Synthetic approaches to racemic porantheridine and 8-epihalosaline via a nitroso diels-alder cycloaddition/ring-rearrangement metathesis sequence

Article abstract of DOI:10.1021/jo100768d

The application of a sequence involving a nitroso Diels-Alder cycloaddition and a ring-rearrangement metathesis to the total synthesis of (±)-8-epihalosaline and the formal synthesis of (±)-porantheridine is described. The formation of the 2,6-trans-disubstituted piperidine backbone of porantheridine has been accomplished by addition of a Grignard reagent onto an N-benzylpiperidone followed by a highly diastereoselective reduction of the imminium intermediate in one pot.

Full text of DOI:10.1021/jo100768d

pubs.acs.org/joc
8-epihalosaline (2) are syn-2-(2-hydroxyalkyl)piperidine
Synthetic Approaches to Racemic Porantheridine and
8-Epihalosaline via a Nitroso Diels-Alder
Cycloaddition/Ring-Rearrangement Metathesis
Sequence
alkaloids (Figure 1). The tricyclic porantheridine (1)2 was
isolated from Poranthera corymbosa and 8-epihalosaline (2)3
from Andrachne aspera Spreng.
Pierre Sancibrao, Delphine Karila, Cyrille Kouklovsky,*
and Guillaume Vincent*
Laboratoire de Chimie des Proceꢀdeꢀs et Substances Naturelles,
^
ꢀ
ICMMO, CNRS UMR 8182, Bat 410, Universite de
Paris-Sud-11, F-91405 Orsay, France
FIGURE 1. syn-2-(2-Hydroxyalkyl)piperidine alkaloids.
cyrille.kouklovsky@u-psud.fr; guillaume.vincent@u-psud.fr
Received April 22, 2010
As part of the involvement of our group in the develop-
ment of the nitroso Diels-Alder (NDA) reaction4,5 we pro-
posed the realization of the total syntheses of these alkaloids
via the ring-rearrangement metathesis (RRM)6 of NDA
cycloadducts (Scheme 1).
It has been demonstrated by our research group that
strained bicyclic cis-3,6-dihydro-1,2-oxazines with an alkene
side chain obtained by NDA cycloaddition could be treated with
Grubbs’ II metathesis catalyst (G-II) in the presence of an external
alkene to induce ring-opening metathesis (ROM), ring-closing
metathesis (RCM), and cross-metathesis (CM) to yield isoxazolo-
pyridinones 5.7 Such a structure (with R=Me, 5a) could be seen as
a precursor of 8-epihalosaline and porantheridine.
In practice, the synthesis of 5a started with the conver-
sion of but-3-enoic acid 6 to the corresponding hydroxamic
acid 7. Oxidation of the latter one with sodium periodate
in presence of cyclopentadiene led to the desired nitroso
Diels-Alder adduct 4 in 61% yield from 6. The ring-
rearrangement metathesis was then performed with 10 mol %
of Grubbs’ II catalyst (G-II) and an excess of but-2-ene gas
affording the expected isoxazolopyridinone 5a (75% yield).
No significant amount of the isoxazolopyridinonethatdid not
undergo cross-metathesis (R=H) was observed as is usually
the case with terminal alkenes as cross-metathesis partners.7
The application of a sequence involving a nitroso Diels-
Alder cycloaddition and a ring-rearrangement metathe-
sis to the total synthesis of (()-8-epihalosaline and the
formal synthesis of (()-porantheridine is described. The
formation of the 2,6-trans-disubstituted piperidine back-
bone of porantheridine has been accomplished by addi-
tion of a Grignard reagent onto an N-benzylpiperidone
followed by a highly diastereoselective reduction of the
imminium intermediate in one pot.
ꢀ
(3) Isolation: (a) Hootele, C.; Mill, S. J. Nat. Prod. 2000, 63, 762–764.
Total syntheses: (b) Maio, W. A.; Sinishtaj, S.; Posner, G. H. Org. Lett. 2007,
9, 2673–2676. (c) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276–11282.
(4) Reviews on NDA: (a) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc.
Jpn. 2007, 80, 595–607. (b) Yamamoto, Y.; Yamamoto, H. Eur. J. Org.
