Facile synthesis of diastereoisomerically and optically pure 2-substituted hexahydro-1H-pyrrolizin-3-ones

Article abstract of DOI:10.1002/hlca.200590158

We report a short synthetic route that provides optically active 2-substituted hexahydro-1H-pyrrolizin-3-ones in four steps from commercially available Boc (tert-but(oxy)carbonyl))-protected proline. Diastereoisomers (-)-11 and (-)-12 were assembled from the proline-derived aldehyde (-)-8 and ylide 9 via a Wittig reaction and subsequent catalytic hydrogenation (Scheme 3). Cleavage of the Boc protecting group under acidic conditions, followed by intramolecular cyclization, afforded the desired hexahydro-1H-pyrrolizinones (-)-1 and (+)-13. Applying the same protocol to ylide 19 afforded hexahydro-1H-pyrrolizinones (-)-25 and (-)-26 (Scheme 5). The absolute configuration of the target compounds was determined by a combination of NMR studies (Figs. 1 and 2) and X-ray crystallographic analysis (Fig. 3).

Full text of DOI:10.1002/hlca.200590158

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Facile Synthesis of Diastereoisomerically and Optically Pure 2-Substituted
Hexahydro-1H-pyrrolizin-3-ones
by Romain Siegrist, Corinne Baumgartner, Paul Seiler, and FranÁois Diederich*
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule, ETH-Hˆnggerberg, HCI,
CH-8093 Z¸rich
(e-mail: diederich@org.chem.ethz.ch)
We report a short synthetic route that provides optically active 2-substituted hexahydro-1H-pyrrolizin-3-
ones in four steps from commercially available Boc (tert-but(oxy)carbonyl))-protected proline. Diastereoisom-
ers (À)-11 and (À)-12 were assembled from the proline-derived aldehyde (À)-8 and ylide 9 via a Wittig reaction
and subsequent catalytic hydrogenation (Scheme 3). Cleavage of the Boc protecting group under acidic
conditions, followed by intramolecular cyclization, afforded the desired hexahydro-1H-pyrrolizinones (À)-1 and
(‡)-13. Applying the same protocol to ylide 19 afforded hexahydro-1H-pyrrolizinones (À)-25 and (À)-26
(Scheme 5). The absolute configuration of the target compounds was determined by a combination of NMR
studies (Figs. 1 and 2) and X-ray crystallographic analysis (Fig. 3).
1. Introduction. In the course of our search for new, nonpeptidic inhibitors for the
enzyme Pin1 [1][2], a peptidyl prolyl cis/trans isomerase [3] involved in the control of
the cell cycle, that has been proposed as a new anti-cancer target, we became interested
in the development of 2-mono- and 2,5-disubstituted −pyrrolizidin-3-one× ( ˆ hexahy-
dro-1H-pyrrolizin-3-one ˆ 4-azabicyclo[3.3.0]octan-3-one) derivatives (Scheme 1).
Only a few examples of diastereoisomerically pure 2,5-disubstituted derivatives have
been reported in the literature [4]. A larger number of 2-substituted pyrrolizidinones
have been prepared [5], although often as inseparable mixtures of diastereoisomers
[6 11]. Here, we describe a versatile new synthesis of diastereoisomerically and
optically pure 2-substituted pyrrolizidinones starting from l-proline. The same route is
amenable to the preparation of 2,5-disubstituted derivatives, which will be reported
later.
Scheme 1. Synthesis of 2-Mono- and 2,5-Disubstituted Hexahydro-1H-pyrrolizin-3-ones Starting from l-Proline
2. Results and Discussion. In analogy to the synthesis of 2-methyl derivatives
described in the literature [5], we envisioned preparing compound (À)-1 by alkylation
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

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of the parent pyrrolizidinone (À)-2. To this end, the bicyclic lactam (À)-2 was
synthesized according to a known procedure with an overall yield of 54% [12].
Treatment of (À)-2 with LDA (for abbreviations, see Scheme captions), followed by
addition of bromide 3, afforded diastereoisomers (À)-4 and (À)-5 in a disappointingly
low total yield of 27%, which could not be increased upon variation of the reaction
conditions (Scheme 2). Analogous alkylations with more-potent electrophiles, such as
MeI [5], PhCH2Br, and allyl bromide [13], or aldehydes [7], had previously given good
results. But to install our functionalized substituents in reasonable yield, another
strategy would be required.
Scheme 2. First Attempted Synthesis of (À)-1
a) THF, 508, 21 h; 94%. b) 1. Pd/C, H2, AcOEt, 208, 6 h; 88%; 2. TFA, CH2Cl2, 08, 1 h; 3. DMAP (cat.), py, D,
16 h; 70%. c) 1. LDA, THF, À 788, 15 min.; 2. 3, À 788 ! 208, 14 h; 27%. TFA ˆ CF3COOH, DMAP ˆ 4-
(dimethylamino)pyridine, py ˆ pyridine, LDA ˆ lithium diisopropylamide, TBDMS ˆ (t-Bu)Me2Si.
In a next step, we decided to introduce the new substituent during a Wittig reaction
(Scheme 3). The new synthesis started from commercially available Boc-proline (À)-6
that was reduced according to the procedure of Pettit et al. [14]. The resulting Boc-
prolinol (À)-7 was oxidized to the corresponding aldehyde (À)-8 under mild conditions
that are reported to proceed without detectable racemization [14]. The optically active
aldehyde (À)-8 was subjected in situ to a Wittig reaction with ylide 9, and the a,b-
unsaturated lactone 10 was isolated as an inseparable mixture of (E)- and (Z)-
diastereoisomers. Catalytic hydrogenation with Pd/C afforded the two lactones (À)-11
and (À)-12 that were separated by column chromatography. At this point, no structural
assignment was possible, and the synthesis was continued with both isomers
independently. Acidic removal of the Boc group, followed by cyclization in pyridine
with a catalytic amount of DMAP, yielded the desired pyrrolizidinones (‡)-13 and (À)-
1. NOE Measurements were performed on the two compounds (Fig. 1). Upon

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Scheme 3. Synthesis of 2-Substituted Hexahydro-1H-pyrrolizinones (‡)-13 and (À)-1
a) BH3 ¥ THF, THF, 08 ! 208, 3.5 h; 93%. b) SO3 ¥ py, Et3N, Me2SO, 58, 2.5 h. c) 9, THF, 508, 22 h; 84% (from
(À)-7). d) H2, Pd/C, AcOEt, 208, 14 h; 33% of (À)-11, 66% of (À)-12. e) 1. TFA, CH2Cl2, 08, 1 h; 2. DMAP
(cat.), py, D, 15 h; 75 77%. f) (À)-(R)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride, py, 08, 2 h; 79%.
