New Diastereoselective Route to 2-Substituted cis-(2S,5S)- and trans-(2S,5R)-5-Alkylpyrrolidines as Indolizidine and Pyrrolizidine Scaffolds

Article abstract of DOI:10.1002/ejoc.200300393

A new and short stereoselective route to the synthesis of enantiopure cis-2,5-disubstituted pyrrolidines as indolizidine or pyrrolizidine scaffolds has been developed. The method, which uses (S)-pyroglutamic acid as a chiral starting material, is based on the ring opening of N-protected 7-lactams by alkyl phenyl sulfone carbanions, followed by desulfonylation and reductive amination of alkyl 7-amino ketones. The diastereoselectivity depends on the substitution of the starting γ-lactams, and on the alkyl group of the phenyl sulfone. Total cis diastereoselectivity was observed in the formation of tert-butyl 5-alkylprolinates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300393

FULL PAPER
New Diastereoselective Route to 2-Substituted cis-(2S,5S)- and trans-(2S,5R)-
5-Alkylpyrrolidines as Indolizidine and Pyrrolizidine Scaffolds
[a]
[a]
[a]
`
Antonio J. Mota, Angele Chiaroni, and Nicole Langlois*
Keywords: Alkyl phenyl sulfone / Carbanions / Alkaloids / Pyrrolidines / Pyroglutamic acid / Reductive amination /
Lactams / Ring opening
A new and short stereoselective route to the synthesis of en-
antiopure cis-2,5-disubstituted pyrrolidines as indolizidine or
pyrrolizidine scaffolds has been developed. The method,
which uses (S)-pyroglutamic acid as a chiral starting ma-
terial, is based on the ring opening of N-protected γ-lactams
by alkyl phenyl sulfone carbanions, followed by desulfonyl-
ation and reductive amination of alkyl γ-amino ketones. The
diastereoselectivity depends on the substitution of the start-
ing γ-lactams, and on the alkyl group of the phenyl sulfone.
Total cis diastereoselectivity was observed in the formation
of tert-butyl 5-alkylprolinates.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
of ants belonging to the same Solenopsis genus[7] or to
Monomorium species.[8]
Pyrrolidines are very important constituents in many liv-
ing organisms,[1,2] present in plants and several animals
either themselves, or as components of more complex alka-
loids. Among them, several indolizidines and pyrrolizidines
bearing alkyl chains in the position α to the nitrogen exert
control and protective functions against other living organ-
isms, and are biologically significant.[3] Of the examples
shown in Figure 1, the 3,5-dialkylindolizidine monomorine
I (1) is a trail pheromone of the Pharaoh ant Monomorium
pharaonis L.,[4] whereas indolizidine (Ϫ)-223AB (2) is a con-
stituent of the poison frog Dendrobates histrionicus.[5] No-
tably, its less widespread cis-3,5-dialkylated analogue 3 has
been isolated both from amphibians and from the Solen-
opsis Diplorhoptrum worker ant.[6] Pyrrolizidine alkaloids
such as (Ϫ)-xenovenine (4) have been found in the venom
Among the strategies to synthesize these bicyclic alka-
loids so far developed, cyclization steps of conveniently 2,5-
disubstituted pyrrolidines[9] are well documented.[10Ϫ15]
A
new synthetic route to 5-alkylprolinols starting from either
of the available enantiomers of pyroglutamic acid, as out-
lined in the general Scheme 1, is therefore described here.
This route, illustrated with the (2S) enantiomers used in this
work, involves ring opening of the derived 2-substituted N-
(alkoxycarbonyl)pyrrolidinones (A) with the anions of alkyl
phenyl sulfones (here methyl and decyl phenyl sulfones), fol-
lowed by desulfonylation of the resulting β-keto sulfones
B and subsequent cyclization of C by reductive amination.
Figure 1. Some examples of naturally occurring 3,5-dialkylindolizi-
dines and pyrrolizidines
[a]
Institut de Chimie des Substances Naturelles
C.N.R.S., Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax: (internat.) ϩ33-(0)1-69077247
Scheme 1. General scheme for the synthesis of 2,5-disubstituted
pyrrolidines as indolizidine scaffolds
E-mail: nicole.langlois@icsn.cnrs-gif.fr
Eur. J. Org. Chem. 2003, 4187Ϫ4198
DOI: 10.1002/ejoc.200300393
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4187

A. J. Mota, A. Chiaroni, N. Langlois
FULL PAPER
Indeed, the cis (D, R2 ϭ CH2OH) or trans (E, R2
ϭ
Some assays were conducted with tert-butyl N-(benzyl-
CH2OH) 5-alkyl-2-(hydroxymethyl)pyrrolidines could be oxycarbonyl)pyroglutamate (5)[25] in order to determine the
excellent intermediates in the synthesis of indolizidines and ratio of the carbanion needed for an efficient conversion.
pyrrolizidines related to 1Ϫ4, natural or not, since the On going from the use of one equivalent of the sulfone car-
hydroxymethyl group can be converted into appropriate banion to the use of two equivalents the yield of the β-keto
functions for formation of the bicyclic skeletons.[11Ϫ15] This sulfone 11 increased as expected, (49 to 74%, respectively).
approach is of special interest, due to the relative rarity of This is probably due to the fact that the generated β-keto
synthetic routes to 2,5-cis configurations in pyrrolidine sub- sulfone is more acidic and can reprotonate the lithio(phen-
stituents in the literature.[11,15,16]
ylsulfonyl)methane,[20,26] but no evidence for lactam open-
ing by a carbanion of the resulting β-keto sulfone was
found. Unlike in the reported additions to esters,[27] the use
of methyl phenyl sulfone dilithium was shown to be less
efficient in our case, producing a more complex mixture.
Further results obtained with monolithiated methyl phenyl
sulfone and other protected γ-lactams 6 to 10[28] derived
from (S)-pyroglutaminol are summarized in Table 1.
Some benzyl (phenylsulfonyl)acetate (17) was formed in
the reactions of 5Ϫ7, through monocarbanion attack of the
N-benzyloxycarbonyl groups (Entries 1Ϫ3). This partial N-
protecting group displacement was completely avoided with
the sterically hindered derivatives 8Ϫ10. Thus, protection
with N-Boc groups, much less amenable to nucleophilic at-
tack, resulted in improved yields of the corresponding β-
keto sulfones (Table 1, cf. Entries 1 and 4, 2 and 5, 3 and 6).
Because of the presence of ester functions at C-2, racem-
Results and Discussion
The first key step is based on the fact that the presence
of N-protecting alkoxycarbonyl (or sulfonyl) groups is well
known to enhance considerably the electrophilic character
of lactam carbonyl groups, due to their electron-with-
drawing aptitude.[17Ϫ19] With respect to carbon nucleophilic
additions, ring openings of such pyrrolidinones with
Grignard reagents or aryllithium are well demonstrated.[19]
However, only a few examples accounted for the reactivity
of alkyl phenyl sulfone anions in nucleophilic addition to
activated β-,[20] γ-[21] and δ-lactam carbonyls.[22] We there-
fore recently reported[23] reactions between deprotonated
methyl phenyl sulfone and several functionalised N-(alkoxy-
carbonyl)pyrrolidinones derived from (S)-pyroglutamic ization could occur with derivatives 5 and 8. For this rea-
acid, and the use of one of the resulting β-keto sulfones son, it was important to evaluate the enantiopurity of the
in the synthesis of tert-butyl cis-5-alkylprolinates. Here we derived β-keto sulfones, principally of compound 11, which
complete these preliminary results, showing that the β-keto was used further in the synthesis of cis-2,5-disubstituted
sulfones constitute useful intermediates in the synthesis of pyrrolidines. Two independent methods were employed in
cis-5-alkyl-2-(hydroxymethyl)pyrrolidines.
order to determine the enantiomeric excess of 11. 1H NMR
The ring-opening reactions (Scheme 2) were carried out spectra in the presence of [Eu(hfc)3] as chiral shift reagent
by employing PhSO2Me/nBuLi as nucleophilic agent[24] in and chiral HPLC, with comparison with the corresponding
anhydrous THF at Ϫ72 °C.
racemate synthesized in the same way, indicated the absence
Scheme 2. Ring opening of N-alkoxycarbonyl-γ-lactams by lithio(phenylsulfonyl)methane
Table 1. Ring opening of N-alkoxycarbonyl-γ-lactams by lithio(phenylsulfonyl)methane (THF, Ϫ72 °C)
Entry
Lactam
R1
R2
X
β-Keto sulfone (%)
PhSO2CH2CO2R1 (%)
1
2
3
4
5
6
5
6
Bn
Bn
Bn
tBu
tBu
tBu
tBu
O
11 (74)
12 (58)
13 (62)
14 (95)
15 (84)
16 (90)
17 (21)
17 (25)
EVE[a]
TBS
tBu
H2
H2
O
H2
H2
7
17 (18)
8
9
10
not observed
not observed
not observed
EVE
TBS
[a]
EVE ϭ CH(Me)OEt.
4188
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Eur. J. Org. Chem. 2003, 4187Ϫ4198

Indolizidine and Pyrrolizidine Scaffolds
FULL PAPER
Scheme 3. Ring opening of N-alkoxycarbonyl-γ-lactams by lithio(phenylsulfonyl)decane
of racemization [ee Ͼ 95% (1H NMR), ee 99% (chiral some extent lower than in the case of methyl phenyl sulfone.
HPLC)].[29a]
This could be due to the difference in acidity between these
We next turned our attention towards the preparation of two sulfones,[32] to steric factors or to a retroaddition pro-
β-keto sulfones substituted with long alkyl chains, as cess, since appreciable quantities of starting lactams were
models for the introduction of the alkyl substituents present recovered, even when the conversion seemed complete by
in the alkaloids 1Ϫ4. With the phenylsulfonyl methyl ke- TLC analysis of the reaction mixture.
Hydrogenation of 2-substituted ∆1-pyrroline intermedi-
ates is known to afford cis-2,5-disubstituted pyrroli-
dines,[16,33] particularly cis-5-alkylprolinates.[34] Thus, in or-
der to develop a stereoselective and efficient route to cis-
2,5-disubstituted pyrrolidines, the sulfones 11Ϫ13 and
19Ϫ21 were desulfonylated with 4Ϫ5% sodium amalgam in
MeOH at room temperature, giving rise to the correspond-
ing alkyl ketones 26Ϫ31 in moderate to high yields. Sub-
sequent reductive amination of these ketones under N-de-
protection conditions (H2, 1 atm), with Pd(OH)2 as catalyst,
afforded the corresponding pyrrolidines 32Ϫ37 in high
yields (Table 3, Scheme 4).
tones 11 to 16 in hand, C-alkylations with alkyl halides
could be envisioned for this purpose, but these reactions
could be complicated by O-alkylations, as previously ob-
served with β-keto sulfoxides.[30] Consequently, the opening
of N-alkoxycarbonyl-γ-lactams with the monolithiated car-
banion of decyl phenyl sulfone 18[31] was investigated as an
example that might be extendable to other long alkyl
chains. The sulfone 18 was prepared in high yield (91%) by
alkylation of methyl phenyl sulfone with 1-bromononane in
THF at low temperature. It was used to open the lactams
5 to 10, by the same procedure as used for methyl phenyl
sulfone, and afforded β-keto sulfones 19 to 24 as dia-
stereomeric mixtures (Scheme 3). The results are summar-
ized in Table 2.
In the reaction affording tert-butyl 5-alkylprolinates, the
absence of racemization during desulfonylation with so-
dium amalgam was verified by chiral HPLC of 26 (ee
98.5%).[29b] As expected, the reductive aminations of the
tert-butyl esters 26 and 29 were found to be completely ster-
eoselective, giving rise exclusively to the cis-5-disubstituted
prolinates 32 and 35, in 91 and 93% yields, respectively.
However, the generally high stereoselectivity in the forma-
tion of disubstituted pyrrolidines by reductive amination
under hydrogen[33,35] was not observed in the cases of the
2-hydroxymethyl derivatives 27, 28 and 30, which produced
mixtures, the cis diastereomers always being the major
ones (Table 4).
Table 2. Ring opening of N-alkoxycarbonyl-γ-lactams by lithio-
(phenylsulfonyl)decane (THF, Ϫ72 °C)
Entry
Lactam
β-Keto sulfone (%)
PhSO2CH(R)CO2R1
R ϭ C9H19 (%)
1
2
3
4
5
6
5
19 (69)
20 (58)
21 (50)
22 (72)
23 (75)
24 (74)
25 (7)
25 (7)
25 (10)
Ϫ
Ϫ
Ϫ
6
7
8
9
10
The compositions of the mixtures depend on the alkyl
The N-protecting group displacement of N-(benzyloxy- groups on the ketones (CH2R1), better stereoselectivity be-
carbonyl)-γ-lactams 5Ϫ7 to afford 25 was minimized with ing found in the case of 5-decylpyrrolidines [R1
ϭ
decyl phenyl sulfone, but the yields of the ketones are to (CH2)8Me] than in the case of 5-methylpyrrolidines (R1 ϭ
Table 3. Desulfonylation of β-keto sulfones followed by reductive amination
Entry
Sulfone
(1 equiv.)
