Stereoselective synthesis of 2,6-disubstituted piperidines using the iridium-catalyzed allylic cyclization as configurational switch: Asymmetric total synthesis of (+)-241 D and related piperidine alkaloids

Article abstract of DOI:10.1002/chem.200802525

Total stereoselective synthesis of the dendrobate alkaloid (+)-241D, its C6-epimer, and a spruce alkaloid, was presented. The configurational switch allows preparation of each of the eight stereoisomers with high selectivity, due to availability of enanti

Full text of DOI:10.1002/chem.200802525

DOI: 10.1002/chem.200802525
Stereoselective Synthesis of 2,6-Disubstituted Piperidines Using the Iridium-
Catalyzed Allylic Cyclization as Configurational Switch: Asymmetric Total
Synthesis of (+)-241D and Related Piperidine Alkaloids
Christian Gnamm, Caroline M. Krauter, Kerstin Brçdner, and Gꢀnter Helmchen*[a]
Piperidines are prominent structural units of alkaloids,
which often display interesting biological activities.[1] There-
fore, the stereoselective synthesis of piperidine derivatives is
important for organic and medicinal chemistry.[2]
Many routes for the construction of piperidines involve a
ꢀ
ring closure by C N bond formation. As most alkaloids pos-
sess a chirality center at C2 and/or C6 (see examples in
Figure 1), stereoselectivity is essential. Indeed, high levels of
Scheme 1. Double stereodifferentiation: interplay between substrate- and
reagent- induced selectivity ([Ir]=Ir catalyst; L*=L1 or L2).
(12b) and (2R,4S,6S)-2-methyl-6-propylpiperidin-4-ol (2), a
spruce alkaloid (Figure 1).
Figure 1. Examples of naturally occurring 2,6-disubstituted 4-hydroxypi-
The overall strategy of the syntheses is described in
Scheme 2. Key steps are two asymmetric Ir-catalyzed allylic
substitutions and an addition of Brownꢀs chiral allylboron
peridines.
diastereoselectivity have been achieved by substrate con-
trol.[3] A drawback of this approach is that only one of a
pair of diastereoisomers can be provided. We have now de-
veloped a method based on an Ir-catalyzed asymmetric allyl-
ic substitution (see Scheme 1),[4] which allows generation of
either diastereomer by external (reagent) control. To the
best of our knowledge, such a configurational switch to
obtain both possible diastereomers with high diastereoselec-
tivity has not been achieved for an allylic substitution,[5]
while it has been developed for other reactions, most promi-
nently the Katsuki–Sharpless epoxidation.[6]
reagent Ipc2BACTHUNGETRNNU(G allyl) to an intermediate aldehyde. Given the
availability of both enantiomers of all the chiral reagents,
the configurational switch allows preparation of each of the
eight stereoisomers with high selectivity.
As applications of this approach, we present total synthe-
ses of the dendrobate alkaloid (+)-241D (1), its C6-epimer
Scheme 2. Retrosynthetic analysis of 2,6-disubstituted hydroxypiperi-
dines.
[a] Dipl.-Chem. C. Gnamm, C. M. Krauter, K. Brçdner,
Prof. Dr. G. Helmchen
The synthesis of the cyclization precursor 8 started with
the known Ir-catalyzed amination of trans-crotyl methyl car-
Organisch-Chemisches Institut der Universitꢁt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
bonate with HNACTHNUTRGNE(NUG CHO)Boc, an ammonia equivalent
(Scheme 3).[7] A preparative scale of 77 mmol with a catalyst
loading of 1 mol% was employed. The catalyst was pre-
E-mail: g.helmchen@oci.uni-heidelberg.de
2050
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Chem. Eur. J. 2009, 15, 2050 – 2054

COMMUNICATION
Scheme 4. Ir-catalyzed cyclizations.
slightly reduced selectivity of 9a/9b=6:94. The yield was
slightly lower with ligand ent-L1, while the diastereoselec-
tivity of 4:96 was even higher than that achieved with ent-
L2. The Z isomer in the substrate did not markedly inter-
fere.[17] These results impressively demonstrate the high
level of stereocontrol induced by the Ir-catalysts.
