Synthesis of 2,3-disubstituted pyrrolidines and piperidines via one-pot oxidative decarboxylation-β-iodination of amino acids

Article abstract of DOI:10.1021/jo015877a

A new synthesis of 2,3-disubstituted pyrrolidines and piperidines is described. This mild procedure is based on the one-pot oxidative decarboxylation-β -iodination of α-amino acid carbamates or amides. The iodine is introduced at the previously unfunction

Full text of DOI:10.1021/jo015877a

7796
J . Org. Chem. 2001, 66, 7796-7803
Syn th esis of 2,3-Disu bstitu ted P yr r olid in es a n d P ip er id in es via
On e-P ot Oxid a tive Deca r boxyla tion -â-Iod in a tion of Am in o Acid s
Alicia Boto, Rosendo Herna´ndez,* Yolanda de Leo´n, and Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiologı´a del C.S.I.C., Carretera de La Esperanza 3,
38206-La Laguna, Tenerife, Spain
rhernandez@ipna.csic.es
Received J une 28, 2001
A new synthesis of 2,3-disubstituted pyrrolidines and piperidines is described. This mild procedure
is based on the one-pot oxidative decarboxylation-â-iodination of R-amino acid carbamates or
amides. The iodine is introduced at the previously unfunctionalized 3-position. Different substituents
can be introduced at C-2, e.g., hydroxy, alkoxy, allyl, alkyl, etc. A trans relationship between the
C-2 and C-3 substituents is exclusively obtained. The influence of the solvent and the ring size of
the starting amino acid are studied, as well as the nature of the protecting group on the nitrogen.
The stereoselectivity of the reaction was also studied using chiral methyl (2S,4S)-4-acetyloxyproline-
1-carboxylate (8). The products obtained can be manipulated to give bicyclic systems present in
many natural products. By using the tandem decarboxylation-iodination-alkylation reaction,
2-substituted-3-iodopyrrolidines are formed, which are precursors of 2-substituted-2,5-dihydro-
pyrrols.
Sch em e 1. Str a tegy for th e Syn th esis of
2,3-Disu bstitu ted P yr r olid in es (n ) 0) a n d
P ip er id in es (n ) 1)
In tr od u ction
Many natural products present piperidine or pyrroli-
dine rings in their structures,1 from simple compounds
such as coniine, the active principle in the poison of
hemlock,1a to complex alkaloids such as those belonging
to the Amarillydaceae family.1b These natural products
have often shown significant biological activity and in
many cases have been used as therapeutic agents.2
Furthermore, these heterocyclic rings are also of interest
in synthetic organic chemistry as chiral auxiliaries.3
These facts have stimulated efforts for the development
of the stereocontrolled synthesis of this class of com-
pounds.4
We have recently reported our initial results on the
synthesis of 2-substituted piperidine and pyrrolidine
rings from R-amino acids (Scheme 1) using a tandem
radical decarboxylation-oxidation reaction.5 Thus, treat-
ing the R-amino acid (I) with (diacetoxyiodo)benzene
(DIB) and iodine,6 under irradiation with visible light, a
carboxyl radical (II) is generated. This radical evolves by
loss of CO2, giving a new C-radical (III).7 The latter is
oxidized by excess reagent, giving a N-acyliminium ion
(IV), which can be trapped inter- or intramolecularly by
nitrogen, oxygen, or carbon nucleophiles.8 The final
products (V) were the 2-substituted piperidines (n ) 1)
or pyrrolidines (n ) 0). This one-pot process used as
(1) (a) Coniine: Beak, P.; Stehle, N. W.; Wilkinson, T. J . Org. Lett.
2000, 2, 155-158 and references therein. (b) Pyrrole, pyrrolidine,
pyridine, piperidine, and tropane alkaloids: O’Hagan, D. Nat. Prod.
Rep. 2000, 17, 435-446. (c) Indolizidine and quinolizidine alkaloids:
Michael, J . P. Nat. Prod. Rep. 2000, 17, 579-602. (d) Pyrrolizidine
alkaloids: Liddell, J . R. Nat. Prod. Rep. 2000, 17, 455-462. (e)
Quinoline, quinazoline, and acridone alkaloids: Michael, J . P. Nat.
Prod. Rep. 2000, 17, 603-620. (f) Stemona alkaloids: Pilli, R. A.;
Oliveira, M. C. F. Nat. Prod. Rep. 2000, 17, 117-127. (g) Amarylli-
daceae alkaloids: Lewis, J . R. Nat. Prod. Rep. 2000, 17, 57-84. (h)
Swainsonine and analogues: El Nemr, A. Tetrahedron 2000, 56, 8579-
8629. (i) Other reviews of interest: Pichon, M.; Figadere, B. Tetrahe-
dron: Asymmetry 1996, 7, 927-964. (j) Braekman, J . C.; Daloze, D.
In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1990; Vol. 6, pp 421-466. (k) Elbein, A.;
Molyneux, R. I. In The Alkaloids, Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1990; Vol. 5, pp 1-54. (l)
Attygalle, A. B.; Morgan, E. D. Chem. Soc. Rev. 1984, 13, 245-278.
(2) (a) Elliott, R. L.; Kopecka, H.; Lin, N.-H.; He, Y.; Garvey, D. S.
Synthesis 1995, 772-774. (b) Basha, F. Z.; Debernardis, J . F. Pure
Appl. Chem. 1994, 66, 2201-2204. (c) Lin, N.-H.; Carrera, G. M., J r.;
Anderson, D. J . J . Med. Chem. 1994, 37, 3542-3553.
(3) (a) Ahrendt, K. A.; Borths, C. J .; MacMillan, D. W. C. J . Am.
Chem. Soc. 2000, 122, 4243-4244 and references therein. (b) Brouwer,
A. J .; van der Linden, H. J .; Liskamp, R. M. J . J . Org. Chem. 2000,
65, 1750-1757. (c) Rao, V. D.; Periasamy, M. Synthesis 2000, 703-
706. (d) Fache, F.; Schultz, E.; Tommasino, M. L.; Leaire, M. Chem.
Rev. 2000, 100, 2159-2231. (e) Sibi, M. P.; Manyen, S. Tetrahedron
2000, 56, 8033-8061. (f) Enders, D.; Klatt, M. Synthesis 1996, 1403-
1418. (g) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1994, 35,
375-378. (h) Yamamoto, Y.; Hoshino, J .; Fujimoto, Y.; Ohmoto, J .;
Sawadi, S. Synthesis 1993, 298-302. (i) J ones, T. K.; Mohan, J . J .;
Xavier, L. C.; Blacklock, T. J .; Mathre, D. J .; Sohar, P.; J ones, E. T.
T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J . J . J . Org. Chem.
1991, 56, 763-769. (j) Corey, E. J .; Yuen, P.-W.; Hannon, F. J .; Wierda,
D. A. J . Org. Chem. 1990, 55, 784-786. (k) DeNinno, M. P.; Perner,
R. J .; Lijewski, L. Tetrahedron Lett. 1990, 31, 7415-7418. (l) Huryn,
D. M. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 64-75.
10.1021/jo015877a CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/18/2001

Synthesis of Pyrrolidines and Piperidines
J . Org. Chem., Vol. 66, No. 23, 2001 7797
Sch em e 2. Oxid a tive
starting material commercially available amino acids or
easily formed derivatives and took place under mild
conditions, giving good to excellent yields.
Deca r boxyla tion -â-Iod in a tion of r-Am in o Acid sa
In our effort to extend the scope of this interesting
reaction, we were pleased to find that under certain
conditions a new tandem process of decarboxylation-â-
iodination took place, which allowed the synthesis of
2-substituted-3-iodopyrrolidine and piperidine deriva-
tives (VI, Scheme 1).5a Since the iodo group can subse-
quently be replaced by oxygen, nitrogen, and sulfur
nucleophiles or by alkyl chains, its introduction in the
unfunctionalized 3-position seemed extremely promising.
In this article we report on the scope of this reaction, as
well as its stereoselectivity.
Resu lts a n d Discu ssion
The influence of the solvent, the nitrogen protecting
group, and the ring size of the amino acid were studied.
In our previous work,5b-d the decarboxylation reactions
had taken place in dry dichloromethane, and noniodi-
nated products were isolated in good yields. When an
excess of iodine was used and dichloromethane was
replaced by a more polar solvent such as acetonitrile, the
a
Key: (a) DIB, I2, rt, then H2O or MeOH, rt, 1 h (see Table 1).
Ta ble 1. On e-P ot Deca r boxyla tion of r-Am in o
Acid s-Ha logen a tion -Nu cleop h ilic Ad d ition a
iodine
(equiv)
entry
acid
solvent
t (h)
products (%)b
(4) (a) For reviews on the synthesis of piperidines, see: Laschat,
S.; Dickner, T. Synthesis 2000, 1781-1813. (b) Bailey, P. D.; Millwood,
P. A.; Smith, P. D. Chem. Commun. 1998, 633-640. (c) For a review
on saturated nitrogen heterocycles, see: Nadin, A.; Mitchinson, A. J .
Chem. Soc., Perkin Trans. 1 2000, 2862-2892. (d) Synthesis of 1,(7)-
substituted pyrrolizidinones: Despinoy, X. L. N.; McNab, H. Tetrahe-
dron 2000, 56, 6359-6383. (e) For some examples, see: Ungureanu,
I.; Bologa, C.; Chayer, S.; Mann, A. Tetrahedron Lett. 1999, 40, 5315-
5318. (f) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J . J . Org. Chem.
