A flexible carbanionic approach to protected trans-(2R,3S)-2-substituted 3-aminopyrrolidines: Application to the asymmetric synthesis of (+)-absouline

Article abstract of DOI:10.1055/s-2004-837194

Based on the use of phenyl thioether (3S)-7 as a synthetic equivalent to the N- and α-dianions (3S)-2a, a new carbanionic approach to trans-(2R,3S)-2-substituted 3-aminopyrrolidines (10) is described. Application of the method to the asymmetric synthesis

Full text of DOI:10.1055/s-2004-837194

LETTER
231
A Flexible Carbanionic Approach to Protected trans-(2R,3S)-2-Substituted 3-
Aminopyrrolidines: Application to the Asymmetric Synthesis of (+)-Absouline
A
symmetric Syn
i
thesis
a
of (+)-Abso
n
uline Tang,a Yuan-Ping Ruan,a Jian-Liang Ye,a Pei-Qiang Huang*a,b
a
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China
b
The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
Fax +86(592)2186400; E-mail: pqhuang@xmu.edu.cn
Received 18 October 2004
O
X
( )n
Abstract: Based on the use of phenyl thioether (3S)-7 as a synthetic
equivalent to the N- and a-dianions (3S)-2a, a new carbanionic
approach to trans-(2R,3S)-2-substituted 3-aminopyrrolidines (10) is
described. Application of the method to the asymmetric synthesis of
1-aminopyrrolizidine alkaloid (+)-absouline is also reported.
H
( )n
Cl
N
Li
H
N
N
Li
N
MeO
NH2
1 (n = 1; 2)
2 (n = 1; 2; X = NHP;
NH2; OP; OH)
3
Key words: asymmetric synthesis, additions, pyrrolidine, carb-
anions, reductive lithiation
O
H
H
O
H
N
N
H
H
H
OMe
2-Lithiopyrrolidines and 2-lithiopiperidines (1, n = 1, 2)
are important intermediates in organic synthesis.1 Al-
though numerous methods have been developed for gen-
erating these synthetically useful intermediates for
asymmetric C-C bond formation at the C-2 of pyrrolidines
and piperidines,2 the formation of 3-heteroatom-substitut-
ed 2-lithiopyrrolidines and 2-lithiopiperidines (2, n = 1, 2)
remains a challenge. The major difficulties associated
with the formation of 3-hydroxypyrrolidine-2-
carbanions3,4 or 3-hydroxypiperidine-2-carbanions are b-
elimination5 and regioselectivity.6 2-Substituted-3-
aminopyrrolidines7,8 in general, and 1-aminopyrroliz-
idines in particular,9 are key structural features in a num-
ber of natural products and/or pharmaceutically
interesting compounds. Examples include compound 3, a
potent and selective 5-HT antagonist for serotonine recep-
tor,9 1-aminopyrrolizidine10,11 alkaloids absouline (4),12,13
isoabsouline (5),12,13 laburnamine (6),14 and loline.15 In
continuation of our interests to develop 3-substituted 2-
lithiopyrrolidine-based synthetic methodologies for alka-
loids syntheses,4,16 we now wish to report the generation
and asymmetric N-a-C-C bond formation reactions of
chiral non-racemic synthon (3S)-2a (2, n = 1,
X = NHCbz) as well as application of the established
method to the asymmetric synthesis of absouline (4,
Figure 1).
N
N
4 (E)-isomer, (+)-absouline
5 (Z)-isomer, (+)-isoabsouline
6 laburnamine
Figure 1 Some pharmaceutically interesting 3-aminopyrrolizidines
CbzHN
O
CbzN
CbzHN
PhS
El
N
N
N
Boc-t
Boc-t
Boc-t
(3S)-7
(S)-2a
(S)-8
Scheme 1
Thus, our synthesis commenced with known protected 3-
amino-2-pyrrolidinone (S)-8.19 Chemoselective reduc-
tion20 of (S)-8 with sodium borohydride (NaBH4, MeOH,
–15 °C, 1 h) proceeded smoothly to give N,O-acetal (3S)-
9 as a diastereomeric mixture (yield 96%, Scheme 2).
