Thermal Hetero [3 + 2] Cycloaddition of Dipolar Trimethylenemethane to O-Alkyloximes. Straightforward Synthetic Routes to Substituted Pyrrolidines and Prolines

Article abstract of DOI:10.1021/jo972302y

Thermal hetero [3 + 2] cycloaddition reaction of a dipolar trimethylenemethane 2 with an O-alkyloxime produces a substituted pyrrolidine. Thus, heating of a mixture of an alkylidenecyclopropane 1 an anti-O-alkyloxime 3 proceeds smoothly in good yield to give a substituted pyrrolidine 4 bearing a ketene acetal group in its 3-position, which upon hydrolysis under mild conditions gives a 3-alkoxycarbonylpyrrolidine 5 in quantitative yield. On the other hand, the cycloaddition to a syn-oxime is extremely slow. The cycloaddition reaction can be achieved by starting with nearly equimolar quantities of the two starting materials, and the reaction is quite insensitive to the choice of solvent and to the presence of oxygen and water. In the reaction of a substituted methylenecyclopropane 1 (R ≠ H), the reaction may take place with high regio- and stereoselectivity, which is in consonance with the concerted nature of the cycloaddition reaction. The present synthesis represents one of the rare examples of the imine-based route to pyrrolidines, which have been much less explored than the 1,3-dipolar cycloaddition route using olefin and azomethine ylide.

Full text of DOI:10.1021/jo972302y

1694
J . Org. Chem. 1998, 63, 1694-1703
Th er m a l Heter o [3 + 2] Cycloa d d ition of Dip ola r
Tr im eth ylen em eth a n e to O-Alk yloxim es. Str a igh tfor w a r d
Syn th etic Rou tes to Su bstitu ted P yr r olid in es a n d P r olin es
Shigeru Yamago,† Masaharu Nakamura,§ Xiao Qun Wang,‡ Masao Yanagawa,‡
Shuzo Tokumitsu,‡ and Eiichi Nakamura*,§
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Sakyo-ku, Kyoto 606-01, J apan, Department of Chemistry, Tokyo Institute of Technology,
Meguro, Tokyo 152, J apan, and Department of Chemistry, The University of Tokyo,
Bunkyo-ku, Tokyo 113, J apan
Received December 22, 1997
Thermal hetero [3 + 2] cycloaddition reaction of a dipolar trimethylenemethane 2 with an
O-alkyloxime produces a substituted pyrrolidine. Thus, heating of a mixture of an alkylidenecy-
clopropane 1 an anti-O-alkyloxime 3 proceeds smoothly in good yield to give a substituted pyrrolidine
4 bearing a ketene acetal group in its 3-position, which upon hydrolysis under mild conditions
gives a 3-alkoxycarbonylpyrrolidine 5 in quantitative yield. On the other hand, the cycloaddition
to a syn-oxime is extremely slow. The cycloaddition reaction can be achieved by starting with nearly
equimolar quantities of the two starting materials, and the reaction is quite insensitive to the
choice of solvent and to the presence of oxygen and water. In the reaction of a substituted
methylenecyclopropane 1 (R * H), the reaction may take place with high regio- and stereoselectivity,
which is in consonance with the concerted nature of the cycloaddition reaction. The present
synthesis represents one of the rare examples of the imine-based route to pyrrolidines, which have
been much less explored than the 1,3-dipolar cycloaddition route using olefin and azomethine ylide.
Pyrrolidines are among the most common structures
(Scheme 1, route a), and the other involves an all-carbon
1,3-dipole with an imine (route b). The latter route has
long been unsuccessful because of the low reactivity of
imines in cycloadditions as well as the scarcity of ap-
propriate 1,3-dipoles.
in biologically active natural products, and the diversity
of their biological functions as well as their structure has
stimulated efforts for the rapid and controlled synthesis
of this class of compounds.1 Among various synthetic
strategies, concerted cycloadditions, as represented by the
Diels-Alder reaction, possesses a number of ideal prop-
erties, because the reaction may take place with orbital-
controlled stereochemistry and with high “atom economy”,2
starting with neutral reactants without recourse to the
use of any extraneous reagent. Because of such merits,
intensive efforts have been focused on a hetero [3 + 2]
cycloaddition reaction in the synthesis of pyrrolidines.3
An approach to pyrrolidines based on the [3 + 2]
cycloaddition reaction reveals two possibilities. One
involves a 1,3-dipolar cycloaddition of an azomethine
ylide to an olefin which has frequently been studied4
Although trimethylenemethane (TMM)5 and its equiva-
lent6 are seemingly the most promising three-carbon
units for realization of route b, the cycloaddition reaction
of alkyl-substituted diradical TMM species to CdN
double bonds has proved to be a poor synthetic reaction.7
A metal-mediated approach with a Trost-type TMM
precursor and an electron-deficient imine offered a solu-
tion to this problem.8,9 Our discovery of a thermal
cycloaddition of a singlet dipolar TMM species 210 to an
olefin11 as well as a carbonyl compound12 led us to
examine the reaction to a CdN double bond. Since the
cycloaddition of the TMM species to an electron-deficient
(5) (a) Dowd, P. Acc. Chem. Res. 1972, 5, 242. (b) Berson, J . A. Acc.
Chem. Res. 1978, 11, 486. (c) Little, R. D. Chem. Rev. 1986, 86, 875.
(6) Chan, D. M. T. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, p 271. Binger, P.; Bu¨ch, H. M. In Small Ring Compounds in
Organic Synthesis II, de Meijire, A., Ed.; Springer-Verlag: Berlin, 1987;
p 77. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1.
(7) Little, R. D.; Bode, H.; Stone, K. J .; Wallquist, O.; Dannecker,
R. J . Org. Chem. 1985, 50, 2401. This situation has a similarity to the
ineffectiveness of the thermal Diels-Alder reactions with carbonyl
compounds.
(8) J ones, M. D., Kemmitt, R. D. J . Chem. Soc., Chem. Commun.
1986, 1201. Trost, B. M., Marrs, C. M. J . Am. Chem. Soc. 1993, 115,
6636. Trost, B. M.; Matelich, M. C. J . Am. Chem. Soc. 1991, 113, 9007.
Trost, B. M.; Parquette, J . R.; Nu¨bling, C. Tetrahedron Lett. 1995, 36,
2917.
† Kyoto University.
‡ Tokyo Institute of Technology.
§ The University of Tokyo.
(1) Advances in Heterocyclic Natural Product Synthesis; Pearson,
W. H., Ed.; J AI Press Inc: Greenwich, 1990; Vol. 1. Pichon, M.
Tetrahedron: Asymmetry 1996, 7, 927. Ishibashi, H.; Sato, T.; Ikeda,
M. J . Synth. Org. Chem., J pn. 1995, 53, 85. Hirai, Y.; Momose, T. J .
Synth. Org. Chem., J pn. 1993, 51, 25. Hudlicky, T.; Seoane, G.; Price,
J . D.; Gadamasetti, K. G. Synlett 1990, 433.
(2) Trost, B. M. Science 1991, 254, 1471.
(3) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987. Weinreb, S.
M. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 401.
Waldmann, H. Synthesis 1994, 535.
(4) Lown, J . W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; J ohn Wiley & Sons: New York, 1984; Vol. 1, p 653. Vedejs, E. In
Advances in Cycloaddition; Curran, D. P., Ed.; J AI Press Inc: Green-
wich, 1990; Vol. 1, p 33. Padwa, A.; Schoffstall, A. M. In Advances in
Cycloaddition; Curran, D. P., Ed.; J AI Press Inc: Greenwich, 1990;
Vol. 2, p 1. Tominaga, Y.; Hojo, M.; Hosomi, A. J . Synth. Org. Chem.,
J pn. 1992, 50, 48.
(9) Addition/cyclization of a bifunctional allylic reagent represents
a strategic surrogate of the TMM cycloaddition reactions. For a recent
example, see: Trost, B. M.; Bonk, P. J . J . Am. Chem. Soc. 1985, 107,
1778. van der Heide, T. A. J .; van der Bann, J . L.; de Kimpe, V.;
Bickelhaupt, F.; Klumpp, G. W. Tetrahedron Lett. 1993, 34, 3309.
(10) Nakamura, E.; Yamago, S.; Ejiri, S.; Dorigo, A. E.; Morokuma,
K. J . Am. Chem. Soc. 1991, 113, 3183.
S0022-3263(97)02302-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/20/1998

Synthetic Routes to Pyrrolidines and Prolines
J . Org. Chem., Vol. 63, No. 5, 1998 1695
Sch em e 1
ization of the alkylated cyclopropene to the less strained
alkylidenecyclopropane completes the synthesis of the
target molecule 1.
In another approach (eq 2), a purified unsubstituted
cyclopropenone acetal (available in 0.3-1.0-mol scale and
stable in a freezer)13 is deprotonated with BuLi in the
olefin takes place through a concerted transition state
to afford a substituted cyclopentane with high stereo-
control,11 it was particularly interesting to see whether
this would also be the case in the hetero [3 + 2]
cycloaddition reactions.
We report in this paper the cycloaddition reactions of
the dipolar TMM species to O-alkyloximes; this repre-
sents the first synthetically viable construction of pyr-
rolidine skeletons by thermal hetero [3 + 2] cycloaddition
of free TMM species. The cycloaddition reaction is
effected simply by heating an equimolar mixture of an
alkylidenecyclopropane 1 and an appropriate O-alky-
loxime and proceeded with high levels of regio-, stereo-,
and periselectivity with suitable choice of substituents
(Scheme 2). The cycloaddition reaction affords ketene-
acetal-substituted pyrrolidines as primary cycloadducts,
which upon hydrolysis gives pyrrolidine carboxylic acid
esters. This reaction enjoys the full advantages of
concerted cycloaddition process as to the stereocontrol as
well as to the atom economy, therefore making a unique
and useful synthetic entry to pyrrolidines.
presence of HMPA, which stabilizes the lithiocyclopro-
penone acetal, and then alkylated with an alkyl halide.
This method is suitable for the preparation of 1c. The
merits of the use of neopentyl glycol include its simple
NMR signal pattern, the low cost of the diol, and the
synthetically viable rate of TMM formation. For meth-
ylenecyclopropanes corresponding to 1a derived from 1,3-
propanediol and 2,4-pentanediol in stead of neopentyl
glycol, the TMM formation is several times faster, mak-
ing these precursors rather unstable for synthetic use.