1
Fig. 1. NOE Interactions upon irradiation of the H-NMR resonance of the H-atom at C(7a)

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irradiation of the H-atom at the bridgehead C-atom, C(7a)ÀH, long-distance
interactions were observed, as expected, with the backbone H-atom at C(2) of the
trans-product (‡)-13, but not of the cis-product (À)-1. Thus, in four easy steps,
pyrrolizidinone (À)-1 was obtained in 39% yield, whereas the other diastereoisomer
(‡)-13 was isolated in 20% yield.
To demonstrate the optical purity of the newly synthesized compounds, ( Æ )-1 was
prepared. Addition of traces of pyridine during the Wittig reaction between aldehyde
(À)-8 and ylide 9 resulted in full racemization of the produced a,b-unsaturated lactone
10, which was subsequently converted into pyrrolizidinone ( Æ )-1. The racemic alcohol
( Æ )-1 and optically active (À)-1 were transformed into the corresponding Mosher
esters 14 [15]. After complete conversion, but before chromatographic purification, the
Mosher esters were analyzed by 19F-NMR measurements (Fig. 2). For the derivative of
( Æ )-1, two signals representing the two diastereoisomeric products were found in a 1:1
ratio, as expected. For the derivative of (À)-1, only one signal corresponding to pure
diastereoisomer (À)-14 was detected, thereby demonstrating complete retention of
configuration at the stereogenic center introduced with Boc-proline (À)-6.
Fig. 2. 19F-NMR Spectra (CDCl3, 282 MHz) of the Mosher esters derived from (Æ)-1 (top) and (À)-1 (bottom).
The spectra of the crude products were recorded.
To install an amine function at the end of the alkyl chain, alcohols (À)-1 and (‡)-13
were converted via a Mitsunobu reaction into the corresponding phthalimides (‡)-15
and (À)-16, respectively (Scheme 4). Subsequent treatment with MeNH2 afforded the
corresponding amines. Upon storage, the amines underwent facile epimerization so
they were converted directly into the corresponding sulfonamides (À)-17 and (À)-18,
respectively.
By slow evaporation of concentrated hexane solutions, suitable single crystals of
(‡)-15 and (À)-16 were obtained to carry out X-ray crystallographic analysis (Fig. 3),
confirming the previous structural assignments discussed above. The non-planarity of
the amide CÀN bond in these molecules is appreciable. This is evident from the angular

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Scheme 4. Synthesis of Sulfonamides (À)-17 and (À)-18
a) Phthalimide, PPh3, DIAD, THF, 208, 16 h; 76 88%. b) 1. 33% MeNH2 in EtOH, 208, 16 h; 2. PhSO2Cl, Et3N,
CH2Cl2, 08, 2 h; 60 68%. DIAD ˆ Diisopropyl azodicarboxylate. The inversion of absolute configuration at
C(2) results from the introduction of a different functional group at the end of the alkyl chain and a subsequent
change in priority according to the CIP rules.
Fig. 3. X-Ray crystal structures of (‡)-15 (top) and (À)-16 (bottom). Arbitrary numbering. Atomic displace-
ment parameters obtained at 223 K are drawn at the 30% probability level.
strain (S), based on the sum of the three bond angles at N(8) which amounts to 355.278,
and 355.598 for (‡)-15 and (À)-16, respectively (note that when S is expressed in this
way, it does not depend on the bond lengths, as does, for example, the distance of the
atom from the plane of its three bonded neighbors). The external angles at N(8)
(C(1)ÀN(8)ÀC(7)) are 127.738 for (‡)-15, and 127.518 for (À)-16. These values are in
the range of those previously reported for pyrrolizidinones. Indeed, for the 18 crystal
structures deposited with the Cambridge Structural Database (CSD) [16], the external
angle is found in a range from 124.278 to 134.088, and the angular sum in a range from
346.64 to 359.738. Each five-membered ring exhibits an envelope conformation. The
degree of twisting about the N(8)ÀC(7) bond can be estimated by the two torsional
angles w1 (C(1)ÀN(8)ÀC(7)ÀC(6)) and w2 (C(4)ÀN(8))ÀC(7)ÀO(9)) and the twist
angle t ˆ 1/2(w1 ‡ w2) (with the side condition j w1 ‡ w2 j< p, which states that a case

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with w1 ˆ À 1708, w2 ˆ 1758 should be treated as if w1 ˆ À 1708, w2 ˆ À 1858) [17][18].
In the case of a fully planar amide, all three angles would adopt values of Æ 1808. The
values for (‡)-15, however, are w1 ˆ À 160.518, w2 ˆ 174.468, and t ˆ À 173.038, and
those for (À)-16 w1 ˆ 159.848, w2 ˆ 173.158, and t ˆ À 173.358. These values are in good
agreement with those reported by Winkler for (2RS,7aRS)-2-[4-(bromophenyl)methyl]-
pyrrolizidin-3-one (w1 ˆ À 161.58, w2 ˆ 168.08, t ˆ À 176.88) [19].
For the development of Pin1 inhibitors, it was also of interest to elongate the
alcohol side chain. For this purpose, ylide 19 was prepared according to a known
literature procedure [20]. The first attempt to perform the Wittig reaction with Boc-
prolinal (À)-8 under the conditions described above failed, and no trace of the desired
product was detected. Changing the solvent from THF to PhMe permitted the use of
higher temperatures, which, in turn, allowed the isolation of the a,b-unsaturated
lactones (À)-20 and (‡)-21 in 57% overall yield (Scheme 5). Unlike in the g-lactone
series (see above), the (E)- and (Z)-products were easily separated by column
chromatography. According to the hydrogenation protocol (Pd/C, AcOEt) used for
compound 10, the reaction was not complete even after several days. By changing the
solvent to EtOH, the reaction took place quickly, but substantial lactone opening was
observed, and ethyl ester 22 was isolated as a by-product. The use of PtO2 appeared to
Scheme 5. Synthesis of Hexahydro-1H-pyrrolizinones (À)-25 and (À)-26.
a) 19, PhMe, D, 48 h; 18% of (À)-20, 39% of (‡)-21. b) Pd/C, H2, EtOH, 208, 10 % of (‡)-23, 25% of (À)-24,
36% of 22. c) PtO2, H2, AcOEt, 208, 60h; 23% of ( ‡)-23, 44% of (À)-24. d) 1. TFA, CH2Cl2, 08, 1 h; 2. DMAP
(cat.), py, D, 15 h; 80 92%.

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be the best solution; with this catalyst, the reaction went smoothly, and no ring opening
was observed. The hydrogenation appeared to be non-selective and, starting from
either the (E)- or (Z)-adduct, gave a mixture of the two diastereoisomers (‡)-23 and
(À)-24 that were separated by column chromatography. Boc Deprotection and
subsequent cyclization were achieved by the same protocol as described above. The
bicyclic compounds (À)-25 and (À)-26 were easily obtained, in 23 and 11% overall
yield, respectively. The structural assignments were confirmed by NOE measurements
(see Fig. 1).