Chem. 2006, 2031–2043. (c) Yamamoto, H.; Momiyama, N. Chem. Commun.
2005, 3514–3525. (d) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317–
1348. (e) Streith, J.; Defoin, A. Synlett 1996, 189–200. (f) Kibayashi, C.;
Aoyagi, S. Synlett 1995, 873–879. (g) Streith, J.; Defoin, A. Synthesis 1994,
1107–1117.
The abundance of biologically potent piperidines, indoli-
zidines, and quinolizidines has resulted in intense synthetic
efforts during the last decades.1 Porantheridine (1) and
(5) (a) Galvani, G.; Calvet, G.; Blanchard, N.; Kouklovsky, C. Org.
Biomol. Chem. 2008, 6, 1063–1070. (b) Calvet, G.; Guillot, R.; Blanchard, N.;
Kouklovsky, C. Org. Biomol. Chem. 2005, 3, 4395–4401. (c) Calvet, G.;
Dussaussois, M.; Blanchard, N.; Kouklovsky, C. Org. Lett. 2004, 6, 2449–
2451.
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165. (b) Cossy, J.
Chem. Rec. 2005, 5, 70–80. (c) Felpin, F.-X.; Lebreton, J. Tetrahedron 2004,
60, 10127–10153. (d) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729.
(e) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957–5978. (f) Laschat, S.;
Dickner, T. Synthesis 2000, 1781–1813.
(2) Isolation: (a)Denne, W. A.; Johns, S. R.; Lamberton, J. A.; Mathieson,
A. McL.; Suares, H. Tetrahedron Lett. 1972, 13, 1767–1769. (b) Johns, S. R.;
Lamberton, J. A.; Sioumis, A. A.; Suares, H. Aust. J. Chem. 1974, 27, 2025–
2034. Total syntheses: (c) Gossinger, E. Tetrahedron Lett. 1980, 21, 2229–
2232. (d) Comins, D. L.; Hong, H. J. Am. Chem. Soc. 1993, 115, 8851–8852.
(6) Reviews: (a) Holub, N.; Blechert, S. Chem. Asian J. 2007, 2, 1064–
ꢀ
1082. (b) Arjona, O.; Csaky, A. G.; Plumet, J. Eur. J. Org. Chem. 2003, 611–
622. Selected applications in total syntheses: (c) Barbe, G.; Charette, A. G.
J. Am. Chem. Soc. 2008, 130, 13873–13875. (d) Henderson, J. A.; Phillips,
A. J. Angew. Chem., Int. Ed. 2008, 47, 8499–8501. (e) Hart, A. C.; Phillips,
A. J. J. Am. Chem. Soc. 2006, 128, 1094–1095. (f) Weatherhead, G. S.; Cortez,
G. A.; Schrock, R. R.; Hoveyda, A. H. Proc. Natl. Acad. Sci. U.S.A. 2004,
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(e) David, M.; Dhimane, H.; Vanucci-Bacque, C.; Lhommet, G. J. Org. Chem.
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101, 5805–5809. (g) Wrobleski, A.; Sahasrabudhe, K.; Aube, J. J. Am. Chem.
1999, 64, 8402–8405. (f) Takahata, H.; Ouchi, H.; Ichinose, M.; Nemoto, H.
Org. Lett. 2002, 4, 3459–3462. (g) Takahata, H.; Saito, Y.; Ichinose, M. Org.
Biomol. Chem. 2006, 4, 1587–1595. (h) Bates, R.; Lu, Y. J. Org. Chem. 2009, 74,
9460–9474.
Soc. 2002, 124, 9974–9975.
(7) Calvet, G.; Blanchard, N.; Kouklovsky, C. Org. Lett. 2007, 9,
1485–1488.
DOI: 10.1021/jo100768d
r
Published on Web 05/26/2010
J. Org. Chem. 2010, 75, 4333–4336 4333
2010 American Chemical Society

Sancibrao et al.