Cycloa d d ition to O-Alk yloxim es. In view of the low
electrophilicity of imines, it was not unexpected that
attempted reaction of a dipolar TMM 2 with benzalde-
hyde N-phenyl imine did not give the desired [3 + 2]
cycloaddition product.14 We were, however, pleasantly
surprised by the finding that O-alkyloximes take part in
the cycloaddition (eq 3). The following procedure il-
Resu lts
P r ep a r a tion of Alk ylid en ecyclop r op a n on e Ac-
eta ls. Alkylidenecyclopropanone acetals are readily
available on a large scale (0.1-0.5 mol scale) in two or
three steps from 1,3-dichloroacetone (see the Experimen-
tal Section). In the first approach (eq 1), the ketone is
first converted to the corresponding neopentyl glycol
acetal. The acetal is treated with 3 equiv of sodium
amide (cyclization and in situ deprotonation of the
resulting cyclopropenone acetal to generate a 2-sodiocy-
lopropenone acetal) and then with an alkyl iodide to
obtain methyl- and ethyl-substituted cyclopropenone
acetals in ca. 80% overall yield. Base-catalyzed isomer-
lustrates the new pyrrolidine synthesis. A neat mixture
of methylenecyclopropane 1a (4.81 g, 1.20 equiv relative
to the benzyloxime) and methyl glyoxylate O-benzyloxime
(5.01 g, anti:syn ) 93:7) was heated under air (or
nitrogen) for 4 h at 100 °C. 1H NMR analysis of aliquots
of the cooled reaction mixture indicated high-yield forma-
tion of the ketene acetal 4A (R1 ) CH2Ph, R2 ) CO2Me),
which was hydrolyzed in aqueous HCl/THF mixture at
room temperature. Purification through a silica gel
column afforded 5A (7.67 g, 89%; cis:trans ) 71:29). The
(11) (a) Yamago, S.; Nakamura, E. J . Am. Chem. Soc. 1989, 111,
7285. (b) Ejiri, S.; Yamago, S.; Nakamura, E. J . Am. Chem. Soc. 1992,
114, 8707. (c) Yamago, S.; Ejiri, S,; Nakamura, M.; Nakamura, E. J .
Am. Chem. Soc. 1993, 115, 5344. (d) Yamago, S.; Ejiri, S.; Nakamura,
E. Angew. Chem., Int. Ed. Engl. 1995, 34, 2154. (e) For applications
in fullerene science including synthesis of 14C labeled derivatives, see:
Prato, M.; Suzuki, T.; Foroudian, H.; Li, Q.; Khemani, K.; Wudl, F.;
Leonetti, J .; Little, R. D.; White, T.; Rickborn, B.; Yamago, S.;
Nakamura, E. J . Am. Chem. Soc. 1993, 115, 1594; Yamago, S.;
Nakamura, E. Chem. Lett. 1996, 395. Yamago, S.; Tokuyama, H.;
Nakamura, E.; Kikuchi, K.; Kananishi, S.; Sueki, K.; Nakahara, H.;
Enomoto, S.; Ambe, F. Chem. Biol. 1995, 2, 385.
(13) ) Isaka, M.; Ejiri, S.; Nakamura, E. Tetrahedron 1992, 48,
2045-2057.
(12) Yamago, S.; Nakamura, E. J . Org. Chem. 1990, 55, 5553.

1696 J . Org. Chem., Vol. 63, No. 5, 1998
Yamago et al.
Sch em e 2
Ta ble 1. Cycloa d d ition of Meth ylen ecyclop r op a n e 1a
the ketene acetal product 4B with 10% aqueous HCl in
THF. The ketene acetal product was identified by 1H and
13C NMR in the experiments carried out in CD3CN.
Benzaldehyde O-methoxime also reacted with the parent
cyclopropane 1a to give 5C (R1 ) Me, R2 ) Ph) in 70%
yield, but more slowly than p-chlorobenzaldehyde O-
benzyloxime, requiring higher temperature (120-130 °C,
entry 2). Under high-pressure conditions (10 kbar, at 80
°C in CH2Cl2),15 the reaction proceeded faster and gave
5C in 76% yield after hydrolysis (entry 3). The reaction
with the less electrophilic p-anisaldehyde O-methoxime
proceeded only under high pressure (ca. 10 kbar) to give
the cycloadduct 5D (R1 ) Me, R2 ) p-MeOC6H4) in 70%
yield (entry 4). Reactions of O-alkyloximes derived from
heteroaromatic aldehydes also took place smoothly (en-
tries 5 and 6). The reaction with 3-pyridinecarboxalde-
hyde O-benzyloxime afforded a 4-substituted nicotine
derivative 5F (R1 ) CH2Ph, R2 ) 3-pyridyl) in good yield
(entry 6). The reaction with methyl glyoxylate O-
benzyloxime, which is more electron-deficient than the
above substrates, reacted within 1.5 h at 80 °C (79%
yield, entry 7) to provide a new route to proline deriva-
tives. O-Alkyloximes derived from aromatic aldehydes
reacted smoothly with 1a around 100 °C, while aliphatic
aldehyde alkyloximes are poor substrates: the reaction
of 1a and hexanal O-methoxime took place only under
high-pressure conditions (10 kbar, 80 °C, 60 h) to afford
a complex mixture from which the desired cycloadduct
was isolated in low yield. In the above experiments, no
attempts were made to control the stereochemistry of the
hydrolysis of 4 to 5, and a 7:3 mixture of diastereomers
(cis stereochemistry assigned by NOE experiments in
entries 5 and 7) generally formed.
In the above experiments, we noted the significant
difference of the reactivity of anti- and syn-oximes. Syn
isomer being obtained as a minor product in O-alkyloxime
synthesis, we routinely observed that the syn isomer of
the oxime was left unreacted.16 The difference in reactiv-
ity was confirmed in experiments using pure stereoiso-
mers: The reaction of 1a with the pure (>99%) anti-O-
methoxime of 2-furaldehyde in CD3CN was complete in
85 h to give 4E (R1 ) Me, R2 ) 2-furyl) at 100 °C (entry
5), while the reaction of the corresponding 98% pure syn-
O-alkyloxime showed very low conversion after 66 h at
100 °C. After 116 h of heating at this temperature, 4e
formed in 13% yield, together with 37% recovery of the
syn-O-alkyloxime. In these experiments, geometric
w ith O-Alk yloxim e 3a
a
The reactions were carried out by using 1a (1.2 equiv) and an
O-alkyloxime 3 (>90% anti) in CH3CN or CD3CN (1.5 M solution
of the oxime ether) at the indicated temperature unless otherwise
noted; The initial product 4 was hydrolyzed to 5. Conditions other
than the above are (C3H7CN), {CH2Cl2 at 10 kbar pressure}, and
b
[no solvent]. Bath temperature. c Hydrolyzed product. NPG )
d
CH2C(CH3)2CH2OH. The yields are based on analytically pure
isolated products. The product was a 60:40-70:30 mixture of cis
and trans stereoisomers. The cis stereochemistry was determined
for the product in entries 5 and 7 by NOE experiments.
reaction selectively afforded pyrrolidine 4. This reaction
does not require the use of solvent and tolerates various
aprotic solvents (hydrocarbon, haloalkane, nitrile, DMSO).
However, an alkylnitrile solvent was used routinely since
the TMM generation takes place smoothly in a polar
solvent.10 The reaction does not necessarily require
rigorous exclusion of moisture or air and does not appear
to suffer very much from the presence of organic impurity
either.
(14) ) The reaction of 1 with N-acyl and N-tosyl imines gives γ-amino
acid derivatives instead of [3 + 2] cycloadduct; to be published.
(15) Organic High-Pressure Chemsitry; le Noble, W. J ., Ed.; Elsevi-
er: Amsterdam, 1988.
(16) In this respect, O-benzyloximes are superior to O-methoxime,
because the former generally is obtained with higher anti selectivity
(9:1) than the latter (7:3) by the reaction of an aldehyde and the
corresponding alkoxyamine.
The reaction of the parent methylenecyclopropane 1a
has been examined for various anti-O-alkyloximes (Table
1). Thus, the reaction of a near equimolar mixture of 1a
and p-chlorobenzaldehyde O-benzyloxime at 100 °C af-
forded the corresponding pyrrolidine 5B (R1 ) CH2Ph,
R2 ) p-ClC6H4, entry 1) in 99% yield after treatment of

Synthetic Routes to Pyrrolidines and Prolines
J . Org. Chem., Vol. 63, No. 5, 1998 1697
Sch em e 3
Ta ble 2. Cycloa d d ition of Meth ylen ecyclop r op a n e 1b a n d 1c w ith O-Alk yloxim ea
reaction time, hb
entry
1, R )
3, R4
)
(solvent)
% yieldc,d
7:8
9, cis:transd
10, cis:transd
1
2
3
4
5
6
7
8
Me
Me
Me
t-Bu
Me
Ph2CH
Ph
2,6-Me2Ph
4
10
21
16.5
4
8
17
21.5
81 (82)
99 (100)
81 (85)
71 (79)
41 (46)
83 (93)
89 (100)
96 (99)
70:30
82:12
78:22
83:17
77:23
44:56
90:10
91:9
68:32
77:23
71:29
>95:5
52:48
93:7
51:49
43:57
4:>96
7:93
39:61
5:>95
4:>96
6:94
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
>97:3
94:6
(DMSO-d6)
9
36
85 (100)
83 (95)
86:14
84:16
>96:4
>98:2
5:>95
(toluene-d8)
18
(none)
30
40
10
7:93
11e
12
88 (99)
41 (60)
89:11
88:12
>98:2
94:6
3:>97
5:>95
i-Pr
2,4,6-t-Bu3Ph
a
b
The reactions were carried out with pure anti-oxime ether. All reactions were carried out at 80 °C in CD3CN, except in entries 5-7,
where the solvent used is indicated in the parentheses. c The yields in the parentheses are based on the recovery of 3. Corresponding
d
to 2,5- and 2,3-stereochemistry for 9 and 10, respectively. The isomeric ratio was determined by 1H and 13C NMR. The > mark indicates
that the minimum ratio based on the signal/noise ratio. e Corresponding methoxime was used.
Regio- a n d Ster eoselectivity. Having established
the basic reaction protocol for the parent TMM (i.e., R )
H), we next examined the regio- and stereochemistry for
the synthesis of substituted pyrrolidines by using sub-
stituted TMM 2b (i.e., R ) Me). However, the cycload-
dition of the ethylidenecyclopropane 1b and 2-furalde-
hyde O-methoxime did not take place even after heating
at 100 °C for 1 week. p-Chloro- and p-nitrobenzaldehyde
O-benzyloxime were also inert to 1b, presumably due to
steric effects of the TMM substituent R.