Equiv. Na/equiv. Na2HPO4
Time
(min)
Ketone
yield (%)
H2/Pd(OH)2
time (h)
Pyrrolidine
yield (%)
1
2
3
4
5
6
11
12
13
19
20
21
3.1Ϫ5.0
2.7Ϫ5.0
3.0Ϫ5.2
2.9Ϫ4.2
3.0Ϫ4.0
3.0Ϫ4.0
75
45
50
75
75
75
26 (58)
27 (63)
28 (65)
29 (85)
30 (92)
31 (92)
5
6
6
5
6
6
32 (91)
33 (76)
34 (86)
35 (93)
36 (68)
37 (84)
Eur. J. Org. Chem. 2003, 4187Ϫ4198
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4189

A. J. Mota, A. Chiaroni, N. Langlois
FULL PAPER
Scheme 4. Desulfonylation of β-keto sulfones followed by reductive amination
Table 4. Diastereoselectivity in the reductive amination step
Entry Alkyl
ketone
X
R1
R2
2,5-Dialkylpyrrolidine
(cis/trans %)
1
2
3
4
5
6
26
27
28
29
30
31
O
H
H
H
tBu
EVE
TBS
32 (98:0)
H2
H2
O
33 (57:43)
34 (76:24)
35 (Ͼ 98:0)
36 (71:29)
37 (95:5)
(CH2)8Me tBu
H2 (CH2)8Me EVE
H2 CH2)8Me TBS
H; cf. Entries 2 and 5 and Entries 3 and 6). The stereoselec-
tivity also depends on the substituents at C-2. Steric factors
can explain the minor stereoselectivity encountered with the
compounds 27 and 30, in which the flexibility of the ex-
tended 1-ethoxyethoxymethyl group at C-2 (CH2OEVE)
might favour the exposure of the more hindered face, al-
lowing the insertion of H2.
The diastereoselectivity in the formation of 5-methylpyr-
rolidines was directly evaluated by NMR, because the sep-
aration of the diastereomers was difficult. In order to ascer-
tain the configurations deduced from 1H and 13C NMR
spectroscopic data,[12a,36] several chemical correlations were
carried out, as reported below (Scheme 5).
Scheme 5. Chemical correlations between the 2,5-disubstituted
pyrrolidines
LAH reduction of the ester 32 exclusively afforded the the same compounds resulting from reductive amination
previously described cis primary alcohol 38a.[15a] This polar of 28.
compound was rather difficult to handle and readily car-
The 5-decylpyrrolidines 35Ϫ37 were correlated according
1
bonated due to its basic character, and so was converted to the same scheme. In the H NMR of Cbz derivatives 39
into the N-benzyloxycarbonyl derivative 39a. On the other and 42, the methylene signals of the benzyl groups corro-
hand, the mixture of diastereomers 33 was O-deprotected borate previous observations[36] and indicate the relative 2,5
by acid hydrolysis and transformed into the separable N- configurations of these pyrrolidines, with good agreement
benzylcarbamates cis-39a and trans-39b. It is noteworthy between 42a and 39a and between 42b and 39b. The methyl-
that long reaction times were needed in order to avoid kine- ene protons of the tert-butyldimethylsilyloxymethyl groups
tic effects in the formation of these carbamates.[37] The com- in 34 and 37 also show very different patterns in the cis (a)
pound 39b[13] and its enantiomer ent-39b[14] [absolute con- and trans (b) diastereomers and are indicative of their rela-
figuration (2R,5S)] have been already described by two tive 2,5 configurations. However, as none of 5-decyl-pyrroli-
groups, but opposite signs of optical rotation have been suc- dines was known, the configuration of 41a was ascertained
cessively reported in the two cases. This controversy is now by a single-crystal X-ray analysis of its hydrobromide. Fig-
resolved, ent-39b being dextrorotatory.[14a] The configura- ure 2 gives an overview of the molecule. The chemical corre-
tions of 39a and 39b thus being fully established, each dia- lations achieved from the alcohol 42a and from its C-5 epi-
stereomer was protected, as the tert-butyldimethylsilyl de- mer 42b, according to the Scheme 5, allowed confirmation
rivatives 40a and 40b, respectively, and these were N-depro- of the composition of the diastereomer mixture given for
tected to give 34a and 34b (Scheme 5) for comparison with 36 and 37.
4190
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Eur. J. Org. Chem. 2003, 4187Ϫ4198

Indolizidine and Pyrrolizidine Scaffolds
FULL PAPER
obtained after usual workup was purified by chromatography (elu-
ent: heptane/Et2O/MeOH, 50:50:1, v/v) to give benzyl (phenylsul-
fonyl)acetate (17) (61 mg, 21%), recovered methyl phenyl sulfone
(134 mg, 43%) and the keto sulfone 11 (347 mg, 74%) as a colour-
less, thick oil. [α]2D3 ϭ Ϫ5.8 (c ϭ 1.40, CHCl3). IR: ν˜ ϭ 3366, 2979,
2935, 1722, 1523, 1449, 1369, 1323, 1154, 1052 cmϪ1 1H NMR:
.
δ ϭ 7.86 (d, J ϭ 8.1 Hz, 2 H, SO2Ph), 7.66 (dd, 1 H, SO2Ph), 7.55
(dd, J ഠ JЈ ϭ 7.0 Hz, 2 H, SO2Ph), 7.34 (m, 5 H, CH2Ph), 5.38
(br. d, J ϭ 7.5 Hz, 1 H, NH), 5.08 (2d, J ϭ 12.1 Hz, 2 H, PhCH2),
4.19 (m, 1 H, 2-H), 4.11 (s, 2 H, 6-H2), 2.78 (m, 2 H, 4-H2), 2.15
(m, 1 H, 3-Ha), 1.82 (m, 1 H, 3-Hb), 1.45 (s, 9 H, tBu) ppm. 13C
NMR: δ ϭ 197.02 (CO), 170.76 (CO2), 155.99 (NCO2), 138.66 (qC,
Ar), 136.19 (qC, Ar), 134.23, 129.29, 128.48, 128.18, 128.05 (CH,
Ar), 82.60 (qC, tBu), 66.93, 66.84, (PhCH2, C-6), 53.28 (C-2), 40.06
(C-4), 27.88 (CH3, tBu), 26.46 (C-3) ppm. MS (ESI): m/z (%) ϭ
514 (20) [M ϩ K]ϩ, 498 (100) [M ϩ Na]ϩ, 467, 458, 442, 339.
HRMS (ESI): C24H29NO7SNaϩ [MNa]ϩ: 498.1562; found
498.1545.
Figure 2. X-ray structure analysis of 41a hydrobromide: ORTEP
drawing of one molecule of the unit cell.
Conclusion
In conclusion, the opening of N-(alkoxycarbonyl)pyrroli-
dinones derived from (S)-pyroglutamic acid with lithiated
alkyl phenyl sulfones afforded functionalized acyclic β-keto
sulfones in good yields. These synthetic intermediates could The racemate (Ϯ)-11 was synthesized in the same way in order to
1
evaluate the enantiomeric excess. The H NMR spectrum of (Ϯ)-
11 in CDCl3 (0.025 mmol/mL) in the presence of [Eu(hfc)3] as chi-
ral shift reagent (0.0015 mmol/mL) showed splitting of several sig-
nals (PhCH2, 2-H, 6-H2). No splitting of these signals was detected
with 11 under the same conditions, indicating an ee Ͼ 95%; for
be useful, particularly in the diastereoselective preparation
of cis-2,5-disubstituted pyrrolidines. The stereoselectivity
increased when large nucleophiles were employed to open
the lactam ring and when conformationally restricted sub-
stituents were present. Thus, cis-5-alkyl prolinates were ob-
tained with complete diastereoselectivity in only three steps,
chiral HPLC conditions, see ref.[29]
.
starting from the easily available (S)-tert-butyl pyrogluta- The β-keto sulfones 12Ϫ16 and 19Ϫ24 were prepared by the
same procedure.
mate, and carbamates derived from pyroglutaminol gave
better results when O-protected with TBS than with the
flexible 1-ethoxyethyl group. Synthetic precursors of indoli-
zidine and pyrrolizidine alkaloids could be obtained in this
way and the addition of more complex phenyl sulfones can
be also envisioned.
Benzyl (1S)-1-[(1-Ethoxyethoxy)methyl]-4-oxo-5-(phenylsulfonyl)-
pentylcarbamate (12): Starting lactam: 0.45 mmol, yield 58% of a
colourless oil (two diastereomers, owing to the stereogenic centre
in the ethoxyethoxy group), after purification by chromatography
(eluent heptane/Et2O/MeOH, 40:60:1, v/v). [α]2D3 ϭ Ϫ20.8 (c ϭ
0.72, CHCl3). IR: ν˜ ϭ 3369, 2979, 2931, 1719, 1527, 1448, 1322,
1239, 1150, 1136 cmϪ1. H NMR: δ ϭ 7.87 (d, 2 H, SO2Ph), 7.67
1
(dd, 1 H, SO2Ph), 7.56 (dd, J ϭ 7.9, JЈ ϭ 7.3 Hz, 2 H, SO2Ph),
7.35 (m, 5 H, CH2Ph), 5.16 (br. d, J ϭ 8.9 Hz, 0.5 H, NH), 5.08
(2d, J ϭ 12.4 Hz, 2 H, PhCH2), 5.03 (br. d, J ϭ 8.9 Hz, 0.5 H,
NH), 4.65 (2 q, 1 H, OCHO), 4.11 (s, 2 H, 5-H2), 3.73 (m, 1 H, 1-
H), 3.58 (m, 2 H, OCH2), 3.44 (m, 2 H, OCH2), 2.76 (br. m, J ഠ
JЈ ϭ 6.8 Hz, 2 H, 3-H2), 1.79 (m, 2 H, 2-H2), 1.27 (d, J ϭ 5.3 Hz,
3 H, CHCH3), 1.18 (t, J ϭ 7.0 Hz, 3 H, CH2CH3) ppm. 13C NMR:
δ ϭ 197.70 (CO), 156.26 (NCO2), 138.76 (qC, Ar), 136.44 (qC, Ar),
134.16, 129.25, 128.50, 128.19, 128.13, 128.02 (CH, Ar), 99.99,
99.70 (OCHO), 67.15, 66.83, 66.74, 66.70 (PhCH2, C-5), 65.77
(OCH2), 61.39, 61.13 (OCH2), 49.99, 49.96 (C-1), 40.80 (C-3),
25.86 (C-2), 19.65, 19.58 (CHCH3), 15.20, 15.16 (CH2CH3) ppm.
MS (ESI): m/z (%) ϭ 516 (30) [M ϩ K]ϩ, 500 (100) [M ϩ Na]ϩ.
Experimental Section
General: Melting points were determined with a Büchi B-540 ap-
paratus and were uncorrected. Optical rotations were measured
with a Jasco P-1010 polarimeter and the concentrations were given
in g/100 mL. IR spectra (film, CHCl3) were recorded with a
PerkinϪElmer Spectrum BX (FT) instrument. 1H NMR spectra
(CDCl3, CHCl3 δ ϭ 7.26 ppm) were obtained with a Bruker AM-
300 machine. 13C NMR spectra were also recorded with the AM-
300 (75.0 MHz, CDCl3 centred at 77.0 ppm). Mass spectra and
high-resolution mass spectra were measured with Navigator (ESI),
Micromass LC-TOF or Automass Thermo-Finnigan spec-
trometers. Chromatography was performed on silica gel (SDS,
230Ϫ400 mesh) and preparative thin layer chromatography on sil-
ica gel (Merck HF 254 ϩ366). ‘‘Usual workup’’ means that the
organic layer was dried with magnesium sulfate and filtered and
the solvents were evaporated under vacuum
Benzyl (1S)-1-[(1-tert-Butyldimethylsilyl)oxymethyl]-4-oxo-5-(phe-
nylsulfonyl)pentylcarbamate (13): Starting lactam: 0.12 mmol, yield
62% of a colourless, thick oil, after chromatography (eluent:
CH2Cl2). [α]2D3 ϭ Ϫ30.8 (c ϭ 0.50, CHCl3). IR: ν˜ ϭ 3370, 2953,
tert-Butyl (2S)-2-[(Benzyloxycarbonyl)amino]-5-oxo-6-(phenyl-
sulfonyl)hexanoate (11): nBuLi (1.6  solution in hexanes, 1.20 mL,
1.92 mmol) was added to a solution of methyl phenyl sulfone
2930, 2857, 1718, 1524, 1448, 1323, 1253, 1153, 838 cmϪ1 1H
.