Treatment of the diastereomers (3S)-9 with thiophenol in
the presence of p-toluenesulfonic acid monohydrate
(TsOH·H2O) and PPTS in dichloromethane (r.t., 30 h) led
to the desired phenyl sulfide (3S)-721 as a single diastereo-
mer (68% yield). Because of the extensive rotamerism,
the relative stereochemistries of (3S)-7 and (3S)-9 were
not determined.
Because phenyl thioethers were shown to be valuable
precursors to organolithium reagents via reductive lithia-
tion,17 compound (3S)-7 was considered to be a suitable18
synthetic equivalent to synthon (3S)-2a. Thioether (3S)-7
was envisioned to be prepared from the known protected
3-amino-2-pyrrolidinone (S)-819 (Scheme 1).
CbzHN
O
CbzHN
HO
CbzHN
PhS
NaBH4
PhSH,TsOH
MeOH
96%
PPTS
CH2Cl2
68%
N
N
N
Boc-t
Boc-t
Boc-t
(3S)-9
(S)-8
(3S)-7
Scheme 2
SYNLETT 2005, No. 2, pp 0231–0234
0
1.
0
2.
2
0
0
5
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837194; Art ID: U28804ST
© Georg Thieme Verlag Stuttgart · New York

232
T. Tang et al.
LETTER
With the key carbanion precursor (3S)-7 in hand, the key Taking into account that reaction of (3S)-2a with symmet-
reductive lithiation and subsequent nucleophilic reaction ric ketones led to only one diastereomer, while its reaction
were investigated (Scheme 3). Thus, successive treatment with unsymmetrical ketones and aldehydes yielded a dia-
of (3S)-7 with 1.5 molar equivalents of n-butyllithium and stereomeric mixture, it is reasonable to assume that the
freshly prepared lithium naphthalenide (3.0 molar equiv, reaction proceeds with excellent selectivity at the C-2
30 min) at –78 °C, generated the N- and a-dianion (3S)- position of the pyrrolidine ring and low selectivity at the
2a, which was demonstrated by quenching with methanol exocyclic carbinolic center.
to give the corresponding pyrrolidine 10a in 80% yield
(Table 1, entry 1).
To test the scope of the method, trapping of the dianionic
intermediate (3S)-2a with allylating reagents were inves-
tigated (entries 9, 10). While allylation with allyl bromide
CbzHN
PhS
CbzHN
El
gave poor yield of 10i (40%) {pale yellow oil; [a]D20 –8.4
(c 0.9, CHCl3)}, a 57% yield of 10i was obtained by using
more active allyl iodide as an allylation reagent and by
employing a portion-wise addition protocol of allyl io-
dide.
CbzN
n-BuLi, LN
Electrophile
THF, –78 °C
N
N
N
Boc-t
Boc-t
Boc-t
10b–i
(3S)-2a
(3S)-7
+ 10a (El = H)
The extensive rotamerization due to the presence of t-Boc
and Cbz groups in compounds 10b–i, and the absence of
other diastereomers, preclude a straightforward stereo-
chemistry assignment by NMR spectral methods, whereas
on the basis of mechanistic consideration of the carbanion
chemistry,23 it is reasonable to assume that the reductive-
coupling products 10b–i possess trans stereochemistry.
To confirm the stereochemistry of the reaction, and to
demonstrate the power of the method, the asymmetric
synthesis of absouline (4) was envisioned. 1-Aminopyr-
rolizidine alkaloids (+)-absouline (4), (+)-isoabsouline (5)
and their N-oxides were isolated from Nouvelle Calédonie
plants Hugonia oreogena and H. penicillanthemum,12 and
were shown to possess modest antiviral activity. Only one
racemic synthesis of absouline (4)13 has been reported.
Scheme 3
When the dianion (3S)-2a, generated in situ from (3S)-7,
was trapped with acetone (Table 1, entry 2) the desired
nucleophilic addition occurred, and 10b was obtained in
86% yield, which showed only one diastereomer. Besides,
protonated by-product 10a was isolated in 8% yield. Re-
action of the dianion (3S)-2a with cyclohexanone or cy-
clopentanone proceeded with lower yields, and led in each
case to the formation of one diastereomer (10c and 10d,
Table 1, entries 3, 4). Addition of 2-butanone to 2a yield-
ed two diastereomers (10e) in 47:53 ratio (Table 1, entry
5). Reaction of (3S)-2a with aromatic aldehydes gave the
desired products (10f–h) in higher yields (Table 1, entries
6–8).