In contrast, O-alkyloximes derived from glyoxalic acid
F igu r e 1. Time course of the cycloaddition. The reaction was
carried out in an NMR tube in CD3CN at 100 ( 5 °C and was
esters 6 were found to react with the substituted TMM
(Scheme 3). Thus, a combination of sterically unhindered
reactants (substituents on the TMM and the O-alky-
loxime being a methyl groups; R ) R4 ) Me, entry 1,
Table 2) afforded a 70:30 mixture of regioisomers 7 and
8, both of which are 1:1 mixtures as to the relative
stereochemistry for the R and CO2R4 group. When a
bulkier tert-butyl group was employed as the R4 group
in the ester moiety, 7:8 regioselectivity improved slightly
to 82:18 (entry 2). The use of a bulkier i-Pr group as the
TMM substituent R also improved the regioselectivity (to
78:22) and had a large influence on the cis/trans selectiv-
1
monitored by H NMR. Initial concentrations of 3E (R1 ) Me,
R2 ) 2-furyl) and 1a were 1.5 and 1.8 M, respectively. The
decrease of 3E was proportional to the increase of the cycload-
duct 4E for the observed period. After 80 h, the reaction with
the syn-oxime rapidly formed an unidentified side product.
isomerization of the O-alkyloximes was not observed.
Second-order rate constants k for the anti and syn
substrates are, thus, obtained as kanti ) 6.7 × 10-2
M-1‚s-1 and ksyn ) 1.0 × 10-3 M-1‚s-1 (Figure 1). The
anti isomer reacted 67 times faster than the syn isomer.

1698 J . Org. Chem., Vol. 63, No. 5, 1998
Yamago et al.
Sch em e 4
ity in the minor regioisomer 8, improving it to 4:>96
(entry 3). The use of bulkier diphenylmethyl group R4
on the ester moiety showed only small effects on the
regioselectivity but significant effects for the cis/trans
selectivity of both 7 and 8 (entry 4). While the use of
phenyl ester (R4 ) Ph) increased the reactivity of the
O-alkyloxime, the cis/trans selectivity was low (entry 5).
The 2,6-dimethylphenyl ester of the oxime, on the other
hand, gave a near 1:1 mixture of 7 and 8 (entry 6).
Finally, the reaction between a sterically hindered TMM
and an O-alkyloxime (R ) i-Pr and R4 ) t-Bu) took place
with excellent selectivities (a 90:10 mixture of 7:8,
wherein 7 was >97% pure cis and 8 was >96% trans,
entry 7). We found that solvents (toluene, acetonitrile,
DMSO, and no solvent, entries 7-10) exert very small
effects on the selectivities. The use of the very bulky
2,4,6-tri-tert-butylphenyl groups as the R4 group also
resulted in high regioselectivity and cis/trans selectivity,
while the reaction slowed. Hydrolysis of the ketene
acetal 7 and 8 in entry 7 with 1:9 1 M HCl/THF at room-
temperature took place with high diastereoselectivity to
give the trisubstituted pyrrolidines 9 and 10 both as a
single isomer in 79% and 10% isolated yield, respectively
(Scheme 3).
available, goes back to the cyclopropane precursor,17 and
hence few side reactions take place. The cycloaddition
of the TMM to a CdN double bond is faster than the
reaction with triplet molecular oxygen due to the singlet
nature of 2, and hence rigorous exclusion of oxygen was
not necessary.10
The reaction rate of the present cycloaddition show
marked dependence on the stereochemistry of the CdN
double bond. An anti-oxime reacts ca. 70 times faster
than the corresponding syn-oxime, and on the basis of
Huisgen’s criteria,18 this rate difference provides strong
evidence of concerted character of the cycloaddition.,19-
22
The observed rate enhancement at high pressure is
also consistent with the ordered transition state of the
present cycloaddition reaction. As we have already
shown by theoretical analysis and experiments on the
cycloaddition with electron deficient olefins,10,11b the
dipolar TMM shows its 4π nucleophilic character in its
planar conformation (cf. Scheme 4). Therefore, we sug-
(17) Degenerated isomerization of 1 by way of 2 is usually faster
than the cycloaddition to external unsaturated bonds. In the 13C labeled
experiments, the methylene-labeled methylenecyclopropane i isomer-
ized to the cyclopropane labeled ii prior to the cycloaddition, even when
the reactive dimethyl fumarate was used as an acceptor. See also ref
10.
The reactivity of the Z-TMM precursor 11 with the
O-benzyloxime 6 (R4 ) t-Bu) was examined next to find
that 11 is extremely unreactive (100 °C, <8 h, CD3CN).
The reluctance of the (Z)-alkylidene cyclopropanone
acetal to generate the TMM and the rapid isomerization
of this TMM to the more stable E-isomer were noted
previously.10 After 8 h of heating, 11 was found to
isomerize, to some extent, to its E-isomer 1c, and then
the O-benzyloxime 6 started to be consumed. After 43
h, the reaction afforded the cycloadducts (7 and 8) of the
same isomeric distribution as obtained in the reaction of
1c. The results indicated that the Z-TMM species which
forms upon thermolysis did not react with 6 but under-
went isomerization to the E-isomer 2c, which then
afforded 1c as well as 7 and 8.
(18) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633. See
also: Trost, B. M.; Miller, M. L. J . Am. Chem. Soc. 1988, 110, 3687.
(19) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
(20) See for a single electron-transfer pathway of the TMM cyclo-
addition: Yamago, S.; Ejiri, S.; Nakamura, M.; Nakamura, E. J . Am.
Chem. Soc. 1993, 115, 5344.
Discu ssion
(21) While Huisgen experimentally defined the minimum anti/syn
rate difference (kanti/ksyn) for the concerted 1,3-dipolar cycloaddition as
2.6, studies on the cycloaddition of metalated TMM addition with
olefins by Trost revealed a stepwise reaction whose rate difference
We have developed a rapid synthesis of substituted
pyrrolidines by the thermal hetero [3 + 2] cycloaddition
of dipolar TMMs with O-alkyloximes. The reaction does
not require any extraneous reagents (including solvent)
other than the two reactants, the methylenecyclopropane
1 and a nearly equimolar amount of an O-alkyloxime.
The success of the current reaction rests on the reversible
generation of the singlet TMM species 2 from 1.10 TMM
2 generated in a minute quantity reacts either with the
CdN compound or, when there is no CdN compound
k
anti/ ksyn larger than 2.6 and suggested the importance of the magnitude
of the difference. See: Trost, B. M.; Miller, M. L. J . Am. Chem. Soc.
1988, 110, 3687. Whatever the threshold may be, the 67-fold rate
difference in the present cycloaddition is a clear indication of the
concertedness of the cycloaddition.
(22) The stereospecificity of the CdN cannot be certified in the
presence example. Though the stereospecificity of cycloaddition has
been considered to be a reliable criterion for the concertedness of the
cycloaddition, recent studies by Zewail on the retro-Diels-Alder
reaction revealed that the time scale of this conventional criteria is
too slow to certify the concertedness: Horn, B. A.; Herek, J . L.; Zewail,
A. H. J . Am. Chem. Soc. 1996, 118, 8755.

Synthetic Routes to Pyrrolidines and Prolines
J . Org. Chem., Vol. 63, No. 5, 1998 1699
added a small (about 5 mm) cube of sodium. The solution was
stirred until the blue color disappeared. [Gentle stirring (e.g.,
120 rpm) is recommended to avoid loss of the amide base which
may stick to the upper part of the glass flask. This was found
to be a good practice to achieve the most accurate base/
substrate molar ratio.] Pieces of sodium (total 21.44 g, 0.930
mol) were then added over 25 min. After 20 min, the solution
became a dark gray suspension with white precipitate. The
cooling bath was replaced with a dry ice/acetone bath, and the
gas inlet was replaced with a pressure-equalized dropping
funnel containing a solution of the 2,2-bis-(chloromethyl)-5,5-
dimethyl-1,3-dioxane (63.93 g, 0.300 mol) in 150 mL of dry
Et2O. This solution was added dropwise to the slurry of
sodium amide in liquid NH3 over 1 h. The dropping funnel
was rinsed with 20 mL of dry Et2O. The cooling bath was
removed, and the mixture was stirred for 3 h. The flask was
cooled again with a dry ice/acetone bath. After 10 min, a
solution of fleshly distilled ethyl bromide (34.32 g, 0.315 mol)
in 80 mL of dry Et2O was added during 1.5 h through the
dropping funnel.8,9 The funnel was rinsed with 20 mL of dry
ether. After stirring for 15 min, the cooling bath was removed
and the solution was stirred for 1 h. The mixture was cooled
with a dry ice/acetone bath again and solid NH4Cl (20.24 g,
0.378 mol) was added in several portions during 5 min. The
dry ice condenser was removed and ammonia was allowed to
evaporate through the open neck. The cooling bath was
changed to a water bath (ca. 30 °C), and a 1:1 mixture of dry
Et2O and dry pentane (400 mL) was added through the
dropping funnel during 10 min. The water bath temperature
was maintained between 25 and 30 °C. After most of ammonia
was allowed to evaporate in a period of 1.5-2 h, the ethereal
solution was filtered by suction through a pad of Hyflo Super
Cell to remove the inorganic salts. The filter cake was washed
three times with 80 mL of Et2O. The combined filtrate was
concentrated under reduced pressure (30-40 mmHg, 25 °C),
and the residue was distilled through a 15-cm vacuum-jacketed
Vigreux column to yield the title compound as a colorless oil
(34.28 g, 68%; bp 50-52 °C, 1 mmHg). [To obtain a good yield,
it is most important to carry out the distillation quickly (<25
min), but with the bath temperature below 100 °C.] IR (neat)
cm-1 2950, 1730 (w), 1280, 1070, 1020; 1H NMR (270 MHz,
CDCl3) 1.01 (s, 3H), 1.05 (s, 3H), 1.22 (t, J ) 7.3 Hz, 3H), 2.55
(dq, J ) 7.3, 1.2 Hz, 2H), 3.61 (d, J ) 10.3 Hz, 2H), 3.63 (d, J
) 10.3 Hz, 2H), 7.32 (t, J ) 1.2 Hz, 1H). When ethyl bromide
was replaced with solid NH4Cl (3∼4 equiv added to 1-ethyl-
2,2-bis(chloromethyl)-5,5-dimethyl-1,3-dioxane very carefully
in many portions), an unsubstituted cyclopropenone acetal was
obtained after distillation in the same manner in 70-85% yield
on a 0.3-1 mol scale.
P r ep a r a tion of Alk ylid en ecyclop r op a n es: 6,6-Dim eth -
yl-4,8-d ioxa -1-m eth ylen esp ir o[2.5]octa n e (1a ) (Dep r oto-
n a tion -Alk yla tion P r oced u r e). To a solution of 8.41 g of
6,6-dimethyl-4,8-dioxaspiro[2.5]oct-1-ene24 (60.0 mmol) and
10.75 g of HMPA (60.0 mmol) in 60.0 mL of THF was added
36.8 mL of BuLi (1.6 M in hexane) at -78 °C under nitrogen,
and the resulting solution was stirred for 30 min at this
temperature. To this solution was added 9.37 g of io-
domethane (66.0 mmol) during 15 min, the reaction mixture
was gradually warmed to room temperature during 1 h and
was quenched by addition of saturated NH4Cl during 5 min.