3. Conclusions. Starting from commercially available Boc-proline ((À)-6), we
have achieved a facile entry into diastereoisomerically and optically pure 2-substituted
pyrrolizidinones in four steps. The complete optical purity of target molecule (À)-1,
with a 2-hydroxyethyl side chain, was conveniently confirmed by transformation into
the corresponding Mosher ester, followed by 19F-NMR spectroscopic analysis. X-Ray
crystallographic analysis of the phthalimide derivatives (‡)-15 and (À)-16 revealed
nonplanar amide moieties, in agreement with previous structural investigations within
this class of compounds. The synthetic route introduced in this study is also amenable to
the synthesis of 2,5-disubstituted pyrrolizidinones starting from the appropriately
substituted proline derivatives. These developments on the way to inhibitors of Pin1, an
enzyme in the cell cycle that attracts interest as an antitumor target, will be reported in
due course.
Financial support by the Roche Research Foundation (doctoral fellowship for R. S.) is gratefully
acknowledged. We also thank Dr. Carlo Thilgen for help with the nomenclature.
Experimental Part
General. Solvents and reagents were reagent-grade, purchased from commercial suppliers, and used
without further purification unless otherwise stated. The following compounds were prepared according to
literature procedures: pyrrolizidinone (À)-2 [12], bromide 3 [21], Boc-prolinol (À)-7 and Boc-prolinal (À)-8
[14], ylide 9 [22], and 19 [20]. THF was freshly distilled from sodium benzophenone ketyl, CH2Cl2 from CaH2.
Evaporation in vacuo was conducted at H2O aspirator pressure. All products were dried under high vacuum
(10À2 Torr) before anal. characterization. Column chromatography (CC): SiO2 60 (40 63 mm) from Fluka, 0
0.3 bar pressure. TLC: SiO2 60 F245, Merck, visualization by UV light at 245 nm or staining with a soln. of
KMnO4 (3 g) and K2CO3 (20g) in 5% aq. NaOH soln. (5 ml) and H 2O (300 ml). M.p.: B¸chi B540 melting-
point apparatus; uncorrected. Optical rotations: Perkin-Elmer 241 polarimeter, 1-dm cell, l ˆ 589 nm (Na D-
line). IR Spectra [cmÀ1]: Perkin-Elmer 1600-FTIR spectrometer. NMR spectra (1H, 13C, 19F, NOE): Varian
Gemini-300, Varian Gemini-400, and Bruker AMX-500; spectra were recorded at 208 unless otherwise stated
with solvent peak as reference. High-resolution MALDI mass spectra (HR-MS): IonSpec Ultima, 2,5-
dihydroxybenzoic acid (DHB) as matrix. Elemental analyses were performed by the Mikrolabor at the
Laboratorium f¸r Organische Chemie, ETH-Z¸rich.
General Procedure A (GP A) for the Catalytic Hydrogenation of an a,b-Unsaturated Lactone. To a soln. of
the lactone (35.7 mmol) in AcOEt (500 ml), 10% Pd/C or PtO2 (10% (w/w)) was added under Ar. The flask was
evacuated and refilled with H2 (3 Â ). The black suspension was stirred at 208 for 21 h under an H2 atmosphere
(atmospheric pressure), and filtered over Celite. The filtrate was concentrated in vacuo to afford a residue that
was purified by CC (SiO2; hexane/THF 8 :2).
General Procedure B (GP B) for the Intramolecular Cyclization of a Lactone. To an ice-cooled soln. of the
lactone (4.8 mmol) in CH2Cl2 (20ml), TFA (5 ml) was added. The mixture was stirred at 0 8 for 1 h, then
concentrated in vacuo. The resulting residue was dissolved in pyridine (30ml). After addition of a cat. amount
of DMAP, the mixture was heated to reflux for 16 h. The solvent was removed in vacuo, and the resulting residue
was purified by CC (SiO2; CH2Cl2/MeOH 95 :5).

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General Procedure C (GP C) for the Synthesis of a Phthalimide by Mitsunobu Reaction. To a soln. of an
alcohol (1.5 mmol), phthalimide (1.7 mmol), and PPh3 (1.7 mmol) in THF (6 ml), DIAD (1.7 mmol) was added.
The mixture was stirred at 208 for 16 h, then evaporated in vacuo to afford a residue that was purified by CC
(SiO2; cyclohexane/AcOEt/MeOH 2 :1:0.1).
General Procedure D (GP D) for the Conversion of a Phthalimide into a Sulfonamide. A soln. of the
phthalimide (1.3 mmol) in 33% MeNH2 in EtOH (14 ml) was stirred at 208 for 16 h. The volatiles were removed
in vacuo. The resulting residue was taken up in 10% aq. AcOH and washed with CH2Cl2/i-PrOH 3 :1. The aq.
layer was treated with 1m NaOH until a pH > 12 was reached and extracted with CH2Cl2/i-PrOH 3 :1. The comb.
org. phases were dried (MgSO4) and evaporated in vacuo. The resulting amine was dissolved in CH2Cl2 (10ml)
and the soln. cooled to 08. A sulfonyl chloride (1.3 mmol) and Et3N (1.4 mmol) were added, and the mixture was
stirred at 08 for 2 h. The soln. was diluted with CH2Cl2 (30ml) and washed with H 2O and sat. aq. NaCl soln. The
aq. layers were extracted with CH2Cl2/i-PrOH 3 :1. The comb. org. phases were concentrated in vacuo to afford a
residue that was purified by CC (SiO2; AcOEt/MeOH 95 :5).
(À)-(2S,7aS)-2-(2-{[(tert-Butyl)(dimethyl)silyl]oxy}ethyl)-2,3,5,6,7,7a-hexahydro-1H-pyrrolizin-3-one
((À)-4) and (À)-(2R,7aS)-2-(2-{[(tert-Butyl)(dimethyl)silyl]oxy}ethyl)-2,3,5,6,7,7a-hexahydro-1H-pyrrolizin-3-
one ((À)-5). To an ice-cooled soln. of freshly distilled HN(i-Pr)2 (0.12 ml, 0.83 mmol) in THF (2 ml), 1.6m BuLi
in hexane (0.43 ml, 0.69 mmol) was dropwise added. The ice bath was removed, the mixture stirred at 208 for
15 min, then cooled to À 788. A soln. of (À)-2 (86 mg, 0.69 mmol) was slowly added. The mixture was stirred at
À 788 for 1 h. The cooling bath was removed and the mixture was stirred for 10min, then cooled again to À 788.