In a control experiment PACHTNUTRGNENG(U OPh)3 was used as achiral
ligand. The diastereoselectivity in favor of 9a was 65:35;
thus, substrate control is very weak in this system.
Scheme 3. Synthesis of the cyclization precursor 8.
pared from the phosphoramidite ligand L1.[8] The formyl
group was removed by treatment with KOH to give the
Boc-protected amine 3 in 81% yield with 94% ee.[9] Hydro-
The configuration of the cyclization products was assigned
according to a general rule for the steric course of Ir-cata-
lyzed substitutions[4a] and was verified in the case of 9a by
an X-ray crystal structure analysis (Figure 2).[14]
boration/oxidation and Swern reaction of the resultant pri-
mary alcohol[10] furnished the sensitive aldehyde 4 in 89%
yield over two steps.[11] This was treated with (+)-B-allyldi-
ACHTUNGTRENNUNG ACHTUNGTRNE(NUGN allyl)] at low tempera-
isopinocampheylborane[12] [(+)-Ipc2B
ture. A 93:7 mixture (GC) of the homoallylic alcohols anti-5
and syn-5 was obtained.[13] The diastereoisomers could be
separated easily by flash chromatography. The desired alco-
hol anti-5[14] was isolated in 88% yield with >99% ee.[15]
The very high ee is a consequence of double asymmetric in-
duction.
Finally, chain prolongation was carried out by cross meta-
thesis (Grubbsꢀ II catalyst) of the homoallylic alcohol anti-5
and the biscarbonate 6 (5 equiv). The allylic carbonate 7
was produced in 87% yield as 9:1 mixture of E/Z isomers
(1H NMR spectroscopy). Cleavage of the Boc group under
standard conditions gave the cyclization precursor 8 in 96%
yield.
The Ir-catalyzed cyclization of amine 8 (E:Z=9:1) pro-
ceeded smoothly under standard conditions (4 mol% of cat-
alyst; Scheme 4).[16] With L2 as ligand,[8] the piperidine 9a
was obtained in 90% yield with an almost perfect diastereo-
selectivity of 9a/9b=98:2. Upon use of ligand ent-L2, the
diastereoisomer 9b was prepared in 74% yield with only
Figure 2. Molecular structure of 9a from single-crystal X-ray structure
analysis.
The alkaloid (+)-241D (1) was isolated by Daly et al.
from the skin of Dendrobates speciosus, a rare poison frog
of western Panama.[18] This compound was found to be a
potent inhibitor of binding of [3H]perhydrohistrionicotoxin
to nicotinic acetylcholine receptor channels.[19] Subsequent
to a synthesis of the racemate[19] asymmetric syntheses of
(+)-1 and (ꢀ)-1 as well as syntheses of the C4-epimers were
reported.[20]
Our synthesis of 1 is described in Scheme 5. Chain elonga-
tion of 9a by cross metathesis was chosen as key step. Ini-
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2051

G. Helmchen et al.
known. The assignment shown in Figure 1 is based on the
observation that, with one exception (euphococcinine), 2,6-
disubstituted piperidines occurring in conifers possess the
same absolute configuration at the methylated center C2.[21]
Our synthesis of 2 started with the vinypiperidine 10a
(Scheme 6). Oxidative cleavage of the double bond (O3/
Scheme 5. Synthesis of (+)-241D (1) and its C6-epimer 12b: a) CbzCl,
Na2CO3, CH2Cl2/H2O, 0 8C!RT; b) Ac2O, pyridine; c) 1-Nonene
(10 equiv), Grubbsꢀ II catalyst (10 mol%), CH2Cl2, 5 h, reflux (71%,
91% corr.); d) H2, Rh/C (5 mol%), MeOH, 1 h, RT (92%); e) 0.5n
NaOH/MeOH; f) 1-Nonene (10 equiv), Grubbsꢀ II catalyst (10 mol%),
CH2Cl2, 8 h, reflux (46%, 99% corr.); g) H2, Pd(OH)2/C (5 mol%),
MeOH, 1 h, RT (86%).