NMR: δ ϭ 7.87 (d, J ϭ 7.7 Hz, 2 H, SO2Ph), 7.66 (dd, 1 H,
SO2Ph), 7.55 (dd, J ഠ JЈ ϭ 7.2 Hz, 2 H, SO2Ph), 7.34 (m, 5 H,
(311 mg, 1.99 mmol) in dry THF (6.0 mL), stirred at Ϫ72 °C under CH2Ph), 5.07 (2d, J ϭ 12.6 Hz, 2 H, PhCH2), 4.96 (br. d, J ϭ
argon. After the mixture had been stirred at Ϫ72 °C for 0.5 h, a 8.1 Hz, 1 H, NH), 4.11 (s, 2 H, 5-H2), 3.59 (m, 3 H, OCH2, 1-H),
solution of lactam 5 (316 mg, 0.99 mmol) in THF (4.0 mL) was 2.74 (m, 2 H, 3-H2), 1.76 (m, 2 H, 2-H2), 0.87 (s, 9 H, tBu), 0.03
added dropwise. The mixture was stirred at the same temperature
for 1.75 h, and a saturated aqueous solution of NH4Cl (5 mL) was
then added. The cooling bath was removed, water (10 mL) was
added, and the products were extracted with CH2Cl2. The residue
(s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 197.78 (CO), 156.28 (NCO2),
138.77 (qC, Ar), 136.49 (qC, Ar), 134.16, 129.25, 128.50, 128.21,
128.13, 128.05 (CH, Ar), 66.87, 66.68 (PhCH2, C-5), 65.04 (OCH2),
51.42 (C-1), 40.81 (C-3), 25.81 (CH3, tBu), 25.47 (C-2), 18.21 (qC,
Eur. J. Org. Chem. 2003, 4187Ϫ4198
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4191

A. J. Mota, A. Chiaroni, N. Langlois
FULL PAPER
tBu), Ϫ5.56 (SiMe2) ppm. MS (ESI): m/z (%) ϭ 558 (20) [M ϩ δ ϭ 7.75 (m, 2 H, SO2Ph), 7.66 (br. dd, 1 H, SO2Ph), 7.53 (2dd,
K]ϩ, 542 (100) [M ϩ Na]ϩ, 540.
J ϭ 7.9, JЈ ϭ 7.3 Hz, 2 H, SO2Ph), 7.36 (m, 5 H, CH2Ph), 5.35
(br. d, 1 H, NH), 5.11 (br. s, 2 H, PhCH2), 4.24 (m, 1 H, 2-H), 4.05
(m, 1 H, 6-H), 2.98 (m, 1 H, 4-Ha), 2.61 (m, 1 H, 4-Hb), 2.14 (m,
1 H), 1.90 (m, 1 H), 1.83 (m, 2 H, 7-H2), 1.47 (s, 9 H, tBu), 1.18
[m, 14 H, (CH2)7], 0.86 (br. t, J ϭ 6.6 Hz, 3 H, 15-H3) ppm. 13C
NMR: δ ϭ 201.48, 201.45 (CO), 170.85 (CO2), 155.89 (NCO2),
136.35, 136.21 (qC, Ar), 134.25, 129.35, 129.05, 129.03, 128.52,
128.17, 128.08 (CH, Ar), 82.61, 82.57 (qC, tBu), 75.19, 75.13 (C-
6), 66.97 (PhCH2), 53.56, 53.46 (C-2), 41.01 (C-4), 31.77, 29.33,
29.17, 29.14, 29.06 (CH2), 27.94 (CH3, tBu), 27.06, 26.86, 26.45,
26.25, 22.60 (CH2), 14.06 (C-15) ppm. MS (ESI): m/z (%) ϭ 640
(60) [M ϩ K]ϩ, 624 (100) [M ϩ Na]ϩ.
tert-Butyl (2S)-2-[(tert-Butoxycarbonyl)amino]-5-oxo-6-(phenylsul-
fonyl)hexanoate (14): Starting lactam: 2.0 mmol, 95% as colourless
crystals, after chromatography (eluent: heptane/Et2O/MeOH,
50:50:1, v/v). M.p. 101Ϫ102 °C. [α]2D2 ϭ Ϫ2.1 (c ϭ 0.69, CHCl3).
IR: ν˜ ϭ 3380, 2979, 2933, 1718, 1449, 1368, 1323, 1251, 1154 cmϪ1
.
1H NMR: δ ϭ 7.87 (d, J ϭ 8.3 Hz, 2 H, SO2Ph), 7.67 (dd, 1 H,
SO2Ph), 7.56 (dd, J ഠ JЈ ϭ 6.8 Hz, 2 H, SO2Ph), 5.09 (br. d, J ϭ
6.8 Hz, 1 H, NH), 4.17 (2d, J ϭ 12.1 Hz, 2 H, 6-H2), 4.10 (m, 1
H, 2-H), 2.79 (m, 2 H, 4-H2), 2.11 (m, 1 H, 3-Ha), 1.78 (m, 1 H,
3-Hb), 1.44 (s, 9 H, tBu), 1.42 (s, 9 H, tBu) ppm. 13C NMR: δ ϭ
197.10 (CO), 171.15 (CO2), 155.51 (NCO2), 138.70 (qC, Ar),
134.24, 129.31, 128.20 (CH, Ar), 82.34 (qC, tBu), 79.84 (qC, tBu),
66.98 (C-6), 52.84 (C-2), 40.16 (C-4), 28.24 (CH3, tBu), 27.91 (CH3,
tBu), 26.65 (C-3) ppm. MS (ESI): m/z (%) ϭ 480 (20) [M ϩ K]ϩ,
464 (100) [M ϩ Na]ϩ, 442 [MH]ϩ, 408, 349. C21H31NO7S (441.53):
calcd. C 57.12, H 7.08, N 3.17, S 7.26; found C 57.16, H 7.01, N
3.02, S 6.96.
Benzyl (1S)-1-[(1-Ethoxyethoxy)methyl]-4-oxo-5-(phenylsulfonyl)-
tetradecylcarbamate (20): Starting lactam: 0.77 mmol, yield 58% of
a crystalline solid (four diastereomers), after chromatography (elu-
ent heptane/Et2O, 2:1). M.p. 47Ϫ49 °C. IR: ν˜ ϭ 3369, 2927, 2856,
1718, 1526, 1448, 1310, 1236, 1146, 1083 cmϪ1. 1H NMR: δ ϭ 7.76
(br. d, 2 H, SO2Ph), 7.66 (m, 1 H, SO2Ph), 7.53 (m, 2 H, SO2Ph),
7.35 (m, 5 H, CH2Ph), 5.10 (m, 2.5 H, PhCH2, NH), 4.99 (br. d,
J ϭ 9.2 Hz, 0.5 H, NH), 4.66 (br. q, 1 H, CHO), 4.06 (br. s, 1 H,
5-H), 3.77 (m, 1 H, 1-H), 3.59, 3.45 (2 m, 4 H, 2 OCH2), 2.97 (m,
1 H, 3-Ha), 2.61 (m, 1 H, 3-Hb), 1.83 (m, 4 H, 2-H2, 6-H2), 1.28
(d, J ϭ 5.3 Hz, 3 H, CHCH3), 1.18 [m, 17 H, (CH2)7, CH2CH3],
0.86 (t, J ϭ 6.6 Hz, 3 H, 14-H3) ppm. 13C NMR: δ ϭ 202.07,
202.04 (CO), 156.08 (NCO2), 136.50, 136.47 (qC, Ar), 134.20,
134.18, 129.39, 129.00, 128.50, 128.09, 128.02 (CH, Ar), 99.99,
99.74 (OCHO), 75.17, 75.06 (C-5), 67.12, 66.96, 66.78, 66.70
(PhCH2, OCH2), 61.38, 61.15 (OCH2), 50.53, 50.42, 50.29, 50.19
(C-1), 42.03, 41.92 (C-3), 31.78, 29.35, 29.20, 29.17, 29.15, 29.07,
27.15, 27.10, 26.87, 26.85, 25.89, 25.84, 25.59, 22.61 (CH2), 19.70,
19.63 (CHCH3), 15.25, 15.22 (CH2CH3), 14.06 (C-14) ppm. MS
(ESI): m/z (%) ϭ 642 (15) [M ϩ K]ϩ, 624 (100) [M ϩ Na]ϩ, 439.
C33H49NO7S (603.80): calcd. C 65.64, H 8.18, N 2.32, S 5.31; found
C 65.64, H 7.97, N 2.26, S 5.12.
tert-Butyl (1S)-1-[(1-Ethoxyethoxy)methyl]-4-oxo-5-(phenylsulfonyl)-
pentylcarbamate (15): Starting lactam: 0.20 mmol, 84% as colour-
less crystals (two diastereomers), after chromatography (eluent:
heptane/Et2O/MeOH, 60:40:1). M.p. 60Ϫ63 °C. [α]2D3 ϭ Ϫ24.8 (c ϭ
0.50, CHCl3). IR: ν˜ ϭ 3379, 2978, 2932, 1711, 1516, 1448, 1323,
1247, 1155 cmϪ1. 1H NMR: δ ϭ 7.88 (d, J ϭ 8.1 Hz, 2 H, SO2Ph),
7.67 (dd, 1 H, SO2Ph), 7.56 (dd, J ഠ JЈ ϭ 7.5 Hz, 2 H, SO2Ph),
4.89 (br. d, J ϭ 8.3 Hz, 0.5 H, NH), 4.75 (br. d, J ϭ 8.7 Hz, 0.5
H, NH), 4.64 (m, 1 H, OCHO), 4.18 (2 d, J ϭ 13.8 Hz, 2 H, 5-
H2), 3.52, 3.45 (2 m, 5 H, 2 OCH2, 1-H), 2.77 (m, 2 H, 3-H2), 1.78
(2 m, 2 H, 2-H2), 1.42 (s, 9 H, tBu), 1.27 (d, J ϭ 5.3 Hz, 3 H,
CHCH3), 1.18 (2 t, J ϭ 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR:
δ ϭ 197.81, 197.78 (CO), 155.80 (NCO2), 138.80 (qC, Ar), 134.18,
129.28, 128.23 (CH, Ar), 100.09, 99.71 (OCHO), 79.34, 79.29 (qC,
tBu), 67.54, 67.01, 66.92 (C-5, OCH2), 61.43, 61.13 (OCH2), 49.33,
49.26 (C-1), 40.85 (C-3), 28.33 (CH3, tBu), 26.06 (C-2), 19.71, 19.62
(CHCH3), 15.22, 15.18 (CH2CH3) ppm. MS (ESI): m/z (%) ϭ 482
(15) [M ϩ K]ϩ, 466 (100) [M ϩ Na]ϩ, 410. C21H33NO7S (443.55):
calcd. C 56.86, H 7.50, N 3.16, S 7.23; found C 57.07, H 7.52, N
3.01, S 7.02.
Benzyl (1S)-1-[(1-tert-Butyldimethylsilyl)oxymethyl]-4-oxo-5-(phe-
nylsulfonyl)tetradecylcarbamate (21): Starting lactam: 1.19 mmol,
yield 56% of a colourless oil (two diastereomers), after chromatog-
raphy (eluent: CH2Cl2). IR: ν˜ ϭ 3438, 3375, 2954, 2928, 2856, 1720,
1
1511, 1466, 1448, 1310, 1253, 1148, 838 cmϪ1. H NMR: δ ϭ 7.75
tert-Butyl (1S)-1-[(tert-Butyldimethylsilyl)oxymethyl]-4-oxo-5-(phen-
ylsulfonyl)pentylcarbamate (16): Starting lactam: 0.10 mmol, 90%
as colourless crystals, after chromatography (eluent: CH2Cl2). M.p.
74Ϫ76 °C. [α]2D3 ϭ Ϫ33.7 (c ϭ 0.60, CHCl3). IR: ν˜ ϭ 3388, 2930,
(m, 2 H, SO2Ph), 7.66 (m, 1 H, SO2Ph), 7.54 (2dd, J ϭ 7.3, JЈ ϭ
7.0 Hz, 2 H, SO2Ph), 7.35 (m, 5 H, CH2Ph), 5.10 (br. s, 2 H,
PhCH2), 4.93 (br. s, 1 H, NH), 4.07 (br. dd, J ϭ 11.3, JЈ ϭ 7.0 Hz,
1 H, 5-H), 3.66 (m, 1 H, 1-H), 3.62 (m, OCH2), 2.95 (m, 1 H, 3-
Ha), 2.61 (m, 1 H, 3-Hb), 1.83 (m, 4 H, 2-H2, 6-H2), 1.19 [m, 14
H, (CH2)7], 0.88 (m, 12 H, tBu, 14-H3), 0.04 (s, 6 H, SiMe2) ppm.
13C NMR: δ ϭ 202.15, 202.12 (CO), 155.14, 155.09 (NCO2), 136.47
(qC, Ar), 134.20, 129.39, 128.99, 128.52, 128.50, 128.10, 128.05
(CH, Ar), 75.16, 75.05 (C-5), 66.67 (PhCH2), 64.99, 64.86 (OCH2),
51.88, 51.65 (C-1), 42.05, 41.90 (C-3), 31.79, 29.35, 29.17, 29.15,
29.07, 27.10, 26.88, 26.84 (CH2), 25.84 (CH3, tBu), 25.44, 25.15,
22.61 (CH2), 18.24 (qC, tBu), 14.06 (C-14), Ϫ5.53 (SiMe2) ppm.
MS (ESI): m/z (%) ϭ 684 (22) [M ϩ K]ϩ, 668 (100) [M ϩ Na]ϩ.
2857, 1709, 1499, 1448, 1391, 1323, 1252, 1156, 1112, 838 cmϪ1
.