JOCNote
SCHEME 1. The Nitroso Diels-Alder (NDA) Cycloaddition/
Ring Rearrangement Metathesis (RRM) Sequence
SCHEME 3. Retrosynthesis of Porantheridine
SCHEME 4. Unsuccessful Formation of the 2,6-Trans-Disub-
stituted Piperidine 13
SCHEME 2. Total Synthesis of (()-8-Epihalosaline
deliver the 2,6-trans-disubstituted piperidinic core 13 of
porantheridine.11
In accord with the retrosynthetic scheme, the O-benzyl and
N-Boc compound 14 was formed. Unfortunately, the addition
of allylmagnesium bromide resulted in the opening of the
N-Boc lactam and in the formation of alcohol 15 after hydride
reduction instead of the expected piperidine 13 (Scheme 4).
We postulated that switching the N-Boc electron-with-
drawing group to an N-alkyl group would prevent the
opening of the lactam upon addition of the organometallic
reagent. In fact, the stereoselective formation of 2,6-trans-
disubstituted piperidines by direct addition of an organome-
tallic reagent to N-alkylpiperidones followed by a hydride
reducing agent has been overlooked since the pioneering
work of Fowler with organolithium reagents,12-15 although
several groups have reported the synthesis of cis-substituted
indolizidine or quinolizidine skeletons by a similar sequence
on bicyclic lactams.16 We decided to investigate this trans-
formation with N-benzylpiperidone 16.
The synthesis of 8-epihalosaline is described in Scheme 2.
Hydrogenation of the double bonds over Rh-C delivered 9
as the major product along with N-O cleavage product 10
and the deoxygenated compound 8 in a 10:1:1.5 (9/10/8)
mixture.8 Complete cleavage of the N-O bond was effected
with subjection of the previous mixture with Mo(CO)6 and
9
NaBH4 to yield 10 (57% over two steps). Finally, (()-8-
epihalosaline (2) was obtained by reduction of the amide
with LiAlH4 in 88% yield. All spectroscopic data of 2 were in
agreement with the published data of 8-epihalosaline.3
The retrosynthetic analysis of porantheridine is described
in Scheme 3. Addition of an allyl Grignard reagent to the
N-Boc lactam 11 would lead to imminium species 12 of which
the favored conformation has a pseudoaxial alkyl group at
C2 to minimize steric interactions between the alkyl side
chain at C2 and the nitrogen substituent.10 The stereoelec-
tronically preferred axial addition of an hydride should
Addition of allylmagnesium bromide onto dibenzylated
compound 16 at room temperature followed by addition of
sodium cyanoborohydride in acetic acid delivered stereose-
lectively the desired 2,6-trans-disubstituted piperidine 17 but
(12) (a) Hwang, Y. C.; Chu, M.; Fowler, F. W. J. Org. Chem. 1985, 50,
ꢀ
ꢀ ꢀ
3885–3890. (b) Freville, S.; Bonin, M.; Celerier, J.-P.; Husson, H.-P.;
Lhommet, G.; Quirion, J.-C.; Thuy, V. M. Tetrahedron 1997, 53, 8447–8456.
(13) One related example of 2,3-cis-disubstituted piperidines from
N-alkylpiperidones has been reported: Micouin, L.; Quirion, J.-C.; Husson,
H.-P. Tetrahedron Lett. 1996, 37, 849–852.
(8) The use of other hydrogenation catalysts resulted in the extensive
formation of dehydrogenation compound 8.
€
(9) Zhang, D.; Suling, C.; Miller, M. J. J. Org. Chem. 1998, 63, 885–888.
(10) (a) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984, 106, 1010–1018.
For a review, see: (b) Johnson, F. J. Chem. Rev. 1968, 68, 375–413.
(14) For related syntheses of 2,5-disubstituted pyrrolidines from
N-alkylpyrrolidinones, see ref 12a and: Shibagaki, M.; Matsushita, H.;
Kaneko, H. Heterocycles 1986, 24, 2315–2319.
ꢀ
(11) (a) Mill, S.; Hootele., C. Can. J. Chem. 1996, 74, 2434–2443.
(b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296. (c) Deslonchamps, P.
In Stereoelectronic Effects in Organic Chemistry; Pergamon: New York, 1983;
Chapter 6.
(15) For the synthesis of 2,6-trans-disubstituted piperidines from thio-
lactams, see: Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org.