Our synthesis started with 10i (Scheme 4). The introduc-
tion of the hydroxyl group was achieved by treating al-
kene 10i with 0.3 molar equivalents of borane dimethyl
sulfide complex in hexane at 25–30 °C for 12 hours, fol-
lowed by hydrogen peroxide oxidation of the trialkylbo-
rane intermediate under basic conditions (3 M NaOH).
The desired terminal alcohol 11 was obtained in 50%
yield. Mesylation (MsCl, Et3N, CH2Cl2, 5 h) of 11 at –40
°C to 0 °C gave mesylate 12 in 90% yield. Treatment of
12 with 3 M HCl solution followed by basification with 1
M NaOH to pH 11–12 furnished, in one pot, the desired
Table 1 Results of the Reaction between Dianion (3S)-2a and
Electrophiles21,22
Entry
Electrophile
10 (Yield, %)a
10a (%)a
(Selectivity)b
1
2
MeOH
80
8
MeCOMe
10b (86)
20
3
(CH2)5CO
10c (65)
10
12
19
11
25
16
26
10
deprotection–cyclisation24 product 13 {yellow oil; [a]D
+10.8 (c 0.5, CHCl3); lit.10a [a]D –18.15 (c 2.7, CHCl3)
20
4
(CH2)4CO
10d (56)
for the antipode} in 71% yield. Subjecting of compound
13 to hydrogenolysis conditions (H2 1 atm, 10% Pd/C, 6
M HCl, r.t.) yielded labile 1-aminopyrrolizidine 1410a,11
5
MeCOEt
10e (49) (47:53)
10f (71) (20:80)
10g (72) (39:61)
10h (69) (17:83)
10i (40)
6
PhCHO
20
20
{[a]D +26.5 (c 0.7, MeOH); lit.10a [a]D –24.1 (c 5.5,
MeOH) for the antipode} in 78% yield, which was isolat-
ed as its dihydrochloride salt {colorless solid; mp 140–
141 °C (EtOH–Et2O); [a]D20 +15.4 (c 1.2, H2O)}. Finally,
coupling of the free base of (+)-14 with (E)-para-meth-
oxycinnamic acid using DCC as a coupling agent afforded
(+)-absouline (4)25 as a colorless solid, mp 170–171 °C
7
p-MeOC6H4CHO
2,4-Cl2C6H3CHO
CH2=CHCH2Br
CH2=CHCH2I
8
9
10
10i (57)
(EtOAc–PE); [a]D +46.0 (c 1.2, CHCl3) {Lit.12 mp
20
a Isolated yield.
186 °C; Lit.13 amorphous; Lit.12 [a]D +57.0 (c 1.0, CHCl3)
for natural absouline; lit.13 [a]D +26 (c 1.05, CHCl3) for
synthetic (1S,8R)-(+)-absouline and [a]D –34 (c 0.91,
CHCl3) for synthetic (1R,8S)-(–)-absouline} in 46% yield.
b Diastereoselectivity (at the carbinolic center) determined by HPLC.
Synlett 2005, No. 2, 231–234 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of (+)-Absouline
233
(2) For representative approaches to optically active a-
HPLC analysis on a Chiralcel OD-H column (eluent: hep-
tane–EtOH 90:10 + 0.1% Et3N; 0.75 mL/min, l = 290
nm) showed that our synthetic (+)-absouline (4,
tR = 12.011 min) is identical with that of natural
absouline26 (4, tR = 12.009 min). In addition, since racem-
ic 14 has been converted to racemic 5-HT antagonist for
serotonine receptor 39 and alkaloid laburnamine (6),14 re-
spectively, the synthesis of (+)-14 also provides a ready
precursor for the asymmetric synthesis of 3 and labur-
namine (6).
lithiopyrrolidines and a-lithiopiperidines, see: (a) Meyers,
A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem. Soc. 1985,
107, 7974. (b) Huang, P.-Q.; Arseniyadis, S.; Husson, H.-P.
Tetrahedron Lett. 1987, 28, 547. (c) Gawley, R. E.; Hart, G.