1H NMR: δ ϭ 7.89 (d, J ϭ 8.1 Hz, 2 H, SO2Ph), 7.67 (dd, 1 H,
SO2Ph), 7.57 (dd, J ϭ 7.2 Hz, 2 H, SO2Ph), 4.67 (br. d, J ϭ 8.0 Hz,
1 H, NH), 4.19 (2 d, J ϭ 13.5 Hz, 2 H, 5-H2), 3.55 (m, 3 H, OCH2,
5-H), 2.77 (m, 2 H, 3-H2), 1.80 (m, 1 H, 2-Ha), 1.67 (m, 1 H, 2-
Hb), 1.43 (s, 9 H, CO2tBu), 0.88 (s, 9 H, SitBu), 0.04 (s, 6 H, SiMe2)
ppm. 13C NMR: δ ϭ 197.90 (CO), 155.88 (NCO2), 138.81 (qC,
Ar), 134.18, 129.28, 128.25 (CH, Ar), 79.32 (qC, CO2tBu), 67.05
(C-5), 65.16 (OCH2), 50.77 (C-1), 40.87 (C-3), 28.36 (CH3,
CO2tBu), 25.84 (CH3, SitBu), 25.68 (C-2), 18.25 (qC, SitBu), Ϫ5.53
(SiMe2) ppm. MS (ESI): m/z (%) ϭ 524 (15) [M ϩ K]ϩ, 508 (100)
[M ϩ Na]ϩ. C23H39NO6SSi (485.68): calcd. C 56.87, H 8.09, N
2.88, S 6.60; found C 56.87, H 8.07, N 2.75, S 6.51.
tert-Butyl (2S)-2-[(tert-Butoxycarbonyl)amino-5-oxo-6-(phenylsul-
fonyl)pentadecanoate (22): Starting lactam: 0.37 mmol, yield 72% of
a colourless oil (two diastereomers), after chromatography (eluent:
CH2Cl2). [α]2D5 ϭ ϩ2.0 (c ϭ 0.74, CHCl3). IR: ν˜ ϭ 3381, 2928,
tert-Butyl
(2S)-2-[(Benzyloxycarbonyl)amino]-5-oxo-6-(phenylsul-
2856, 1715, 1504, 1448, 1367, 1320, 1310, 1251, 1153 cmϪ1 1H
.
fonyl)pentadecanoate (19): Starting lactam: 0.98 mmol, yield 69% of NMR: δ ϭ 7.76 (m, 2 H, SO2Ph), 7.68 (dd, 1 H, SO2Ph), 7.56 (dd,
a colourless oil (two diastereomers), after chromatography (eluent:
J ϭ 7.9, JЈ ϭ 7.7 Hz, 2 H, SO2Ph), 5.06 (br. s, 1 H, NH), 4.14 (br.
s, 1 H, 2-H), 4.06 (m, 1 H, 6-H), 2.98 (m, 1 H, 4-Ha), 2.63 (m, 1
heptane/Et2O, 2:1). [α]2D3 ϭ ϩ2.92 (c ϭ 1.45, CHCl3). IR: ν˜ ϭ 3368,
2927, 2856, 1721, 1523, 1449, 1369, 1310, 1153 cmϪ1 1H NMR: H, 4-Hb), 2.09 (m, 1 H, 3-Ha), 1.89 (m, 1 H, 3-Hb), 1.83 (m, 2 H,
.
4192
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4187Ϫ4198

Indolizidine and Pyrrolizidine Scaffolds
FULL PAPER
7-H2), 1.47 (s, 9 H, tBu), 1.44 (2 s, 9 H, tBu), 1.20 [m, 14 H, (CO), 171.10 (CO2), 155.97 (NCO2), 136.26 (qC, Ar), 128.51,
(CH2)7], 0.86 (t, J ϭ 6.6 Hz, 3 H, 15-H3) ppm. 13C NMR: δ ϭ
128.17, 128.10 (CH, Ar), 82.39 (qC, tBu), 66.93 (PhCH2), 53.81
201.56, 201.50 (CO), 171.27 (CO2), 155.47 (NCO2), 136.43 (qC, (C-2), 39.28 (C-4), 29.98 (C-6), 27.95 (CH3, tBu), 26.73 (C-3) ppm.
Ar), 134.25, 129.35, 129.04 (CH, Ar), 82.31, 82.27 (qC, tBu), 79.83
(qC, tBu), 75.22 (C-6), 53.19, 53.02 (C-2), 41.09 (C-4), 31.75, 29.33,
29.20, 29.13, 29.07 (CH2), 28.29 (CH3, tBu), 27.96 (CH3, tBu),
27.05, 26.87, 26.62, 26.31 (CH2), 14.05 (C-15) ppm. MS (EI): m/z
(%) ϭ 568 [MHϩ, weak], 512, 466, 456, 412, 394, 366, 207, 57 (100).
MS (ESI): m/z (%) ϭ 358 (59) [M ϩ Na]ϩ, 302 (100), 227. HRMS
(ESI): C18H25NO5Na [MNa]ϩ: 358.1586; found 358.1605.
The ketones 27, 28, and 29Ϫ31 were prepared in the same manner.
Benzyl (1S)-1-[(1-Ethoxyethoxy)methyl]-4-oxopentylcarbamate (27):
Starting keto sulfone: 0.80 mmol, 63% as an oil (two dia-
stereomers), after chromatography (eluent: heptane/Et2O/MeOH,
50:75:1). [α]2D3 ϭ Ϫ15.3 (c ϭ 0.67, CHCl3). IR: ν˜ ϭ 3333, 2978,
2934, 1715, 1530, 1240, 1135, 1083, 1060 cmϪ1. 1H NMR: δ ϭ 7.35
(m, 5 H, Ph), 5.09 (br. s, 1 H, PhCH, ϩ 0.5 H, masked NH), 5.07
(br. d, J ϭ 9.0 Hz, 0.5 H, NH), 4.79 (2 q, J ϭ 5.3 Hz, 0.5 H,
OCHO), 4.65 (2 q, J ϭ 5.3 Hz, 0.5 H, OCHO), 4.61, 4.48 (2 d, J ϭ
11.9 Hz, 1 H, PhCH), 3.76 (m, 1 H, 1-H), 3.58, 3.45 (2 m, 4 H, 2
OCH2), 2.50 (m, 2 H, 3-H2), 2.10 (2 s, 3 H, 5-H3), 1.81 (m, 2 H,
2-H2), 1.35, 1.27 (2 d, J ϭ 5.3 Hz, 3 H, CHCH3), 1.17 (t, J ϭ
7.0 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 208.28 (CO), 156.14
(NCO2), 137.99, 137.95, 136.47 (qC, Ar), 128.45, 128.37, 128.06,
128.02, 127.99, 127.56 (CH, Ar), 99.92, 99.67, 99.49, 99.35
(OCHO), 67.66, 67.39, 67.14, 66.86, 66.61 (PhCH2, OCH2), 61.30,
61.03 (OCH2), 50.61, 50.53 (C-1), 40.05 (C-3), 29.94 (C-5), 26.10
(C-2), 19.65, 19.58, 19.51 (CHCH3), 15.20, 15.17 (CH2CH3) ppm.
MS (EI): m/z (%) ϭ 338 (0.25) [MH]ϩ, 292, 248, 234, 190, 156,
134, 107, 91 (100).
tert-Butyl (1S)-1-[(1-Ethoxyethoxy)methyl]-4-oxo-5-(phenylsulfonyl)-
tetradecylcarbamate (23): Starting lactam: 0.14 mmol, yield 75% of
a colourless oil (four diastereomers), after chromatography (eluent:
CH2Cl2). IR: ν˜ ϭ 3383, 2927, 2856, 1713, 1448, 1309, 1148, 1083
cmϪ1. 1H NMR: δ ϭ 7.76 (m, 2 H, SO2Ph), 7.67 (dd, 1 H, SO2Ph),
7.55 (dd, J ϭ 7.7, JЈ ϭ 7.3 Hz, 2 H, SO2Ph), 4.82, 4.72 (2 br. d,
J ϭ 8.7 Hz, 1 H, NH), 4.67 (m, 1 H, OCHO), 4.07 (dd, J ϭ 14.5,
JЈ ϭ 7.2 Hz, 1 H, 5-H), 3.65, 3.44 (2 m, 5 H, 2 OCH2, 1-H), 2.97
(m, 1 H, 3-Ha), 2.63 (m, 1 H, 3-Hb), 1.82 (m, 4 H, 2-H2, 6-H2),
1.44, 1.43 (2 s, 9 H, tBu), 1.29 (d, J ϭ 5.5 Hz, 3 H, CHCH3), 1.19
[m, 17 H, (CH2)7, CH2CH3], 0.86 (t, J ϭ 6.6 Hz, 3 H, 14-H3) ppm.
13C NMR: δ ϭ 202.14, 202.09 (CO), 155.73, 155.64 (NCO2), 136.50
(qC, Ar), 134.20, 129.39, 129.01 (CH, Ar), 100.05, 99.71 (CHO),
79.30 (qC, tBu), 75.20, 75.10 (C-5), 67.51, 67.27, 66.95, 66.71
(OCH2), 61.36, 61.13 (OCH2), 49.86, 49.72, 49.55, 49.47 (C-1),
42.04, 41.90 (C-3), 31.77, 29.34, 29.23, 29.14, 29.08 (CH2), 28.36
(CH3, tBu), 27.16, 27.07, 26.86, 25.99, 25.69, 22.60 (CH2), 19.76,
19.65 (CHCH3), 15.26, 15.24 (CH2CH3), 14.05 (C-14) ppm.
Benzyl (1S)-[1-(tert-Butyldimethylsilyl)oxymethyl]-4-oxopentylcar-
bamate (28): Starting keto sulfone: 0.29 mmol, yield 65% of a
colourless oil, after chromatography (eluent: heptane/Et2O/MeOH,
50:50:1. [α]2D3 ϭ Ϫ24.7 (c ϭ 0.60, CHCl3). IR: ν˜ ϭ 3343, 3336,
tert-Butyl
(phenylsulfonyl)tetradecylcarbamate
(1S)-1-[(1-tert-Butyldimethylsilyl)oxymethyl]-4-oxo-5-
(24): Starting lactam:
0.12 mmol, yield 74% of a colourless oil (two diastereomers), after
chromatography (eluent: CH2Cl2). IR: ν˜ ϭ 3448, 3390, 2955, 2927,
2856, 1716, 1498, 1447, 1365, 1320, 1309, 1251, 1172, 1151, 837
1
2955, 2930, 2857, 1716, 1530, 1252, 837 cmϪ1. H NMR: δ ϭ 7.36
(m, 5 H, Ph), 5.10 (2d, J ϭ 12.1 Hz, 2 H, PhCH2), 4.45 (br. d, J ϭ
7.9 Hz, 1 H, NH), 3.66 (m, 1 H, 1-H), 3.62 (br. s, 2 H, OCH2),
2.51 (m, 2 H, 3-H2), 2.12 (s, 3 H, 5-H3), 1.80 (m, 2 H, 2-H2), 0.87
(s, 9 H, tBu), 0.04 (s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 208.41
(CO), 156.18 (NCO2), 136.55 (qC, Ar), 128.48, 128.07, 128.04 (CH,
Ar), 66.60, 65.11 (PhCH2, OCH2), 52.03 (C-1), 40.09 (C-3), 29.97
(C-5), 25.82 (CH3, tBu), 25.73 (C-2), 18.22 (qC, tBu), Ϫ 5.54
(SiMe2) ppm. MS (ESI): m/z (%) ϭ 418 (82) [M ϩ K]ϩ, 403, 402
(100) [M ϩ Na]ϩ, 390.
1
cmϪ1. H NMR: δ ϭ 7.77 (br. d, 2 H, SO2Ph), 7.67 (br. dd, 1 H,
SO2Ph), 7.55 (dd, J ϭ 7.7, JЈ ϭ 7.3 Hz, 2 H, SO2Ph), 4.65 (br. s, 1
H, NH), 4.09 (dd, J ϭ 14.1, JЈ ϭ 7.0 Hz, 1 H, 5-H), 3.58 (m, 3 H,
OCH2, 1-H), 2.95 (m, 1 H, 3-Ha), 2.62 (m, 1 H, 3-Hb), 1.81 (m, 4
H, 2-H2, 6-H2), 1.44, 1.43 (2 s, 9 H, CO2tBu), 1.19 [m, 14 H,
(CH2)7], 0.89 (s, 9 H, SitBu), 0.86 (t, J ϭ 7.0 Hz, 3 H, 14-H3), 0.05,
0.04 (2 s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 202.23, 202.18 (CO),
155.70, 155.65 (NCO2), 136.52, 136.47 (qC, Ar), 134.18, 129.38,
128.98 (CH, Ar), 79.23 (qC, CO2tBu), 75.19, 75.08 (C-5), 65.13,
64.96 (OCH2), 51.26, 50.96 (C-1), 42.06, 41.88 (C-3), 31.76, 29.34,
29.22, 29.16, 29.13, 29.07, 29.06 (CH2), 28.37 (CH3, CO2tBu),
27.14, 27.06, 26.86 (CH2), 25.86 (CH3, SitBu), 25.58, 25.23, 22.60
(CH2), 18.26 (qC, SitBu), 14.05 (C-14), Ϫ5.48 (SiMe), Ϫ5.52
(SiMe) ppm. MS (EI): m/z (%) ϭ 612 [(MH)ϩ, weak], 538, 498,
454, 366, 116 (100).
tert-Butyl (2S)-2-[(tert-Butoxycarbonyl)amino]-5-oxopentadecanoate
(29): Starting keto sulfone: 0.47 mmol, yield 85% of a colourless
oil, after chromatography (eluent: heptane/Et2O, 2:1). [α]2D3 ϭ ϩ5.6
(c ϭ 1.43, CHCl3). IR: ν˜ ϭ 3347, 2926, 2855, 1718, 1524, 1455,
1368, 1252, 1223, 1156 cmϪ1 1H NMR: δ ϭ 7.34 (m, 5 H, Ph),
.