A soln. of 3 (196 mg, 0.82 mmol) in THF (2 ml) was slowly added. The mixture was stirred for 16 h, during which
time the temp. rose from À 788 to 208. Sat. aq. NH4Cl soln. was added. The mixture was extracted with Et2O and
CH2Cl2. The comb. org. phases were dried (MgSO4) and evaporated. The residue was purified by CC (SiO2;
CH2Cl2/MeOH 98 :2), affording (À)-4 (28 mg, 14%) and (À)-5 (25 mg, 13%).
Data of (À)-4. White solid. M.p. 47 488. [a]2D0 ˆ À 8.6 (c ˆ 1.00, CHCl3). IR (neat): 2954w, 2927m, 2903w,
2879m, 2856w, 1669s, 1485w, 1470w, 1457w, 1448w, 1417m, 1386w, 1359w, 1328m, 1318m, 1304w, 1270w, 1250m,
1103m, 1078m, 1050m, 1023w, 1004w, 969m, 953m, 938w, 90 8m, 874m, 857m, 829s, 80 9m, 769s, 757m, 741m,
718m, 664m. 1H-NMR (300 MHz, CDCl3): 0.05 (s, 6 H); 0.89 (s, 9 H); 1.22 1.50( m, 3 H); 1.93 2.23 (m, 4 H);
2.53 (ddd, J ˆ 12.1, 7.8, 6.2, 1 H); 2.84 2.96 (m, 1 H); 3.03 3.10 (m, 1 H); 3.49 3.58 (m, 1 H); 3.64 3.84 (m,
3 H). 13C-NMR (75 MHz, CDCl3): À 5.1; 18.5; 26.2; 27.1; 32.6; 34.4; 36.4; 41.2; 44.1; 59.9; 61.6; 176.1. HR-
‡
‡
MALDI-MS: 306.1858 ([M ‡ Na] , C15H29NO2SiNa ; calc. 306.1860).
Data of (À)-5. Colorless oil. [a]2D0 ˆ À 4.7 (c ˆ 1.00, CHCl3). IR (neat): 2953w, 2929w, 2857w, 1690s, 1472w,
1462w, 1408m, 1360w, 1331w, 1287w, 1253m, 1095s, 1006w, 939w, 913w, 832s, 774s, 726w, 663m. 1H-NMR
(300 MHz, CDCl3): 0.05 (s, 6 H); 0 .89 (s, 9 H); 1.19 1.33 (m, 1 H); 1.67 1.79 (m, 1 H); 1.91 (ddd, J ˆ 13.1, 9.2,
6.7, 1 H); 1.94 2.16 (m, 5 H); 2.63 2.72 (m, 1 H); 3.01 3.09 (m, 1 H); 3.52 3.61 (m, 1 H); 3.70 3.77 ( m,
2 H); 3.81 3.90( m, 1 H). 13C-NMR (75 MHz, CDCl3): À 5.1; 18.4; 26.0; 26.9; 32.1; 32.2; 35.0; 41.3; 44.2; 60.5;
‡
‡
61.5; 177.6. HR-MALDI-MS: 284.2038 (MH , C15H30NO2Si ; calc. 284.2040). Anal. calc. for C15H29NO2Si
(283.49): C 63.55, H 10.31, N 4.94; found C 63.56, H 10.31, 4.92.
tert-Butyl (2S)-2-[(2,3,4,5-Tetrahydro-2-oxofuran-3-ylidene)methyl]pyrrolidine-1-carboxylate (10). To a
soln. of (À)-8 (6.06 g, 30.4 mmol) in THF (150 ml), ylide 9 (21.10g, 60.9 mmol) was added. The resulting
suspension was stirred at 508 for 24 h. The solids were removed by filtration, and the filtrate was evaporated. CC
(SiO2; hexane/AcOEt 7:3) furnished 10 (6.82 g, 84%) as a 1:2 mixture of (E)- and (Z)-diastereoisomers. White
solid. M.p. 91 ! 1218. IR (neat): 2972w, 2910w, 1739s, 1678s, 1479w, 1436w, 1387s, 1364s, 1308m, 1249m, 1203s,
1
1167s, 1105s, 1026s. H-NMR (300 MHz, 363 K, C2D2Cl4): 1.37 (s, 2.7 H); 1.38 (s, 6.3 H); 1.53 1.94 (m, 3 H);
2.10( ddd, J ˆ 15.3, 12.5, 7.8, 0.7 H); 2.18 2.30 (m, 0.3 H); 2.74 2.87 (m, 1.4 H); 2.94 3.06 (m, 0.6 H); 3.29
3.49 (m, 2 H); 4.23 4.39 (m, 2.7 H); 5.30 5.37 ( m, 0.3 H); 6.09 (dt, J ˆ 8.4, 2.3, 0.3 H); 6.54 (dt, J ˆ 8.1, 2.8,
0.7 H). 13C-NMR (125 MHz, 363 K, C2D2Cl4): 24.1; 24.9; 28.6; 28.8; 31.8; 32.9; 46.7; 46.8; 54.3; 56.5; 65.5 (2 Â );
79.2; 79.5; 79.6; 79.8; 122.7; 124.7; 140.9; 145.7; 154.2; 154.4; 169.3; 171.1. HR-MALDI-MS: 290.1357 ([M ‡
‡
‡
Na] , C14H21NO4Na ; calc. 290.1368). Anal. calc. for C14H21NO4 (267.32): C 62.90, H 7.92, N 5.24; found C 63.02,
H 7.92, N 5.10.
(À)-tert-Butyl (2S)-2-{[(3S)-2,3,4,5-Tetrahydro-2-oxofuran-3-yl]methyl}pyrrolidine-1-carboxylate ((À)-11)
and (À)-tert-Butyl (2S)-2-{[(3R)-2,3,4,5-Tetrahydro-2-oxofuran-3-yl]methyl}pyrrolidine-1-carboxylate ((À)-
12). GP A, starting from 10 (9.50g, 35.7 mmol), afforded, after purification, ( À)-11 (3.18 g, 33%) and (À)-12
(6.36 g, 66%).
Data of (À)-11. White solid. M.p. 59 608. [a]2D0 ˆ À 13.6 (c ˆ 1.00, CHCl3). IR (neat): 2966w, 2903w,
2881w, 1754s, 1684s, 1478w, 1465w, 1397s, 1364s, 1309w, 1252w, 1212m, 1157s, 1100s, 1024s. 1H-NMR (300 MHz,
363 K, C2D2Cl4): 1.42 (s, 9 H); 1.62 2.19 (m, 7 H); 2.46 2.55 (m, 2 H); 3.24 (ddd, J ˆ 11.2, 7.0, 4.9, 1 H); 3.41

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(ddd, J ˆ 11.2, 7.4, 7.4, 1 H); 3.92 4.00 (m, 1 H); 4.11 (dt, J ˆ 8.1, 6.4, 1 H); 4.26 (dt, J ˆ 8.9, 2.7, 1 H). 13C-NMR
(125 MHz, 363 K, C2D2Cl4): 23.8; 28.9; 29.8; 31.5; 36.3; 37.3; 46.6; 55.6; 66.7; 79.5; 155.1; 179.3. HR-MALDI-
‡
‡
MS: 292.1513 ([M ‡ Na] , C14H23NO4Na ; calc. 292.1525). Anal. calc. for C14H23NO4 (269.34): C 62.43, H 8.61,
N 5.20; found C 62.36, H 8.47, N 5.16.