1999, 64, 1979-1985. (g) Nadin, A. J . Chem. Soc., Perkin Trans. 1
1998, 3493-3513. (h) Sudau, A.; Nubbemeyer, U. Angew. Chem., Int.
Ed. 1998, 37, 1140-1143. (f) Chan, P. W. H.; Cottrell, I. F.; Moloney,
M. G. Tetrahedron Lett. 1997, 38, 5891-5894. (g) Bardou, A.; Ce´lerie´r,
J . P.; Lhommet, G. Tetrahedron Lett. 1997, 38, 8507-8510. (h) Blot,
J .; Bardou, A.; Bellec, C.; Fargeau-Bellassoued, M.-C.; Ce´lerie´r, J . P.;
Lhommet, G.; Gardette, D.; Gramain, J .-C. Tetrahedron Lett. 1997,
38, 8511-8514.
(5) (a) Boto, A.; Herna´ndez, R.; Sua´rez, E. Tetrahedron Lett. 2000,
41, 2495-2498. (b) Boto, A.; Herna´ndez, R.; Sua´rez, E. Tetrahedron
Lett. 2000, 41, 2899-2902. (c) Boto, A.; Herna´ndez, R.; Sua´rez, E. J .
Org. Chem. 2000, 65, 4930-4937. (d) Boto, A.; Herna´ndez, R.; Sua´rez,
E. Tetrahedron Lett. 1999, 40, 5945-5948.
(6) For recent reviews on organohypervalent iodine compounds in
radical reactions, see: Togo, H.; Katohgi, M. Synlett 2001, 565-581
and reference therein.
(7) (a) Electrochemical decarboxylation: Matsumura, Y.; Shirakawa,
Y.; Satoh, Y.; Umimo, M.; Tanaka, T.; Maki, T.; Onomura, O. Org. Lett.
2000, 2, 1689-1691. (b) Synthetic applications of anodic electrochem-
istry, e.g., decarboxylation: Moeller, K. D. Tetrahedron 2000, 56, 9527-
9554. (c) Other decarboxylations of amino acids: Corcoran, R. C.;
Green, J . M. Tetrahedron Lett. 1990, 31, 6827-6830. (d) Seebach, D.;
Charczuk, R.; Gerber, C.; Renaud, P.; Berner, H.; Schneider, H. Helv.
Chim. Acta 1989, 72, 401-425. (e) Gledhill, A. P.; McCall, C. J .;
Threadgill, M. D. J . Org. Chem. 1986, 51, 3196-3201 and references
therein. (f) Oxidative photodecarboxylation of R-hydroxyacids: Itoh,
A.; Kodama, T.; Inagaki, S.; Masaki, Y. Org. Lett. 2000, 2, 331-333
and references therein.
(8) Recent reviews on N-acyliminium chemistry: (a) Bur, S. K.;
Martin, S. F. Tetrahedron 2001, 57, 3221-3242. (b) Speckamp, W. N.;
Moolenaar, M. J . Tetrahedron 2000, 56, 3817-3856. (c) Padwa, A.
Chem. Comm. 1998, 1417-1424. (d) De Koning, H.; Moolenar, M. J .;
Hiemstra, H.; Speckamp, W. N. In Studies in Natural Products
Chemistry; Atta-ur-Raman, Ed.; Elsevier: Amsterdam, 1993; Vol. 13,
pp 473-518. (e) Hiemstra, H.; Speckamp, W. N. In Comprehensive
Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, pp 1047-1082. (f) Overman, L. E.; Ricca, D. J . In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2, pp 1007-1046 and references
therein. (g) For recent articles on the generation of acyliminium ions,
see: Yoshida, J -i; Okajima, M.; Suga, S. Tetrahedron Lett. 2001, 42,
2173-2176 and references therein. (h) For a discussion of the stereo-
selectivity of nucleophilic addition to N-acyliminium ions, see: Herdeis,
C.; Engel, W. Tetrahedron: Asymmetry 1991, 2, 945-948. (i) For
stereoselective addition to related oxonium ions: Romero, J . A. C.;
Tabacco, S. A.; Woerpel, K. A. J . Am. Chem. Soc. 2000, 122, 168-169.
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1e
1e
1e
1f
2
2
2
2.5
2
2
2
2
2
MeCN
MeCNc
MeCN
MeCN
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
3
3
5
18
25
5
3
3
3
5
2a (15), 3a (66)
3a (6); 4a (62)
2b (8); 3b (54)
2c (4); 3c (69)
2d (35)
3e (9); 5e (36)
3e (35)
3e (9); 4e (62)
2f (59); 3f (8)
3f (19)
c
10
1f
2
a
The reaction was conducted in dry solvents at room temper-
ature under nitrogen. Two equivalents of DIB were used. After
the time noted, the reaction was poured into 10% aqueous Na2S2O3
b
and extracted with CH2Cl2. Yields are for products isolated after
chromatography on silica gel. c The reaction was quenched with
dry methanol and stirred for 1 h before workup.
decarboxylation of proline carbamate derivatives 1a -c5c,9
(Scheme 2) afforded the 3-iodinated pyrrolidines 3a -c
as the major products (Table 1). Thus, when N-(methyl-
oxycarbonyl)-L-proline 1a 9d (Table 1, entry 1) was treated
with DIB and iodine in acetonitrile at room temperature,
followed by aqueous workup, 2-hydroxy-3-iodopyrrolidine
3a (Scheme 2) was obtained in good yields, along with
noniodinated analogue 2a .5c When the reaction was
quenched with dry methanol before workup, 3-iodo-2-
methoxypyrrolidine 4a was obtained as the major product
(entry 2). The isolated 2,3-disubstituted product was
exclusively trans (for a plausible mechanism, see later).
Similar results were observed in the decarboxylation of
(9) (a) Williams, R. M. Synthesis of Optically Active Amino Acids;
Pergamon Press: Oxford, 1989. (b) Remuzon, P. Tetrahedron 1996,
52, 13803-13835. (c) Parsons, A. F. Tetrahedron 1996, 52, 4149-4147.
(d) Product 1a : Irie, H.; Nakanishi, H.; Fujii, N.; Mizuno, Y.; Fushimi,
T.; Funakoshi, S.; Yahima, H. Chem. Lett. 1980, 705-708. (e) Product
1b is commercially available from Aldrich, but it was prepared from
proline: Furniss, B. S.; Hamaford, A. J .; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry; Addison-Wesley-
Longman: Essex, 1996; p 762. (f) Product 1d : Yamada, K.; Takeda,
M.; Iwakuma, T. J . Chem. Soc., Perkin Trans. 1 1983, 265-270. (g)
Product 1e: Shono, T.; Matsumura, Y.; Onomura, O.; Sato, M. J . Org.
Chem. 1988, 53, 4118-4121. (h) Product 1f: Nakai, H.; Sato, Y.;
Mizoguchi, T. Synthesis 1982, 141-143. (i) For a synthesis related to
compound 8, see: Robinson, J . K.; Lee, V.; Claridge, T. D. W.; Baldwin,
J . E.; Schofield, C. J . Tetrahedron 1998, 54, 981-996.

7798 J . Org. Chem., Vol. 66, No. 23, 2001
Boto et al.
the proline benzyl carbamate 1b9e and the proline phenyl
carbamate 1c5c (entries 3 and 4), which gave iododeriva-
tives 3b and 3c, together with the minor hemiaminals
2b5c and 2c,5c respectively. However, the iodination of the
phenyl carbamate 1c required longer reaction times.
When the amide derivative 1d 9f was reacted under
similar conditions (entry 5), only the noniodinated prod-
uct 2d 5c was isolated, even after extended reaction times.
The results obtained with these proline derivatives
suggest that the stronger the electron-withdrawing group
on the nitrogen (amides > phenyl carbamates > benzyl
or methyl carbamates), the more difficult the iodination.
The influence of the ring size in the reaction results
was determined next, using (()-pipecolinic acid deriva-
tives 1e-f (Scheme 2). To our surprise, when pipecolinic
acid methyl carbamate 1e9g was decarboxylated in ac-
etonitrile, followed by aqueous workup (entry 6), a 3,3-
diiodinated compound 5e was formed as the major
product, along with the monoiododerivative 3e. When the
reaction was carried out in dichloromethane (entry 7),
the major product was the 2-hydroxy-3-iodopiperidine 3e.
The yield of monoiodinated products was doubled when
the reaction was quenched with dry methanol (entry 8),
giving trans-3-iodo-2-methoxypiperidine 4e as the major
product (62%) together with 3e (9%). A possible explana-
tion for the higher yields will be given later. The reaction
was then studied with an amide derivative 1f9h (entries
9 and 10). Interestingly, when the benzamide 1f was
reacted in dichloromethane (entry 9), the 3-iodinated
piperidine 3f was obtained along with noniodinated
compound 2f,5c which existed mainly as the aldehyde
tautomer.10 The photolysis in acetonitrile, however,
afforded a complex mixture (entry 10), from which
iododerivative 3f could be isolated.
Sch em e 3. Gen er a tion of Bicyclic N,O-Aceta lsa
a
Key: (a) DIB (2 equiv), I2 (1 equiv), CH2Cl2, 3 h, rt, then
2-hexen-1-ol, 1.5 h, 71%; (b) Bu3SnH, AIBN cat., PhH, 80 °C, 4 h,
83%.