5.36 (br. d, J ϭ 8.0 Hz, 1 H, NH), 5.09 (2 d, J ϭ 12.6 Hz, 2 H,
PhCH2), 4.21 (m, J ഠ JЈ ϭ 8.1, JЈЈ ϭ 4.9 Hz, 1 H, 2-H), 2.46 (m,
2 H, 4-H2), 2.36 (dd, J ഠ JЈ ഠ 7.4 Hz, 2 H, 6-H2), 2.11 (m, 1 H,
3-Ha), 1.87 (m, 1 H, 3-Hb), 1.53 (m, 2 H, 7-H2), 1.45 (br. s, 9 H,
tBu), 1.25 [br. s, 14 H, (CH2)7], 0.87 (br. t, J ϭ 7.0 Hz, 3 H, 15-
H3) ppm. 13C NMR: δ ϭ 210.00 (CO), 171.13 (CO2), 155.94
(NCO2), 136.26 (qC, Ar), 128.47, 128.11, 128.05 (CH, Ar), 82.27
(qC, tBu), 66.87 (PhCH2), 53.87 (C-2), 42.89, 38.30 (C-4, C-6),
31.84, 29.52, 29.43, 29.36, 29.27, 29.17 [(CH2)6], 27.92 (CH3, tBu),
26.66 (C-3), 23.77, 22.63 [(CH2)2], 14.06 (C-15) ppm. MS (ESI): m/
z (%) ϭ 500 (12) [M ϩ K]ϩ, 484 (100) [M ϩ Na]ϩ, 428.
tert-Butyl (2S)-2-[(Benzyloxycarbonyl)amino]-5-oxohexanoate (26):
Sodium amalgam (4Ϫ5%, 840 mg, 1.64 mmol) and Na2HPO4
(379 mg, 2.67 mmol) were added under argon to a solution of β-
keto sulfone 11 (254 mg, 0.534 mmol) in dry MeOH (5.0 mL). The
solution was stirred vigorously for 75 min at room temp., and
CH2Cl2 (10 mL) and water (5 mL) were then added. The aqueous
phase was extracted three times with CH2Cl2, and after usual
workup, the residue was purified by chromatography (eluent: hep-
tane/Et2O/MeOH, 50:50:1) to give the methylketone 26 (103 mg,
58%) as a colourless oil, together with recovered starting material
(54 mg, 21%). Compound 26: [α]2D3 ϭ ϩ6.7 (c ϭ 0.45, CHCl3). IR: Benzyl (1S)-1-[(1-Ethoxyethoxy)methyl]-4-oxotetradecylcarbamate
ν˜ ϭ 3343, 2978, 2932, 1731, 1714, 1531, 1455, 1369, 1225, 1154, (30): Starting keto sulfone: 0.42 mmol, yield 92% of a white, crys-
1059 cmϪ1 1H NMR: δ ϭ 7.35 (m, 5 H, Ph), 5.35 (br. d, J ϭ talline solid (two diastereomers), after chromatography (eluent:
7.7 Hz, 1 H, NH), 5.10 (2d, J ϭ 11.9 Hz, 2 H, PhCH2), 4.22 (m, 1
.
heptane/Et2O, 2:1). M.p. 59Ϫ61 °C. [α]2D4 ϭ Ϫ13.3 (c ϭ 0.60,
H, 2-H), 2.51 (m, 2 H, 4-H2), 2.13 (m, 4 H, masked 3-Ha, 6-H3), CHCl3). IR: ν˜ ϭ 3316, 2923, 2851, 1703 (sh), 1691, 1545, 1061
1.86 (m, 1 H, 3-Hb), 1.46 (s, 9 H, tBu) ppm. 13C NMR: δ ϭ 207.53 cmϪ1. H NMR: δ ϭ 7.34 (m, 5 H, Ph), 5.08 (br. s, 2 H, PhCH2
1
Eur. J. Org. Chem. 2003, 4187Ϫ4198
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4193

A. J. Mota, A. Chiaroni, N. Langlois
FULL PAPER
ϩ 0.5 H, masked NH), 4.99 (br. d, 0.5 H, NH), 4.65 (q, J ϭ 5.4 Hz,
cis- and trans-(2S)-2-[(tert-Butylsilyloxy)methyl]-5-methylpyrroli-
1 H, OCHO), 3.73 (m, 1 H, 1-H), 3.57, 3.43 (2 m, 4 H, 2 OCH2), dines (34): Yield 86% of a semi-solid gum (two diastereomers, cis/
2.46 (m, 2 H, 3-H2), 2.36 (dd, J ഠ JЈ ഠ 7.4 Hz, 2 H, 5-H2), 1.81 trans 76:24), after chromatography (eluent: EtOAc/MeOH/
(m, 2 H, 2-H2), 1.52 (m, 2 H, 6-H2), 1.26 (d, 3 H, CHCH3), 1.24
[m, 14 H, (CH2)7], 1.17 (2 t, J ϭ 7.1 Hz, 3 H, CH2CH3), 0.87 (t, 777 cmϪ1. H NMR: δ ϭ 3.66 (dd, J ϭ 10.0, JЈ ϭ 4.7 Hz, 0.76 H,
J ϭ 7.0 Hz, 3 H, 14-H3) ppm. 13C NMR: δ ϭ 210.82 (CO), 156.14
OCHa, cis), 3.56 (dd, JЈ ϭ 5.0 Hz, 0.76 H, OCHb, cis), 3.51 (br. d,
(NCO2), 136.54 (qC, Ar), 128.46, 128.06, 128.04, 127.98 (CH, Ar), 0.48 H, OCH2, trans), 3.37 (m, 0.24 H, 2-H, trans), 3.27 (m, 0.24
99.90, 99.66 (OCHO), 67.11, 66.88, 66.57 (PhCH2, OCH2), 61.28, H, 5-H, trans), 3.16 (m, 2-H, 5-H, cis), 2.87 (br. s, 1 H, NH), 1.88,
NH4OH, 9:1:0.1). IR: ν˜ ϭ 3306, 2956, 2930, 2858, 1254, 1105, 837,
1
60.99 (OCH2), 50.75, 50.68 (C-1), 42.91, 39.18 (C-3, C-5), 31.85, 1.74 (2m, 2 H), 1.59 (m, 0.76 H, cis), 1.47 (m, 0.24 H, trans), 1.29
29.53, 29.44, 29.38, 29.27, 29.20 (CH2), 26.08 (C-2), 23.80, 22.63 (m, 0.24 H, trans), 1.25 (m, 0.76 H, cis), 1.18 (d, J ϭ 6.3 Hz,
(CH2), 19.66, 19.59 (CHCH3), 15.22, 15.20 (CH2CH3), 14.07 (C- CHCH3, cis), 1.15 (d, J ϭ 6.3 Hz, CHCH3, trans), 0.88 (br. s, 9 H,
14) ppm. MS (ESI): m/z (%) ϭ 486 (92) [M ϩ Na]ϩ, 413 (100), 393,
360. C27H45NO5 (463.64): calcd. C 69.94, H 9.78, N 3.02; found C
70.05, H 9.81, N 2.79.
tBu), 0.04 (br. s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 65.98, 65.75
(OCH2), 60.48, 59.14 (C-2), 54.85, 52.98 (C-5), 33.82, 33.58 and
27.87, 27.83 (C-4, C-3), 25.86 (CH3, tBu), 21.49, 21.06 (CHCH3),
18.24 (qC, tBu), Ϫ5.37 (SiMe), Ϫ5.43 (SiMe) ppm. MS (ESI): m/z
(%) ϭ 230 (100) [MH]ϩ, 214.
Benzyl (1S)-1-[(1-tert-Butyldimethylsilyl)oxymethyl]-4-oxotetrade-
cylcarbamate (31): Starting keto sulfone: 0.60 mmol, yield 92% of
a colourless oil, after chromatography (eluent: heptane/Et2O, 3:1).
[α]2D3 ϭ Ϫ19.5 (c ϭ 1.29, CHCl3). IR: ν˜ ϭ 3443, 3342, 2927, 2856,
tert-Butyl (2S,5S)-5-Decylprolinate (35): Yield 93% of a colourless
oil. [α]2D3 ϭ Ϫ12.8 (c ϭ 0.54, CHCl3). IR: ν˜ ϭ 3341, 3292, 2957,
2925, 2854, 1729, 1459, 1367, 1226, 1158 cmϪ1. 1H NMR: δ ϭ 3.60
(dd, J ϭ 9.0, JЈ ϭ 5.3 Hz, 1 H, 2-H), 2.96 (m, 1 H, 5-H), 2.04 (m,
1 H, 3-Ha), 1.94 (br. s, 1 H, NH), 1.83 (m, 2 H, 3-Hb, 4-Ha), 1.54
(m, 1Ј-Ha), 1.44 (s, 10 H, tBu ϩ 1Ј-Hb), 1.24 [m, 16 H, (CH2)8],
1.18 (m, 1 H, 4-Hb), 0.86 (t, J ϭ 6.8 Hz, 3 H, CH2CH3) ppm. 13C
NMR: δ ϭ 174.69 (CO2), 80.86 (qC, tBu), 60.68, 60.36 (C-2, C-5),
35.90, 31.87, 31.83, 30.72, 29.75, 29.58, 29.30 (C-3, C-4, (CH2)n],
28.00 (CH3, tBu), 27.42, 22.65 (2 CH2), 14.08 (CH3) ppm. MS
(ESI): m/z (%) ϭ 528, 312 (100) [MH]ϩ, 256. HRMS (ESI):
C19H38NO2 [MH]ϩ: 312.2902; found 312.2940.
1714, 1527, 1465, 1252, 837 cmϪ1 1H NMR: δ ϭ 7.34 (m, 5 H,
.
Ph), 5.08 (2d, J ϭ 12.5 Hz, 2 H, PhCH2), 4.95 (br. d, J ϭ 8.6 Hz,
1 H, NH), 3.64 (m, 1 H, 1-H), 3.61 (br. s, 2 H, OCH2), 2.46 (m, 2
H, 3-H2), 2.36 (dd, J ഠ JЈ ഠ 7.3 Hz, 2 H, 5-H2), 1.78 (m, 2 H, 2-
H2), 1.52 (m, 2 H, 6-H2), 1.25 [m, 14 H, (CH2)7], 0.88 (m, 12 H,
tBu, 14-H3), 0.03 (s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 210.84 (CO),
156.14 (NCO2), 136.55 (qC, Ar), 128.44, 128.02, 127.98 (CH, Ar),
66.54, 65.12 (PhCH2, OCH2), 52.16 (C-1), 42.89, 39.17 (C-3, C-5),
31.83, 29.52, 29.42, 29.36, 29.25, 29.18 [(CH2)6], 25.80 (CH3, tBu),
25.64 (C-2), 23.79, 22.62 [(CH2)2], 18.20 (qC, tBu), 14.06 (C-14),
Ϫ5.56 (SiMe2) ppm. MS (ESI): m/z (%) ϭ 529 (15) [MH ϩ Na]ϩ,
528 (100) [M ϩ Na]ϩ.
cis- and trans-(2S)-5-Decyl-2-[(1-ethoxy)ethoxymethyl]pyrrolidines
(36): 68%, as an oil (four diastereomers), after chromatography
(eluent: heptane/Et2O/MeOH/Et3N, 50:50:1:few drops to
40:20:1:few drops). IR: ν˜ ϭ 3347, 2924, 2855, 1461, 1380, 1135
cmϪ1. 1H NMR: δ ϭ 4.66 (m, 1 H, OCHO), 3.62, 3.43, 3.30, 3.20,
3.05, 2.93 (6 m, 6 H, 2 OCH2, 2-H, 5-H), 1.96 (br. s, 1 H, NH),
1.89, 1.79 (2 m, 2 H, 3-Ha, 4-Ha), 1.41, 1.31 (2 m, 3 H, 3-Hb, 4-
Hb, 1Ј-Ha), 1.27 (d, J ϭ 5.4 Hz, 3 H, CHCH3), 1.22 [m, 17 H, 1Ј-
Hb, (CH2)8], 1.16 (t, J ϭ 7.1 Hz, 3 H, OCH2CH3), 0.84 (t, J ϭ
6.9 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 99.91, 99.75, 99.58,
99.50 (OCHO), 69.40, 68.67, 68.51, 68.27 (OCH2), 61.08, 60.97,
60.91 (OCH2), 59.47, 59.38, 58.15, 58.11, 57.72, 57.61, 57.00, 56.93
(C-2, C-5), 36.78, 36.58, 31.90, 31.88, 31.83, 31.11, 31.01, 29.77,
29.74, 29.55, 29.26, 28.23, 28.19, 27.70, 27.48, 27.45, 27.29, 22.61
(C-3, C-4, (CH2)n], 19.80, 19.75, 19.71 (CHCH3), 15.23
(OCH2CH3), 14.04 (CH2CH3) ppm. MS (ESI): m/z (%) ϭ 336 (22)
[M ϩ Na]ϩ, 314 (10) [MH]ϩ, 268, 243, 242 (100), 224.
tert-Butyl (2S, 5S)-5-Methylprolinate (32): Pd(OH)2 (50 mg) was
added to a solution of methylketone 26 (220 mg, 0.657 mmol) in
dry MeOH (10 mL). The mixture was stirred under H2 (1 atm) at
room temp. for 6 h and filtered, and the catalyst was washed several
times with MeOH. The solution was evaporated to dryness. The
residue was percolated through silica gel (eluent: heptane/EtOAc/
Et3N 50:50:few drops) to give pure pyrrolidine 32 (110.5 mg, 91%)
as a colourless oil. [α]2D3 ϭ Ϫ11.8 (c ϭ 0.74). IR: ν˜ ϭ 3432, 3339,
3294, 2966, 2932, 2873, 1727, 1458, 1368, 1228, 1159 cmϪ1 1H
.