Chem. 2003, 68, 1919–1928.
4334 J. Org. Chem. Vol. 75, No. 12, 2010

Sancibrao et al.
JOCNote
SCHEME 5. Formation of the 2,6-Trans-Disubstituted
N-Benzylpiperidine 17
SCHEME 6. Cross-Metathesis and Formal Synthesis of
(()-Porantheridine
in low yield with recovery of the starting piperidone 16
(Scheme 5). Running the Grignard reaction in refluxing
THF with a large excess of allylmagnesium bromide (7 equiv)
during 3 h delivered 17 in 17% yields along with the product
of double allyl addition. Lowering the temperature to 50 °C
allowed us to obtain 17 in 51% yields. Eventually reducing
the excess of the Grignard reagent to 3 equiv and the reaction
time to 30 min resulted in a satisfactory 70% yield of 17 as a
single diastereoisomer.17 Presumably, the N-alkyliminium
intermediate derived from 16 adopts the same conformation
as the N-acyliminium intermediate 12.
Cross-metathesis with methyl vinyl ketone was next re-
quired to complete the synthesis of porantheridine. Despite
tremendous efforts, this operation was unproductive with
N-benzylpiperidine 17, most probably because of the coordina-
tion of the active ruthenium intermediate 18 by the lone pair of
the nitrogen that prevents the reaction with the methyl vinyl
ketone. Addition of Ti(O-i-Pr)4 or Bronsted acids did not lead
to any improvement.18 To circumvent this problem, the N-benzyl
group was replaced by a CO2Me electron-withdrawing group.19
To our satisfaction, the cross-metathesis compound 20 was thus
obtained in 41% yields over two steps with Grubbs-Hoveyda
II catalyst (H-II).
metathesis sequence as demonstrated by the syntheses of the
piperidinic alkaloids (()-8-epihalosaline and (()-porantheri-
dine. In addition, the formation of the 2,6-trans-disubstituted
piperidine framework of porantheridine features a rare Grignard
addition onto an N-alkyl lactam followed by a highly diaster-
eoselective reduction in one pot.
Experimental Section
2-(3-Butenoyl)-2-aza-3-oxabicyclo[2.2.1]-5-heptene (4). To a
solution of N-hydroxysuccinimide (1.49 g, 12.95 mmol) in dichloro-
methane (15 mL) at 0 °C were added dicyclohexylcarbodiimide
(2.55 g, 12.36 mmol) and but-3-enoic acid (1 mL, 11.77 mmol). The
mixture was stirred for 2 h, and the insoluble dicyclohexylurea
formed was removed by filtration. The filtrate was concentrated,
and the crude hydroxamic acid was solubilized in diethyl ether and
water. Hydroxylamine hydrochloride (2.03 g, 29.2 mmol) and
sodium carbonate (2.1 g, 19.9 mmol) were successively added at
0 °C, and the mixture was stirred for 12 h. The heterogeneous
mixture was then filtered with ethyl acetate. The filtrate was
concentrated to yield the crude hydroxamic acid. Methanol
and water were added to the crude hydroxamic acid, and then
cyclopentadiene (5.07 mL, 61.5 mmol) and sodium periodate
(3.73 mmol, 18.5 mmol) were successively added at 0 °C. The
reaction was stirred for 30 min at 0 °C and 1.5 h at rt. The reaction
wasthenquenchedwithanaqueous saturatedsolutionofNaHCO3
and extracted twice with ethyl acetate. The organic phase was dried
with Na2SO4, filtered, and concentrated. The crude was purified
by flash column chromatography (20% to 30% and 50%
EtOAc/cyclohexane) to yield 1.24 g (61%) of the desired nitroso
Hydrogenation of 20 with PdCl2 allowed us to remove the
O-benzyl protecting group and reduce the double bond of the
enone and gave rise to compound 21, which is an intermedi-
ate in the synthesis of porantheridine by Takahata.2g All
spectroscopic data of compound 21 were in agreement with
the published data. We have thus accomplished a formal
synthesis of (()-porantheridine (1) (Scheme 6).
In summary, the present work highlights the synthetic utility
of a nitroso Diels-Alder cycloaddition/ring-rearrangement
(16) Selected examples: (a) Hwang, Y. C.; Fowler, F. W. J. Org. Chem.