C.; Bartolotti, L. J. J. Org. Chem. 1989, 54, 175.
(d) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am.
Chem. Soc. 1993, 115, 2622. (e) Wu, S.; Lee, S.; Beak, P. J.
Am. Chem. Soc. 1996, 118, 715. (f) Coldham, I.; Hufton, R.;
Snowden, D. J. Am. Chem. Soc. 1996, 118, 5322.
(g) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien,
P. J. Am. Chem. Soc. 2002, 124, 11870. (h) Wiberg, K. B.;
Bailey, W. F. Angew. Chem. Int. Ed. 2000, 39, 2127.
(i) Watson, R. T.; Gore, V. K.; Chandupatla, K. R.; Dieter,
R. K.; Snyder, J. P. J. Org. Chem. 2004, 69, 6105.
(3) For a racemic synthetic equivalent to synthon 2b (X = OH,
OP), see: Thompson, S. H. J.; Subramanian, R. S.; Roberts,
J. K.; Hadley, M. S. J. Chem. Soc., Chem. Commun. 1994,
933.
(4) For chiral non-racemic synthetic equivalents to synthon 2b
(X = OH, OP), see: (a) Huang, P.-Q.; Wu, T.-J.; Ruan, Y.-P.
Org. Lett. 2003, 5, 4341. (b) Huang, P.-Q.; Deng, J. Synlett
2004, 247.
CbzHN
CbzHN
BH3·SMe2, hexane
EtOH, 3 M NaOH, H2O2
50%
N
N
X
Boc-t
Boc-t
MsCl, Et3N
CH2Cl2
11 X = OH
12 X = OMs
10i
90%
3M HCl, diox.
r.t., 12 h;
NH2
NHCbz
H
N
H
Pd/C, H2
(5) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(6) (a) Sunose, M.; Peakman, T. M.; Charmant, J. P. H.;
Gallagher, T.; Macdonald, S. J. F. Chem. Commun. 1998,
1723. (b) Pandey, G.; Chakrabarti, D. Tetrahedron Lett.
1998, 39, 8371; and references cited therein.
6M HCl
78%
basification
71%
N
·2HCl
14
13
O
H
H
(7) For approaches to optically active 2-substituted 3-
aminopyrrolidines, see: (a) Iwanami, S.; Takashima, M.;
Hirata, Y.; Hasegawa, O.; Usuda, S. J. Med. Chem. 1981, 24,
1224. (b) Drugs Future 1991, 16, 95. (c) Andres, C. J.; Lee,
P. H.; Nguyen, T. H.; Meyers, A. I. J. Org. Chem. 1995, 60,
3189. (d) Huang, P.-Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.;
Huang, Y. Q.; Zheng, H.; Gao, J. Tetrahedron 1998, 54,
12547. (e) Borthwick, A. D.; Crame, A. J.; Davies, D. E.;
Exall, A. M.; Jackson, D. L.; Mason, A. M.; Pennell, A. M.
K.; Weingarten, G. G. Synlett 2000, 504. (f) Cooke, J. W.
B.; Berry, M. B.; Caine, D. M.; Cardwell, K. S.; Cook, J. S.;
Hodgson, A. J. Org. Chem. 2001, 66, 334. (g) Andrews, D.
M.; Carey, S. J.; Chaignot, H.; Coomber, B. A.; Gray, N. M.;
Hind, S. L.; Jones, P. S.; Mills, G.; Robinson, J. E.; Slater,
M. J. Org. Lett. 2002, 4, 4475.
An-p
N
H
N
HO2C
H
OMe
DCC, DMAP,
CH2Cl2, 0 °C to r.t.
46%
4 (1S,8R)-(+)-absouline
Scheme 4
In summary, protected 3-amino-2-thiophenyl-pyrrolidine
7 was shown to be a valuable synthetic equivalent to dian-
ion 2a. The latter reacted with C-electrophiles to give the
C-C bond formation products 10b–i in 49–86% yields,
with excellent stereoselectivity at the newly formed C-2
stereogenic center. The diprotected (2R,3S)-2-allyl-3-
aminopyrrolidine (10i) was converted to (+)-absouline (4)
in five steps.
(8) For approaches to racemic 2-substituted 3-
aminopyrrolidines, see: (a) MacDonald, S. J. F.; Clarke, G.