Data of (À)-12. White solid. M.p. 103 1048. [a]2D0 ˆ À 39.7 (c ˆ 1.00, CHCl3). IR (neat): 2976w, 2869w,
1746s, 1698s, 1684s, 1455m, 1392s, 1380s, 1368s, 1348m, 1252m, 1153s, 1128m, 1098s, 1019s. 1H-NMR (300 MHz,
363 K, C2D2Cl4): 1.42 (s, 9 H); 1.62 2.03 (m, 7 H); 2.32 2.49 (m, 2 H); 3.23 3.41 (m, 2 H); 3.78 3.86 (m,
1 H); 4.12 (dt, J ˆ 8.9, 6.6, 1 H); 4.28 (dt, J ˆ 8.9, 3.1, 1 H). 13C-NMR (125 MHz, 363 K, C2D2Cl4): 23.4; 28.7;
‡
29.0; 30.4; 35.9; 37.4; 46.3; 56.0; 66.4; 79.2; 154.4; 178.9. HR-MALDI-MS: 292.1514 ([ M ‡ Na] ,
‡
C14H23NO4Na ; calc. 292.1525). Anal. calc. for C14H23NO4 (269.34): C 62.43, H 8.61, N 5.20; found C 62.54,
H 8.52, N 5.16.
(À)-(2R,7aS)-2,3,5,6,7,7a-Hexahydro-2-(hydroxyethyl)-1H-pyrrolizin-3-one ((À)-1). GP B, starting from
(À)-12 (1.30g, 4.8 mmol), afforded ( À)-1 (616 mg, 75%). Yellow oil. [a]2D0 ˆ À 18.8 (c ˆ 1.00, CHCl3). IR
1
(neat): 3382w, 2939w, 2877w, 1660s, 1418m, 1330m, 1288m, 1208w, 1046m. H-NMR (400 MHz, CDCl3): 1.23
1.35 (m, 1 H); 1.77 1.86 (m, 1 H); 1.90 2.21 ( m, 6 H); 2.71 2.80( m, 1 H); 3.04 3.12 (m, 1 H); 3.47 (br. s,
1 H); 3.53 3.62 (m, 1 H); 3.78 3.87 (m, 2 H); 3.88 3.94 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 26.8; 32.0;
‡
‡
32.8; 35.4; 41.3; 45.6; 60.8; 61.8; 178.0. HR-MALDI-MS: 192.0995 ([M ‡ Na] , C9H15NO2Na ; calc. 192.1000).
Anal. calc. for C9H15NO2 (169.22): C 63.88, H 8.93, N 8.28; found C 63.87, H 8.88, N 8.35.
(‡)-(2S,7aS)-2,3,5,6,7,7a-Hexahydro-2-(hydroxyethyl)-1H-pyrrolizin-3-one ((‡)-13). GP B, starting from
(À)-11 (538 mg, 2.0mmol), afforded ( ‡)-13 ( 260mg, 77%). Yellow oil. [ a]2D0 ˆ ‡ 25.4 (c ˆ 1.01, CHCl3). IR
(neat): 3388w, 2927w, 2876w, 1659s, 1455m, 1423m, 1330m, 1288m, 1183w, 1144w, 1049m. 1H-NMR (500 MHz,
CDCl3): 1.31 1.40( m, 1 H); 1.45 (dt, J ˆ 12.2, 8.8, 1 H); 1.66 1.71 (m, 1 H); 1.83 (br. s, 1 H); 1.89 1.96 (m,
1 H); 2.00 2.11 (m, 2 H); 2.12 2.19 (m, 1 H); 2.49 (ddd, J ˆ 12.2, 7.7, 6.1, 1 H); 2.95 3.02 (m, 1 H); 3.07 3.12
(m, 1 H); 3.50 3.56 ( m, 1 H); 3.67 3.72 (m, 1 H); 3.76 3.81 (m, 1 H); 3.83 3.89 (m, 1 H). 13C-NMR
‡
(75 MHz, CDCl3): 27.0; 32.3; 34.4; 36.5; 41.1; 47.9; 60.5; 62.1; 176.1. HR-MALDI-MS: 192.0997 ([M ‡ Na] ,
‡
C9H15NO2Na ; calc. 192.1000). Anal. calc. for C9H15NO2 (169.22): C 63.88, H 8.93, N 8.28; found C 63.89, H 8.81,
N 8.33.
(À)-2-[(2R,7aS)-2,3,5,6,7,7a-Hexahydro-3-oxo-1H-pyrrolizin-2-yl]ethyl (2S)-3,3,3-Trifluoro-2-methoxy-2-
phenylpropanoate ((À)-14). To an ice-cooled soln. of (À)-1 (61 mg, 0.36 mmol) in pyridine (2 ml), (À)-(R)-
a-methoxy-a-(trifluoromethyl)phenylacetyl chloride (100 mg, 0.40 mmol) was added. The mixture was stirred
at 08 for 2 h, then diluted with Et2O. The mixture was washed with H2O, 1n HCl, H2O, 5% aq. Na2CO3 soln., sat.
aq. NaCl soln., dried (Na2SO4), and evaporated to afford (À)-14 (110mg, 79%). Pale yellow oil. [ a]2D0 ˆ À 49.5
(c ˆ 1.00, CHCl3). IR (neat): 2951w, 2879w, 1746m, 1683s, 1452w, 1418w, 1331w, 1266m, 1258m, 1163s, 1120m,
1081w, 1020m, 998m, 964w, 915w, 882w, 820w, 766w, 718m, 698m, 646w. 1H-NMR (300 MHz, CDCl3): 1.15 1.31
(m, 1 H); 1.83 2.23 (m, 7 H); 2.55 2.64 (m, 1 H); 2.99 3.08 (m, 1 H); 3.51 3.60( m, 4 H); 3.75 3.85 (m,
1 H); 4.39 4.52 (m, 2 H); 7.38 7.43 (m, 3 H); 7.50 7.53 ( m, 2 H). 13C-NMR (75 MHz, CDCl3): 26.8; 30.7; 31.6;
2
1
32.0; 41.4; 43.7; 55.5; 60.4; 64.8; 84.6 ( q, J(C,F) ˆ 27.5); 123.2 (q, J(C,F) ˆ 287.7); 127.2; 128.4; 129.5; 132.1;
‡
‡
166.3; 176.2. HR-MALDI-MS: 408.1386 ([M ‡ Na] , C19H22NO4F3Na ; calc. 408.1393). Anal. calc. for
C19H22NO4F3 (385.38): C 59.22, H 5.75, N 3.63; found C 59.10, H 5.74, N 3.85.