NMR: δ ϭ 3.64 (dd, J ϭ 9.0, JЈ ϭ 5.1 Hz, 1 H, 2-H), 3.14 (m, 1
H, H-5), 2.41 (br. s, 1 H, NH), 2.07 (m, 1 H, 3-Ha), 1.87 (m, 2 H,
3-Hb, 4-Ha), 1.45 (s, 9 H, tBu), 1.21 (d ϩ m, J ϭ 6.4 Hz, 4 H,
CH3, 4-Hb) ppm. 13C NMR: δ ϭ 174.48 (CO2), 81.08 (qC, tBu),
60.91 (C-2), 55.56 (C-5), 33.54, 31.10 (C-3, C-4), 28.00 (CH3, tBu),
20.50 (CH3) ppm. MS (ESI): m/z (%) ϭ 208 (25) [M ϩ Na]ϩ, 187,
186 (100) [MH]ϩ, 130. HRMS (ESI): C10H20NO2 (MHϩ,
186.1494); found 186.1508.
cis- and trans-(2S)-2-[(tert-Butylsilyloxy)methyl]-5-decylpyrrolidines
cis- and trans-(2S)-2-[(1-Ethoxyethoxy)methyl]-5-methylpyrrolidines (37): Yield 84% of a colourless oil (two diastereomers cis/trans,
(33): Yield 89% of a semi-solid gum (four diastereomers), after per-
94:6). [α]2D2 ϭ ϩ2.7 (c ϭ 0.82, CHCl3). IR: ν˜ ϭ 3351, 3306, 2955,
1
colation on silica gel (eluent: EtOAc/MeOH/NH4OH, 10:1:0.1 to
2926, 2855, 1464, 1253, 1092, 837, 776 cmϪ1. H NMR: δ ϭ 3.61
5:1/0.1). IR: ν˜ ϭ 3403, 2974, 2934, 1382, 1136, 1088, 1057 cmϪ1
.
(dd, J ϭ 9.9, JЈ ϭ 4.7 Hz, 0.94 H, OCHa, cis), 3.53 (dd, JЈ ϭ
1H NMR: δ ϭ 5.76 (br. s, 1 H, NH), 4.73, 4.68 (2 m, 1 H, OCHO), 5.1 Hz, 0.94 H, OCHb, cis), 3.46 (d, J ϭ 6.0 Hz, 0.12 H, OCH2,
3.78Ϫ3.27 (3 m, 6 H, 2-H, 5-H, 2 OCH2), 2.03, 1.93, 1.68, 1.50 (4 trans), 3.28 (m, 0.06 H, 2-H, trans), 3.12 (m, 0.94 H, 2-H, cis), 3.04
m, 4 H, 3-H2, 4-H2), 1.32 (4 d, 6 H, 2 CHCH3), 1.18 (2 t, 3 H, (m, 0.06 H, 5-H, trans), 2.95 (m, 0.94 H, 5-H, cis), 1.81 (m, 2 H,
CH2CH3) ppm. 13C NMR: δ ϭ 100.39, 100.07, 100.04, 99.93 NH, 4-Ha), 1.71 (m, 1 H, 3-Ha), 1.49 (m, 1 H, 3-Hb), 1.24 (m, 19
(OCHO), 67.82, 66.99, 66.54, 66.46 (OCH2), 61.64, 61.42, 61.18,
61.14 (OCH2), 58.63, 58.60, 57.51, 57.46 (C-2), 55.30, 55.26, 54.87,
54.79 (C-5), 33.11, 33.07, 32.58, 32.49 and 27.71, 27.69, 27.58,
27.42 (C-4, C-3), 19.98, 19.85, 19.76, 19.69, 19.38, 19.30 (2
H, 4-Hb, (CH2)9], 0.88 (s, 9 H, tBu), 0.86 (t, J ϭ 7.0 Hz, 3 H, CH3),
0.04 (s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 66.13, 66.08 (OCH2),
60.15, 59.67 (C-2, C-5, cis), 58.98, 57.52 (C-2, C-5, trans), 36.95
(C-4, trans), 36.60 (C-4, cis), 31.99, 31.88, 31.70, 29.84, 29.80,
CHCH3), 15.29, 15.27, 15.25 (CH2CH3) ppm. MS (ESI): m/z (%) ϭ 29.59, 29.31, 27.58, 27.44, 27.39 [C-3, (CH2)8], 25.90 (CH3, tBu),
210 (32) [M ϩ Na]ϩ, 188 (100) [MH]ϩ, 142, 116. HRMS (ESI): 22.65 (CH2), 18.28 (qC, tBu), 14.09 (CH2CH3), Ϫ5.37 (SiMe),
C10H22NO2 [MHϩ]: 188.1645; found 188.1599.
4194
Ϫ5.39 (SiMe) ppm. MS (ESI): m/z (%) ϭ 356 (67) [MH]ϩ, 224
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4187Ϫ4198

Indolizidine and Pyrrolizidine Scaffolds
FULL PAPER
(100). HRMS (ESI): C21H46NOSi [MHϩ]: 356.3349; found
356.3389.
ent-39b: [α]2D3 ϭ ϩ43.8 (c ϭ 0.40, CHCl3).[14a] In both cases the
opposite signs were successively reported in further papers by the
same groups.[13b,14b]
(2S,5S)-2-(Hydroxymethyl)-5-methylpyrrolidine
(38a): LiAlH4
(25 mg) was added to a solution of the pyrrolidine 32 (92 mg, (2S,5S)-N-(Benzyloxycarbonyl)-2-[(tert-butyldimethylsilyloxy)-
0.50 mmol) in dry THF (4 mL), and the mixture was heated at
reflux for 2.5 h. After the mixture was cooled, diethyl ether satu-
methyl]-5-methylpyrrolidine (40a): The cis diastereomer 39a (14 mg,
0.056 mmol) was treated with imidazole (9.0 mg, 0.132 mmol) and
rated with water (2 mL) and finally several drops of water were tert-butyldimethylsilyl chloride (10.0 mg, 0.066 mmol) in a mixture
added, and the solution was filtered, the solid was washed several
times with THF/MeOH (1:1), and the solution was evaporated to
dryness under reduced pressure. The residue was purified by chro-
of CH2Cl2 (0.8 mL) and dry DMF (0.2 mL) at room temp. After
15 h, diethyl ether (1 mL) was added, the solution was filtered, and
the filtrate was concentrated under reduced pressure. The residue
matography (eluent: CH2Cl2/MeOH/NH4OH, 5:1:0.1) to give the was purified by preparative TLC (eluent: heptane/Et2O, 2:1, v/v) to
pyrrolidine 38a (35 mg, 62%, not optimized) as a thick, colourless
oil that spontaneously transformed into its carbonate. Data for the
base: [α]2D3 ϭ ϩ12.7 (c ϭ 0.7, EtOH), ref.: [α]2D5 ϭ ϩ8.8 (c ϭ 0.40,
afford 40a (16 mg, 80%) as a colourless oil. [α]2D4 ϭ Ϫ28.6 (c ϭ
1.51, CHCl3). IR: ν˜ ϭ 2956, 2930, 2857, 1703, 1405, 1352, 1094,
1
837, 775 cmϪ1. H NMR: δ ϭ 7.35 (m, 5 H, Ph), 5.12 (br. s, 2 H,
1
EtOH).[15a] IR: ν˜ ϭ 3307, 2960, 2928, 2872, 1410 cmϪ1. H NMR
PhCH2), 3.91 (m, 2 H, 2-H, 5-H), 3.71, 3.46 (2 br. m, 2 H, OCH2),
(CDCl3 ϩ ε D2O/NaOD): δ ϭ 4.69 (br. s, 1 H, NH), 3.56 (dd, J ϭ
1.98 (m, 2 H, 3-Ha, 4-Hb), 1.86 (m, 1 H, 3-Hb), 1.61 (m, 1 H, 4-
10.3, JЈ ϭ 3.8 Hz, 1 H, OCHa), 3.35 (dd, JЈ ϭ 5.8 Hz, 1 H, OCHb), Hb), 1.22 (br. d, 3 H, CH3), 0.87 (s, 9 H, tBu), 0.04, 0.01 (2 br. s,
3.30 (masked m, 1 H, 2-H), 3.22 (m, 1 H, 5-H), 1.82 (m, 2 H, 3- 6 H, SiMe2) ppm. MS (ESI): m/z (%) ϭ 402 (20) [M ϩ K]ϩ, 386
Ha, 4-Ha), 1.57 (m, 1 H, 3-Hb), 1.29 (m, 1 H, 4-Hb), 1.13 (d, J ϭ
6.2 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3 ϩ ε of D2O/NaOD):
δ ϭ 65.16 (OCH2), 58.95 (C-2), 54.32 (C-5), 33.35, 27.71 (C-4, C-
3), 21.81 (CH3) ppm.
(100) [M ϩ Na]ϩ, 364 (56) [MH]ϩ, 320, 256.
(2S,5R)-N-(Benzyloxycarbonyl)-2-[(tert-butyldimethylsilyloxy)-
methyl]-5-methylpyrrolidine (40b): The trans diastereomer 39b
(14 mg, 0.056 mmol) was transformed exactly as described above
into 40b (17 mg, 85%), as an oil. [α]2D4 ϭ Ϫ53.3 (c ϭ 1.63, CHCl3).
O-Deprotection of 33: cis- and trans-(2S)-2-(Hydroxymethyl)-5-
methylpyrrolidines (38): The mixture of cis- and trans-(2S)-2-[(1-
ethoxyethoxy)methyl]-5-methylpyrrolidines (33, 50.0 mg, 0.267
IR: ν˜ ϭ 2955, 2930, 2857, 1703, 1406, 1353, 1090, 836, 776 cmϪ1
.
1H NMR (two conformers): δ ϭ 7.35 (m, 5 H, Ph), 5.15, 5.07 (2
mmol) was treated with HCl (1 , 0.3 mL) in THF (2.7 mL) dd, 2 H, PhCH2), 3.98, 3.92, 3.84 (3 m, 2 H, 5-H, 2-H), 3.75 (dd,
for 3 h at room temp. The solution was then concentrated under
J ϭ 9.9, JЈ ϭ 3.0 Hz, OCHa, conformer 1), 3.64 (dd, JЈ ϭ 3.6 Hz,
OCHb, conformer 1), 3.63 (dd, J ϭ 9.7 Hz, OCHa, conformer 2),
3.36 (dd, JЈ ϭ 8.1 Hz, OCHb, conformer 2), 2.21Ϫ1.89 (m, 3 H,
reduced pressure to provide the pyrrolidine 38 hydrochlorides
1
(30.0 mg, 74%) as a pale yellow oil. H NMR of the bases (CDCl3
ϩ ε D2O/NaOD) allowed the accurate evaluation of the cis/trans 3-H2, 4-Ha), 1.47 (m, 1 H, 4-Hb), 1.20, 1.13 (2 d, J ഠ 6 Hz, 3 H,
ratio as 57:43.
CH3), 0.88, 0.84 (2 s, 9 H, tBu), 0.04, 0.02 (2 s, 3 H, SiMe), Ϫ0.07
(s, 3 H, SiMe) ppm. MS (ESI): m/z (%) ϭ 386 (100) [M ϩ Na]ϩ,
364 (20) [MH]ϩ, 286, 256.