D. E.; Dowle, M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis,
G. G. A.; Johnson, M. R.; Shah, P.; Upton, R. J.; Walls, S. B.
J. Org. Chem. 1999, 64, 5166. (b) Norton Matos, M. R. P.;
Afonso, C. A. M.; Batey, R. A. Tetrahedron Lett. 2001, 42,
7007. (c) Suero, R.; Gorgojo, J. M.; Aurrecoechea, M.
Tetrahedron 2002, 58, 6211.
Acknowledgment
The authors are grateful to the National Science Fund for Distin-
guished Young Investigators, the NSF of China (20272048;
203900505) and the Ministry of Education (Key Project 104201)
for financial support.
(9) Flynn, D. L.; Zabrowski, D. L.; Becker, D. P.; Nosal, R.;
Villamil, C. I.; Gullickson, G. W.; Moummi, C.; Yang, D.-
C. J. Med. Chem. 1992, 35, 1489.
(10) (a) For a recent asymmetric synthesis of 1-
aminopyrrolizidine, see: Giri, N.; Petrini, M.; Profeta, R. J.
Org. Chem. 2004, 69, 7303. (b) For an approach to optically
active 1-aminopyrrolizidin-3-one derivative, see: Langlois,
N.; Radom, M.-O. Tetrahedron Lett. 1998, 39, 857.
(11) For approaches to racemic 1-aminopyrrolizidines, see:
(a) Suri, K. A.; Suri, O. P.; Sawhney, R. S.; Gupta, O. P.;
Atal, C. K. Indian J. Chem., Sect. B 1977, 15, 972. (b) Suri,
K. A.; Suri, O. P.; Atal, C. K. Indian J. Chem., Sect. B 1983,
22, 822. (c) Zabrowski, D. L.; Becker, D. P.; Nosal, R.;
Villamil, C. I.; Gullikson, G. W.; Moummi, C.; Yang, D.-C.
J. Med. Chem. 1992, 35, 1486. (d) Ref. 13.
References
(1) For reviews involving the generation and application of a-
lithioamines, see: (a) Gant, T. G.; Meyers, A. I. Tetrahedron
1994, 50, 2297. (b) Beak, P.; Basu, A.; Gallagher, D. J.;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
552. (c) Gawley, R. E. Curr. Org. Chem. 1997, 1, 71.
(d) Kessar, S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
(e) Katritzky, A.; Qi, M. Tetrahedron 1998, 54, 2647.
(f) Husson, H. P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383.
(g) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem.
Soc. Rev. 2000, 29, 109.
Synlett 2005, No. 2, 231–234 © Thieme Stuttgart · New York

234
T. Tang et al.
LETTER
(12) Ikhiri, K.; Ahond, A.; Poupat, C.; Potier, P.; Pusset, J.;
Sévenet, T. J. Nat. Prod. 1987, 50, 626.
(13) For preparation of both enantiomers of absouline by racemic
synthesis followed by chiral HPLC separation, see:
Christine, C.; Ikhiri, K.; Ahond, A.; Mourabit, A. A.; Poupat,
C.; Potier, P. Tetrahedron 2000, 56, 1837.
(14) Neuner-Jehle, N.; Nesvadba, H.; Spiteller, G. Monatsh.
Chem. 1965, 96, 321.
(15) (a) Glass, R. S.; Deardorff, D. R.; Gains, L. H. Tetrahedron
Lett. 1978, 2965. (b) Wilson, S. R.; Sawicki, R. A.;
Huffman, J. C. J. Org. Chem. 1981, 46, 3887.
M solution in n-hexane, 0.69 mmol) and freshly prepared
lithium naphthalenide (1.5 M solution in THF, 1.36 mmol).
After being stirred for 30 min, an electrophile (0.70 mmol)
was added. The stirring was maintained at –78 °C for 1 h,
then allowed to warm to 0 °C. A sat. aq solution of NH4Cl
was added and the mixture was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over Na2SO4,
filtered and concentrated in vacuo. Flash chromatography
(EtOAc–petroleum ether = 1:3) of the crude afforded the
desired product 10b–i and a small amount of reduced
product 10a.
(c) Tufariello, J. J.; Merckler, H.; Winzenberg, K. J. Org.