ꢀ
1985, 50, 2719–2726. (b) Aube, J.; Rafferty, P. S.; Milligan, G. L. Hetero-
cycles 1993, 35, 1141–1147. (c) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki,
M. J. Org. Chem. 1995, 60, 398–404. (d) Comins, D. L.; Zheng, X.; Goehring,
R. R. Org. Lett. 2002, 4, 1611–1613. (e) Gracias, V.; Zeng, Y.; Desai, P.;
Aube, J. Org. Lett. 2003, 5, 4999–5001. (f) Yuguchi, M.; Tokuda, M.; Orito,
K. Bull. Chem. Soc. Jpn. 2004, 77, 1031–1032. (g) Snider, B. B.; Grabowski,
J. F. J. Org. Chem. 2007, 72, 1039–1042. (h) Ghosh, P.; Judd, W. R.; Ribelin,
1
Diels-Alder cycloadduct 4. H NMR (CDCl3): 6.50 (br s, 1H),
ꢀ
T.; Aube, J. Org. Lett. 2009, 11, 4140–4142.
6.29 (d, J = 4.5 Hz, 1H); 5.87-5.77 (m, 1H); 5.27-5.03 (m, 4H);
3.05 (dd, J = 20.2, 8.5 Hz, 1H); 2.92 (br s, 1H); 1.92 (d, J = 10.4
Hz, 1H), 1.77 (d, J = 10.4 Hz, 1H). 13C NMR (CDCl3): 174.9,
136.2, 132.4, 130.0, 118.0, 84.1, 61,8, 48.2, 39.7. IR (cm-1): 3020,
1728, 1670, 1369, 1174, 924, 848, 802. HRMS (ESI): calcd 188.0682
(C9H11NO2Na; [M þ Na]þ), found 188.0697.
(17) The 2,6-trans-configuration was determined by the chemical shift
of C4 at 20.4 ppm, which is in agreement with typical values reported for
2,6-trans-disubstituted piperidine models. See ref 11a and: Eliel, E. L.;
Kandasamy, D.; Yen, C.-y.; Hargrave, K. D. J. Am. Chem. Soc. 1980, 102,
3698–3707.
(18) Compain, P. Adv. Synth. Catal. 2007, 349, 1829–1846.
(19) (a) Barth, M. M.; Binet, J. L.; Thomas, D. M.; de Fornel, D. C.;
Samreth, S.; Schuber, F. J.; Renaut, P. P. J. Med. Chem. 1996, 39, 2302–2312.
(b) D’hooghe, M.; Dejaegher, Y.; De Kimpe, N. Tetrahedron 2008, 64, 4575–
4584.
2-(1-Propenyl)isoxazolo[2,3-a]pyridin-7-one (5a). To the nitroso
Diels-Alder cycloadduct 4 (840.0 mg, 5.09 mmol) in degassed
toluene (100 mL) under argon at -78 °C was added the metathesis
J. Org. Chem. Vol. 75, No. 12, 2010 4335

Sancibrao et al.
JOCNote
catalyst (216.0 mg, 0.254 mmol) G-II, and but-2-ene was bubbled
in the reaction mixture at -78 °C for 2 min. The mixture was then
heated to 80 °C for 3 h, 216.0 mg (0.254 mmol) of the metathesis
catalyst was added, and the mixture was again heated to 80 °C for
3 h. After cooling, the reaction mixture was concentrated and then
purified by silica gel flash column chromatography (5% MeOH/
AcOEt), and 682.0 mg of isoxazolopyridone 5a (75%) was
isolated as a yellow oil. 1H NMR (CDCl3): 5.90-5.72 (m, 3H),
5.49 (dd, J = 15.0, 7.5 Hz, 1H), 4.74 (q, J = 8.2 Hz, 1H), 4.52-
4.45 (m, 1H), 3.19 (ddt, J = 21.5, 5.0, 2.2 Hz, 1H); 2.98 (dt,
J = 21.2, 3.6 Hz, 1H), 2.65 (dt, J = 11.8, 6.3 Hz, 1H), 1.80 (dd,
J = 11.8, 9.0 Hz, 1H), 1.71 (d, J = 6.4 Hz, 3H). 13C NMR
(CDCl3): 161.6, 131.6, 128.5, 123.0, 122.5, 81.6, 60.3, 40.9, 33.8,
17.7. IR (cm-1): 2925, 1671, 1448, 1404, 1303, 966, 858, 737,
702. HRMS (ESI): calcd 202.0844 (C10H13NO2Na; [M þ Na]þ),
found 202.0850.