Sch em e 4. P r op osed Mech a n ism for th e
F or m a tion of Iod in a ted P r od u cts
This kind of product may be very useful to obtain bicyclic
N,O-acetals, which are present in natural products such
as (()-physovenine11a,b and madindolines A and B.11c,d In
effect, by treating piperidine 6 with tributyltin hydride
and AIBN in benzene,12 cyclic N,O-acetal 7 was obtained
in 83% yield and in a 3:1 diastereomeric ratio.
A plausible mechanism for this one-pot decarboxyla-
tion-iodination is outlined in Scheme 4. We have seen
before (Scheme 1) that an acyliminium intermediate (IV)
can be trapped by nucleophiles to give noniodinated
piperidines (n ) 1) or pyrrolidines (n ) 0) (V). However,
in an alternative route (Scheme 4), (IV) could equilibrate
with its corresponding enecarbamate (VII), which is
subsequently iodinated to give N-acyliminium ion (VIII).
This intermediate can then be trapped by nucleophiles
(e.g., water, alcohols) to afford monoiodinated piperidines
or pyrrolidines (VI). Since the bulky iodine group hinders
the approach of the nucleophile from the same face, only
the 2,3-trans-disubstituted products are formed. In the
case of six-membered rings, the N-acyliminium ion (VIII,
n ) 1) may equilibrate with enecarbamate (IX). The
iodination of the latter and subsequent trapping of the
resultant acyliminium intermediate with nucleophiles
explains the formation of the diiodo compound (X). Each
step of the sequence must take place in excellent yields
to account for the overall yields obtained.
In summary, the decarboxylation-iodination of car-
bamate derivatives afforded yields better than those of
amides. When five-membered rings derived from car-
bamates were involved, the iodination took place in
acetonitrile but not in dichloromethane. No iodination
was observed with amides, even in acetonitrile. In the
decarboxylation of pipecolinic carbamates, diiodinated
products were obtained as the major products in aceto-
nitrile, while monoiodinated ones were formed in dichlo-
romethane. In this way, by choosing the reaction condi-
tions, different non-, mono-, or diiododerivatives can be
synthesized.
As concluded from the results displayed in Table 1, in
the decarboxylation-oxidation of pipecolinic derivative
1e, the yield of the 2-alkoxypiperidine 4e (entry 8) is
greater than that of 2-hydroxypiperidine 3e (entry 7).
This may indicate that the 2-hydroxy-3-iodopiperidines
are less stable than the 2-alkoxy counterparts, and hence,
to obtain better yields of the 3-iodopiperidines, the
reaction should be quenched with dry alcohols. To check
this point, we studied the photolysis of (()-pipecolinic
acid methyl carbamate 1e in dichloromethane, quenching
with dry 2-hexen-1-ol (Scheme 3). To our pleasure, (()-
2-(2′-hexenyloxy)-3-iodo piperidine 6 was obtained in 71%
yield after purification by column chromatography. Only
the trans product was isolated, as in the previous cases.
The N-acyliminium-enamide equilibrium has been
reported under acid catalysis, usually affording dimeric
(11) (a) Osagawa, K.; Taniguchi, T.; Tanaka, K. Tetrahedron Lett.
2001, 42, 1049-1052. (b) ElAzab, A. S.; Taniguchi, T.; Osagawa, K.
Org. Lett. 2000, 2, 2757-2759. (c) Hosokawa, S.; Sekiguchi, K.; Hayase,
K.; Hirukawa, Y.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 6435-
6439. (d) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.;
Hayashi, M.; Komiyama, K.; Omura, S. J . Am. Chem. Soc. 2000, 122,
2122-2123.
(12) (a) Matos, M. R. P. N.; Afonso, C. A. M.; McGarvey, T.; Lee, P.;
Batey, R. A. Tetrahedron Lett. 1999, 40, 9189-9193 and references
therein. (b) For related work with O,O-acetals, see: Yamazaki, O.;
Yamaguchi, K.; Yokoyama, M.; Togo, H. J . Org. Chem. 2000, 65, 5440-
5442.
(10) (a) Herna´ndez, R.; Melia´n, D.; Sua´rez, E. J . Org. Chem. 1994,
59, 2766-2772. (b) Ciufolini, M. A.; Wood, C. Y. Tetrahedron Lett. 1986,
27, 5085-5088. (c) For related ω-hydroxy aldehyde-hemiacetal tau-
tomerism, see: El-Kadem, H. S. Carbohydrate Chemistry: Monosac-
charides and their Oligomers; Academic Press: San Diego, 1988; pp
15-56.

Synthesis of Pyrrolidines and Piperidines
J . Org. Chem., Vol. 66, No. 23, 2001 7799
Sch em e 5. Syn th esis of Ch ir a l 2,3-Disu bstitu ted
P yr r olid in es a n d Der ived Bicyclic System sa
appears as a broad singlet, due to the trans arrangement
of H-C2 and H-C3. The signal at δ 4.18 (H-C3) also
appears as a broad singlet, confirming a trans disposition
with respect to H-C2 and to H-C4. As for the other
diastereomer 9b, the 1H NMR spectrum for the major
rotamer shows a doublet (J ) 1.8 Hz) at δ 5.78 (H-C2),
a double doublet at δ 4.43 (J ) 5.8, 1.8 Hz, H-C3), and
a dd at δ 4.90 (J ) 11.2, 5.8 Hz, H-C4). These results
correspond to a trans disposition between H-C2 and
H-C3 and a cis arrangement between H-C3 and H-C4.
Under similar reaction conditions, but quenching with
dry methanol and adding a catalytic amount of TsOH,
(2S,3R,4S)- and (2R,3S,4S)-2-methoxy-3-iodo-4-acetoxy
compounds 10a and 10b were isolated as the major
products (10a :10b, 1:1, 44%), together with the 2-hy-
droxy-3-iododerivatives 9a and 9b (9a :9b, 4:1, 15%). The
diastereomers 10a and 10b could be easily separated by
column chromatography. As occurred with 9a and 9b,
each of the 2-methoxy derivatives 10a and 10b was
obtained as a mixture of two rotamers at room temper-
ature. However, only one rotamer was observed in the
NMR spectrum on heating at 70 °C because of the faster
rotamer interconversion. Thus, the NMR spectrum at 70
°C for compound 10a showed a broad singlet at δ 5.46
(H-C2) and a singlet at δ 4.23 (H-C3). These signals are
assignable to a trans disposition between H-C2 and
H-C3 and between H-C3 and H-C4. For compound 10b,
a broad singlet at δ 5.45 (H-C2), a doublet at δ 4.55 (J
) 5 Hz, H-C3), and a ddd at δ 4.72 (J ) 7.6, 7.5, 5.0 Hz,
H-C4) are observed, involving a 2,3-trans and a 3,4-cis
relationships.
a
Key: (a) DIB (2 equiv), I2 (2 equiv), MeCN, 5 h, then H2O,
53% (9a :9b, 3:2); (b) DIB (2 equiv), I2 (2 equiv), MeCN, 5 h, then
MeOH, TsOH catalytic, 12 h, 56% (10a :10b, 2:1); (c) allyltribu-
tyltin, AIBN cat., PhH, 80 °C, 92%; (d) Allyltrimethylsilane,
BF3‚Et2O, CH2Cl2, 0 °C, 99%; (e) DIB, I2, MeCN, 3 h, then
allyltrimethylsilane, BF3‚Et2O, 0 °C, 4 h, 42% (11a :11b, 10:1); (f)
allyltributyltin, AIBN cat., PhH, 80 °C, 99%; (g) Grubbs’ catalyst,
CH2Cl2, reflux, 95%.
The 2-hydroxy or 2-methoxy-3-iodopyrrolidines are
useful chiral synthons from which other 2,3-disubstituted
pyrrolidines can be easily formed. For instance, using a
radical allylation at C-3 the pyrrolidine 11 (Scheme 5)
was obtained in excellent yield. Also, when an ionic
allylation at C-2 was carried out, the diallylated pyrro-
lidine 12 was isolated. Both reactions took place with
side products.13 The halogenation of enamides and en-
ecarbamates has also been described14 and applied to the
synthesis of natural products such as (()-mesembrine,14c
(()-elsewine,14c (-)-sedacrine,14d and gelsemine.14e
The stereoselectivity of the reaction using chiral sub-
strates was studied next. The starting material used was
the readily available trans-4-hydroxy-L-proline derivative
89h (Scheme 5). On treatment with DIB-iodine, followed
by aqueous workup, the (2S,3R,4S)- and (2R,3S,4S)-2-
hydroxy-3-iodo-4-acetoxypyrrolidines 9a and 9b were
obtained after 5 h in 53% yield (9a :9b, 1.5:1). Both
diastereomers could be separated by column chromatog-
raphy on silica gel, and at room temperature each of them
was found to be a mixture of two rotamers, which could
be observed by NMR at 26 °C. When the temperature of
the NMR experiment was increased to 70 °C, a complex
1
complete stereoselectivity. Thus, the H NMR spectrum
at 70 °C of product 11 showed a broad singlet at δ 4.96
(H-C2), involving a trans relationship between this
proton and H-C3. A ddd corresponding to H-C4 was
observed at δ 4.89; the J 3,4 ) 2.8 Hz involves a trans
relationship between H-C3 and H-C4. The double reso-
nance experiments also supported the assigned (2S,3R,4R)
configuration.