The aqueous layer was extracted with ether, and the combined
organic extracts were washed with saturated NaHCO3 and
saturated NaCl, dried over Na2SO4, and concentrated in vacuo
to afford an oily product (10.30 g). To a solution of the crude
product in 10.3 mL of ether was slowly added a solution of
1.35 g of potassium tert-butoxide (12.0 mmol) and 2.80 g of
DMSO (36.0 mmol) in 10.0 mL of ether at 0 °C under nitrogen.
After the solution was stirred for 2 h at room temperature,
the reaction mixture was quenched by addition of saturated
NH4Cl. The aqueous phase was extracted with ether, and the
gest that the stereoselective cycloaddition of the isopro-
pyl-substituted TMM 2c (R ) i-Pr) with anti-oximes took
place mainly via regio- and stereo-defined five-centered
transition states schematically represented as A (Scheme
4). In these transition states, the oxime substrate
bearing a bulky R4 group is so oriented that it avoids
interaction with a methyl group of the i-Pr group. The
relatively low regiosteering power of the R and R4
substituents of low steric demand (i.e., methyl) (as well
as the lack of solvent effects, Table 2) suggests that
neither OR1 nor CO2R4 group acts as an electronic
stereochemistry-directing group but rather indicates that
the regio- and stereochemistry of the reaction is con-
trolled by the steric bulk of the OR1 and CO2R4 groups.
This stands in contrast to the solvent-polarity-sensitive
endo selectivity of the same TMM (2c) to substituted
acrylic acid esters.11b
Exp er im en ta l Section
Gen er a l. All 1H NMR spectra taken at 270, 400, or 500
MHz and 13C NMR spectra at 67.5, 100, or 125 MHz are
reported in ppm (δ). IR spectra are reported in cm-1
. GC
analysis was performed on a capillary column (0.25 mm i.d.
× 25 m) coated with HR-1. Recycle preparative HPLC was
performed on a J apan Analytical Industry LC-908 machine
equipped with GPC columns (J AIGEL 1H and 2H) using
CHCl3 as eluent.
Ma ter ia ls. Unless otherwise noted, materials were ob-
tained from commercial suppliers and were used without
purification. Ethereal solvents were distilled from benzophe-
none ketyl immediately under nitrogen before use. MeCN,
EtCN, CH2Cl2 were distilled successively from P2O5 and K2-
CO3 and stored over molecular sieves.
P r ep a r a t ion of 1-E t h yl-2,2-b is(ch lor om et h yl)-5,5-d i-
m eth yl-1,3-d ioxa n e. A mixture of 1,3-dichloroacetone (152
g, 1.20 mol, an irritant), neopentyl glycol (138 g, 1.32 mol),
p-toluenesulfonic acid (4.6 g, 0.024 mol), and benzene (100 mL)
was refluxed for 19 h in a 500-mL round-bottomed flask
equipped with a Dean-Stark trap and a condenser for azeo-
tropic removal of water. After completion of the formation of
H2O, the solution was partitioned between hexane (500 mL)
and saturated NaHCO3 (200 mL). The organic phase was
washed with water (100 mL) and saturated NaCl (100 mL),
dried over MgSO4, and concentrated on a rotary evaporator.
Distillation of the residue yielded, after about 5 g of forerun,
249 g (97%) of the title compound as a colorless oil (bp 99-
100 °C, 3.5 mmHg). The product was spectroscopically pure.
Spectral properties: IR (neat) cm-1 2950, 2860, 1105, 1025,
770; 1H NMR (270 MHz, CDCl3) 1.00 (s, 6H), 3.57 (s, 4H), 3.80
(s, 4H).
P r ep a r a tion of 1-Eth yl-6,6-d im eth yl-4,7-d ioxa sp ir o-
[2,5]oct-1-en e a n d 6,6-Dim eth yl-4,7-d ioxa sp ir o[2,5]oct-1-
en e (On e-P ot Cycliza tion -Alk yla tion P r oced u r e).
A
solution of sodium amide in liquid ammonia was prepared
according to a procedure previously described.23 An oven-dried
2000-mL three-necked, round-bottomed flask was equipped
with a mechanical stirrer, a nitrogen gas inlet, and a dry ice/
acetone condenser protected with a drying tube containing
potassium hydroxide pellets. The flask was flushed with
nitrogen and was placed in a dry ice/acetone bath. The
nitrogen source was replaced with a hose connected to a
cylinder of ammonia. Gaseous ammonia was introduced to the
flask to collect ca. 400 mL of liquid NH3 and gentle stirring
was started. The gas inlet was replaced with a glass stopper
and the dry ice/acetone bath was replaced with a -35 °C bath
(electronic temperature control or a dry ice/trichloroethylene
bath). Crystals of Fe(NO3)3‚9H2O (0.3 g) were added through
the stoppered neck. To the resulting orange solution was
(24) Isaka, M.; Matsuzawa, S.; Yamago, S.; Ejiri, S.; Miyachi, Y.;
Nakamura, E. J . Org. Chem. 1989, 54, 4727. Isaka, M.; Ejiri, S.;
Nakamura, E. Tetrahedron 1992, 48, 2045.
(23) Hancock, E. M.; Cope, A. C. Organic Synthesis; Wiley: New
York, 1955; Collect. Vol. 3, p 219.

1700 J . Org. Chem., Vol. 63, No. 5, 1998
Yamago et al.
combined extracts were washed with saturated NaHCO3 and
saturated NaCl, dried over Na2SO4, and concentrated in vacuo
to afford an oily product (8.90 g). Purification on silica gel
(89 g, elution with 4% ether/pentane) followed by distillation
under reduced pressure (bp 72-73 °C/18 mmHg) afforded 6.46
g of the title compound 1a (70% yield). IR (neat) 3150(w),
°C over 20 min under nitrogen. After stirring for 1 h at this
temperature, the solution was warmed to -50 °C and then
room temperature after 1.5 h, and the solution was stirred
for 19 h at this temperature. After the solution was quenched
by addition of 20.0 mL of buffer (pH ) 4.01) and 20.0 mL of
water, the mixture was added in 20.0 mL of ether and was
separated. The aqueous layer was extracted with ether, and
the combined organic extracts were washed with saturated
NaHCO3 and saturated NaCl and dried over Na2SO4. The
solvent was removed to afford an oily product (16.29 g). The
crude product was purified by chromatography with silica gel
(490 g, elution with 4% ethyl acetate/hexane) to afford the 5,5-
dimethyl-3,7-dioxa-1-isobutylspiro[2.5]oct-1-ene in 29% yield
(5.78 g). To a solution of 1.96 g of 5,5-dimethyl-3,7-dioxa-1-
isobutylspiro[2.5]oct-1-ene (10.0 mmol) in 30.0 mL of ether was
added 227 mg of potassium tert-butoxide (2.0 mmol) in 2.50
mL of DMSO and ether (1:2 v/v) at -23 °C under nitrogen.
After being stirred for 15 min at this temperature, the solution
was warmed to 0 °C and stirred for 1 h. Then the solution
was quenched by addition of saturated NH4Cl. The aqueous
layer was extracted with ether, the combined organic extracts
were washed with saturated NaCl and dried over Na2SO4, and
the solvent was removed to afford an oily product. Purification
on silica gel (97 g, elution with 3% ethyl acetate/hexane)
afforded 1.79 g of the isobutylidenecyclopropanone acetal 1c
and 11 as a colorless oil (9.1 mmol, 91% yield, a 89:11 mixture
of 1c and 11). The diastereomers were separated by recycling
HPLC. The overall yield was over 26%. (E)-6,6-Dim eth yl-
4,8-d ioxa -1-isobu tylid en esp ir o[2.5]octa n e (1c): IR (neat)
2958, 2904, 2870, 2362, 1774, 1745, 1468, 1394, 1363, 1350,
1250, 1130, 1074, 1026, 852, 760; 1H NMR (400 MHz, CDCl3)
1.00 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.09 (d, J ) 6.4 Hz, 6H,
CH3), 1.59 (br s, 2H, CH2), 2.51 (dq, J ) 7.0, 6.4 Hz, 1H,
CH3CH), 3.61 (s, 2H, OCH2), 3.62 (s, 2H, OCH2), 6.19 (dt, J )
7.0, 3.6 Hz, 1H, CdCH); 13C NMR (100 MHz, CDCl3) 17.89
(CH2), 21.93 (CH3, 2C), 22.28 (CH3), 22.47 (CH3), 30.71-
(CH3CH), 76.67 (OCH2, 2C), 84.00 (OC), 122.68 (CHdC),
128.13 (CdCH). (Z)-6,6-Dim et h yl-4,8-d ioxa -1-isob u t yli-
d en esp ir o[2.5]octa n e (11): IR (neat) 3851, 2958, 2870, 2360,
2341, 1778, 1469, 1412, 1394, 1362, 1348, 1215, 1128, 1070,
1038, 1003; 1H NMR (400 MHz, CDCl3) 0.84 (s, 3H, CH3), 1.12
(d, J ) 6.4 Hz, 6H, CH3), 1.44 (t, J ) 3.0 Hz, 2H, CH2), 2.45-
2.60 (m, 1H, CH3CH), 3.62 (dd, J ) 10.2, 9.0 Hz, 4H, OCH2),
5.82-5.88 (m, 1H, CdCH); 13C NMR (100 MHz, CDCl3) 17.16
(CH2), 21.73 (CH3, 2 C), 22.01 (CH3), 22.82 (CH3), 30.88 (CH3C),
31,41 (CH3CH), 76.20 (OCH2, 2C), 85.43 (OC), 121.99 (CdCH),
131.02 (CdCH).
1
1270, 1255, 1245, 1150, 1140, 1070, 1030, 1015, 970, 905; H
NMR (CDCl3, 270 MHz) 1.04 (s, 3H), 1.06 (s, 3H), 1.62 (dd, J
) 3.1, 2.4 Hz, 2H), 3.63 (s, 4H), 5.45 (t, J ) 2.4 Hz, 1H), 5.81
(t, J ) 3.1 Hz, 1H); 13C NMR (CDCl3, 67.5 MHz) 18.47 (t), 22.25
(q), 22.34 (q), 30.84 (s), 76.78 (t, two overlapping signals) 84.70
(s), 105.67 (t), 134.63 (s). Anal. Calcd for C9H14O2: C, 70.10;
H, 9.15. Found: C, 70.02; H, 9.25.