(2S,5S)-N-(Benzyloxycarbonyl)-2-(hydroxymethyl)-5-methyl-
pyrrolidine (39a): Na2CO3 (21 mg, 0.198 mmol) and benzyl chloro-
formate (15 µL, 0.105 mmol) were added with vigorous stirring to
38a as the hydrochloride (15.0 mg, 0.099 mmol) in a mixture of
CH2Cl2 (1 mL) and H2O (0.3 mL). After 2.5 h, CH2Cl2 (2 mL) and
(2S,5S)-2-[(tert-Butylsilyl)oxymethyl]-5-methylpyrrolidine
Pd(OH)2 (4 mg) was added to solution of 40a (15 mg,
0.041 mmol) in dry MeOH (1.5 mL). The solution was stirred for
(34a):
a
water (2 mL) were added, the aqueous phase was extracted with 4 h under H2 (1 atm), the catalyst was filtered off and washed sev-
CH2Cl2, and, after usual workup, the residue was purified by pre-
parative TLC (eluent: heptane/Et2O, 1:1, v/v) to give the N-benzyl-
oxycarbonyl derivative 39a (20.0 mg, 81%) as an oil. [α]2D3 ϭ Ϫ7.5
(c ϭ 1.92, CHCl3). IR: ν˜ ϭ 3429, 2967, 2877, 1694, 1682, 1412,
eral times with MeOH, and the solution was evaporated under re-
duced pressure. The residue was purified by chromatography (elu-
ent: EtOAc/MeOH/NH4OH, 5:1:0.1, v/v) to give the pure pyrroli-
dine 34a (7 mg, 74%) as a colourless oil. [α]2D4 ϭ ϩ2.6 (c ϭ 0.61,
1353, 1300, 1098 cmϪ1. 1H NMR: δ ϭ 7.36 (m, 5 H, Ph), 5.15 (2d, CHCl3). IR: ν˜ ϭ 3306, 2956, 2929, 2858, 1472, 1462, 1255, 1107,
1
J ϭ 12.3 Hz, 2 H, PhCH2), 4.61 (br. s, 1 H, OH), 4.05 (m, 1 H, H-
836, 776 cmϪ1. H NMR: δ ϭ 3.65 (dd, J ϭ 10.0, JЈ ϭ 4.6 Hz, 1
5), 3.99 (m, 1 H, H-2), 3.71 (br. d, 1 H, OCHa), 3.59 (dd, J ϭ 11.2, H, OCHa), 3.55 (dd, JЈ ϭ 5.0 Hz, 1 H, OCHb), 3.15 (m, 2 H, 2-
JЈ ϭ 7.2 Hz, 1 H, OCHb), 1.97 (m, 2 H, 3-Ha, 4-Hb), 1.71 (m, 1 H, 5-H), 1.91 (br. s, 1 H, NH), 1.82, 1.73 (2 m, 2 H, 4-Ha, 3-Ha),
H, 3-Hb), 1.58 (m, 1 H, 4-Hb), 1.18 (br. d, J ϭ 5.7 Hz, 3 H, CH3) 1.56 (m, 1 H, 3-Hb), 1.25 (m, 1 H, 4-Hb), 1.15 (d, J ϭ 6.2 Hz, 3
ppm. 13C NMR: δ ϭ 157.38 (NCO2), 136.45 (qC, Ar), 128.50, H, CHCH3), 0.89 (s, 9 H, tBu), 0.05 (s, 6 H, SiMe2) ppm. 13C
128.04, 127.86 (CH, Ar), 68.20, 67.24 (PhCH2, OCH2), 61.99 (C-
2), 54.85 (C-5), 31.31, 26.75 (C-4, C-3), 21.43 (CH3) ppm. MS (EI):
m/z (%) ϭ 249 (1.1) [M]ϩ, 218, 174, 91 (100).
NMR: δ ϭ 65.90 (OCH2), 60.54 (C-2), 54.88 (C-5), 33.66, 27.92 (C-
4, C-3), 25.91 (CH3, tBu), 21.19 (CHCH3), 18.30 (qC, tBu), Ϫ5.38
(SiMe2) ppm. MS (ESI): m/z (%) ϭ 252 (3) [M ϩ Na]ϩ, 231
(100) [MH2]ϩ.
cis- and trans-(2S)-N-(Benzyloxycarbonyl)-2-(hydroxymethyl)-5-
methylpyrrolidine (39): The mixture of the pyrrolidines 38 (as hy- (2S,5R)-2-[(tert-Butylsilyloxy)methyl]-5-methylpyrrolidine
(34b):
drochlorides) obtained by O-deprotection of pyrrolidines 33 (see
above), was converted into the N-Cbz derivatives as described for
pure 38a (with a longer reaction time to avoid kinetic effects in the
formation of these carbamates)[37] to give the mixture of dia-
stereomers 39 (42 mg, 86%) as a colourless oil. The diastereomers
Compound 40b (16 mg, 0.303 mmol) was N-deprotected exactly as
described above, affording pyrrolidine 34b (8 mg, 84%) as a colour-
less oil. [α]2D4 ϭ ϩ1.6 (c ϭ 0.60, CHCl3). IR: ν˜ ϭ 3344, 3306, 2957,
1
2929, 2857, 1471, 1463, 1255, 1096, 837, 775 cmϪ1. H NMR: δ ϭ
3.49 (d, 2 H, OCH2), 3.36 (m, 1 H, 2-H), 3.25 (m, 1 H, 5-H), 2.03
were separated by chromatography (eluent: heptane/EtOAc, 3:2, v/ (br. s, 1 H, NH), 1.93, 1.90 (2 m, 2 H, 3-Ha, 4-Hb), 1.45 (m, 1 H,
v) to provide first the cis diastereoisomer 39a (data described
3-Hb), 1.30 (m, 1 H, 4-Hb), 1.12 (d, J ϭ 6.2 Hz, 3 H, CHCH3),
above) and then the trans isomer 39b as a colourless oil. [α]2D3
ϭ
0.89 (s, 9 H, tBu), 0.05 (s, 6 H, SiMe2) ppm. 13C NMR: δ ϭ 66.19
Ϫ45.3 (c ϭ 0.70, CHCl3) [ref. [α]2D3 ϭ Ϫ45.8 (c ϭ 3.895, CHCl3),[13a] (OCH2), 59.19 (C-2), 52.87 (C-5), 33.92, 27.98 (C-4, C-3), 25.93
Eur. J. Org. Chem. 2003, 4187Ϫ4198
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4195

A. J. Mota, A. Chiaroni, N. Langlois
FULL PAPER
(CH3, tBu), 21.72 (CHCH3), 18.31 (qC, tBu), Ϫ5.34 (SiMe2) ppm. 128.47, 128.04, 127.90 (CH, Ar), 68.24, 67.22 (PhCH2, OCH2),
MS (ESI): m/z (%) ϭ 252 (12) [M ϩ Na]ϩ, 231 (100) [MH2]ϩ.
61.70, 59.30 (C-2, C-5), 35.27, 31.87, 29.56, 29.52, 29.47, 29.30,
28.89 [C-3, C-4, (CH2)6], 26.76, 26.40, 22.65 [(CH2)3], 14.09 (CH3)
ppm. HRMS (ESI): C23H37NO3Na [MNaϩ] 398.2671, found
398.2681.
X-ray Crystal Structure Analysis of (2S,5S)-5-Decyl-2-(hydroxy-
methyl)pyrrolidine Hydrobromide (41a hydrobromide): (2S,5S)-5-
Decyl-2-(hydroxymethyl)pyrrolidine (41a, see below) in methanol
solution was treated dropwise with a dilute methanolic solution of
HBr until pH 2Ϫ3. After evaporation to dryness, the residue was
crystallised in acetone to give the hydrobromide as colourless crys-
tals. M.p. 86 °C.
b) From cis- and trans-(2S)-5-Decyl-2-[(1-ethoxyethoxy)methyl]pyr-
rolidines (36): The mixture of pyrrolidines 36 (74 mg, 0.236 mmol)
was O-deprotected with 0.25  HCl in THF and treated with
Na2CO3 and benzyl chloroformate as described for the mixture 33,
for 5 h. After usual workup, the residue was purified by chromatog-
raphy (eluent: heptane/Et2O, 2:1 v/v) to give first the (2S,5S) dia-
stereomer 42a [60 mg; all the data are identical with those described
above, MS(ESI): m/z (%) ϭ 414 [M ϩ K]ϩ, 398 (100) [M ϩ Na]ϩ,
376 [MH]ϩ, 332, 242], and then (2S,5R)-42b (24 mg, oil), in a 97%
yield for both compounds:
Crystallographic Data: Fragile, colourless crystal of 0.025 ϫ 0.05
ϫ 0.50 mm. (C15H32NO)ϩ BrϪ, Mw ϭ 322.33. The compound crys-
tallizes in the monoclinic system, space group P21, Z ϭ 4: four
molecules in the unit cell, of parameters: a ϭ 9.607(9), b ϭ
3
˚
˚
7.664(7), c ϭ 23.602(22) A, β ϭ 91.54(3)°. V ϭ 1737 A , dcalcd.
ϭ
1.232 g·cmϪ3, F(000) ϭ 688, λ(Mo-Kα) ϭ 0.71073 A, µ ϭ 2.36
˚
mmϪ1 (absorption corrections without effect). Data were measured (2S,5R)-N-(Benzyloxycarbonyl)-5-decyl-2-(hydroxymethyl)-
with a NoniusϪKappa CCD area-detector diffractometer, by use
of graphite-monochromated Mo-Kα radiation, in phi scans, up to
θ ϭ 27.4°. A full sphere of 29056 data was collected, affording
pyrrolidine (42b): [α]2D3 ϭ Ϫ40.0 (c ϭ 1.52, CHCl3). IR: ν˜ ϭ 3429,
2924, 2854, 1701, 1677, 1454, 1411, 1355, 1110 cmϪ1 1H NMR:
.
δ ϭ 7.35 (m, 5 H, Ph), 5.19, 5.09 (2 d, J ϭ 12.3 Hz, 2 H, PhCH2),
4.05 (m, 1 H, 2-H), 3.83 (ddd, J ϭ 9.0, JЈ ϭ 8.2, JЈЈ ϭ 2.4 Hz, 1
H, 5-H), 3.71 (m, 1 H, OCHa), 3.63 (m, 1 H, OCHb), 2.04 (m, 1
H, 3-Ha), 1.92 (m, 1 H, 4-Ha), 1.66 (m, 3 H, 3-Hb, 4-Hb, 1Ј-H),
1.27, 1.19 [2 m, 17 H, 1Ј-Hb, (CH2)8], 0.88 (t, J ϭ 7.0 Hz, 3 H,
CH3) ppm. 13C NMR: δ ϭ 156.65 (NCO2), 136.45 (qC, Ar),
13668 monoclinic reflections, of which 7067 were unique (Rint
ϭ
0.086). 4833 of these reflections were considered as observed having
Fo Ն 4 σ (Fo). The structure was solved by direct methods with the
aid of the program SHELXS-86 and refined anisotropically by full-
matrix, least-squares, based upon unique F2 with the aid of the
SHELXL-93 program.[38] The hydrogen atoms, not located, were 128.47, 128.02, 127.93 (CH, Ar), 67.24, 67.14 (PhCH2, OCH2),
calculated at theoretical positions (except for those of the hydroxy
groups), and assigned an isotropic displacement parameter equiva-
lent to 1.10 that of the bonded atom. Thus, refinement of 327 pa-
rameters converged to R1(F) ϭ 0.1222 for the 4833 observed reflec-
tions and wR2(F2) ϭ 0.2774 for all the unique data with a good-
ness-of-fit factor S of 1.141. The residual electron density was
60.31, 59.04 (C-2, C-5), 33.58, 31.89, 29.57, 29.51, 29.41, 29.32,
28.15 (C-3, C-4, (CH2)6], 26.67, 26.43, 22.67 (CH2)3], 14.11 (CH3)
ppm. MS (ESI): m/z (%) ϭ 414 (13) [M ϩ K]ϩ, 398 (100) [M ϩ
Na]ϩ, 376 [MH]ϩ, 332, 268.
(2S,5S)-N-(Benzyloxycarbonyl)-2-[(tert-butyldimethylsilyloxy)-
methyl]-5-decylpyrrolidine (43a): Compound 42a (23 mg,
0.061 mmol) was O-silylated as indicated for 39a. The crude prod-
uct was purified by preparative TLC (eluent: heptane/Et2O, 2:1, v/
v) to afford 43a (26 mg, 87%) as a colourless oil. [α]2D4 ϭ Ϫ11.9
(c ϭ 1.00, CHCl3). IR: ν˜ ϭ 2955, 2927, 2855, 1704, 1464, 1406,
found between Ϫ0.86 and 1.774 e·AϪ3 near the bromine ions (1.37
˚
˚
A), probably due to the absorption. The two molecules of the asym-
metric unit are nearly the same, linked together by a hydrogen bond
˚
of 2.856 A through their hydroxy groups. This study confirmed the
stereochemistry (S) at carbon atoms C2 and C5, with the orien-
tation (cis) of the substituents at these atoms and the absolute con-
figuration, deduced from the differences between the Bijvoe¨t
pairs induced by the anomalous diffraction of bromine atoms.
CCDC-213180 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ44Ϫ1223/336Ϫ033; E-mail:
deposit@ccdc.cam.ac.uk].
1097, 836 cmϪ1 1H NMR (two conformers): δ ϭ 7.34 (m, 5 H,
.