1
For product 12 the H NMR spectrum at 70 °C showed
a ddd at δ 4.94 (J ) 5.9, 2.8, 2.5 Hz, H-C4), a multiplet
at δ 2.25 (H-C3), and a multiplet at δ 3.83 (H-C2). The
irradiation of the signal at δ 2.25 (H-C3) did not affect
the signal at δ 3.83 (H-C2), indicating a trans relation-
ship between both protons. The assigned stereochemistry
was also supported by 2D-NMR experiments.
The route from 8 to 12 can be shortened even further
by a new tandem decarboxylation-â-iodination-allyl-
ation reaction. Thus, once the decarboxylation of 8 was
completed, allyltrimethylsilane and boron trifluoride
were added at 0 °C to the reaction mixture. In this way,
products 13a (2S,3S,4S) and 13b (2R,3R,4S) were ob-
tained in a remarkable 10:1 diastereomeric ratio (42%
overall yield). Both isomers were easily separated by
column chromatography.
1
mixture was formed. The H NMR data at 26 °C of the
major rotamer of 9a support the assigned stereochemis-
try. Thus, the signal at δ 5.79, corresponding to H-C2,
(13) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-
4416. (b) Wijnberg, J . B. P. A.; Boer, J . J . J .; Speckamp, W. N. Rec.
Trav. Chim. Pays-Bas. 1978, 97, 227-231. (c) Schoemaker, H. E.; Boer-
Terpstra, Tj.; Dijkink, J .; Speckamp, W. N. Tetrahedron 1980, 36, 143-
148.
(14) (a) Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki,
T. Tetrahedron 2000, 56, 7411-7422. (b) Billon-Souquet, F.; Martens,
T.; Royer, J . Tetrahedron 1996, 52, 15127-15136 and references
therein. (c) Matsumura, Y.; Terauchi, J .; Yamamoto, T.; Konno, T.;
Shono, T. Tetrahedron 1993, 49, 8503-8512. (d) Driessens, F.; Hootele´,
C. Can. J . Chem. 1991, 69, 211-217. (e) Earley, W. G.; Oh, T.;
Overman, L. E. Tetrahedron Lett. 1988, 29, 3785-3788. (f) Shono, T.;
Matsumura, Y.; Onomura, O.; Ogaki, M.; Kanazana, T. J . Org. Chem.
1987, 52, 536-541. (g) Torii, S.; Inokuchi, T.; Akahosi, M.; Kubota,
M. Synthesis 1987, 242-245.
For each diastereomer 13a or 13b, a mixture of two
rotamers is observed at room temperature. By heating
to 70 °C, the interconversion between rotamers is en-
hanced, and only one rotamer can be observed by NMR.

7800 J . Org. Chem., Vol. 66, No. 23, 2001
Boto et al.
Sch em e 6. Exp ed ien t Syn th esis of
2-Su bstitu ted -2,5-Dih yd r op yr r olsa
easy and, to our pleasure, even took place by dissolving
15 in chloroform-d; the reaction was completed in hours
at room temperature and was accelerated by heating to
70 °C. In this way, in just two steps, 2-substituted 2,5-
dihydropyrroles can be obtained from easily available
proline derivatives.
In summary, we have developed a promising method-
ology to obtain 2,3-disubstituted pyrrolidines and pip-
eridines from commercial amino acids, using a one-pot
decarboxylation-iodination reaction. The introduction of
the substituents in positions 2 and 3 is exclusively trans.
The influence of the solvent, the ring size, and the
protecting group on the nitrogen of the starting amino
acid are studied. Thus, by simply changing these features
we can obtain mono-, di- or noniodinated pyrrolidines or
piperidines. When a chiral C-4 is present in the amino
acid, the reaction gives mainly the 2,3-trans, 3,4-trans
3-iododerivative. The resulting products can be manipu-
lated to give bicyclic systems present in many natural
products. Moreover, by a new tandem decarboxylation-
iodination-alkylation reaction the trans 2-substituted-
3-iodopyrrolidines are formed. These can be easily dehy-
droiodinated to 2-substituted 2,5-dihydropyrrols. In this
way a double bond is introduced at two previously
unfunctionalized positions. The application of this meth-
odology as the key step in the synthesis of alkaloids is
underway and will be reported in due course.
a
Key: (a) DIB (2 equiv), I2 (1 equiv), MeCN, 3 h, rt, then
CH2dC(OAc)Me, BF3‚Et2O, 0 °C, 4 h, 56%; (b) DBU, CH2Cl2, rt,
12 h, 99% or CDCl3, 70 °C, 1 h, 99%.
The 1H NMR spectrum and double resonance experi-
ments at 70 °C of the major isomer 13a permit a trans
relationship to be established between H-C3 and H-C4
(J 3,4 ) 2.3 Hz) and for H-C3 and H-C2 (J 3,2 ) 2.1 Hz).
Treating 13a with allyltributyltin and AIBN in ben-
zene afforded diallyl derivative 12 in 92% yield and 99%
stereoselectivity. This compound was transformed via a
metathesis reaction15 into the hexahydroindole derivative
14 in 95% yield. In this way, an easily obtained hydroxy-
proline derivative was transformed in just three steps
and with high stereoselectivity into a highly functional-
ized bicyclic compound. The polyhydroindole rings are
present in Amarillydaceae,16 Sceletium,17 Strychnos,18
and Aspidosperma19 alkaloids, among others,20 and pep-
tides such as Aeruginosins.21
Moreover, this one-pot decarboxylation-iodination-
alkylation process also allows the introduction of a double
bond at two previously unfunctionalized positions. Thus,
when proline derivative 1a (Scheme 6) was treated with
DIB and iodine followed by addition of isopropenyl
acetate and BF3‚Et2O, the (()-iodopyrrolidine 15 was
obtained in 56% yield. This compound, on treatment with
DBU, afforded the 2,5-dihydropyrrol 16 in quantitative
yield. The elimination reaction proved to be extremely
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined with
a hot-stage apparatus and are uncorrected. Optical rotations
were measured at the sodium line at room temperature in
CHCl3 solutions. IR spectra were recorded in CHCl3 solutions.
Mass spectra were determined at 70 eV unless otherwise
specified. NMR spectra were determined at 500 MHz for 1H
and 50.3 or 125.7 MHz for 13C in CDCl3 unless otherwise
stated, in the presence of TMS as internal standard. For most
of the compounds described, there is an equilibrium between
rotamers at room temperature, causing splitting or broadening
of the signals in the NMR experiment. In many cases, the
conversion between rotamers was made faster by heating the
products to 70 °C, causing the split signals to coalesce. In a
few cases, however, the complexity of the spectrum was not
reduced on heating, or it was even increased, as for compounds
9a and 9b, and hence, the temperature of the experiment is
recorded for each case. Merck silica gel 60 PF254 and 60 PF
(0.063-0.2 mm) were used for thin-layer chromatography and
column chromatography, respectively. The TLC analyses were
conducted by spraying the layer either with 0.5% vanillin in
H2SO4/EtOH (4:1) or with 0.25% ninhydrin in EtOH and
heating till development of color. The reactions involving air-
or moisture-sensitive materials were carried out under a
nitrogen atmosphere. Commercially available reagents and
solvents were analytical grade or were purified by standard
procedures prior to use.22 All of the starting unprotected amino
acids were commercially available.
(15) For recent reviews, see: (a) Hoveyda, A.; Schrock, R. R. Chem.
Eur. J . 2001, 7, 945-950. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (c) Maier, M. E. Angew. Chem., Int. Ed. 2000,
39, 2073-2077. (d) Roy, R.; Das, S. K. Chem. Comm. 2000, 519-529.
(e) Buchmaiser, M. R. Chem. Rev. 2000, 100, 1565-1604. (f) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (g) Philips, A. J .; Abell,
A. D. Aldrichimica Acta 1999, 32, 75-98. (h) Pandit, U.K.; Overkleeft,
H. S.; Borer, B. C.; Biera¨ugel, H. Eur. J . Org. Chem. 1999, 959-968.
(i) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371-388. (j)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (k)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036-2056.
(16) (a) Meyers, A. I.; Watson, D. J . Tetrahedron Lett. 2000, 41,
1519-1522. (b) Parsons, A. F.; Williams, D. A. J . Tetrahedron 2000,
56, 7217-7228.
(17) (a) Lewis, J . R. Nat. Prod. Rep. 2001, 18, 95-128 and references
therein. (b) Rigby, J . H.; Dong, W. Org. Lett. 2000, 2, 1673-1675 and
references therein. (c) Meyers, A. I.; Watson, D. J . Tetrahedron Lett.
2000, 41, 1519-22. (d) Taber, D. F.; Neubert, T. D. J . Org. Chem. 2001,
66, 143-147.
(18) (a) Dictionary of Alkaloids; Southon, I. W., Buckingham, J .,
Eds.; Chapman and Hall: London, 1989. (b) Chataigner, I.; Hess, E.;
Toupet, L.; Piettre, S. R. Org. Lett. 2001, 3, 515-518. (c) Zard, S. Z.;
Dauge, D.; Cassayre, J . Synlett 2000, 471-474.
(19) (a) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Schulte, M.; J ones,
K. Chem. Comm. 2001, 209-210. (b) Bonjoch, J .; Sole, D. Chem. Rev.
2000, 100, 3455-3482.