6,6-Dim et h yl-4,8-d ioxa -1-et h ylid en esp ir o[2.5]oct a n e
(1b). To a solution of 7.99 g of 6,6-dimethyl-4,8-dioxaspiro-
[2.5]oct-1-ene (57.0 mmol) and 32.25 g of HMPA (180.0 mmol)
in 90.0 mL of THF was added 37.0 mL of BuLi (1.54 M hexane
solution) at -72 °C under nitrogen, and the resulting solution
was stirred for 15 min at this temperature. To this was added
a solution of 10.61 g of ethyl iodide (68.0 mmol) in 30.0 mL of
THF through a cannula at -55 to -50 °C over 20 min under
nitrogen. After stirring for 1 h at this temperature, the
solution was gradually warmed to room temperature during
1 h and was quenched by addition of 20.0 mL of saturated
NH4Cl and 10.0 mL of water. The aqueous layer was extracted
with ether, the combined organic extracts were washed with
saturated NaCl and dried over Na2SO4, and the solvent was
removed to afford an oil (15.80 g). To a solution of the crude
product in 90.0 mL of ether were added 1.28 g of potassium
tert-butoxide (11.4 mmol) and 2.67 g of DMSO (34.2 mmol) in
10.0 mL of ether at 0 °C under nitrogen. After being stirred
for 15 min at this temperature, the solution was quenched by
addition of saturated NH4Cl. The aqueous layer was extracted
with ether, the combined organic extracts were washed with
saturated NaCl and dried over Na2SO4, and the solvent was
removed to afford product. Purification on silica gel (120 g,
elution with 5% ethyl acetate/hexane) afforded 8.37 g of the
ethylidenecyclopropanone acetal 1b as a white solid (49.8
mmol, 87% yield, a 88:12 mixture of E- and Z-isomers).
Recrystallization from hexane (-20 °C) afforded the pure
E-isomer. The mother liquor was concentrated, and the
resulting mixture was subjected to recycling preparative HPLC
to obtain the pure Z-isomer. The geometry of the olefins was
assigned on the basis of the high-field shift (steric compression
effect) of the cyclopropane methylene carbon cis to the methyl
group in each isomer and was finally confirmed by X-ray
crystallographic analysis of the E-isomer.25 IR (neat, deter-
mined for a 88:12 mixture) 1265, 1250, 1145, 1130, 1115, 1080,
1055, 1040, 1010. Anal. (determined for a 88:12 mixture)
Calcd for C10H16O2: C, 71.39; H, 9.59. Found: C, 71.24; H,
9.29. (E)-6,6-Dim eth yl-4,8-d ioxa -1-eth ylid en esp ir o[2.5]-
octa n e (E-1b): 1H NMR (270 MHz, CDCl3) 1.01 (s, 3H), 1.09
(s, 3H), 1.51 (dq, J ) 3.1, 2.2 Hz, 2H), 1.84 (dt, J ) 6.4, 2.2
Hz, 3H), 3.60 (d, J ) 10.0 Hz, 2H), 3.63 (d, J ) 10.0 Hz, 2H),
6.28 (tq, J ) 6.4, 3.1 Hz, 1H); 13C NMR (67.5 MHz, CDCl3)
16.69 (t), 17.30 (q), 22.46 (q), 22.67 (q), 31.01 (s), 76.90 (t, two
overlapping signals), 85.53 (s), 116.91 (d), 126.22 (s). (Z)-6,6-
Dim et h yl-4,8-d ioxa -1-et h ylid en esp ir o[2.5]oct a n e (Z-
1b): 1H NMR (270 MHz, CDCl3) 0.96 (s, 3H), 1.17 (s, 3H), 1.51
(dq, J ) 2.7, 2.5 Hz, 2H), 1.95 (dt, J ) 7.0, 2.7 Hz, 3H), 3.64
(s, 4H), 5.83 (tq, J ) 7.0, 2.5 Hz, 1H); 13C NMR (67.5 MHz,
CDCl3) 18.26 (t), 18.32 (q), 22.49 (q), 22.76 (q), 30.98 (s), 76.78
(t, two overlapping signals), 85.65 (s), 117.94 (d), 125.70 (s).
P r ep a r a t ion of Alk yloxim es (3): Met h yl Glyoxyla t e
O-Ben zyloxim e. To a suspension of 18.01 g of dimethyl
tartrate (200.0 mmol) in 390.0 mL of ether was added 55.77 g
of HIO4‚2H2O (244.7 mmol) for 15 min at 0 °C under nitrogen,
and resulting suspension was stirred for 25 min at this
temperature and then allowed to warm to room temperature.
The suspension was stirred with 15.50 g of dried, powdered
molecular sieve (4A) for 25 min. The reaction mixture was
passed through a Celite pad, and the filtrate was concentrated
in vacuo and was distilled over 4.20 g of P2O5 at 50-70 °C
(28.5-30.0 mmHg) to afford an oily product. To a suspension
of 32.00 g of BnONH2‚HCl (200.5 mmol) and 23.73 g of pyridine
(300.0 mmol) in 100.0 mL of CH2Cl2 was added a solution of
the oily product in 20.00 mL of CH2Cl2 through a cannula over
10 min at room temperature under nitrogen. After being
stirred for 1 h, the mixture was added 50.0 mL of water. The
aqueous layer was extracted with ether, and the combined
organic extracts were washed with saturated NaCl and dried
over MgSO4, and the solvent was removed to afford a crude
product. Purification on silica gel (406 g, elution with 9% ethyl
acetate/hexane) afforded 33.42 g of the title compound as a
colorless oil (173.0 mmol, 87% yield, a 93:7 mixture of anti
and syn isomer). The diastereomer mixture was subjected to
recycling preparative HPLC to obtain the pure anti-isomer.
Anal. (determined for a 93:7 mixture) Calcd for C10H11NO3:
C, 62.17; H, 5.74; N, 7.25. Found: C, 62.36; H, 5.87; N, 7.42.
anti-isomer: IR (neat) 3064, 3033, 2952, 2885, 1724, 1600,
6,6-D im e t h y l-4,8-d io x a -1-is o b u t y lid e n e s p ir o [2.5]-
octa n e (1c a n d 11). To a solution of 14.02 g of 6,6-dimethyl-
4,8-dioxaspiro[2.5]oct-1-ene (100.0 mmol) and 45.32 g of HMPA
(250.0 mmol) in 150.0 mL of THF was added 66.0 mL of BuLi
(1.67 M hexane solution) at -72 °C under nitrogen, and the
resulting solution was stirred for 30 min at this temperature.
To this was added a solution of 22.39 g of isobutyl iodide (121.6
mmol) in 30.0 mL of THF through a dropping funnel at -70
(25) Takenaka, Y.; Ejiri, S.; Yamago, S.; Nakamura, E.; Ohashi, Y.
Manuscript in preparation.

Synthetic Routes to Pyrrolidines and Prolines
J . Org. Chem., Vol. 63, No. 5, 1998 1701
1496, 1454, 1439, 1369, 1327, 1273, 1207, 1182, 1047, 1001,
924, 868, 760, 735, 698, 615, 536, 492; 1H NMR (400 MHz,
CDCl3) 3.84 (s, 3H, CO2CH3), 5.28 (s, 2H, OCH2Ph), 7.38 (s,
5H, C6H5), 7.52 (s, 1H, NdCH); 13C NMR (100 MHz, CDCl3)
52.53 (CH3), 78.15 (OCH2Ph), 128.52 (CH), 128 55 (CH, 2C),
128.87 (CH, 2C), 140.88 (NdCH).
(CH2OH), 69.70 (CO2CH2), 70.18 (NCH), 75.73 (OCH2), 127.69
(CH), 128.12 (CH, 2C), 128.34 (CH, 2C), 128.52 (CH, 2C),
129.14 (CH, 2C), 133.05 (C), 137.37 (C), 139.07 (C), 174.76
(CdO). Anal. Calcd for C23H28NO4Cl: C, 66.10; H, 6.75; N,
3.35. Found: C, 65.99; H, 6.67; N, 3.16. Min or d ia ster e-
om er of 5B: IR (neat) 3430, 1735, 1492, 1370, 1192, 1091,
1050, 1017, 728, 700; 1H NMR (400 MHz, CDCl3) 0.90 (s, 3H,
CH3), 0.91 (s, 3H, CH3), 2.06-2.22 (m, 1 H, CH2), 2.20 (br s,
1H, OH), 2.36-2.48 (m, 1H, CH2), 3.04-3.18 (m, 2H, CHCO2,
NCH2), 3.26 (s, 2H, CH2OH), 3.57-3.66 (m, 1H, NCH2), 3.94
(dd, J ) 9.8, 8.8 Hz, 1H, NCH), 3.95 (d, J ) 10.7 Hz, 1H,
CO2CH2), 3.99 (d, J ) 10.7 Hz, 1H, CO2CH2), 4.42 (d, J ) 11.2
Hz, 1H, OCH2), 4.49 (d, J ) 11.2 Hz, 1H, OCH2), 7.08-7.16
(m, 2H, Ph), 7.20-7.27 (m, 3H, Ph), 7.28 (d, J ) 9.1 Hz, 2H,
p-ClC6H4), 7.35 (d, J ) 9.1 Hz, 2H, p-ClC6H4); 13C NMR (100
MHz, CDCl3) 21.44 (CH3, 2C), 33.54 (CH2), 36.47 (C), 39.48
(CHCO2), 58.74 (NCH2), 68.16 (CH2OH), 69.81 (CO2CH2), 70.90
(NCH), 75.87 (OCH2), 127.73 (CH), 128.16 (CH, 2C), 128.38
(CH, 2C), 128.64 (CH, 2C), 129.17 (CH, 2C), 133.08 (C), 137.39
(C), 139.29 (C), 174.78 (CdO). Anal. Calcd for C23H28NO4Cl:
C, 66.10; H, 6.75; N, 3.35. Found: C, 66.14; H, 7.13; N, 3.26.
Cycloa d d ition of 1a w ith p-Ch lor oben za ld eh yd e O-
Ben zyloxim e in C3H7CN. A solution of 1a (0.79 g, 5.09
mmol) and p-chlorobenzaldehyde O-benzyloxime (1.02 g, 4.15
mmol, >99.8% anti) in C3H7CN (0.95 mL) was heated for 30 h
at 100 °C under nitrogen. The reaction mixture was treated
with 10% aqueous HCl (1.0 N) in THF (2.0 mL) and stirred
for 35 min. After the usual workup, purification of the
resulting crude mixture by chromatography with silica gel (102
g, elution with 25% and 40% ethyl acetate in hexane) afforded
5B in 90% yield (1.56 g) as a 72:28 diastereomeric mixture.
Cycloa d d ition of 1a w ith p-Ch lor oben za ld eh yd e O-
Ben zyloxim e w ith ou t Solven t. A mixture of 1a (0.79 g, 5.09
mmol) and p-chlorobenzaldehyde O-benzyloxime (1.02 g, 4.15
mmol, >99.8% anti) was heated for 46 h at 100 °C under
nitrogen. The reaction mixture was treated with 10% aqueous
HCl (1 N) in THF (2 mL) and stirred for 30 min. After usual
workup, purification of the resulting crude mixture by chro-
matography with silica gel (100 g, elution with 25% and 40%
ethyl acetate in hexane) afforded 5B in 98% yield (1.70 g) as
a 73:27 diastereomeric mixture.
a n ti-ter t-Bu tyl Glyoxyla te O-Ben zyloxim e. To 100.0
t
mL of BuOH was added 375.0 mL of BuLi (1.60 M hexane
solution) over 35 min at 0 °C under nitrogen, and the resulting
solution was stirred for 30 min at this temperature. The
solution was added a solution of 45.89 g of fumaryl chloride
(300.0 mmol) in 130.0 mL of ether through a dropping funnel
at room temperature for 1.5 h. The solution became brown.