Ph), 5.12 (s, 2 H, PhCH2), 3.89 (m, 1 H, 2-H), 3.81 (m, 1 H, 5-H),
3.71, 3.44 (2 m, 2 H, OCH2), 1.94, 1.88 (2 m, 3 H, 3-H2, 4-Ha),
1.65 (m, 1 H, 4-Hb), 1.25 [m, 18 H, (CH2)9], 0.88 (t, J ϭ 6.5 Hz ϩ
s, 12 H, CH3, tBu), 0.03, 0.00 (2 br. s, 6 H, SiMe2) ppm. 13C NMR:
δ ϭ 155.32 (NCO2), 136.97 (qC, Ar), 128.38, 127.94, 127.78 (CH,
Ar), 66.53 (PhCH2), 64.31, 63.49 (OCH2), 60.18, 59.64, 59.39, 58.71
(C-2, C-5), 35.36, 35.15, 31.89, 29.60, 29.32, 26.31 [C-3, C-4,
(CH2)8], 25.90 (CH3, tBu), 22.67 (CH2), 18.27 (qC, tBu), 14.10
(CH3), Ϫ5.40 (SiMe), Ϫ5.46 (SiMe) ppm. MS (ESI): m/z (%) ϭ
528 (42) [M ϩ K]ϩ, 512 (100) [M ϩ Na]ϩ, 490 [MH]ϩ.
(2S,5S)-N-(Benzyloxycarbonyl)-5-decyl-2-(hydroxymethyl)-
pyrrolidine (42a):
(2S,5R)-N-(Benzyloxycarbonyl)-2-[(tert-butyldimethylsilyloxy)-
methyl]-5-decylpyrrolidine (43b): The trans diastereomer 42b
(13 mg, 0.037 mmol) was silylated exactly as described above, giv-
ing rise to 43b (11 mg, 65%) as a colourless oil. [α]2D3 ϭ Ϫ50.3 (c ϭ
0.50, CHCl3). IR: ν˜ ϭ 2954, 2926, 2855, 1702, 1406, 1100, 836
a) From tert-Butyl (2S,5S)-5-Decylprolinate (35): LiAlH4 reduction
of the tert-butyl ester 35 (125 mg, 0.401 mmol), as described for 32,
afforded (2S,5S)-5-decyl-2-(hydroxymethyl)pyrrolidine (41a) con-
verted to its hydrochloride (83 mg, 75%), which was treated with
Na2CO3 and benzyl chloroformate in CH2Cl2/H2O (3:1) as de-
scribed for 38a, to give the N-Cbz derivative 42a (93 mg, 84%) as
a colourless oil. [α]2D3 ϭ ϩ5.1 (c ϭ 0.40, CHCl3). IR: ν˜ ϭ 3428,
cmϪ1 1H NMR: δ ϭ 7.34 (m, 5 H, Ph), 5.19, 5.07 (2 dd, 2 H,
.
PhCH2), 3.89, 3.77 (2 m, 5-H, 2-H, OCHa, conformer 1), 3.64 (m,
1 H, OCHb , conformer 1, OCHa, conformer 2), 3.35 (dd, J ϭ 9.6,
JЈ ϭ 8.1 Hz, OCHb, conformer 2), 2.10Ϫ1.80 (m, 3 H, 3-H2, 4-
2954, 2925, 2854, 1698, 1678, 1455, 1413, 1355, 1111 cmϪ1 1H
.
NMR: δ ϭ 7.35 (m, 5 H, Ph), 5.15 (2 d, J ϭ 12.3 Hz, 2 H, PhCH2), Ha), 1.61 (m, 1 H, 4-Hb), 1.25, 1.23 [2 m, 18 H, (CH2)9], 0.87, 0.83
4.64 (br. s, 1 H, OH), 4.00 (m, 1 H, 2-H), 3.92 (m, 1 H, 5-H), 3.70 (2 s, 12 H, CH3, tBu), 0.04, 0.02 (2 s, 3 H, SiMe) Ϫ0.07 (s, 3 H,
(br. d, 1 H, OCHa), 3.57 (dd, J ϭ 10.4, JЈ ϭ 7.7 Hz, 1 H, OCHb), SiMe) ppm. 13C NMR: δ ϭ 154.45, 154.14 (NCO2), 136.98, 136.86
1.99 (m, 1 H, 3-Ha), 1.86 (m, 1 H, 4-Hb), 1.63 (m, 3 H, 3-Hb, 4- (qC, Ar), 128.45, 128.37, 128.22, 127.93, 127.82, 127.78 (CH, Ar),
Hb,1Ј-Ha), 1.23 [2 m, 17 H, 1Ј-Hb, (CH2)8], 0.88 (br. t, J ϭ 7.0 Hz, 66.51, 66.42 (PhCH2), 63.15, 62.39 (OCH2), 59.05, 58.89, 58.55,
3 H, CH3) ppm. 13C NMR: δ ϭ 157.58 (NCO2), 136.38 (qC, Ar), 58.37 (C-2, C-5), 34.05, 32.60, 31.91, 30.30, 29.68, 29.60, 29.50,
4196
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4187Ϫ4198

Indolizidine and Pyrrolizidine Scaffolds
FULL PAPER
[3c]
Inc., 1995, vol. 47, chapter 4, p. 227Ϫ354.
J. W. Daly, The
Alkaloids: Chemistry and Biology, (Ed.: G. A. Cordell), Aca-
demic Press, 1998, vol. 50, chapter 4, p. 141Ϫ169.
F. J. Ritter, I. E. M. Rotgans, E. Talman, P. E. J. Verwiel, F.
Stein, Experientia 1973, 29, 530Ϫ531.
29.33, 27.85, 26.69, 26.62, 26.48, 25.93 (C-3, C-4, (CH2)n], 25.88,
25.84 (CH3, tBu), 25.42, 22.68 (CH2), 18.19 (qC, tBu), 14.12 (CH3),
Ϫ5.41, Ϫ5.44, Ϫ5.49, Ϫ5.51 (SiMe2) ppm. MS (ESI): m/z (%) ϭ
512 (100) [M ϩ Na]ϩ, 427.
[4]
[5]
J. W. Daly, T. F. Spande, N. Whittaker, R. J. Highet, D. Feigl,
N. Nishimori, T. Tokuyama, C. W. Myers, J. Nat. Prod. 1986,
49, 265Ϫ280.
J. P. Michael, The Alkaloids: Chemistry and Biology, (Ed.: G. A.
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T. H. Jones, M. S. Blum, H. M. Fales, C. R. Thompson, J. Org.
Chem. 1980, 45, 4778Ϫ4780.
Compounds 43 from 37: Na2CO3 (59 mg, 0.577 mmol) and CbzCl
(41 µL, 0.287 mmol) were added to a solution of the pyrrolidine
mixture 37 (90 mg, 0.253 mmol) in CH2Cl2 (4 mL)/H2O (1 mL) and
the mixture was vigorously stirred for 5 h. After usual workup, the
residue was purified by preparative TLC (eluent: heptane/Et2O, 2:1
v/v) to afford first pyrrolidine 43b (5 mg), and then 43a (100 mg)
in 83% yield for both diastereomers, all data being identical, respec-
tively, with those described above.
[6]
[7]
[8]
J. R. Liddell, Nat. Prod. Rep. 1996, 13, 187Ϫ193.
[9] [9a]
`
M. Pichon, B. Figadere, Tetrahedron: Asymmetry 1996, 7,
[9b]
927Ϫ964 and references cited therein.
V. M. Arredondo, S.
(2S,5S)-2-[(tert-Butylsilyloxy)methyl]-5-decylpyrrolidine
(37a):
Tian, F. E. McDonald, T. J. Marks, J. Am. Chem. Soc. 1999,
121, 3633Ϫ3639. [9c] Q. Wang, N. A. Sasaki, C. Riche, P. Potier,
J. Org. Chem. 1999, 64, 8602Ϫ8607.
Pd(OH)2 (5 mg) was added to solution of 43a (26 mg,
a
0.053 mmol) in dry MeOH (1.5 mL). The solution was stirred for
3 h under H2 (1 atm), filtered, with washing several times with
MeOH, and concentrated under reduced pressure. The residue was
purified by chromatography (eluent: heptane/Et2O/MeOH/NEt3,
10:10:1:drops, v/v) to give the pure pyrrolidine 37a (15 mg, 79%).
Oil. [α]2D4 ϭ ϩ2.5 (c ϭ 0.61, CHCl3). IR (film): ν˜ ϭ 2955, 2926,
[10] [10a] For examples see (racemic): R. V. Stevens, A. W. M. Lee, J.
Chem. Soc., Chem. Commun. 1982, 102Ϫ104. Enantioselective
[10b]
synthesis:
S. Takano, S. Otaki, K. Ogasawara, J. Chem.
[10c]
Soc., Chem. Commun. 1983, 1172Ϫ1174.
S. Arseniyadis, P.
Q. Huang, H.-P. Husson, Tetrahedron Lett. 1988, 29,
1391Ϫ1394. [10d] N. Yamazaki, C. Kibayashi, Tetrahedron Lett.
2855, 1463, 1254, 1092, 837, 776 cmϪ1 1H NMR: δ ϭ 3.62 (dd,
.
1988, 29, 5767Ϫ5768. [10e] N. Machinaga, C. Kibayashi, J. Org.
J ϭ 9.9, JЈ ϭ 4.7 Hz, 1 H, OCHa), 3.54 (dd, JЈ ϭ 5.2 Hz, 1 H,
OCHb), 3.13 (m, 1 H, 2-H), 2.95 (m, 1 H, 5-H), 1.88 (br. s, 1 H,
NH), 1.85, 1.71 (2 m, 2 H, 4-Ha, 3-Ha), 1.50 (m, 1 H, 3-Hb), 1.30
(masked m, 3 H, 4-Hb, 1Ј-H2), 1.25 [m, 16 H, (CH2)8], 0.89 (s, 9
H, tBu), 0.87 (t, J ϭ 6.9 Hz, 3 H, CH3), 0.04 (s, 6 H, SiMe2) ppm.
13C NMR: δ ϭ 66.04 (OCH2), 60.16 (C-2), 59.70 (C-5), 36.59,
31.89, 31.72, 29.85, 29.60, 29.33, 27.45, 27.44 (C-3, C-4, (CH2)8],
25.92 (CH3, tBu), 22.67 (CH2), 18.30 (qC, tBu), 14.10 (CH3), Ϫ5.37
(SiMe2) ppm. MS (ESI): m/z (%) ϭ 357 (100) [MH2]ϩ, 356
[MH]ϩ, 224.
[10f]
Chem. 1992, 57, 5178Ϫ5189.
R. Bloch, C. Brillet-Fernan-
dez, P. Kuhn, G. Mandville, Heterocycles 1994, 38, 1589Ϫ1594.
[10g] R. A. Pilli, L. C. Dias, A. O. Maldaner, J. Org. Chem. 1995,
60, 717Ϫ722.
T. Momose, N. Toyooka, S. Seki, Y. Hirai, Chem. Pharm. Bull.
1990, 38, 2072Ϫ2074.
[11]
[12] [12a]
´ ´
O. Provot, J.-P. Celerier, H. Petit, G. Lhommet, J. Org.
Chem. 1992, 57, 2163Ϫ2166. [12b] C. Celimene, H. Dhimane, G.
Lhommet, Tetrahedron 1998, 54, 10457Ϫ10468 and references
cited therein.
´
`
[13] [13a] H. Takahata, H. Bandoh, T. Momose, Tetrahedron: Asym-
metry 1991, 2, 351Ϫ352. [13b] H. Takahata, H. Bandoh, T. Mo-
mose, J. Org. Chem. 1992, 57, 4401Ϫ4404.
(2S,5R)-2-[(tert-Butylsilyloxy)methyl]-5-decylpyrrolidine
(37b):
Compound 43b (11 mg, 0.022 mmol) afforded pyrrolidine 37b
(7 mg, 88%) exactly as described above. Oil. [α]2D4 ϭ ϩ3.7 (c ϭ 0.77,
CHCl3). IR (film): ν˜ ϭ 3350, 2955, 2926, 2855, 1463, 1255, 1096,
[14] [14a]
Y. Yausa, J. Ando, S. Shibuya, J. Chem. Soc., Chem. Com-
[14b]
mun. 1994, 455Ϫ456.
Y. Yausa, J. Ando, S. Shibuya, J.
Chem. Soc., Perkin Trans. 1 1996, 465Ϫ473.
837, 776 cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 3.47 (d, J ϭ
.
[15] [15a] H. Pettersson-Fasth, S. W. Riesinger, J.-E. Bäckvall, J. Org.
[15b]
5.9 Hz, 2 H, OCH2), 3.30 (m, 1 H, 2-H), 3.06 (m, 1 H, 5-H), 1.90
(m, 4 H, NH, 4-Ha, 3-H2), 1.41 (m, 1 H, 4-Hb), 1.25 [m, 18 H,
(CH2)9], 0.89 (s, 9 H, tBu), 0.87 (t, J ϭ 6.9 Hz, 3 H, CH3), 0.05 (s,
6 H, SiMe2) ppm. 13C NMR: δ ϭ 66.10 (OCH2), 59.00 (C-2), 57.57
(C-5), 36.88, 31.98, 31.90, 29.81, 29.62, 29.33, 27.58, 27.39 (C-3, C-
4, (CH2)8], 25.93 (tBu), 22.67 (CH2), 18.30 (qC, tBu), 14.11 (CH3),
Ϫ5.30 (SiMe), Ϫ5.34 (SiMe) ppm. MS (ESI): m/z (%) ϭ 356 (100)
[MH]ϩ, 224.
Chem. 1995, 60, 6091Ϫ6096.
S. W. Riesinger, J. Löfstedt,
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