Oxid a tive Deca r boxyla tion of r-Am in o Acid s. Gen er a l
P r oced u r es. Meth od A. A solution of the acid 1a (173 mg,
1.0 mmol) in acetonitrile (15 mL) was treated with (diacetoxy-
iodo)benzene (DIB) (644 mg, 2 mmol) and iodine (308 mg, 2
mmol) under nitrogen. After stirring at room temperature for
3 h, the reaction mixture was poured into 10% aqueous sodium
thiosulfate and extracted with dichloromethane. The organic
layer was washed with brine, dried (Na2SO4), and evaporated
under vacuum. The residue was immediately purified by
column chromatography (hexanes-ethyl acetate, 4:1) yielding
(20) (a) Boger, D. L.; Santilla´n, A., J r.; Searcey, M.; Brunette, S. R.;
Wolkenberg, S. E.; Hedrick, M. P.; J in, Q. J . Org. Chem. 2000, 65,
4101-4111. (b) Padwa, A.; Dimitroff, M.; Liu, B. Org. Lett. 2000, 2,
3233-3235. (c) J acobi, P. A.; Lee, K. J . Am. Chem. Soc. 2000, 122,
4295-4303. (d) Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.;
Muraoka, O.; Tanabe, G.; Ishibashi, H. Tetrahedron Lett. 2001, 42,
1729-1732. (e) Martin, S. F.; Humphrey, J . M.; Ali, A. Hillier, M. C.
J . Am. Chem. Soc. 1999, 121, 866-867.
(21) (a) Wipf, P.; Methot, J .-L. Org. Lett. 2000, 2, 4213-4216. (b)
Murakami, M.; Ishida, K.; Okino, T.; Okita, Y.; Matsuda, H.; Yamagu-
chi, K. Tetrahedron Lett. 1995, 36, 2785-2788 and references therein.
(22) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: New York, 1988.

Synthesis of Pyrrolidines and Piperidines
J . Org. Chem., Vol. 66, No. 23, 2001 7801
the iodinated derivative 3a (173 mg, 0.64 mmol, 64%) and the
nonhalogenated hemiaminal 2a (18 mg, 0.12 mmol, 12%).
Meth od B. The reaction was performed with 1a as above,
adding dry methanol (1 mL) when TLC analysis showed
consumption of the starting material (3 h). Then, the reaction
mixture was stirred for 1 h, followed by workup and purifica-
tion as previously described, yielding compounds 3a (16 mg,
6%) and 4a (176 mg, 62%).
4.3 Hz), 2.89 (1H, ddd, J ) 11.8, 11.8, 3.4 Hz), 1.85 (1H, m),
1.76 (1H, m), 1.65-1.58 (2H, m), 1.15-1.40 (8H, m), 0.84 (3H,
dd, J ) 7.1, 6.9 Hz); δ minor diastereomer 5.65 (1H, d, J )
3.4 Hz), 4.06 (1H, dd, J ) 7.4, 7.1 Hz), 3.87 (1H, dd, J ) 8.0,
8.0 Hz), 3.65 (3H, s), 3.46 (1H, dd, J ) 10.5, 7.9 Hz), 2.84 (1H,
ddd, J ) 12.8, 12.8, 2.8 Hz), 1.84 (1H, m), 1.58-1.65 (3H, m),
1.15-1.40 (8H, m), 0.86 (3H, dd, J ) 7.4, 7.3 Hz); 13C NMR
(125.7 MHz, 26 °C) δ major isomer 155.6 (C), 83.0 (CH), 70.5
(CH2), 52.7 (CH3), 44.6 (CH), 40.7 (CH), 39.4 (CH2), 33.5 (CH2),
30.0 (CH2), 26.1 (CH2), 22.8 (CH2), 22.5 (CH2), 13.9 (CH3); δ
minor isomer 156.6 (C), 84.7 (CH), 70.0 (CH2), 52.7 (CH3), 41.9
(CH), 37.7 (CH), 33.5 (CH2), 30.3 (CH2), 26.6 (CH2), 26.1 (CH2),
22.8 (CH2), 19.6 (CH2), 13.4 (CH3); MS (EI) m/z (rel intensity)
210 (M+ - Me, 3), 149 (100); HRMS calcd for C12H20NO2
210.1494, found 210.1471. Anal. Calcd for C13H23NO3: C,
64.70; H, 9.61; N, 5.80. Found: C, 64.59; H, 9.86; N, 5.66.
Meth yl (2S,3R,4S)-4-Acetyloxy-2-h yd r oxy-3-iod op yr -
r olid in e-1-ca r boxyla te (9a ) a n d Meth yl (2R,3S,4S)-4-
Acetyloxy-2-h ydr oxy-3-iodopyr r olidin e-1-car boxylate (9b).
A solution of the acid 8 (150 mg, 0.65 mmol) in acetonitrile
(19 mL) was treated with DIB (410 mg, 1.3 mmol) and iodine
(300 mg, 1.2 mmol) under nitrogen. After stirring at room
temperature for 5 h, the reaction mixture was poured into
saturated sodium bicarbonate and extracted with dichlo-
romethane. The organic layer was washed with sodium thio-
sulfate and brine, dried (Na2SO4), and evaporated under
vacuum. Flash column chromatography on silica gel (hexanes-
EtOAc, 80:20) afforded 2-hydroxy-3-iododerivatives 9a (68 mg,
0.2 mmol, 32%) and 9b (45 mg, 0.13 mmol, 21%). Compound
9a : two rotamers at 26 °C (1.5:1); syrup; IR 3576, 3444, 1735,
Meth yl (2R*,3S*)-2-Hyd r oxy-3-iod o-1-p yr r olid in eca r -
boxyla te (3a ). Two rotamers at 26 °C (2:1); one rotamer at
70 °C; syrup; IR 3586, 3394, 2892, 1691, 1451, 1382 cm-1; 1H
NMR (500 MHz, 70 °C) δ 5.68 (1H, br s), 4.16 (1H, d, J ) 5.0
Hz), 3.70 (3H, s), 3.56 (2H, m), 2.52 (1H, m), 2.10 (1H, m); 13
C
NMR (125.7 MHz, 26 °C) δ major rotamer 155.9 (C), 89.5 (CH),
52.8 (CH3), 44.6 (CH2), 33.8 (CH2), 27.0 (CH); δ minor rotamer
154.8 (C), 89.0 (CH), 52.8 (CH3), 45.0 (CH2), 32.8 (CH2), 28.0
(CH); MS (FAB) m/z (rel intensity) 272 (M+ + H, 5), 254 (39),
154 (100). Anal. Calcd for C6H10INO3: C 26.59; H 3.72; N 5.17.
Found: C, 26.79; H, 3.96; N, 5.12.
Meth yl (2R*,3S*)-3-Iod o-2-m eth oxy-1-p yr r olid in eca r -
boxyla te (4a ). Two rotamers at 26 °C (2:1); one rotamer at
1
70 °C; syrup; IR 1702, 1447, 1384, 1078 cm-1; H NMR (500
MHz, 70 °C) δ 5.35 (1H, br s), 4.20 (1H, d, J ) 5.2 Hz), 3.74
(3H, s), 3.65 (1H, m), 3.46 (1H, dd, J ) 9.0, 9.1 Hz), 3.38 (3H,
s), 2.50 (1H, m), 2.11 (1H, dd, J ) 6.8, 14.3 Hz); 13C NMR (125.7
MHz, 26 °C) δ major rotamer 156.1 (C), 96.5 (CH), 56.3 (CH3),
52.7 (CH3), 44.5 (CH2), 33.7 (CH2), 25.6 (CH); δ_minor rotamer
155.3 (C), 96.1 (CH), 55.7 (CH3), 52.8 (CH3), 44.7 (CH2), 32.7
(CH2), 26.3 (CH); MS (EI) m/z (rel intensity) 285 (M+, 2), 254
(M+ - OMe, 100); HRMS calcd for C7H12INO3 284.9862, found
284.9878. Anal. Calcd for C7H12INO3: C 29.49; H, 4.24; N 4.91.
Found: C, 29.63; H, 4.46; N, 4.95.
1
1694 cm-1; H NMR (500 MHz, 26 °C) δ major rotamer 5.79
(1H, br s), 5.32 (1H, d, J ) 4.4 Hz), 4.18 (1H, br s), 4.06 (1H,
dd, J ) 6.0, 12.7 Hz), 3.90 (1H, br s, OH), 3.76 (3H, s), 3.70
(1H, d, J ) 11.8 Hz), 2.10 (3H, s); δ minor rotamer, 5.68 (1H,
s), 5.36 (1H, d, J ) 3.9 Hz), 4.22 (1H, brs), 4.12 (1H, m), 3.79
(3H, s), 3.77 (1H, m), 3.2 (1H, br s, OH), 2.10 (3H, s); 13C NMR
(125.7 MHz, 26 °C) δ major rotamer 169.9 (C), 155.4 (C), 90.0
(CH), 79.0 (CH), 52.9 (CH3), 49.8 (CH2), 25.0 (CH), 20.8 (CH3);
δ minor rotamer 169.9 (C), 154.6 (C), 89.5 (CH), 78.2 (CH),
53.1 (CH3), 50.3 (CH2), 26.0 (CH), 20.8 (CH3); MS (EI) m/z (rel
intensity) 329 (M+, <1), 328 (M+ - H, 4), 312 (34), 252 (93),
142 (100); HRMS calcd for C8H12INO5 328.9760, found 328.9764.