After being stirred for 5 h, the solution was quenched by
addition of 120.0 mL of water. The combined organic extracts
were washed with saturated NaHCO3 and saturated NaCl and
dried over Na2SO4, and the solvent was removed to afford
brown crystals. Recrystallization from hexane afforded di-tert-
butyl fumarate (46.24 g, 202.5 mmol, 68% yield). To a solution
of 11.40 g of di-tert-butyl fumarate (49.9 mmol) and 0.50 mL
of pyridine in 50.00 mL of CH2Cl2 was bubbled with O3 in O2
at -23 °C for 4.5 h. Excess O3 was removed by passing O2
through the solution. To the solution was added 6.21 g of
dimethyl sulfide (100.0 mmol) and the mixture was warmed
to room temperature. The solvent was removed to afford an
oily product (14.40 g). To a suspension 15.96 g of BnONH2‚HCl
(100.0 mmol) and 11.07 g of pyridine (139.9 mmol) in 90.0 mL
of CH2Cl2 was added a solution of the crude oil in 20.0 mL of
CH2Cl2 through a cannula over 15 min at room temperature
under nitrogen. After being stirred 2.5 h, to the mixture was
added 50.0 mL of water. The aqueous layer was extracted with
CH2Cl2, the combined organic extracts were washed with
saturated NaCl and dried over MgSO4, and the solvent was
removed to afford a crude product (25.37 g). Purification on
silica gel (150 g, elution with 8% ethyl acetate/hexane) afforded
14.02 g of the title compound as a colorless oil (59.6 mmol,
60% yield). The overall yield of three steps was 41%. IR (neat)
2979, 2935, 1738, 1714, 1599, 1477, 1456, 1394, 1369, 1336,
1279, 1259, 1214, 1159, 1047, 1026, 972, 922, 843, 781, 737,
698; 1H NMR (400 MHz, CDCl3) 1.52 (s, 9H, CH3), 5.27 (s, 2H,
OCH2), 7.35 (br s, 5H, C6H5), 7.47 (s, 1H, CHdN); 13C NMR
(100 MHz, CDCl3) 27.97 (CH3, 3C), 77.81 (OCH2), 82.65
(OC(CH3)3), 128.37 (CH), 128.52 (CH, 2C), 128.57 (CH, 2C),
136.16 (C), 142.40 (NdCH), 160.98 (CdO). Anal. Calcd for
4-(2,2-Dim eth yl-3-h ydr oxypr opoxycar bon yl)-1-m eth oxy-
2-p h en ylp yr r olid in e (5C). A solution of 1a (555 mg, 3.6
mmol) and benzaldehyde O-methyloxime (406 mg, 3.0 mmol,
98% anti) in CH2Cl2 (0.9 mL) was heated at 80 °C under 10
kbar for 21 h. The crude mixture was treated with 10% v/v
water in THF (2.0 mL) and acetic acid (50 mL) for 30 min at
room temperature. Solvent was removed, and the resulting
crude material was purified by chromatography with silica gel
(20 g, elution with 30% ethyl acetate in hexane) to afford the
title compound (5C) in 76% yield (700 mg) as a 70:30 mixture
of two diastereomers. The diastereomers were separated by
recycling HPLC for characterization. Ma jor d ia ster eom er
C
13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.31; H,
7.35; N, 5.93.
Cycloa d d ition Rea ction of Meth ylen ecyclop r op a n e
(1a ) a n d Oxim e Eth er s: 1-Ben zyloxy-2-(4′-ch lor op h en yl)-
4-(2,2-d im e t h yl-3-h yd r oxyp r op oxyca r b on yl)p yr r oli-
d in e (5B). A solution of 1a (185 mg, 1.2 mmol) and p-chlo-
robenzaldehyde O-benzyloxime (246 mg, 1.0 mmol, >99.8%
anti) in CD3CN (0.23 mL) in a sealed NMR tube was heated
for 31 h at 100 °C. The reaction mixture was treated with
10% aqueous HCl (1.0 N) in THF (1.0 mL) and stirred for 25
min. After usual workup (addition of saturated NaHCO3,
extraction with ether, washing organic extracts with saturated
NaCl, drying over Na2SO4, and concentration in vacuo),
purification of the resulting crude mixture by chromatography
with silica gel (14 g, elution with 40% ethyl acetate in hexane)
afforded the title compound 5B in 99% yield (415 mg) as a
64:36 diastereomeric mixture. These diastereomers were
separated by preparative recycle HPLC for characterization.
Ma jor d ia ster eom er of 5B: IR (neat) 3450, 1724, 1496, 1373,
1188, 1092, 1050, 1019, 701; 1H NMR (400 MHz, CDCl3) 0.91
(s, 6H, CH3), 2.00 (br dt, J ) 12.7, 9.3 Hz, 1H, CH2), 2.26 (br
s, 1H, OH), 2.46 (ddd, J ) 12.7, 8.8, 5.4 Hz, 1H, CH2), 3.03-
3.18 (m, 2H, CHCO2, NCH2), 3.28 (s, 2H, CH2OH), 3.61 (dd, J
) 8.8, 7.8 Hz, 1H, NCH2), 3.93 (d, J ) 11.2 Hz, 1H, CO2CH2),
3.98 (d, J ) 11.2 Hz, 1H, CO2CH2), 4.01 (dd, J ) 9.3, 8.8 Hz,
1H, NCH), 4.41 (d, J ) 11.2 Hz, 1H, OCH2), 4.46 (d, J ) 11.2
Hz, 1H, OCH2), 7.06-7.16 (m, 2H, C6H5), 7.19-7.27 (m, 3H,
C6H5), 7.28 (d, J ) 8.3 Hz, 2H, p-ClC6H4), 7.33 (d, J ) 8.3 Hz,
2H, p-ClC6H4); 13C NMR (100 MHz, CDCl3) 21.39 (CH3, 2C),
33.24 (CH2), 36.39 (C), 39.09 (CHCO2), 58.39 (NCH2), 68.07
1
of 5C: IR (neat) 3440, 1735, 1142, 1060, 703; H NMR (500
MHz, CDCl3) 0.93 (s, 6H, CH3), 2.12-2.23 (m, 1H, CH2), 2.42
(br s, 1H, OH), 2.46 (ddd, J ) 13.3, 9.6, 7.8 Hz, 1H, CH2), 3.09
(dd, J ) 10.5, 9.1 Hz, 1H, CH2N), 3.11-3.20 (m, 1H, CHCO2),
3.31 (s, 2H, CH2OH), 3.35 (s, 3H, OCH3), 3.76 (dd, J ) 10.5,
3.7 Hz, 1H, CH2N), 3.93 (dd, J ) 10.1, 7.8 Hz, 1H, CHN), 3.97
(d, J ) 11.0 Hz, 1H, CH2O), 4.01 (d, J ) 11.0 Hz, 1H, CH2O),
7.23-7.29 (m, 1H, C6H5), 7.31-7.36 (m, 2H, C6H5), 7.42-7.46
(m, 2H, C6H5); 13C NMR (100 MHz, CDCl3) 21.41 (CH3, 2C),
33.82 (CH2), 36.44 (C), 39.51 (CHCO2), 57.32 (CH2N), 61.05
(OCH3), 68.15 (CH2OH), 69.82 (CH2O), 71.38 (CHN), 127.36
(CH), 127.53 (CH, 2C), 128.24 (CH, 2C), 140.68 (C), 174.89
(CdO). Anal. Calcd for C17H25NO4: C, 66.42; H, 8.20; N, 4.56.
Found: C, 66.22; H, 8.48; N, 4.44. Min or d ia ster eom er of
5C: IR (neat) 3440, 1732, 1182, 1055, 1021, 700; 1H NMR (400
MHz, CDCl3) 0.94 (s, 6H, CH3), 2.07 (br dd, J ) 23.0, 10.3 Hz,
1H, CH2), 2.29 (br s, 1H, OH), 2.51 (ddd, J ) 13.2, 8.3, 4.9 Hz,
1H, CH2), 3.08 (dd, J ) 19.0, 10.3 Hz, 1H, CH2N), 3.13-3.23
(m, 1H, CHCO2), 3.31 (s, 2H, CH2OH), 3.35 (s, 3H, OCH3), 3.76
(dd, J ) 10.3, 7.8 Hz, 1H, CH2N), 3.96 (d, J ) 11.2 Hz, 1H,
CH2O), 3.94-4.03 (m, 1H, CHN), 4.01 (d, J ) 11.2 Hz, 1H,
CH2O), 7.24-7.31 (m, 1H, C6H5), 7.31-7.38 (m, 2H, C6H5),

1702 J . Org. Chem., Vol. 63, No. 5, 1998
Yamago et al.
7.40-7.46 (m, 2H, C6H5); 13C NMR (100 MHz, CDCl3) 21.43
(CH3, 2C), 33.35 (CH2), 36.46 (C), 39.20 (CHCO2), 57.83
(CH2N), 61.07 (OCH3), 68.11 (CH2OH), 69.68 (CH2O), 70.67
(CHN), 127.38 (CH), 127.53 (CH, 2C), 128.27 (CH, 2 C), 140.57
(C), 175.00 (CdO). Anal. Calcd for C17H25NO4: C, 66.42; H,
8.20; N, 4.56. Found: C, 66.28; H, 8.50; N, 4.43.