(‡)-2-{2-[(2S,7aS)-2,3,5,6,7,7a-Hexahydro-3-oxo-1H-pyrrolizin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione
((‡)-15). GP C, starting from (À)-1 (245 mg, 1.5 mmol), afforded (‡)-15 (395 mg, 76%). White solid. M.p.
106 1098. [a]2D0 ˆ ‡ 20.2 (c ˆ 1.00, CHCl3). IR (neat): 2944w, 2889w, 2863w, 1770m, 1708s, 1681s, 1454m,
1434m, 1399s, 1371s, 1332m, 1189m, 1069m, 1012m. 1H-NMR (300 MHz, CDCl3): 1.22 1.34 (m, 1 H); 1.79 2.24
(m, 7 H); 2.56 2.65 (m, 1 H); 3.04 (ddd, J ˆ 11.7, 8.6, 3.3, 1 H); 3.57 (ddd, J ˆ 11.7, 7.8, 7.8, 1 H); 3.77 3.92 (m,
3 H); 7.70 7.74 ( m, 2 H); 7.81 7.85 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 26.8; 30.9; 31.6; 32.1; 36.3; 41.4; 44.7;
‡
‡
60.4; 123.2; 132.0; 133.9; 168.1; 176.4. HR-MALDI-MS: 299.1390 (MH , C17H19N2O3 ; calc. 299.1396). Anal.
calc. for C17H18N2O3 (298.34): C 68.44, H 6.08, N 9.39; found C 68.46, H 6.22, N 9.27. X-Ray crystal structure: see
Fig. 3.
(À)-2-{2-[(2R,7aS)-2,3,5,6,7,7a-Hexahydro-3-oxo-1H-pyrrolizin-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione
((À)-16). GP C, starting from alcohol (‡)-13 (204 mg, 1.2 mmol), afforded (À)-16 (318 mg, 88%). White solid.
M.p. 159 1618. [a]2D0 ˆ À 13.7 (c ˆ 1.00, CHCl3). IR (neat): 2971w, 2951w, 2866w, 1769w, 1707s, 1675s, 1456w,
1437m, 1403s, 1374s, 1333m, 1189m, 1050m, 1011m. 1H-NMR (300 MHz, CDCl3): 1.24 1.36 (m, 1 H); 1.43 (dt,
J ˆ 12.1, 8.7, 1 H); 1.59 1.72 (m, 1 H); 1.93 2.13 (m, 3 H); 2.28 2.39 (m, 1 H); 2.63 (ddd, J ˆ 12.1, 7.7, 6.1,
1 H); 2.75 2.86 (m, 1 H); 3.01 3.08 (m, 1 H); 3.49 (ddd, J ˆ 11.5, 7.8, 7.8, 1 H); 3.75 3.84 (m, 3 H); 7.70 7.74
(m, 2 H); 7.81 7.87 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 27.0; 30.4; 32.4; 35.7; 36.2; 41.1; 44.6; 59.6; 123.1;

Helvetica Chimica Acta Vol. 88 (2005)
2259
‡
‡
132.0; 133.8; 168.2; 174.4. HR-MALDI-MS: 299.1388 ( MH , C17H19N2O3 ; calc. 299.1396). Anal. calc. for
C17H18N2O3 (298.34): C 68.44, H 6.08, N 9.39; found C 68.41, H 6.01, N 9.31. X-Ray crystal structure: see Fig. 3.
(À)-N-{2-[(2S,7aS)-2,3,5,6,7,7a-Hexahydro-3-oxo-1H-pyrrolizin-2-yl]ethyl}benzenesulfonamide ((À)-17).
GP D, starting from (‡)-15 (400 mg, 1.3 mmol) and PhSO2Cl (0.17 ml, 1.3 mmol), afforded (À)-17 (244 mg,
60%). Colorless oil. [a]2D0 ˆ À 41.9 (c ˆ 1.00, CHCl3). IR (neat): 3151w, 2943w, 2877w, 1659s, 1446m, 1325s,
1155s, 1093m, 690s. 1H-NMR (300 MHz, CDCl3): 1.21 1.32 (m, 1 H); 1.79 1.86 (m, 1 H); 1.88 2.17 (m, 6 H);
2.62 (ddd, J ˆ 16.1, 8.0, 4.0, 1 H); 3.01 2.24 (m, 3 H); 3.54 (ddd, J ˆ 11.8, 7.9, 7.9, 1 H); 3.78 3.88 (m, 1 H);
5.75 5.79 (m, 1 H); 7.47 7.59 (m, 3 H); 7.86 7.90( m, 2 H). 13C-NMR (75 MHz, CDCl3): 26.8; 32.0; 32.2; 32.8;
‡
41.3; 42.0; 45.0; 60.6; 126.9; 128.9; 132.3; 140.2; 176.9. HR-MALDI-MS: 331.1089 ([M ‡ Na] ,
‡
C15H20N2O3SNa ; calc. 331.1092). Anal. calc. for C15H20N2O3S (308.40): C 58.42, H 6.54, N 9.08; found C
58.49, H 6.73, N 9.17.
(À)-N-{2-[(2R,7aS)-2,3,5,6,7,7a-Hexahydro-3-oxohexahydro-1H-pyrrolizin-2-yl]ethyl}benzenesulfonamide
((À)-18). GP D, starting from (À)-16 (200 mg, 0.7 mmol) and PhSO2Cl (0.08 ml, 0.7 mmol), afforded (À)-18
(139 mg, 68%). White solid. M.p. 141 1428. [a]2D0 ˆ À 106.0 (c ˆ 0.99, CHCl3). IR (neat): 3326w, 2956w,
2927w, 2869w, 1694m, 1641s, 1453m, 1320s, 1148s, 1098s, 753s, 688s. 1H-NMR (300 MHz, CDCl3): 1.43 1.64 (m,
3 H); 1.74 2.05 (m, 4 H); 2.39 2.55 (m, 2 H); 3.16 3.25 (m, 1 H); 3.31 3.44 (m, 3 H); 3.82 3.90( m, 1 H);
5.55 (br. s, 1 H); 7.49 7.62 (m, 3 H); 7.82 7.86 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 24.1; 28.3; 30.7; 38.3; 38.8;
‡
‡
40.4; 48.6; 59.4; 127.4; 129.0; 132.5; 137.8; 179.7. HR-MALDI-MS: 331.1085 ([M ‡ Na] , C15H20N2O3SNa ; calc.
331.1092). Anal. calc. for C15H20N2O3S (308.40): C 58.42, H 6.54, N 9.08; found C 58.44, H 6.83, N 8.83.