Scheme 6. Synthesis of the spruce alkaloid 2.
tially, N-protection by salt formation was probed. The at-
tempts were not successful, partially because of low solubili-
ty of the salts in dichloromethane. Next, protecting groups
at both O and N were introduced by using standard proce-
dures. Thus, the carbamate 10a was prepared and treated
with 1-nonene in the presence of Grubbsꢀ II catalyst
(10 mol%). The cross metathesis product was obtained in
71% yield, the starting material was partially recovered
(20%). Catalytic hydrogenation (Rh/C) furnished the free
amine 11a in 92% yield. No epimerization was found for
this step within the limits of detection (1H NMR spectrosco-
py). Finally, the acetate was hydrolyzed to give the natural
product 1, the spectroscopic properties of which were in full
agreement with those reported. An overall yield of 27%
was achieved.
The synthesis of the C6-epimer of 1 through an analogous
route was straightforward. Protection of 9b gave 10b in
good yield. However, 10b was significantly less reactive
than 10a in the cross metathesis reaction. After testing sev-
eral reaction conditions we had to settle with incomplete
conversion and a moderate isolated yield of 46%; fortunate-
ly, the starting material was fully recovered (53%). Similar-
ly, hydrogenation of 10b by using Rh/C as catalyst was not
possible; Pd(OH)2 on charcoal was used instead, and amine
11b was obtained in 86% yield. Other than anticipated, no
epimerization occurred (1H NMR spectroscopy). Hydrolysis
gave the amino alcohol 12b in 95% yield.[14] This concluded
the first synthesis of the C6-epimer of the alkaloid (+)-
241D (1). The overall yield was 15%.
SMe2) gave the aldehyde 13, which was subjected to a
Wittig olefination to complement the C3 side chain. The
olefin 14 was obtained in 81% yield as a mixture of isomers
(Z/E=87:13, 1H NMR spectroscopy). Catalytic hydrogena-
tion with Pd(OH)2/C as catalyst and subsequent hydrolysis
furnished 2 in the form of colorless polyhedra ([a]2D0 =+8.8,
c=0.43 in MeOH, >99% ee)[14] in an overall yield of 24%.
In conclusion, we are presenting the first example of a
configurational switch for Ir-catalyzed allylic cyclizations,
which allows both possible diastereoisomeric products to be
generated with very high selectivity. The application of this
method to an asymmetric synthesis of the alkaloid (+)-
241D (1) and to the first asymmetric synthesis of its C6-
epimer 12b are reported. Furthermore, the first stereoselec-
tive synthesis of the spruce alkaloid (2R,4S,6S)-2-methyl-6-
propylpiperidin-4-ol (2) is presented. Extension of our
method to syntheses of Prosopis alkaloids is under active in-
vestigation.
Experimental Section
General procedure for Ir-catalyzed cyclization reactions: Success with the
following procedures requires dry THF (<30 mgLꢀ1 of H2O, Karl–Fisch-
er titration). A Schlenk tube was dried under argon with a heat gun and
charged with a solution of [{IrCl
ACHTUNGTRENNUNG
(0.04 mmol) in anhydrous THF. Anhydrous 1,5,7-triazabicycloACHTUNGTRENNUNG
5-ene (TBD; 11.1 mg, 0.08 mmol) was added, and the mixture was stirred
for 5 min (L2) or 1 h (L1). Then the carbonate 8 (217.3 mg, 1 mmol) was
added and the mixture was stirred until control by TLC (CH2Cl2/MeOH
The piperidine derivative 2 has been identified as a trace
alkaloid in extracts from Colorado blue spruce (Picea pun-
gens) by Stermitz et al.[21] Its structure was deduced from
GC/MS data and on the basis of analogy to similar alkaloids
and was verified by a synthesis of the racemic compound.
The absolute configuration and optical rotation were un-
4:1, Rf(8)=0.4, RfACTHNUGTRNENUG(9a)=0.3, RfCAHUTNGTREN(NUNG 9b)=0.3) revealed complete conversion.