4-(2,2-Dim eth yl-3-h ydr oxypr opoxycar bon yl)-1-m eth oxy-
2-(4′-m eth oxyp h en yl)p yr r olid in e (5D). A solution of 1a
(432 mg, 2.8 mmol) and p-anisaldehyde O-methyloxime (413
mg, 2.5 mmol, >99% anti) in of CH2Cl2 (0.8 mL) was heated
at 80 °C under 10 kbar for 24 h. The crude mixture was
treated with 10% v/v water in THF (2.0 mL) and acetic acid
(50 mL) for 30 min at room temperature, and purification by
chromatography with silica gel (20 g, elution with 40% ethyl
acetate in hexane) afforded the title compound (5D) in 70%
yield (590 mg) as a 70:30 mixture of two diastereomers. The
diastereomers were separated by recycling HPLC. Ma jor
d ia ster eom er of 5D: IR (neat) 3450, 1732, 1615, 1516, 1248,
tr a n s-5E: IR (neat) 3460, 1730, 1182, 1053, 1020, 932; 1H
NMR (400 MHz, CDCl3) 0.93 (s, 6H, CH3), 2.28-2.44 (m, 1H,
CH2), 2.41 (br s, 1H, OH), 2.44-2.55 (m, 1H, CH2), 3.17 (dd, J
) 7.8, 7.3 Hz, 1H, CH2N), 3.18-3.27 (m, 1H, CHCO2), 3.31
(br s, 2H, CH2OH), 3.37 (s, 3H, OCH3), 3.63 (dd, J ) 10.2, 7.3
Hz, 1H, CH2N), 3.95 (d, J ) 10.7 Hz, 1H, CH2O), 4.01 (d, J )
10.7 Hz, 1H, CH2O), 4.20 (t, J ) 8.3 Hz, 1H, CHN), 6.28 (d, J
) 2.9 Hz, 1H, CH), 6.34 (dd, J ) 2.9, 1.7 H, 1H, CH), 7.39-
7.42 (m, 1H, CH); 13C NMR (100 MHz, CDCl3) 21.40 (CH3, 2C),
29.87 (CH2), 36.43 (C), 40.10 (CHCO2), 58.22 (CH2N), 60.78
(OCH3), 64.44 (CH2OH), 68.02 (CH2O), 69.71 (CHN), 107.68
(CH), 110.17 (CH), 142.10 (CH), 152.76 (C), 174.92 (CdO).
1
1178, 1057, 1038, 830, 735; H NMR (400 MHz, CDCl3), 0.93
(s, 6H, CH3), 2.17 (br s 1H, CH2), 2.42 (ddd, J ) 13.2, 9.8, 7.3
Hz, 1H, CH2), 2.55 (br s, 1H, OH), 3.07 (dd, J ) 10.3, 9.3 Hz,
1H, CH2N), 3.10-3.19 (m, 1H, CHCO2), 3.32 (br s, 2H, CH2-
OH), 3.33 (s, 3H, OCH3), 3.75 (dd, J ) 10.3, 3.4 Hz, 1H, CH2N),
3.79 (s, 3H, OCH3), 3.87 (dd, J ) 9.8, 7.8 Hz, 1H, CHN), 3.97
(d, J ) 11.2 Hz, 1H, CH2O), 4.01 (d, J ) 11.2 Hz, 1H, CH2O),
6.87 (d, 2H, J ) 8.8 Hz, C6H4), 7.35 (d, 2H, J ) 8.8 Hz, C6H4);
13C NMR (100 MHz, CDCl3) 21.38 (CH3, 2C), 33.57 (CH2), 36.38
(C), 39.43 (CHCO2), 55.10 (OCH3), 57.20 (CH2N), 61.01 (OCH3),
68.10 (CH2OH), 69.78 (CH2O), 70.77 (CHN), 113.57 (CH, 2C),
128.65 (CH, 2C), 132.49 (C), 158.84 (C), 174.89 (CdO). Anal.
Calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C,
64.29; H, 7.89; N, 4.00. Min or d ia ster eom er of 5D: IR
(neat) 3440, 1732, 1612, 1513, 1245, 1175, 1052, 1038, 829,
732; 1H NMR (400 MHz, CDCl3) 0.93 (s, 6H, CH3), 2.06 (br q,
J ) 11.2 Hz, 1H, CH2), 2.31 (br s, 1H, OH), 2.46 (ddd, J )
13.2, 7.8, 4.4 Hz, 1H, CH2), 3.05 (dd, J ) 9.8, 9.6 Hz, 1H,
CH2N), 3.15-3.22 (m, 1H, CHCO2), 3.31 (br s, 2H, CH2OH),
3.32 (s, 3H, OCH3), 3.73 (dd, J ) 10.3, 8.3 Hz, 1H, CH2N),
3.80 (s, 3H, OCH3), 3.92-4.00 (m, 1H, CHN), 3.95 (d, J ) 10.7
Hz, 1H, CH2O), 4.01 (d, J ) 10.7 Hz, 1H, CH2O), 6.88 (d, J )
8.8 Hz, 2H, C6H4), 7.33 (d, J ) 8.8 H, 2H, C6H5); 13C NMR
(100 MHz, CDCl3) 21.42 (CH3, 2C), 33.20 (CH2), 36.45 (C),
39.16 (CHCO2), 55.17 (OCH3), 57.80 (CH2N), 61.07 (OCH3),
68.10 (CH2OH), 69.67 (CH2O), 70.13 (CHN), 113.63 (CH, 2C),
128.69 (CH, 2C), 132.39 (C), 158.90 (C), 175.08 (CdO). Anal.
Calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C,
63.89; H, 8.24; N, 4.02.
4-(2,2-Dim eth yl-3-h ydr oxypr opoxycar bon yl)-1-m eth oxy-
2-(2′-fu r yl)p yr r olid in e (5E). A solution of 1a (152 mg, 1.0
mmol) and 2-furaldehyde O-methyloxime (109 mg, 0.87 mmol)
in CD3CN (0.34 mL) in a sealed NMR tube was heated for 85
h at 100 °C. To the mixture was added water (0.5 mL) and
silica gel (0.5 g), and the slurry was stirred for 1 h. Purifica-
tion by chromatography with silica gel (3.8 g, elution with 40%
ethyl acetate in hexane) afforded the title compound 5E in 90%
yield (234 mg) as a 60:40 diastereomeric mixture. These
diastereomers were separated by preparative recycle HPLC
for characterization. An NOE experiment revealed that the
major isomer had cis stereochemistry (see below). cis-5E: IR
(neat) 3450, 1732, 1193, 1065, 1011, 738; 1H NMR (400 MHz,
CDCl3) 0.93 (s, 6H, CH3), 2.39-2.52 (m, 2H, CH2), 2.53 (br s,
1H, OH), 3.19-3.30 (m, 2H, CH2N, CHCO2), 3.30 (br s, 2H,
CH2OH), 3.42 (br s, 3H, OCH3), 3.47-3.57 (m, 1H, CH2N), 3.96
(d, J ) 11.2 Hz, 1H, CH2O), 4.00 (d, J ) 11.2 Hz, 1H, CH2O),
4.21 (t, J ) 8.1 Hz, 1H, CHN), 6.29-6.35 (m, 2H, CH), 7.37-
7.40 (m, 1H, CH); 13C NMR (100 MHz, CDCl3) 21.38 (CH3, 2C),
30.32 (CH2), 36.38 (C), 40.81 (CHCO2), 57.78 (CH2N), 60.57
(OCH3), 65.15 (CH2OH), 68.02 (CH2O), 69.75 (CHN), 107.51
(CH), 110.15 (CH), 142.08 (CH), 153.16 (C), 174.67 (CdO).
Anal. Calcd for
C15H23NO5: C, 60.59; H, 7.80; N, 4.71.
Found: C, 60.29; H, 7.99; N, 4.60.
1-Ben zyloxy-4-(2,2-d im eth yl-3-h yd r oxyp r op oxyca r bo-
n yl)-2-(3′-p yr id yl)p yr r olid in e (5F ). A solution of 1a (101.8
mg, 0.66 mmol) and 3-pyridinecarbaldehyde O-benzyloxime
(127.4 mg, 0.60 mmol, 97.4% anti) in CD3CN (0.23 mL) in a
sealed NMR tube was heated for 29 h at 100 °C. After solvent
was removed, purification by chromatography with silica gel
(14 g, elution with 40% ethyl acetate in hexane) afforded the
title compound (5F ) in 66% yield (151.1 mg) as a 70:30
diastereomeric mixture. Spectra were taken for a 7:3 mixtures
of the isomers. IR (neat) 3350, 1735, 1372, 1192, 1057, 1030,
735, 700; 1H NMR (400 MHz, CDCl3) 0.92 (s, 4.2H, (CH3)2),
0.93 (s, 1.8H, (CH3)2), 1.98-2.12 (m, 0.3H, CH2), 2.12-2.26
(m, 0.7H, CH2), 2.40-2.57 (m, 1H, CH2), 3.07-3.22 (m, 2H,
CHCO2, NCH2), 3.30 (s, 1.4H, CH2OH), 3.33 (s, 0.6H, CH2OH),
3.48 (br s, OH), 3.62-3.70 (m, 1H, NCH2), 3.93-4.04 (m, 3H,
CO2CH2, NCH), 4.42 (d, J ) 11.2 Hz, 0.7H, OCH2Ph), 4.39-
4.50 (m, 0.6H, OCH2Ph), 4.49 (d, J ) 11.2 Hz, 0.7H, OCH2-
Ph), 7.06-7.14 (m, 1H, Py), 7.20-7.32 (m, 5H, C6H5), 7.71 (br
d, J ) 6.4 Hz, 0.3H, Py), 7.77 (br d, J ) 7.8 Hz, 0.7H, Py),
8.57 (br s, 1H, Py), 8.64 (br s, 1H, Py); 13C NMR (100 MHz,
CDCl3) 21.42 (CH3, 2C), 32.97 (CH2, 0.3C), 33.16 (CH2, 0.7C),
36.36 (C, 1C), 39.18 (CH, 0.3C), 39.57 (CH, 0.7C), 58.07 (NCH2,
0.7C), 58.46 (NCH2, 0.3C), 67.97 (CH2OH, 1C), 68.46 (NCH,
0.3C), 68.94 (NCH, 0.7C), 69.83 (CH2OCO, 0.3C), 69.89 (CH2-
OCO, 0.7C), 75.74 (CH2O, 0.3C), 75.80 (CH2O, 0.7C), 123.58
(CH, 0.3C), 123.69 (CH, 0.7C), 127.78 (CH, 1C), 128.13 (CH,
2C), 128.54 (CH, 0.6C), 128.61 (CH, 1.4C), 135.67 (CH, 0.3C),
135.79 (CH, 0.7C), 136.63 (C, 0.3C), 136.74 (C, 0.7C), 137.10
(C, 1C), 148.18 (CH, 0.7C), 148.36 (CH, 0.3C), 148.95 (CH,
0.7C), 149.08 (CH, 0.3C), 174.40 (CdO, 0.7C), 174.48 (CdO,
0.3C). Anal. Calcd for C22H28N2O4: C, 68.72; H, 7.34; N, 7.29.
Found: C, 68.92; H, 7.30; N, 7.23.
1-Ben zyloxy-4-(2,2-d im eth yl-3-h yd r oxyp r op oxyca r bo-
n yl)-2-m eth oxyca r bon ylp yr r olid in e (5A). A solution of 1a
(185 mg, 1.20 mmol) and methyl glyoxylate O-benzyloxime
(193 mg, 1.00 mmol, 91% anti) in CD3CN (0.31 mL) in a sealed
NMR tube was heated for 1.5 h at 80 °C. The reaction mixture
was treated with water (10 mL) and silica gel (100 mg) for 1
h at room temperature and the silica gel was removed.
Purification by chromatography with silica gel (12 g, elution
with 43% ethyl acetate in hexane) afforded the title compound
(5A) in 79% yield (289 mg) as a 73:27 diastereomeric mixture.
