica gel, pure ether]: IR (neat) 2928 (s),
(E)-Hexa h yd r o-8-(m eth oxyca r bon yl)m eth ylid en e-7H-
in d olizid in e (32). Employing general procedure A, the E
isomer 9 (30 mg, 0.1 mmol) was treated with phenol (0.25 g,
2.7 mmol) and TMSCl (1.0 mmol, 0.12 mL) in CH2Cl2 at 25 °C
to afford pure 32 (13 mg, 74%) after purification by column
chromatography: IR (neat) 2951 (s), 2881 (s), 1715 (s); 1H NMR
δ 1.89-2.09 (m, 4H), 2.11-2.28 (m, 1H), 2.28-2.42 (m, 1H),
2.65-2.78 (m, 1H), 2.85-2.95 (m, 1H), 3.40-3.50 (m, 1H),
3.50-3.68 (m, 3H), 3.71 (s, 3H), 4.02-4.15 (m, 1H), 6.22 (s,
1H); 13C NMR δ 23.0, 28.5, 30.0, 31.6, 44.7, 44.9, 51.5, 63.7,
119.4, 153.0, 165.5; mass spectrum, m/z (relative intensity) 195
(M+, 19), 194 (M+ - 1, 15), 180 (M+ - CH3, 100), 167 (16), 136
(84), 122 (21), 108 (19), 79 (11), 55 (11).
(E)-Octa h yd r o-1-(m eth oxy)ca r bon ylm eth ylid en e-2H-
qu in olizin e (33). Employing general procedure A, the (E)-
isomer of methyl 3-[[(1,1-dimethylethoxy)carbonyl]-2-piperi-
dinyl]-6-chloro-2-hexenoate (30c) (80 mg, 0.24 mmol) was
treated with phenol (0.65 g, 6.9 mmol) and TMSCl (2.4 mmol,
0.30 mL) in 2 mL of CH2Cl2. The crude material was purified
by column chromatography directly without washing with
NaOH (10%) affording pure 33 (32 mg, 67%) as a colorless oil:
IR (neat) 2945 (s), 2860 (m), 2760 (m), 1710 (s) cm-1; 1H NMR
(CDCl3) δ 1.19-1.42 (m, 1H), 1.47-1.68 (m, 3H), 1.68-2.04
(m, 5H), 2.11-2.36 (m, 2H), 2.36-2.50 (m, 1H), 2.92 (d, J )
11.4 Hz, 2H), 3.67 (s, 3H), 3.83 (d, J ) 13.2 Hz, 1H), 5.71 (s,
1H); 13C NMR (CDCl3) δ 24.2, 25.0, 25.7, 28.1, 28.4, 51.0, 56.2,
57.3, 65.6, 112.8, 160.0, 167.4; mass spectrum, m/z (relative
intensity) 209 (M+, 23), 194 (M+ - CH3, 100), 180 (16), 167
(11), 150 (45), 136 (27), 124 (15).
1
2851 (s), 1715 (s), 1690 (s) cm-1; H NMR (CDCl3) δ 1.58 (s,
3H), 1.62 (s, 3H), 2.87 (s, 3H), 2.98 (s, 2H), 3.92 (s, 2H); 13C
NMR (CDCl3) δ 19.5, 20.8, 29.3, 35.4, 53.6, 120.1, 125.7, 173.6;
mass spectrum, m/z (relative intensity) 139 (M+, 58), 124 (M+
- CH3, 100), 110 (10), 96 (26), 82 (30), 67 (93).
4-(3-Ch lor op r op yl)-1,5-d ih yd r o-1-m eth yl-2H-p yr r ol-2-
on e (24). Employing general procedure A, the coupling product
10b (80 mg, 0.3 mmol) was treated with phenol (0.70 g, 7.5
mmol) and TMSCl (2.3 mmol, 0.30 mL) in 3 mL of CH2Cl2
affording pure 24 (39 mg, 86%) as a colorless oil: IR (neat)
3087 (w), 2960 (m), 2923 (m), 1684 (s), 1445 (m) cm-1; 1H NMR
(CDCl3) δ 1.94-2.13 (m, 2H), 2.52 (t, J ) 7.2 Hz, 2H), 2.99 (s,
3H), 3.58 (t, J ) 6.3 Hz, 2H), 3.86 (s, 2H), 5.87 (t, J ) 1.5 Hz,
1H); 13C NMR (CDCl3) δ 26.6, 28.3, 30.3, 43.9, 56.4, 122.7,
157.1, 171.7; mass spectrum, m/z (relative intensity) 175 (M+
+ 2, 05), 173 (M+, 15), 110 (M+ - CH2CH2Cl, 100), 96 (29), 82
(13); high-resolution mass spectrum m/z 173.0607 (M+) (calcd
for C8H12ClNO 173.0607).
1-Bu tyl-5,6,7,7a -tetr a h yd r o-3H-p yr r olizin -3-on e (26).