The mixture was concentrated and analyzed by GC with respect to the
ratio of diastereomers.[16] The crude product was subjected to flash
column chromatography (silica gel, CH2Cl2/MeOH 4:1 to 3:1). Analyti-
cally pure samples were obtained by sublimation under reduced pressure.
2052
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Chem. Eur. J. 2009, 15, 2050 – 2054

Stereoselective Synthesis of 2,6-Disubstituted Piperidines
COMMUNICATION
Physical data for selected compounds:
Acknowledgements
(ꢀ)-(2R,4S,6R)-2-Methyl-6-vinylpiperidin-4-ol (9a): Rf =0.3 (CH2Cl2/
MeOH 4:1); colorless needles; m.p. 82–838C; [a]2D0 =ꢀ4.7 (c=0.34 in
acetone, >99% ee); 1H NMR (300 MHz, CDCl3): d=5.82 (ddd, J=17.1,
10.5, 6.6 Hz, 1H; =CH), 5.16 (ddd, J=17.3, 1.3, 1.3 Hz, 1H; =CHEHZ),
5.04 (ddd, J=10.4, 1.1, 1.1 Hz, 1H; =CHEHZ), 3.69 (dddd, J=11.1, 11.1,
4.6, 4.6 Hz, 1H; CHOH), 3.20–3.13 (m, 1H; 6-H), 2.80–2.69 (m, 1H; 2-
H), 2.11 (brs, 2H; NH, OH), 2.01–1.90 (m, 2H; 3-HaHb, 5-HaHb), 1.22–
0.99 (m, 2H; 3-HaHb, 5-HaHb), 1.13 ppm (d, J=6.2 Hz, 3H; CH3);
13C NMR (75 MHz, CDCl3): d=140.28 (d, =CH), 114.96 (t, =CH2), 68.99
(d, CHOH), 57.74 (d, C-6), 50.26 (d, C-2), 43.33, 41.16 (2t, C-3, C-5),
22.36 ppm (q, CH3); HRMS (EI+): m/z calcd for C8H15NO+: 141.1148;
found: 141.1142 [M]+.
This work was supported by the Studienstiftung des deutschen Volkes.
We thank Prof. Frank R. Stermitz (Colorado State University) for send-
ing us a sample of racemic 2, Dr. Frank Rominger (Universitꢁt Heidel-
berg) for the crystal structure analyses, and Prof. Dr. K. Ditrich (BASF
AG) for enantiomerically pure 1-arylethylamines.
Keywords: alkaloids · allylic amination · heterocycles ·
iridium · total synthesis
(+)-(2R,4S,6S)-2-Methyl-6-vinylpiperidin-4-ol (9b): Rf =0.3 (CH2Cl2/
MeOH 4:1); colorless solid, m.p. 38–408C; [a]2D0 =+69.2 (c=0.27 in ace-
tone, >99% ee); 1H NMR (500 MHz, CDCl3): d=5.97 (ddd, J=17.3,
10.8, 5.6 Hz, 1H; =CH), 5.13 (ddd, J=17.4, 1.4, 1.4 Hz, 1H; =CHEHZ),
5.12 (ddd, J=10.5, 1.4, 1.4 Hz, 1H; CH=CHEHZ), 3.84 (dddd, J=11.0,
11.0, 4.5, 4.5 Hz, 1H; CHOH), 3.80–3.76 (m, 1H; 6-H), 3.01–2.94 (m,
1H; 2-H), 2.05–1.98 (m, 3H; 5-HaHb, OH, NH), 1.95–1.91 (m, 1H; 3-
HaHb), 1.58 (ddd, J=12.4, 11.3, 5.5 Hz, 1H; 5-HaHb), 1.10–1.02 (m, 1H;
3-HaHb), 1.08 ppm (d, J=6.4 Hz, 3H; CH3); 13C NMR (125 MHz,
CDCl3): d=140.06 (d, =CH), 115.20 (t, =CH2), 65.52 (d, CHOH), 54.46
(d, C-6), 44.93 (d, C-2), 44.18 (t, C-3), 38.68 (t, C-5), 22.76 ppm (q, CH3);
HRMS (EI+): m/z calcd for C8H15NO+: 141.1148; found: 141.1167
[M]+.