The diastereomers were separated by preparative recycling
HPLC for characterization. An NOE experiment revealed that
the major isomer had cis stereochemistry (see below). cis-
5A: IR (neat) 3440, 1738, 1202, 1051; 1H NMR (400 MHz,
CDCl3) 0.89 (s, 6H, CH3), 2.24 (br s, 1H, OH), 2.31-2.50 (m,
2H, CH2), 3.12-3.24 (m, 1H, CHCO2), 3.27 (br s, 2H, CH2OH),
3.30 (dd, J ) 11.7, 8.3 Hz, 1H, NCH2), 3.52 (dd, J ) 11.7, 6.3
Hz, 1H, NCH2), 3.73 (s, 3H, OCH3), 3.90 (dd, J ) 8.3, 8.3 Hz,
1H, CHCO2), 3.94 (d, J ) 2.4 Hz, 2H, CO2CH2), 4.77 (s, 2H,
OCH2), 7.26-7.39 (m, 5H, C6H5); 13C NMR (100 MHz, CDCl3)
Anal. Calcd for
C15H23NO5: C, 60.59; H, 7.80; N, 4.71.
Found: C, 60.30; H, 8.07; N, 4.66.
The stereochemistry was assigned according to differential
NOE experiments. Irradiation of H1 resulted in an NOE
enhancement of 2.8% at H2, indicating a cis orientation of H1
and H2.

Synthetic Routes to Pyrrolidines and Prolines
J . Org. Chem., Vol. 63, No. 5, 1998 1703
21.43 (CH3, 2C), 29.57 (CH2), 36.41 (C), 41.08 (CHCO2), 52.19
(OCH3), 58.90 (CH2N), 68.01 (CH2OH), 69.56 (CHN), 69.77
(CO2CH2), 75.59 (OCH2), 127.91 (p-Ph), 128.29 (o-Ph, 2C),
128.68 (m-Ph, 2C), 137.09 (ipso-Ph), 171.62 (CdO), 174.00
(CdO). Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45; N, 3.83.
Found: C, 62.15; H, 7.39; N, 3.62.
The stereochemistry was assigned according to differential
NOE experiments. Irradiation of H1 resulted in an NOE
enhancement of 3.8% at H2, indicating a cis orientation of H1
and H2.
10.0, 10.0 Hz, 1H, CH2), 2.27 (ddd, J ) 13.0, 8.0, 5.0 Hz, 1H,
CH2), 2.78 (ddd, J ) 10.0, 8.0, 5.0 Hz, 1H, CHCO2), 3.30 (dd,
J ) 8.0, 4.0 Hz, 3H, NCH, CH2OH), 3.83 (dd, J ) 10.0, 8.0
Hz, 1H, NCHCO2), 3.93 (s, 2H, CO2CH2), 4.78 (d, J ) 11 Hz,
1H, OCH2Ph), 4.95 (d, J ) 11 Hz, 1H, OCH2Ph), 7.25-7.35
(m, 5H, C6H5); 13C NMR (100 MHz, CDCl3) 16.98 (CH3), 19.67
(CH3), 21.50 (CH3, 2C), 28.03 (CH3, 3C), 29.12 (CH3CH), 30.06
(CH2), 36.47 (CH3C), 40.81 (CHCO2), 68.08 (CH2OH), 69.41
(NCHCO2), 69.83 (CO2CH2), 75.94 (NCH), 76.51 (OCH2), 81.19
(OCCH3), 127.84 (CH), 128.28(CH, 2C), 128.59 (CH, 2C),
137.17 (C), 171.31 (CO2), 175.54 (CO2). Anal. Calcd for C25H39
-
NO6: C, 66.79; H, 8.74; N, 3.12. Found: C, 66.55; H, 8.44; N,
3.35.
The stereochemistry was assigned according to differential
NOE experiments. Irradiation of H1 resulted in an NOE
enhancement of 5.9% at H3 and irradiation of H3 resulted in
an NOE enhancement of 7.5% at H2, indicating a cis orienta-
tion of H1, H2, and H3.
tr a n s-5A: IR (neat) 3400, 1739, 1240, 1182, 1053; 1H NMR
(400 MHz, CDCl3) 0.89 (s, 6H, CH3), 2.12 (br s, 1H, OH), 2.18-
2.33 (m, 1H, CH2), 2.43-2.56 (m, 1H, CH2), 3.10-3.25 (m, 2H,
NCH2CHCO2), 4.10 (m, 3H, NCH, CO2CH2), 4.78 (s, 2H,
OCH2), 7.26-7.39 (m, 5H, C6H5); 13C NMR (100 MHz, CDCl3)
21.39 (CH3, 2C), 28.90 (CH2), 36.40 (C), 40.35 (CHCO2), 52.11
(OCH3), 58.97 (CH2N), 68.06 (CH2OH), 68.92 (CHN), 69.80
(CO2CH2), 75.67 (OCH2), 127.88 (p-Ph), 128.26 (o-Ph, 2C),
128.61 (m-Ph, 2C), 137.17 (ipso-Ph), 171.55 (CdO), 174.29
(CdO). Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45; N, 3.83.
Found: C, 62.63; H, 7.60; N, 3.82.
1-Ben zyloxy-cis-4-(2,2-d im eth yl-3-h yd r oxyp r op oxyca r -
b on yl)-tr a n s-5-isop r op yl-r -2-ter t-m et h oxyca r b on ylp yr -
r olid in e (tr a n s-10): IR (neat) 3510, 2962, 2873, 1732 (CdO),
Cycloa d d ition of 1a w ith Meth yl Glyoxyla te O-Ben -
zyloxim e u n d er Dr y Air w ith ou t Solven t. A mixture of
1a (4.81 g, 31 mmol) and methyl glyoxylate O-benzyloxime
(5.01 g, anti:syn ) 93:7, 25.9 mmol) was heated for 4 h at 100
°C. After 1H NMR analysis of the reaction mixture indicated
near quantitative formation of the ketene acetal,the reaction
mixture was treated with 10% aqueous HCl (1.0 N) in THF
(5.0 mL) and stirred for 1 h. After usual workup, purification
by chromatography with silica gel (100 g, elution with 8% and
45% ethyl acetate in hexane) afforded cycloadduct 5A in 89%
yield (8.40 g, 23.0 mmol) as a 71:29 diastereomeric mixture.
Cycloa d d ition of 1c w ith Glyoxa lic Acid ter t-Bu tyl
Ester O-Ben zyloxim e. 1-Ben zyloxy-cis-4-(2,2-d im eth yl-
3-h ydr oxypr opoxycar bon yl)-cis-5-isopr opyl-r -2-ter t-m eth -
oxyca r bon ylp yr r olid in e (cis-9). A solution of 1c (177 mg,
0.9 mmol) and glyoxalic acid tert-butyl ester O-benzyloxime 3
(176 mg, 0.75 mmol, >99% anti) in CD3CN (0.35 mL) in a
sealed NMR tube was heated for 17 h at 100 °C. The reaction
mixture was treated with 10% aqueous HCl (1.0 N) in THF
(2.0 mL) and stirred for 5 min. After usual workup (addition
of saturated NaHCO3, extraction with ether, washing organic
extracts with saturated NaCl, drying over Na2SO4, and
concentration in vacuo), purification by chromatography with
silica gel (22 g, elution with 24% and 30% ethyl acetate in
hexane) afforded the titled compound (cis-9) and 1-benzyloxy-
cis-4-(2,2-dimethyl-3-hydroxypropoxycarbonyl)-trans-3-isopro-
pyl-r-2-tert-methoxycarbonylpyrrolidine (trans-10) in 79% (266
mg) and 10% (34 mg) yields. The ratio of diastereomers (cis-
1
1473, 1456, 1392, 1369, 1255, 1155, 1054, 847, 748, 698; H
NMR (400 MHz, CDCl3) 0.91 (s, 6H, CCH3), 0.93 (d, J ) 6.8
Hz, 3H, CHCH3), 0.95 (d, J ) 6.8 Hz, 3H, CHCH3), 1.48 (s,
9H, OCCH3), 1.81 (dq, J ) 6.8, 6.8 Hz, 1H, CH3CH), 2.52 (m,
1H, CH3CHCH), 2.90 (dd, J ) 8.0, 5.0 Hz, 1H, CHCO2), 3.23
(dd, J ) 11.5, 8.0 Hz, 1H, CH2), 3.28 (s, 2H, CH2OH), 3.48
(dd, J ) 11.5, 8.0 Hz, 1H, CH2), 3.52 (d, J ) 6.8 Hz, 1H,
NCHCO2), 3.94 (s, 2H, CO2CH2), 4.74 (s, 2H, OCH2Ph), 7.25-
7.35 (m, 5H, C6H5); 13C NMR (100 MHz, CDCl3) 20.44
(CHCH3), 20.51 (CHCH3), 21.53 (CCH3, 2 C), 27.97 (OCCH3,
3 C), 31.57 (CH3CH), 36.46 (CH3C), 44.20 (CH3CHCH), 45.56
(CHCO2), 59.54 (CH2), 68.11 (CH2OH), 69.83 (CO2CH2), 74.13
(NCHCO2), 75.48 (OCH2Ph), 81.30 (OCCH3), 127.84 (CH),
128.26 (CH, 2C), 128.59 (CH, 2C), 137.28 (C), 171.17 (CO2),
175.57 (CO2). Anal. Calcd for C25H39NO6: C, 66.79; H, 8.74;
N, 3.12. Found: C, 66.56; H, 8.49; N, 3.40.
The stereochemistry was assigned according to differential
NOE experiments. Irradiation of H2 resulted in an NOE
enhancement of 11.5% and 6.5% at H1 and H3, indicating a
trans orientation of H1, H2, and H3.
1
9:tr a n s-9 and cis-10:tr a n s-10) was determined by H NMR
and 13C NMR. NOE experiments revealed that 9 had 2,4-cis
and 2,5-cis stereochemistry, and that 10 was 2,3-trans and 2,4-
cis stereochemisty.
Ack n ow led gm en t. This work was supported by
Grant-in-Aid for Scientific Research on Priority Areas
(No. 283, “Innovative Synthetic Reactions”) from Mon-
busho, J apan.
cis-9: IR (neat) 3523 (OH), 2962, 2873, 1732 (CdO), 1456,
1369, 1257, 1225, 1157, 1052, 912, 847, 735, 698, 528; 1H NMR
(400 MHz, CDCl3) 0.92 (s, 6H, CCH3), 0.93 (d, J ) 8.0 Hz, 3H,
CHCH3), 1.00 (d, J ) 8.0 Hz, 3H, CHCH3), 1.49 (s, 9H, OCCH3),
2.00 (dq, J ) 8.0, 8.0 Hz, 1H, CH3CH), 2.10 (ddd, J ) 13.0,
J O972302Y