Anal. Calcd for C8H12INO5: C, 29.18; H, 3.68; N, 4.26. Found:
C, 29.48; H, 3.88; N, 4.31. Compound 9b: two rotamers at 26
Meth yl (2R*,3S*)-2-[(2E)-2-Hexen yloxy]-3-iod o-1-p ip -
er id in eca r boxyla te (6). A solution of the acid 1e (260 mg,
1.4 mmol) in dichloromethane (19 mL) was treated with DIB
(895 mg, 2.8 mmol) and iodine (308 mg, 1.2 mmol) under
nitrogen. After stirring at room temperature for 3 h, the
reaction mixture was quenched with 2-hexen-1-ol and after
another 1.5 h, the mixture was poured into 10% aqueous
sodium thiosulfate and extracted with dichloromethane. The
organic layer was washed with brine, dried (Na2SO4), and
evaporated under vacuum. The residue was immediately
purified by column chromatography (hexanes-EtOAc, 4:1)
yielding the iodinated derivative 6 (362 mg, 0.99 mmol, 71%):
two rotamers at 26 °C (2:1.5); syrup; IR 1694, 1448, 1270 cm-1
;
°C (1.8:1); syrup; IR 3578, 3458, 1702, 1454 cm-1 1H NMR
;
1H NMR (500 MHz, 26 °C) δ 5.52-5.46 (3H, m), 4.37 (1H, m),
3.93-3.70 (3H, m), 3.65 (3H, s), 2.94 (1H, m), 2.05 (1H, m),
1.90 (3H, m), 1.75 (1H, d, J ) 14.6 Hz), 1.40 (1H, m), 1.30
(2H, ddd, J ) 7.4, 7.4, 7.4 Hz), 0.81 (3H, dd, J ) 7.4, 7.4 Hz);
13C NMR (125.7 MHz, 26 °C) δ major rotamer 135.2 (CH),
125.4 (CH), 84.0 (CH), 68.0 (CH2), 52.7 (CH3), 38.1 (CH2), 34.3
(CH2), 30.1 (CH), 28.0 (CH2), 22.0 (CH2), 20.9 (CH2), 13.5 (CH3);
δ minor rotamer 135.0 (CH), 125.4 (CH), 84.0 (CH), 68.4 (CH2),
52.7 (CH3), 38.5 (CH2), 34.3 (CH2), 29.7 (CH), 28.0 (CH2), 22.0
(CH2), 21.1 (CH2), 13.5 (CH3); the signal of the carbamate
carbonyl could not be observed; MS (EI) m/z (rel intensity) 284
(M+ - C6H11, 1), 268 (M+ - C6H11O, 100), 188 (30), 141 (98);
HRMS calcd for C7H11INO3 283.9784, found 283.9809. Anal.
Calcd for C13H22INO3: C, 42.52; H, 6.04; N, 3.81. Found: C,
42.26; H, 6.23; N, 3.95.
(500 MHz, 25 °C) δ major rotamer 5.78 (1H, d, J ) 1.8 Hz),
4.90 (1H, ddd, J ) 6.1, 6.1, 5.8 Hz), 4.43 (1H, dd, J ) 5.8, 1.8
Hz), 3.97 (1H, brs, OH), 3.82 (1H, dd, J ) 6.1, 11.1 Hz), 3.76
(3H, s), 3.51 (1H, dd, J ) 6.0, 11.1 Hz), 2.1 (3H, s); δ minor
rotamer 5.72 (1H, br s), 4.90 (1H, dd, J ) 11.2, 5.8 Hz), 4.90
(1H, br s), 4.40 (1H, m), 4.17 (1H, br s, OH), 4.07 (1H, m),
3.78 (3H, s), 3.61 (1H, dd, J ) 6.0, 11.0 Hz), 2.08 (3H, s); 13C
NMR (125.7 MHz, 25 °C) δ major rotamer 169.8 (C), 157.7 (C),
89.1 (CH), 70.7 (CH), 52.9 (CH3), 48.4 (CH2), 29.5 (CH), 20.9
(CH3); δ minor rotamer 169.8 (C), 155.5 (C), 88.7 (CH), 70.2
(CH), 53.1 (CH3), 48.5 (CH2), 30.8 (CH), 20.7 (CH3); MS (EI)
m/z (rel intensity) 329 (M+, <1), 312 (M+ - OH, 2), 142 (100);
HRMS calcd for C8H11INO4 311.9733, found 311.9744. Anal.
Calcd for C8H12INO5: C, 29.18; H, 3.68; N, 4.26. Found: C,
29.25; H, 3.93; N, 4.16.
Meth yl (2R*,3a R*,7a R*)-3-Bu tylh exa h yd r ofu r o[2,3b]-
p yr id in e-7(4H)-ca r boxyla te (7). A solution of methyl car-
boxylate 6 (160 mg, 0.44 mmol) and a catalytic amount of
AIBN (10 mg) in dry benzene (10 mL), under nitrogen, was
treated with tributyltin hydride (0.5 mL, 1.8 mmol) at room
temperature. Then the reaction was heated to 80 °C for 4 h.
The reaction mixture was allowed to cool to room temperature,
the solvent was evaporated under vacuum, and the residue
was purified by column chromatography (first elution with
hexanes to remove the tin reagent, followed by hexanes-
EtOAc, 80:20), yielding 7 (86 mg, 83%): two unseparable
diastereomers (3:1 at 70 °C); syrup; IR 1694, 1448, 1352, 1018
Meth yl (2S,3R,4S)-4-Acetyloxy-3-iodo-2-m eth oxy-1-pyr -
r olid in eca r b oxyla t e (10a ) a n d Met h yl (2R,3S,4S)-4-
Acet yloxy-3-iod o-2-m et h oxy-1-p yr r olid in eca r b oxyla t e
(10b). A solution of the acid 8 (150 mg, 0.65 mmol) in
acetonitrile (19 mL) was treated with DIB (410 mg, 1.3 mmol)
and iodine (300 mg, 1.2 mmol) under nitrogen. After stirring
at room temperature for 5 h, the reaction mixture was
quenched with dry methanol. A catalytic amount of TsOH was
added, and the reaction mixture was stirred for 2 h. It was
then poured into saturated sodium bicarbonate and extracted
with dichloromethane. The organic layer was washed with
sodium thiosulfate and brine, dried (Na2SO4), and evaporated
under vacuum. Column chromatography on silica gel (hex-
anes-EtOAc, 90:10) afforded 2-methoxy-3-iododerivatives 10a
(47 mg, 0.14 mmol, 21%) and 10b (51 mg, 0.15 mmol, 23%),
1
cm-1; H NMR (500 MHz, 70 °C) δ major diastereomer 5.59
(1H, d, J ) 5.1 Hz), 4.02 (1H, dd, J ) 8.8, 7.5 Hz), 3.81 (1H,
ddd, J ) 12.8, 4.3, 4.3 Hz), 3.66 (3H, s), 3.36 (1H, dd, J ) 8.8,

7802 J . Org. Chem., Vol. 66, No. 23, 2001
Boto et al.
together with 2-hydroxy-3-iodo derivatives 9a (26 mg, 0.08
mmol, 12%) and 9b (6 mg, 0.02 mmol, 3%) (59% overall yield).
Compound 10a : two rotamers at 26 °C (1.4:1); one rotamer
at 70 °C; syrup; [R]D +3 (c ) 0.61); IR 1740, 1714, 1450, 1385
(11) 166 (100); HRMS calcd for C14H21NO4 267.1471, found
267.1475. Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N,
5.24. Found: C, 62.76; H, 8.14; N, 5.24.
Met h yl
(2S,3S,4S)-4-Acet yloxy-2-a llyl-3-iod o-1-p yr -
1
cm-1; H NMR (500 MHz, 70 °C) δ 5.46 (1H, br s), 5.34 (1H,
r olid in eca r b oxyla t e (13a ) a n d Met h yl (2R,3R,4S)-4-
Acetyloxy-2-a llyl-3-iod o-1-p yr r olid in eca r boxyla te (13b).
A solution of the acid 8 (106 mg, 0.46 mmol) in acetonitrile
(12 mL) was treated with DIB (297 mg, 0.96 mmol) and iodine
(130 mg, 0.5 mmol) under nitrogen. After stirring at room
temperature for 3.5 h, the reaction was cooled at 0 °C, and an
excess of allyltrimethylsilane was added (0.7 mL, 4.6 mmol).
Then, BF3‚Et2O (0.18 mL, 0.96 mmol) was added dropwise.