[1] G. M. Strunz, J. A. Findlay in The Alkaloids, Vol. 26 (Ed.: A.
Brossi), Academic Press, New York, 1985, pp. 89–183.
[2] Reviews: a) M. G. P. Buffat, Tetrahedron 2004, 60, 1701–1729; b) F.-
X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 3693–3712.
[3] a) H. Yokoyama, H. Ejiri, M. Miyazawa, S. Yamaguchi, Y. Hirai,
Tetrahedron: Asymmetry 2007, 18, 852–856; b) H. Makabe, L. K.
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Weihofen, Chem. Commun. 2007, 675–691; b) R. Takeuchi, S.
Kezuka, Synthesis 2006, 3349–3366; c) H. Miyabe, Y. Takemoto,
Synlett 2005, 1641–1655.
[5] Sequential Ir-catalyzed inter- and intramolecular aminations of bi-
sallylic substrates only yield the trans-diastereomer with high selec-
tivity: C. Welter, A. Dahnz, B. Brunner, S. Streiff, P. Dꢃbon, G.
Helmchen, Org. Lett. 2005, 7, 1239–1242. For other intramolecular
Ir- and Pd-catalyzed allylic substitutions see: C. Welter, O. Koch, G.
Lipowsky, G. Helmchen, Chem. Commun. 2004, 896–897 and B. M.
Trost, M. J. Krische, R. Radinov, G. Zanoni, J. Am. Chem. Soc.
1996, 118, 6297–6298, respectively. Recently, Miyabe and Takemoto
and co-workers reported a highly stereoselective Ir-catalyzed double
allylation of guanidines: H. Miyabe, K. Yoshida, V. K. Reddy, Y.
Takemoto, J. Org. Chem. 2009, 74, 305–311.
(+)-(2R,4S,6S)-2-Methyl-6-nonylpiperidin-4-ol [(+)-241D] (1): Colorless
needles, m.p. 108–1098C, [a]2D0 =+5.9 (c=0.65 in MeOH, >99% ee);
1H NMR (500 MHz, CDCl3): d=3.66 (dddd, J=11.0, 11.0, 4.6, 4.6 Hz,
1H; CHOH), 2.71 (dqd, J=11.1, 6.3, 2.3 Hz, 1H; 2-H), 2.56 (dddd, J=
11.0, 6.4, 6.4, 2.2 Hz, 1H; 6-H), 2.01–1.93 (m, 4H; 3-Heq, 5-Heq, NH,
OH), 1.49–1.37 (m, 2H; 1’-H), 1.36–1.21 (m, 14H; CH2(n-nonyl)), 1.14 (d,
J=6.4 Hz, 3H; CH3CHN), 1.05 (ddd, J=11.6, 11.6, 11.6 Hz, 1H; 3-Hax),
1.00 (ddd, J=11.5, 11.5, 11.5 Hz, 1H; 5-Hax), 0.88 ppm (t, J=7.0 Hz, 3H;
CH3CH2); 13C NMR (125 MHz, CDCl3): d=69.43 (d, CHOH), 55.02 (d,
C-6), 50.36 (d, C-2), 43.86 (t, C-3), 41.63 (t, C-5), 36.73 (t, C-1’), 32.04,
29.87, 29.71, 29.69, 29.46, 26.15 (6t, CH2(n-nonyl)), 22.81 (t, CH2CH3), 22.41
(q, CH3CHN), 14.26 ppm (q, CH3CH2); HRMS (FAB+): m/z calcd for
C15H32NO+: 242.2478; found: 242.2453 [M+H]+.
[6] R. A. Johnson, K. B. Sharpless, Catalytic Asymmetric Synthesis, 2nd
ed. (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, pp. 231–280.
[7] S. Fçrster, G. Helmchen, Synlett 2008, 831–836.
[8] a) Preparation of L1: B. L. Feringa, Acc. Chem. Res. 2000, 33, 346–
353. b) Preparation of L2: K. Tissot-Croset, D. Polet, S. Gille, C.