(2S*,6S*,20R*)-2-(20-Benzyloxypentyl)-6-(4-oxo-2-pentenyl)-
1-methoxycarbonylpiperidine (20). To compound 17 (47.1 mg,
0.1203 mmol) in CHCl3 were added K2CO3 (166 mg, 1.2 mmol)
and methyl chloroformate (190 μL, 2.45 mmol). The mixture
was stirred at 85 °C. Additional K2CO3 (85 mg, 0.61 mmol) and
methyl chloroformate (95 μL, 1.22 mmol) were added after 48
and 60 h. After a total time of 72 h, the reaction mixture was
filtered with CH2Cl2 and concentrated. The crude mixture was
dissolved in toluene (2.4 mL), and then methyl vinyl ketone
(60 μL, 0.736 mmol) and HoveydaII catalyst H-II (11.3 mg, 0.018
mmol) were added. The reaction was stirred at 80 °C for 30 min
under microwave irradiation. The reaction was charged again
with Hoveyda II catalyst (11.3 mg, 0.018 mmol) and stirred again
for 30 min under microwave irradiation at 80 °C. The crude
mixture was then purified by flash chromatography (20-30%
AcOEt/cyclohexane) to afford 19.8 mg (41%) of expected com-
pound 20 as a yellow oil. 1H NMR (CDCl3): 7.35-7.26 (m, 5H),
6.74 (ddd, J = 15.4, 8.2, 6.4 Hz, 1H), 6.08 (d, J = 15.4 Hz, 1H),
4.56 (d, J = 11.6 Hz, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.09-4.02
(m, 1H), 3.95-3.87 (m, 1H), 3.67 (s, 3H), 3.47-3.39 (m, 1H),
2.75-2.65 (m, 1H), 2.44-2.35 (m, 1H), 2.28 (s, 3H), 2.04-1.93
(m, 1H), 1.78-1.29 (m, 11H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR
(CDCl3): 198.5, 156.6, 145.2, 139.0, 132.9, 128.4, 128.2, 127.8,
127.5, 127.4, 76.4, 70.3, 52.3, 51.8, 49.4, 38.1, 37.5, 36.1, 27.0, 24.9,
24.8, 18.7, 15.0, 14.4. IR (cm-1): 2929, 2870, 1694, 1674, 1445,
1362, 1253, 1098, 980, 735, 698. HRMS (ESI): calcd 424.2445
(C24H35NO4Na; [M þ Na]þ) found 424.2451.
8-Epihalosaline (2). A solution of 10 (78.9 mg, 0.426 mmol) in
THF (4 mL) was added dropwise at 0 °C to a suspension of
LiAlH4 (48.3 mg, 1.28 mmol) in THF (3 mL). The reaction
mixture was stirred at reflux for 3 h. The reaction was then
cooled to 0 °C, 4 mL of water was added dropwise with caution,
and 5 mL of AcOEt was also added. The white suspension was
then filtered over Celite with AcOEt. The filtrate was concen-
trated and purified by silica gel flash chromatography (90%
CH2Cl2, 8% MeOH, 2% NH4OH) to yield 63.9 mg (88%) of
1
8-epihalosaline 2. H NMR (CDCl3): 3.79-3.69 (m, 1H), 3.05
(br d, J = 13.3 Hz, 1H), 3.00 (br s, 1H), 2.74 (tt, J = 10.3, 2.5 Hz,
1H), 2.59 (dd, J = 13.3, 2.5 Hz, 1H), 1.85-1.77 (m, 1H),
1.68-1.03 (m, 12H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR
(CDCl3) 72.7, 58.3, 45.8, 42.3, 40.5, 33.9, 27.1, 24.4, 18.7, 14.2;
IR (cm-1) 3055, 2933, 1712, 1422, 1363, 1265, 739; HRMS (ESI)
calcd 172.1701 (C10H22NO; [M þ H]þ), found 172.1701.