The reaction mixture was allowed to reach room temperature
(1 h) and stirred for other 2 h. The solution was poured into
saturated sodium bicarbonate and extracted with dichlo-
romethane. The organic layer was washed with 10% aqueous
sodium thiosulfate and brine, dried (Na2SO4), and evaporated
under vacuum. Column chromatography on silica gel (hex-
anes-EtOAc, 90:10) afforded allyl derivatives 13a (60 mg, 0.17
mmol, 37%) and 13b (6 mg, 0.017 mmol, 4%) (41% global yield,
13a :13b, 10:1). Compound 13a : two rotamers at 26 °C (1.5:
1); one rotamer at 70 °C; oil; [R]D +10 (c ) 0.71); IR 1744, 1697,
1454, 1385, 1123 cm-1; 1H NMR (500 MHz, 70 °C) δ 5.80 (1H,
m), 5.38 (1H, ddd, J ) 5.1, 2.3, 2.3 Hz), 5.15 (1H, d, J ) 10.3
Hz), 5.10 (1H, dd, J ) 17.1, 1.5 Hz), 4.34 (1H, m), 4.27 (1H, d,
J ) 2.1 Hz), 4.21 (1H, dd, J ) 12.7, 5.8 Hz), 3.75 (3H, s), 3.48
(1H, dd, J ) 12.7, 2.1 Hz), 2.67 (1H, m), 2.38 (1H, ddd, J )
14.4, 8.8, 8.5 Hz), 2.07 (3H, s); 13C NMR (125.7 MHz, 26 °C) δ
major rotamer 169.5 (C), 155.0 (C), 133.5 (CH), 118.5 (CH2),
80.3 (CH), 68.2 (CH), 52.7 (CH3), 50.0 (CH2), 38.5 (CH2), 23.5
(CH), 20.8 (CH3); δ minor rotamer 169.5 (C), 155.0 (C), 133.7
(CH), 118.6 (CH2), 79.5 (CH), 68.2 (CH), 52.7 (CH3), 50.4 (CH2),
39.2 (CH2), 24.5 (CH), 20.8 (CH3); MS (EI) m/z (rel intensity)
312 (M+ - C3H5, 19), 252 (60), 125 (100); HRMS calcd for
dd, J ) 6.0, 1.8 Hz), 4.23 (1H, s), 4.16 (1H, dd, J ) 12.6, 6.0
Hz), 3.78 (3H, s), 3.57 (1H, dd, J ) 12.6, 1.7 Hz), 3.44 (3H, s),
2.06 (3H, s); 13C NMR (125.7 MHz, 70 °C) δ 170.0 (C), 155.7
(C), 97.3 (CH), 79.4 (CH), 56.6 (CH3), 52.9 (CH3), 50.3 (CH2),
24.9 (CH), 20.7 (CH3); MS (EI) m/z (rel intensity) 312 (M+
OMe, 29), 284 (9), 252 (33), 156 (100), 125 (94); HRMS calcd
for C8H11INO4 311.9733, found 311.9744. Anal. Calcd for C9H14
-
-
INO5: C, 31.50; H, 4.11; N, 4.08. Found: C, 31.55; H, 4.29; N,
4.03. Compound 10b: two rotamers at 26 °C (1.6:1); one
rotamer at 70 °C; syrup; [R]D -22 (c ) 0.42); IR 1748, 1711,
1450, 1387, 1258 cm-1; 1H NMR (500 MHz, 70 °C) δ 5.45 (1H,
br s), 4.72 (1H, ddd, J ) 7.6, 7.5, 5.0 Hz), 4.55 (1H, d, J ) 5
Hz), 3.78 (3H, s), 3.73 (1H, dd, J ) 10.8, 7.5 Hz), 3.5 (1H, m),
3.45 (3H, s), 2.11 (3H, s); 13C NMR (125.7 MHz, 26 °C) δ major
rotamer 169.9 (C), 155.9 (C), 95.9 (CH), 70.8 (CH), 56.8 (CH3),
53.0 (CH3), 47.6 (CH2), 30.8 (CH), 20.9 (CH3); δ minor rotamer
169.9 (C), 155.9 (C), 95.7 (CH), 70.2 (CH), 56.3 (CH3), 53.0
(CH3), 47.8 (CH2), 31.5 (CH), 20.9 (CH3); MS (EI) m/z (rel
intensity) 312 (M+ - OMe, 21), 284 (12), 252 (13), 156 (100);
HRMS calcd for C8H11INO4 311.9733, found 311.9730. Anal.
Calcd for C9H14INO5: C, 31.50; H, 4.11; N, 4.08. Found: C,
31.82; H, 3.79; N, 3.91.
Met h yl (2S,3R,4R)-4-Acet yloxy-3-a llyl-2-m et h oxy-1-
p yr r olid in eca r boxyla te (11). A solution of 3-iodo-2-methoxy-
1-pyrrolidine derivative 10a (90 mg, 0.26 mmol) and a catalytic
amount of AIBN (10 mg) in dry benzene (7 mL), under
nitrogen, was treated with allyltributyltin (0.26 mL, 1.23
mmol) at room temperature. Then the reaction was heated to
80 °C for 4 h. The reaction mixture was allowed to cool to room
temperature, the solvent was evaporated under vacuum, and
the residue was purified by column chromatography (first
elution with hexanes to remove the tin reagent and then with
hexanes-EtOAc, 4:1), yielding 11 (61 mg, 91%): two rotamers
at 26 °C (2.1:1); one rotamer at 70 °C; syrup; [R]D +12 (c )
C8H11INO4 311.9733, found 311.9725. Anal. Calcd for C11H16
-
INO4: C, 37.41; H, 4.57; N, 3.97. Found: C, 37.51; H, 4.41; N,
3.91. Compound 13b: two rotamers at 26 °C (1.6:1); one
rotamer at 70 °C; oil; [R]D -13 (c ) 1.16); IR 1745, 1700, 1453,
1389 cm-1 1H NMR (500 MHz, 70 °C) δ 5.76 (1H, m), 5.16
;
1
0.318); IR 1732, 1707, 1451 cm-1; H NMR (500 MHz, 70 °C)
(1H, d, J ) 11.4 Hz), 5.15 (1H, d, J ) 15.3 Hz), 4.80 (1H, ddd,
J ) 5.2, 5.2, 5.2 Hz), 4.41 (1H, dd, J ) 4.7, 4.7 Hz), 4.32 (1H,
m), 3.74 (3H, s), 3.69 (1H, dd, J ) 11.7, 4.9 Hz), 3.60 (1H, dd,
J ) 11.7, 5.8 Hz), 2.53 (2H, m), 2.10 (3H, s); 13C NMR (125.7
MHz, 26 °C) δ major rotamer 169.9 (C), 154.9 (C), 132.4 (CH),
119.4 (CH2), 71.6 (CH), 66.1 (CH), 52.6 (CH3), 49.7 (CH2), 36.0
(CH2), 27.4 (CH), 21.1 (CH3); δ minor rotamer 169.9 (C), 155.0
(C), 133.4 (CH), 119.4 (CH2), 71.3 (CH), 65.8 (CH), 52.6 (CH3),
50.0 (CH2), 36.8 (CH2), 28.0 (CH), 21.1 (CH3); MS (EI) m/z (rel
intensity) 312 (M+ - C3H5, 100), 252 (M+ - C3H5 - AcOH, 4);
HRMS calcd for C8H11INO4 311.9733, found: 311.9729. Anal.
Calcd for C11H16INO4: C, 37.41; H, 4.57; N, 3.97. Found: C,
37.34; H, 4.20; N, 4.18.
δ 5.78 (1H, m), 5.09 (1H, dd, J ) 12.5, 1.2 Hz), 5.08 (1H, dd,
J ) 15.8, 1.3 Hz), 4.96 (1H, br s), 4.89 (1H, ddd, J ) 5.6, 2.8,
2.8 Hz), 3.95 (1H, dd, J ) 12.6, 6.3 Hz), 3.72 (3H, s), 3.41 (1H,
dd, J ) 12.6, 3.2 Hz), 3.36 (3H, s), 2.34 (1H, ddd, J ) 7.2, 7.6,
1.5 Hz), 2.13 (1H, m), 2.06 (1H, m), 2.03 (3H, s); 13C NMR
(125.7 MHz, 70 °C) δ 170.4 (C), 155.80 (C), 134.8 (CH), 117.5
(CH2), 92.9 (CH), 76.0 (CH), 55.9 (CH3), 52.5 (CH3), 51.1 (CH2),
50.2 (CH), 34.7 (CH2), 20.9 (CH3); MS (EI) m/z (rel intensity)
226 (M+ - OMe, 2), 197 (29), 166 (100); HRMS calcd for C11H16
-
NO4 226.1079, found 226.1014. Anal. Calcd for C12H19NO5: C,
56.02; H, 7.44; N, 5.44. Found: C, 55.89; H, 7.75; N, 5.45.
Meth yl (2S,3S,4R)-4-Acetyloxy-2,3-d ia llyl-1-p yr r olid i-
n eca r boxyla te (12). A solution of 3-allyl-2-methoxypyrroli-
dine derivative 11 (30 mg, 0.12 mmol) and allyltrimethylsilane
(0.1 mL, 0.6 mmol) in dry acetonitrile (3 mL) was cooled to 0
°C and treated dropwise with BF3‚Et2O (0.05 mL, 0.24 mmol).