Hawner, A. Alexakis, Synthesis 2004, 2586–2590.
[9] The enantiomer of amine 3 has previously been prepared by other
routes: a) T. Fujisawa, S. Odake, Y. Ogawa, J. Yasuda, Y. Morita, T.
Morikawa, Chem. Pharm. Bull. 2002, 50, 239–252; b) T. Moriwake,
S. Hamano, S. Saito, S. Torii, S. Kashino, J. Org. Chem. 1989, 54,
4114–4120.
[10] The enantiomer of this alcohol has been already described: a) A.
Rae, A. E. Aliev, J. E. Anderson, J. L. Castro, J. Ker, S. Parsons, M.
Stchedroff, S. Thomas, A. B. Tabor, J. Chem. Soc. Perkin Trans. 1
1999, 1933–1941; b) P. Casara, C. Danzin, B. Metcalf, M. Jung, J.
Chem. Soc. Perkin Trans. 1 1985, 2201–2207.
[11] The aldehyde ent-4 has been synthesized before: M. Alcꢄn, M.
Canas, A. Moyano, M. A. Pericꢅs, A. Riera, Tetrahedron Lett. 1994,
35, 1589–1592.
[12] a) H. C. Brown, P. K. Jadhav, J. Am. Chem. Soc. 1983, 105, 2092–
2093; b) U. S. Racherla, H. C. Brown, J. Org. Chem. 1991, 56, 401–
404.
[13] The diastereoselectivity of the allylation was determined by GC
[HP-1 (cross-linked methylsilicon gum), 25 mꢆ0.2 mmꢆ0.33 mm,
1408C isothermal, injector temperature 2508C, detector temperature
(+)-(2R,4S,6R)-2-Methyl-6-nonylpiperidin-4-ol (12b): Colorless needles;
m.p. 898C; [a]2D0 =+10.0 (c=0.57 in MeOH, >99% ee); 1H NMR
(600 MHz, CDCl3): d=3.87 (dddd, J=10.7, 10.7, 4.5, 4.5 Hz, 1H;
CHOH), 3.13–3.10 (m, 1H; 6-H), 2.94–2.88 (m, 1H; 2-H), 1.97–1.93 (m,
1H; 3-HaHb), 1.88–1.84 (m, 1H; 5-HaHb), 1.82 (brs, 2H; NH, OH), 1.55–
1.45 (m, 1H; 1’-HaHb), 1.48 (ddd, J=11.9, 11.6, 5.2 Hz, 1H; 5-HaHb),
1.44–1.38 (m, 1H; 1’-HaHb), 1.30–1.22 (m, 14H; CH2(n-nonyl)), 1.08 (d, J=
6.3 Hz, 3H; CH3CHN), 1.03 (ddd, J=11.4, 11.4, 11.4 Hz, 1H; 3-HaHb),
0.87 ppm (t, J=7.0 Hz, 3H; CH3CH2); 13C NMR (150 MHz, CDCl3): d=
65.71 (d, CHOH), 52.50 (d, C-6), 44.27 (d, C-2), 44.16 (t, C-3), 38.65
(t, C-5), 32.44 (t, C-1’), 32.02, 29.76, 29.76, 29.71, 29.45, 27.16 (6t,
CH2(n-nonyl)), 22.91 (t, CH2CH3), 22.81 (q, CH3CHN), 14.25 ppm (q,
CH3CH2); HRMS (ESI+): m/z calcd for C15H32NO+: 242.2478; found:
242.2483 [M+H]+.