Chem. 1986, 51, 3556.
Data for 10b: Electrophile used: acetone. Yield 86%;
colorless oil; [a]D20 –4.95 (c 1.0, CHCl3). IR (film): nmax
=
(16) Huang, P.-Q.; Zheng, X.; Wang, S.-L.; Ye, J.-L.; Jin, L.-R.;
Chen, Z. Tetrahedron: Asymmetry 1999, 10, 3309.
(17) (a) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978,
43, 1064. (b) Freeman, P. K.; Hutchinson, L. L. J. Org.
Chem. 1980, 45, 1924. (c) Cohen, T.; Matz, J. R. J. Am.
Chem. Soc. 1980, 102, 6900. (d) Tsunoda, T.; Fujiwara, K.;
Yamamoto, Y.; Ito, S. Tetrahedron Lett. 1991, 32, 1975.
(e) For reviews, see: Cohen, T.; Bhupathy, M. Acc. Chem.
Res. 1989, 22, 152. (f) Yus, M. Chem. Soc. Rev. 1996, 25,
155. (g) Cohen, T. Pure Appl. Chem. 1996, 68, 913.
(18) For analogue glycosyl dianions, see: (a) Hoffmann, M.;
Kessler, H. Tetrahedron Lett. 1994, 35, 6067. (b) Urban,
D.; Skrydstrup, T.; Riche, C.; Chiaroni, A.; Beau, J. M.
Chem. Commun. 1996, 1883. (c) Westermann, B.; Walter,
A.; Diedrichs, N. Angew. Chem. Int. Ed. 1999, 38, 3384.
(19) Tang, T.; Zhu, C.; Huang, P.-Q. Heterocycles 2004, 64, in
press (http://www.heterocycles.jp/heterohtml/index.html).
(20) Wijberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1978, 34, 179.
3421, 3319, 2975, 1697, 1669, 1535, 1399, 1246, 1170, 1122
cm–1. 1H NMR (500 MHz, CDCl3): d (rotamers) = 1.15 (br s,
3 H), 1.34 (br s, 3 H), 1.48 (s, 9 H), 1.68–1.78 (m, 1 H), 2.20–
2.32 (m, 1 H), 3.28–3.36 (m, 1 H), 3.60–3.80 (m, 2 H), 4.10–
4.20 (m, 1 H), 4.80–5.00 (m, 2 H), 5.10 (m, 2 H), 7.28–7.40
(m, 5 H). 13C NMR (125 MHz, DMSO-d6): d (rotamers) =
28.26 (1 C), 28.38 (1 C), 29.58 (3 C), 30.19, 30.66, 31.10 (1
C), 43.88, 44.15 (1 C), 49.89 (1 C), 50.38, 50.68 (1 C),
65.57, 65.70 (1 C), 72.22 (1 C), 78.51, 78.83 (1 C), 128.00,
128.06, 128.48, 128.57, 137.23, 137.38 (6 C), 153.72 (1 C),
155.68, 155.97 (1 C). MS (ESI): m/z (%) = 379 (100) [M +
H+], 401 (60) [M + Na+]. HRMS: m/z calcd for [C20H30N2O5
+ H]+: 379.2234; found: 379.2233.
(23) Rychnovsky, S. D.; Skalitzky, D. J. J. Org. Chem. 1992, 57,
4336.
(24) Sibi, M. P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434.
(25) In the reported 1H NMR and 13C NMR spectral data of 1-
aminopyrrolizidine and its derivatives (13,10a 14,10a,12 4,11,12
and 511,12), some differences exist from one to the other. This
may be due to conformational isomerism and/or H-bond
formation in the 1-aminopyrrolizidine ring system. In
addition, these molecules were shown to be labile.
(26) We thank Dr. C. Poupat (Institut de Chimie des Substances
Naturelles, CNRS, France) for sending us a sample of
natural absouline.
(21) All new compounds gave satisfactory analytical and spectral
data.
(22) General Procedure for the One-Pot Synthesis of
Compounds 10a–h:
To a solution of phenyl thioether 7 (0.48 mmol) in anhyd
THF (1.6 mL) at –78 °C was added successively n-BuLi (2.0
Synlett 2005, No. 2, 231–234 © Thieme Stuttgart · New York