Employing general procedure A, the coupling product 6a (156
mg, 0.5 mmol) was treated with phenol (0.71 g, 7.5 mmol) and
TMSCl (2.5 mmol, 0.32 mL) in 5 mL of CH2Cl2 affording pure
26 (64 mg, 71%) as a colorless oil after purification by
chromatography [silica gel, ether/petroleum ether, v/v 1:1]: IR
(neat) 3084 (w), 2962, 2936, 2880, 1702 (s) cm-1 1H NMR
;
(Z)-Oct a h yd r o-1-(m et h oxyca r b on yl)m et h ylid en e-2H-
qu in olizin e (34). Employing general procedure A, the Z
isomer of methyl 3-[[(1,1-dimethylethoxy)carbonyl]-2-piperidi-
nyl]-6-chloro-2-hexenoate [(Z)-30c] (150 mg, 0.43 mmol) was
treated with phenol (1.22 g, 13.0 mmol) and TMSCl (4.5 mmol,
0.56 mL) in 3 mL of CH2Cl2. The crude material was purified
by column chromatography directly without washing with
NaOH (10%) affording pure 34 (51 mg, 56%) as colorless oil:
(CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3H), 1.11-1.30 (m, 1H), 1.30-
1.47 (m, 2H), 1.47-1.64 (m, 2H), 2.02-2.19 (m, 2H), 2.19-
2.42 (m, 3H), 3.15-3.30 (m, 1H), 3.34-3.53 (m, 1H), 4.03-
4.19 (m, 1H), 5.69 (s, 1H); 13C NMR (CDCl3) δ 13.7, 22.4, 28.9,
29.1, 29.3, 29.4, 42.1, 69.0, 121.6, 166.5, 176.7; mass spectrum,
m/z (relative intensity) 179 (M+, 23), 136 (M+ - C3H7, 100),
122 (M+ - C4H9, 15), 109 (44); high-resolution mass spectrum
m/z 179.1309 (M+) (calcd for C11H17NO 179.1310).
1
IR (neat) 2962 (s), 2783 (s), 2706 (s), 1725 (s) cm-1; H NMR
1-(3-Ch lor op r op yl)-5,6,7,7a -tetr a h yd r o-3H-p yr r olizin -
3-on e (27). Employing general procedure A, the coupling
product 6b (35 mg, 0.1 mmol) was treated with phenol (0.24
g, 2.5 mmol) and TMSCl (0.8 mmol, 0.10 mL) in 2 mL of CH2Cl2
affording pure 27 (17 mg, 81%) as a colorless oil after
purification by column chromatography [silica gel, ether/
petroleum ether, v/v 1:1]: IR (neat); 1H NMR (CDCl3) δ 1.06-
1.20 (m, 1H), 1.94-2.15 (m, 3H), 2.15-2.35 (m, 2H), 2.38-
2.62 (m, 2H), 3.15-3.32 (m, 1H), 3.36-3.50 (m, 1H), 3.57 (t, J
) 6.3 Hz, 2H), 4.04-4.23 (m, 1H), 5.69 (s, 1H); 13C NMR
(CDCl3) δ 26.5, 28.9, 29.3, 30.0, 42.1, 43.9, 69.0, 122.2, 164.3,
176.5; mass spectrum, m/z (relative intensity) 201 (M+ + 2,
(CDCl3) δ 1.40-1.65 (m, 1H), 1.69-1.92 (m, 2H), 1.92-2.23
(m, 5H), 2.42-2.60 (m, 1H), 2.84-3.08 (m, 2H), 3.38-3.54 (m,
1H), 3.54-3.70 (m, 3H), 3.67 (s, 3H), 6.40 (s, 1H); 13C NMR
(CDCl3) δ 21.6, 23.1, 28.4, 29.3, 31.5, 44.7, 45.7, 51.4, 61.8,
119.4, 155.5, 165.7; mass spectrum, m/z (relative intensity) 209
(M+, 27), 194 (M+ - CH3, 100), 180 (17), 167 (13), 150 (M+
-
CO2Me, 34), 136 (36), 124 (19).
Ack n ow led gm en t. This work was generously sup-
ported by the National Institutes of Health (GM-60300-
01). Support of the NSF Chemical Instrumentation
Program for purchase of a J EOL 500 MHz NMR
instrument is gratefully acknowledged (CHE-9700278).
We thank Professor Steven J . Stuart for helpful discus-
sions.
isotope peak, 05), 199 (M+, 12), 164 (M+ - Cl, 08), 136 (M+
-
CH2CH2Cl, 100), 122 (13), 109 (23), 80 (13).
1-(3-Ch lor op r op yl)-5,6,7,8-t et r a h yd r o-3H-in d olizin -3-
on e (28). Employing general procedure A, the conjugate
adduct (Z)-30c (150 mg) afforded pure 28 (15 mg, 17%): IR
(neat) 3090 (w), 2941 (s), 2860 (m), 1758 (m), 1692 (s), 1427
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 4c, 5a , and 6a . Data reduction
(IR, 1H NMR, 13C NMR, mass spectrum) for compounds 4c,
5a , 6a ,c,d , 8a , 10a ,c, 11a ,d , 16, 18, 22, 23, 25, 31, and 37b-
e. 13C NMR spectra for 13, 16-22, 24, 26-28, and 32-34. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
(s) cm-1; H NMR (CDCl3) δ 1.01 (qd, J q ) 12.3 Hz, J t ) 3.3
Hz, 1H), 1.19-1.45 (m, 1H), 1.45-1.64 (m, 1H), 1.64-1.87 (br
m, 1H), 1.87-2.23 (m, 4H), 2.23-2.64 (m, 2H), 2.76 (td, J t
)
12.9 Hz, J d ) 3.0 Hz, 1H), 3.60 (td, J t ) 6.0 Hz, J d ) 1.8 Hz,
2H), 3.72 (dd, J d ) 12.0 Hz, J d ) 3.9 Hz, 1H), 4.26 (dd, J d
)
13.5 Hz, J d ) 5.1 Hz, 1H), 5.85 (s, 1H); 13C 23.5, 25.0, 25.6,
30.0, 30.5, 39.0, 43.9, 62.4, 121.4, 161.3, 168.8; mass spectrum,
m/z (relative intensity) 215 (M+ + 2, isotope peak, 03), 213
J O016053W