(+)-(2R,4S,6S)-2-Methyl-6-propylpiperidin-4-ol (2): Colorless polyhedra;
m.p. 94–958C; [a]2D0 =+8.8 (c=0.43 in MeOH, >99% ee); 1H NMR
(500 MHz, CDCl3): d=3.63 (dddd, J=11.0, 11.0, 4.6, 4.6 Hz, 1H;
CHOH), 2.68 (dqd, J=11.0, 6.3, 2.3 Hz, 1H; 2-H), 2.58–2.53 (m, 1H; 6-
H), 1.98–1.90 (m, 2H; 3-HaHb, 5-HaHb), 1.85 (brs, 2H; NH, OH), 1.43–
1.30 (m, 4H; CH2CH2), 1.11 (d, J=6.3 Hz, 3H; CH3CHN), 1.05–0.93 (m,
2H; 3-HaHb, 5-HaHb), 0.90 ppm (t, J=7.1 Hz, 3H; CH3CH2); 13C NMR
(75 MHz, CDCl3): d=69.34 (d, CHOH), 54.66 (d, C-6), 50.28 (d, C-2),
44.00 (t, C-3), 41.78 (t, C-5), 39.06 (t, CH2CH2CH3), 22.55 (q, CH3CHN),
19.29 (t, CH2CH3), 14.28 ppm (CH3CH2); HRMS (ESI+): m/z calcd for
C9H20NO+: 158.1539; found: 158.1539 [M+H]+.
2808C]: tRACHTNUTRGNENUG(anti-5)=17.6 min, tRAHCTUNGTRNEN(UGN syn-5)=19.0 min.
[14] The relative configuration was verified by X-ray crystal structure
analysis. Selected crystallographic data for 9a: colorless needles,
C8H15NO, M=141.21, dimensions 0.68ꢆ0.05ꢆ0.04 mm3, orthorom-
bic, space group P212121, Z=4, a=6.3274(5), b=8.7135(8), c=
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G. Helmchen et al.
15.5742(13) ꢇ, a=90, b=90, g=908, V=858.66(13) ꢇ3, 1calcd
1.092 gcmꢀ1
T=200(2) K, qmax =20.798, radiation MoKa (l=
=
[16] The diastereoselectivity of the cyclizations was determined by GC
as above (column: HP-1), 908C isothermal: t
(9b)=18.2 min.
RACHTUNGTREN(NUNG 9a)=15.5 min, tR-
,
AHCTUNGTRENNUNG
0.71073 ꢇ), 0.38 w scans with CCD area detector, covering a whole
sphere in reciprocal space; 4611 reflections collected, 895 unique
(Rint =0.1046), 643 observed [I>2s(I)]; intensities were corrected
for Lorentz and polarization effects, an empirical absorption correc-
tion was applied using SADABS[22] based on the Laue symmetry of
the reciprocal space, m=0.07 mmꢀ1, min/max transmission=0.95/
1.00, structure solved by direct methods and refined against F2 with
a full-matrix least-squares algorithm by using the SHELXTL-PLUS
(6.10) software package,[23] 99 parameters refined, hydrogen atoms
were treated using appropriate riding models, except of H1 and H4
at the hetero atoms N1 and O4, which were refined isotropically or
restrained, Flack absolute structure parameter ꢀ4(5), goodness of fit
1.07 for observed reflections, final residual values R1(F)=0.054,
wR2(F2)=0.103 for observed reflections, residual electron density
ꢀ0.13 to 0.14 eꢇꢀ3. CCDC-704949 (anti-5), CCDC-704950 (9a),
CCDC-704951 (12b) and CCDC-704952 (2) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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(Z)-8 (Z:E=>90:10) was treated according to Scheme 4, with
(S,S,aS)-L2 as ligand, the cyclization to give 9a was slow and nonse-
lective (9a/9b=63:37, 20%).
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[22] G. M. Sheldrick, Bruker Analytical X-ray-Division, Madison, Wis-
consin 2006.
[15] The enantiomeric excess of anti-5 was determined by GC using a
chiral column (Chrompack permethyl-b-cyclodextrin, 25 mꢆ
0.25 mmꢆ25 mm, 1258C isothermal, injector temperature 2008C, de-
[23] G. M. Sheldrick, Bruker Analytical X-ray-Division, Madison, Wis-
consin 2001.
tector temperature 2508C):
tRACTHNGUTREN[NUG (R,R)-5]=42.0 min, tRACHTUNGERTN[NUNG (S,S)-5]=
45.8 min.
Received: December 2, 2008
Published online: January 29, 2009
2054
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