(À)-tert-Butyl (2S)-2-[(Z)-(3,4,5,6-Tetrahydro-2-oxo-2H-pyran-3-ylidene)methyl]pyrrolidine-1-carboxyl-
ate ((À)-20) and (‡)-tert-Butyl (2S)-2-[(E)-(3,4,5,6-Tetrahydro-2-oxo-2H-pyran-3-ylidene)methyl]pyrrolidine-
1-carboxylate ((‡)-21). To a soln. of (À)-8 (1.70g, 8.45 mmol) in PhMe (40ml), 19 (6.09 g, 16.90 mmol) was
added. The resulting mixture was heated to reflux for 48 h, then cooled to 208 and filtered. The filtrate was
evaporated in vacuo. CC (SiO2; hexane/AcOEt 7:3 ! 1 :1) afforded (À)-20 (428 mg, 18%) and (‡)-21
(928 mg, 39%).
Data of (À)-20: White solid. M.p. 99 1018. [a]2D0 ˆ À 51.9 (c ˆ 1.00, CHCl3). IR (neat): 2977w, 2881w,
1708s, 1680s, 1645w, 1475w, 1443w, 1402s, 1365m, 1347w, 1278w, 1234m, 1164s, 1121s, 1076m, 1007w, 981w, 971w,
918m, 899m, 886m, 860w, 764m, 655w. 1H-NMR (300 MHz, 363 K, C2D2Cl4): 1.37 (s, 9 H); 1.55 1.66 (m, 1 H);
1.73 1.91 (m, 4 H); 2.23 2.35 (m, 1 H); 2.45 2.56 (m, 2 H); 3.33 (dt, J ˆ 10.9, 6.9, 1 H); 3.43 (dt, J ˆ 10.9, 6.9,
1 H); 4.14 4.27 (m, 2 H); 5.00 5.07 (m, 1 H); 5.90 5.94 ( m, 1 H). 13C-NMR (75 MHz, 363 K, C2D2Cl4): 23.7;
‡
24.5; 28.9; 29.5; 33.1; 47.1; 56.7; 68.8; 79.2; 123.9; 149.9; 154.5; 165.0. HR-MALDI-MS: 304.1519 ([M ‡ Na] ,
‡
C15H23NO4Na ; calc. 304.1519). Anal. calc. for C15H23NO4 (281.35): C 64.04, H 8.24, N 4.98; found C 64.28, H
8.14, N 4.90.
Data of (‡)-21: White solid. M.p. 123 1268. [a]2D0 ˆ ‡ 20.0 (c ˆ 1.00, CHCl3). IR (neat): 2971w, 2918w,
1691s, 1638m, 1481w, 1436w, 1398s, 1364m, 1348w, 1309m, 1274w, 1247s, 1166s, 1146s, 1118m, 1098s, 1076m,
1044w, 1014w, 977w, 926m, 886w, 869w, 771m, 739m, 645w. 1H-NMR (300 MHz, 363 K, C2D2Cl4): 1.38 (s, 9 H);
1.58 1.68 (m, 1 H); 1.74 1.97 (m, 4 H); 2.03 2.15 (m, 1 H); 2.36 2.47 (m, 1 H); 2.70 2.81 ( m, 1 H); 3.32
3.47 (m, 2 H); 4.22 4.26 (m, 2 H); 4.37 4.44 (m, 1 H); 6.79 (dt, J ˆ 8.7, 2.3, 1 H). 13C-NMR (75 MHz, 363 K,
C2D2Cl4): 23.0; 23.8; 24.4; 28.8; 32.0; 46.8; 54.9; 68.7; 79.6; 125.0; 146.4; 154.1; 166.0. HR-MALDI-MS: 304.1519
‡
‡
([M ‡ Na] , C15H23NO4Na ; calc. 304.1519). Anal. calc. for C15H23NO4 (281.35): C 64.04, H 8.24, N 4.98; found
C 64.27, H 8.14, N 5.01.
(‡)-tert-Butyl (2S)-2-{[(3R)-3,4,5,6-Tetrahydro-2-oxo-2H-pyran-3-yl]methyl}pyrrolidine-1-carboxylate
((‡)-23) and (À)-tert-Butyl (2S)-2-{[(3S)-3,4,5,6-Tetrahydro-2-oxo-2H-pyran-3-yl]methyl}pyrrolidine-1-car-
boxylate ((À)-24). GP A, starting from (À)-20 (670mg, 2.38 mmol) or ( ‡)-21 (670mg, 2.38 mmol), afforded,
after purification, (‡)-23 (182 mg, 27%) and (À)-24 (358 mg, 53%).
Data of (‡)-23: White solid. M.p. 94 968. [a]2D0 ˆ ‡ 20.3 (c ˆ 1.00, CHCl3). IR (neat): 2968w, 2918w,
2876w, 1722m, 1694s, 1480w, 1446w, 1379s, 1694s, 1480w, 1446w, 1379s, 1365s, 1345w, 1328w, 1311m, 1283m,
1258m, 1248m, 1220w, 1158s, 1113m, 1099s, 1076s, 1033w, 985w, 975w, 960m, 910w, 897w, 881w, 861w, 847w, 770m,
730w, 671m, 647w. 1H-NMR (300 MHz, 363 K, C2D2Cl4): 1.31 1.62 (m, 3 H); 1.42 (s, 9 H); 1.70 1.99 ( m, 5 H);
2.24 (ddd, J ˆ 13.9, 7.2, 5.3, 2 H); 2.47 2.57 (m, 1 H); 3.23 (ddd, J ˆ 10.9, 7.5, 5.0, 1 H); 3.34 3.43 (m, 1 H);
3.93 4.01 (m, 1 H); 4.22 (t, J ˆ 5.9, 2 H). 13C-NMR (75 MHz, 363 K, C2D2Cl4): 22.4; 23.7; 25.7; 28.9; 31.6; 37.1;
‡
‡
37.7; 46.4; 55.2; 68.3; 79.2; 154.9; 174.2. HR-MALDI-MS: 306.1676 ([M ‡ Na] , C15H25NO4Na ; calc.
306.1676). Anal. calc. for C15H25NO4 (283.37): C 63.58, H 8.89, N 4.94; found C 63.73, H 8.90, N 4.90.