The reaction mixture was allowed to warm to room temper-
ature and stirred for 18 h; then it was poured into saturated
aqueous sodium bicarbonate and extracted with dichlo-
romethane. The organic layer was dried, concentrated under
vacuum, and purified by column chromatography (hexanes-
EtOAc, 4:1), yielding 12 (31 mg, 99%): two rotamers at 26 °C
(2:1); one rotamer at 70 °C; syrup; [R]D + 29 (c ) 0.348); IR
1730, 1689, 1453, 1391 cm-1; 1H NMR (C6D6, 500 MHz, 70 °C)
δ 5.79 (1H, dddd, J ) 17.3, 10.1, 7.3, 7.3 Hz), 5.65 (1H, dddd,
J ) 17.3, 10.5, 7.0, 7.0 Hz), 5.10 (1H, dd, J ) 17.3, 0.8 Hz),
5.07 (1H, dd, J ) 10.0, 0.9 Hz), 5.0 (1H, dd, J ) 10.5, 1.1 Hz),
4.99 (1H, dd, J ) 17.5, 1.0 Hz), 4.94 (1H, ddd, J ) 5.9, 2.8, 2.5
Hz), 3.90 (1H, dd, J ) 12.5, 5.9 Hz), 3.83 (1H, m), 3.60 (3H, s),
3.46 (1H, dd, J ) 12.6, 2.1 Hz), 2.80 (1H, m), 2.53 (1H, ddd, J
) 13.7, 8.5, 8.4 Hz), 2.25 (1H, m), 1.96 (2H, m), 1.73 (3H, s);
13C NMR (125.7 MHz, 70 °C) δ 169.9 (C), 155.3 (C), 134.9 (CH),
134.8 (CH), 117.4 (2 × CH2), 76.7 (CH), 61.6 (CH), 52.2 (CH3),
51.4 (CH2), 46.9 (CH), 38.1 (CH2), 36.5 (CH2), 20.8 (CH3); MS
(EI) m/z (rel intensity) 267 (M+, <1), 236 (M+ - OCH3, 1), 226
3-Allyla tion of Meth yl (2S,3S,4S)-4-Acetyloxy-2-a llyl-
3-iod o-1-p yr r olid in eca r boxyla te (13a ). A solution of 2-allyl-
3-iodopyrrolidine derivative 13a (35 mg, 0.1 mmol) and a
catalytic amount of AIBN (5 mg) in dry benzene (4 mL), under
nitrogen, was treated with allyltributyltin (0.1 mL, 0.5 mmol)
at room temperature. The reaction mixture was heated to 80
°C for 4 h and then cooled to room temperature, the solvent
was evaporated under vacuum, and the residue was purified
by column chromatography (first elution with hexanes to
remove the tin reagent and then with hexanes-ΕtOAc, 5:1),
yielding 12 (23 mg, 99%), identical to previously described (vide
supra).
Met h yl (3R,3a S,7a S)-3-Acet yloxy-2,3,3a ,4,7,7a -h exa -
h yd r o-1H-in d ole-1-ca r boxyla te (14). To a solution of the
2,3-diallylpyrrolidine derivative 12 (13 mg, 0.05 mmol) in
dichloromethane (3 mL) was added a catalytic amount of
Grubbs’ catalyst [Cl2(Cy3P)2RudCHPh] (3 mg, 0.0036 mmol);
the reaction was refluxed for 8 h and then stirred at room
temperature overnight. The reaction mixture was evaporated
under vacuum and purified by chromatography on silica gel
(hexanes-EtOAc, 95:5), yielding bicyclic compound 14 (11 mg,
95%): syrup; [R]D +175 (c ) 0.5); IR 1736, 1699, 1454, 1358
cm-1; 1H NMR (500 MHz, 70 °C) δ 5.68 (2H, m), 4.90 (1H, ddd,

Synthesis of Pyrrolidines and Piperidines
J . Org. Chem., Vol. 66, No. 23, 2001 7803
J ) 8.2, 8.2, 8.1 Hz), 4.03 (1H, dd, J ) 11.1, 7.9 Hz), 3.71 (3H,
s), 3.31 (1H, ddd, J ) 10.6, 10.6, 5.3 Hz), 3.22 (1H, dd, J )
11.1, 8.1 Hz), 3.04 (1H, brd, J ) 16.4 Hz), 2.35 (1H, m), 2.12
(1H, m), 2.05 (3H, s), 2.02 (2H, m); 13C NMR (125.7 MHz, 26
°C) δ 170.8 (C), 156.2 (C, br), 125.9 (CH), 125.7 (CH), 73.8 (CH,
br), 57.1 (CH), 52.2 (CH3), 51.0 (CH2), 46.0 (CH, br), 32.8 (CH2,
br), 28.7 (CH2), 20.8 (CH3); MS (EI) m/z (rel intensity) 240 (M+
+ H, <1), 179 (M+ - AcOH, 100); HRMS calcd for C12H18NO4
240.1236, found 240.1265. Anal. Calcd for C12H17NO4: C,
60.24; H, 7.16; N, 5.85. Found: C, 60.47; H, 6.94; N, 6.01.
Meth yl (2S*,3R*)-3-Iod o-2-(2-oxop r op yl)p yr r olid in e-1-
ca r boxyla te (15). A solution of the acid 1a (230 mg, 1.3 mmol)
in acetonitrile (18 mL) was treated with DIB (850 mg, 2.6
mmol) and iodine (335 mg, 1.3 mmol) under nitrogen. After
stirring at room temperature for 3 h, the reaction mixture was
cooled to 0 °C, and then BF3‚Et2O (0.35 mL, 2.6 mmol) and
isopropenyl acetate (0.8 mL, 6.5 mmol) were added. The
reaction mixture was allowed to reach room temperature and
stirred for 4 h; it was then poured into 10% aqueous sodium
thiosulfate and extracted with dichloromethane. The organic
layer was washed with brine, dried (Na2SO4), and evaporated
under vacuum. The residue was immediately purified by
column chromatography (hexanes-EtOAc, 80:20) yielding the
iodinated derivative 15 (229 mg, 56%): two rotamers at 26 °C
(2:1); syrup; IR 1694, 1455, 1389 cm-1; 1H NMR (500 MHz, 26
°C) δ major rotamer 4.47 (1H, br d, J ) 8.5 Hz), 4.30 (1H, br
d, J ) 10.5 Hz), 3.69 (3H, s), 3.66 (1H, m), 3.48 (1H, m), 2.95
(1H, d, J ) 15.5 Hz), 2.44 (1H, m), 2.26 (1H, m), 2.18 (1H, m),
2.17 (3H, s); δ minor rotamer 4.47 (1H, br d, J ) 8.5 Hz), 4.30
(1H, br d, J ) 10.5 Hz), 3.69 (3H, s), 3.66 (1H, m), 3.48 (1H,
m), 2.76 (1H, d, J ) 18 Hz), 2.44 (1H, m), 2.26 (1H, m), 2.18
(1H, m), 2.17 (3H, s); 13C NMR (50.3 MHz, 26 °C) δ major
rotamer 206.1 (C), 155.0 (C), 65.6 (CH), 52.5 (CH3), 46.8 (CH2),
45.2 (CH2), 35.4 (CH2), 30.2 (CH3), 24.7 (CH); δ minor rotamer
206.1 (C), 155.0 (C), 65.1 (CH), 52.5 (CH3), 48.0 (CH2), 45.2
(CH2), 34.5 (CH2), 30.2 (CH3), 25.6 (CH); MS (EI) m/z (rel
intensity) 280 (M+ - OMe, 2), 253 (16), 184 (M+ - I, 83), 183
(19), 142 (100); HRMS calcd for C8H11INO2 279.9835, found
279.9745. Anal. Calcd for C9H14INO3: C, 34.73; H, 4.54; N,
4.50. Found: C, 34.49; H, 4.62; N, 4.80.
Meth yl 2-(2-Oxop r op yl)-2,5-d ih yd r o-1H-p yr r ole-1-ca r -
boxyla te (16). A solution of product 15 (100 mg, 0.32 mmol)
in dichloromethane (50 mL) was treated with DBU (0.1 mL, 2
equiv) and stirred at room temperature for 12 h. The reaction
mixture was poured into 10% HCl and extracted with dichlo-
romethane. After purification by column chromatography
(hexanes-EtOAc, 80:20) the dihydropyrrol 16 was obtained
(54 mg, 99%): one rotamer at 70 °C; syrup; IR 1716, 1519,
1
1265 cm-1; H NMR (500 MHz, 70 °C) δ 5.92 (1H, d, J ) 2.7
Hz), 5.85 (1H, d, J ) 2.6 Hz), 4.65 (1H, m), 3.68 (3H, s), 3.45
(1H, d, J ) 6.6 Hz), 3.42 (1H, d, J ) 6.6 Hz), 2.80 (1H, d, J )
6.5 Hz), 2.78 (1H, d, J ) 6.6 Hz), 2.23 (3H, s); 13C NMR (50.3
MHz, 26 °C) δ 107.1 (CH), 106.0 (CH), 52.07 (CH3), 39.70
(CH2), 28.66 (CH2), 13.50 (CH3); the signals of C-2 and the
carbamate and ketone carbonyls could not be observed; MS
(EI) m/z (rel intensity) 183 (M+, 35), 108 (100), 95 (93); HRMS
calcd for C9H13NO3 183.0895, found 183.0892. Anal. Calcd for
C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 58.91; H, 7.41;
N, 7.52.
Ack n ow led gm en t. This work was supported by
Investigation Program PB96-1461 and PPQ2000-0728
of the Plan Nacional de Investigacio´n Cient´ıfica, De-
sarrollo e Innovacio´n Tecnolo´gica, Ministerio de Ciencia
y Tecnolog´ıa. Y. L. thanks the Ministerio de Ciencia y
Tecnolog´ıa of Spain for a fellowship C.S.I.C.-Formacio´n
en L´ıneas de Intere´s para el Sector Industrial.
Su p p or tin g In for m a tion Ava ila ble: Physical properties
and spectroscopic data for compounds 3b, 3c, 5e, 3e, 4e, and
3f. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O015877A