Data of (À)-24: White solid. Mp. 90 91 8. [a]D20 ˆ À 54.9 (c ˆ 1.00, CHCl3). IR (neat): 2961w, 2870w,
1738m, 1728m, 1664s, 1477w, 1453w, 1392s, 1363m, 1314w, 1256m, 1168s, 1105s, 1069m, 1061m, 993w, 956w, 943w,
1
915w, 871w, 859w, 771m, 730w, 674w, 644w. H-NMR (300 MHz, 363 K, C2D2Cl4): 1.41 (s, 9 H); 1.54 1.99 (m,

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Helvetica Chimica Acta Vol. 88 (2005)
9 H); 1.99 2.11 (m, 1 H); 2.41 2.51 (m, 1 H); 3.21 3.40( m, 2 H); 3.86 3.93 (m, 1 H); 4.23 (dd, J ˆ 6.5, 5.0,
2 H). 13C-NMR (75 MHz, 363 K, C2D2Cl4): 22.3; 23.6; 25.4; 28.9; 30.9; 36.9; 37.8; 46.4; 55.7; 68.1; 79.2; 154.6;
‡
‡
174.2. HR-MALDI-MS: 306.1675 ([M ‡ Na] , C15H25NO4Na ; calc. 306.1676). Anal. calc. for C15H25NO4
(283.37): C 63.58, H 8.89, N 4.94; found C 63.58, H 8.80, N 4.96.
(À)-(2S,7aS)-2,3,5,6,7,7a-Hexahydro-2-(3-hydroxypropyl)-1H-pyrrolizin-3-one ((À)-25). GP B, starting
from (À)-24 (160mg, 0.95 mmol), afforded ( À)-25 (160mg, 92%). Yellow oil. [ a]2D0 ˆ À 17.3 (c ˆ 1.00,
CHCl3). IR (neat): 3378w, 2938w, 2876w, 1654s, 1450m, 1425m, 1331w, 1288w, 1202w, 1176w, 1145w, 1056m,
985w, 90 7w, 880w, 720w, 667m. 1H-NMR (300 MHz, CDCl3): 1.20 1.35 ( m, 1 H); 1.61 1.87 (m, 4 H); 1.90 2.18
(m, 5 H); 2.30(br. s, 1 H); 2.64 2.72 (m, 1 H); 3.0 6 (ddd, J ˆ 11.8, 8.7, 3.7, 1 H); 3.56 (ddd, J ˆ 11.8, 7.8, 7.8,
1 H); 3.62 3.74 (m, 2 H); 3.83 3.92 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 26.9; 29.0; 30.4; 32.3; 32.7; 41.2;
‡
‡
46.5; 60.6; 62.6; 177.5. HR-MALDI-MS: 206.1153 ([M ‡ Na] , C10H17NO2Na ; calc. 206.1151).
(À)-(2R,7aS)-2,3,5,6,7,7a-Hexahydro-2-(3-hydroxypropyl)hexahydro-1H-pyrrolizin-3-one ((À)-26). GP B,
starting from (‡)-23 (150mg, 0.53 mmol), afforded ( À)-26 (78 mg, 80%). Yellow oil. [a]2D0 ˆ À 4.5 (c ˆ 1,
CHCl3). IR (neat): 3384w, 2928w, 2865w, 1659s, 1454m, 1424m, 1331w, 1288w, 1213w, 1183w, 1143w, 1057m,
1036w, 878w, 719m, 622m. 1H-NMR (300 MHz, CDCl3): 1.23 1.51 (m, 3 H); 1.53 1.73 (m, 2 H); 1.87 2.18 (m,
5 H); 2.49 (ddd, J ˆ 12.1, 7.8, 6.2, 1 H); 2.76 2.87 (m, 1 H); 3.04 3.12 (m, 1 H); 3.48 3.57 (m, 1 H); 3.59 3.71
(m, 2 H); 3.75 3.85 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 26.6; 26.9; 30.6; 32.4; 35.7; 41.0; 46.4; 59.6; 62.1;
‡
‡
175.8. HR-MALDI-MS: 206.1152 ([M ‡ Na] , C10H17NO2Na ; calc. 206.1151). Anal. calc. for C10H17NO2
(183.25): C 65.54, H 9.35, N 7.64; found C 65.35, H 9.42, N 7.75.
X-Ray Crystal Structure of (‡)-15. Crystal data at 223(2) K for C17H18N2O3 (Mr ˆ 298.33): orthorhombic,
space group P212121 (No. 19), Dc ˆ 1.316 g cm-3, Z ˆ 4, a ˆ 7.8001(2) ä, b ˆ 8.7746(2) ä, c ˆ 22.0016(5) ä,
V ˆ 1505.85(6) ä3. Bruker-Nonius Kappa-CCD diffractometer, MoKa radiation, l ˆ 0.7107 ä. A colorless
crystal (linear dimensions ca. 0 .2Â 0.2 Â 0.18 mm) was obtained by slow evaporation of a conc. hexane soln. The
structure was solved by direct methods (SIR97) [23] and refined by full-matrix least-squares analysis
(SHELXL-97) [24], using an isotropic extinction correction and w ˆ 1/[s2(Fo2 ) ‡ (0.04532P)2 ‡ 0.1883P],
where P ˆ (F2o ‡ 2F2c )/3. All heavy atoms of (‡)-15 were refined anisotropically, H-atoms isotropically,
ˆ
whereby H-positions are based on stereochemical considerations. Final R(F) ˆ 0.038, wR(F2) 0.092 for 218
parameters and 2998 reflections with I > 2s(I) and 2.50 < q < 27.478 (corresponding R values based on all 3409
reflections are 0.046 and 0.098, resp.).
X-Ray Crystal Structure of (À)-16. Crystal data at 153(2) K for C17H18N2O3 (Mr ˆ 298.33): orthorhombic,
space group P212121 (No. 19), Dc ˆ 1.352 g cmÀ3, Z ˆ 4, a ˆ 7.6825(2) ä, b ˆ 8.7790(3) ä, c ˆ 21.7314(9) ä,
V ˆ 1465.67(9) ä3. Bruker-Nonius Kappa-CCD diffractometer, MoKa radiation, l ˆ 0.7107 ä. A colorless
crystal (linear dimensions ca. 0.15 Â 0.13 Â 0.10 mm) was obtained by slow evaporation of a conc. hexane soln.
The structure was solved by direct methods (SIR97) [23] and refined by full-matrix least-squares analysis
(SHELXL-97) [24], using an isotropic extinction correction, and w ˆ 1/[s2(Fo2 ) ‡ (0.0454P)2 ‡ 0.2969P],
where P ˆ (F2o ‡ 2F2c )/3. All heavy atoms of (À)-16 were refined anisotropically, H-atoms isotropically,
ˆ
whereby H-positions are based on stereochemical considerations. Final R(F) ˆ 0.042, wR(F2) 0.095 for 218
parameters and 2717 reflections with I > 2s(I) and 1.87 < q < 27.498 (corresponding R values based on all 3280
reflections are 0.058 and 0.104, resp.).
Crystallographic data (excluding structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as deposition No. CCDC-270197 and CCDC-
270198. Copies of the data can be obtained, free of charge, on application to the CCDC, 12 union Road,
Cambridge CB2 1EZ UK (fax: ‡ 44(1223)336033; e-mail:deposit@ccdc.cam.ac.uk).
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Received May 4, 2005