(2S*,6S*,20R*)-2-(20-Hydroxypentyl)-6-(4-oxo-2-pentyl)-1-
methoxycarbonylpiperidine (21). To a solution of 20 (21.8 mg,
0.05436 mmol) in MeOH (1.5 mL) under argon was added
1.6 mg (0.009 mmol) of PdCl2. Hydrogen was then bubbled in
the reaction mixture for 10 min, and the reaction was stirred
for 5 h under 1 atm of hydrogen. After being bubbled through
argon for 10 min, the reaction mixture was filtered over Celite
with AcOEt and concentrated. The crude mixture was then
purified by flash chromatography (20-30% to 50% AcOEt/
pentane) to afford 9.6 mg (56%) of expected compound 21 as
a light yellow oil. 1H NMR (CDCl3): 3.96-3.92 (m, 1H),
3.79-3.73 (m, 1H), 3.69 (s, 3H), 3.62-3.54 (m, 1H), 2.47 (t,
J = 5.5 Hz, 2H), 2.14 (s, 3H), 1.87-1.25 (m, 16H), 0.92 (t, J =
7.0 Hz, 3H). 13C NMR (CDCl3): 208.8, 156.7, 69.7, 52.4, 51.9,
49.7, 43.6, 43.2, 40.1, 33.2, 29.9, 25.1, 23.9, 20.9, 18.8, 14.1,
13.9. IR (cm-1): 3422, 2953, 2871, 1693, 1677, 1448, 1372,
(2S*,6S*,20R*)-6-Allyl-1-benzyl-2-(20-benzyloxypentyl)piperidine
(17). To 140.2 mg (0.377 mmol) of 16 in THF (4 mL) was added
dropwise 1.13 mL of a 1 M solution of allylmagnesium bromide in
THF, and the reaction mixture was heated to 45 °C for 30 min (no
starting material was detected by TLC). The reaction was cooled to
0 °C, 120 mg (1.89 mmol) of NaBH3CN and 1 mL of AcOH were
added, and the reaction was stirred for 2 h at 0 °Cand 12h atrt. The
mixture was quenched with a saturated aqueous solution of NaH-
CO3 and then solid NaHCO3 until pH >7. The aqueous phase was
extracted twice with CH2Cl2, and the combined organic phases were
dried over Na2SO4, filtered, and concentrated. The crude was
purified by flash chromatography (10% AcOEt/cyclohexane) to
1328, 1266, 1190, 1116. HRMS (ESI): calcd 336.2145 (C17H31
-
1
afford 104.4 mg (70%) of the desired 2,6-trans-piperidine 17. H
NO4Na; [M þ Na]þ), found 336.2150.
NMR (CDCl3): 7.45-7.18 (m, 10H), 5.78 (dddd, J=17.2, 11.3,
7.1, 6.9 Hz, 1H), 5.00 (d, J = 17.2 Hz, 1H), 4.98 (d, J =10.2 Hz,
1H), 4.40 (s, 2H), 3.77 (d, J = 13.9 Hz, 1H), 3.64 (d, J =13.9 Hz,
1H), 3.48-3.32 (m, 1H), 2.95-2.77 (m, 2H), 2.43-2.27 (m, 1H),
2.24-2.21 (m, 1H), 2.07-1.96(m, 1H),1.60-1.10 (m, 11H), 0.85 (t,
J =7.5 Hz, 3H). 13C NMR (CDCl3): 141.3, 139.1, 137.1, 128.6,
128.5, 128.4, 128.2, 128.0, 127.8, 127.3, 126.5, 126.4, 126.2, 115.5,
76.5, 70.6, 54.2, 50.8, 49.8, 37.3, 36.0, 35.7, 26.9, 24.6, 20.4, 18.6,
14.2, IR (cm-1): 2928, 1494, 1453, 1358, 1067, 910, 731, 697, HRMS
(ESI): calcd 392.2948 (C27H38NO; [M þ H]þ), found 392.2941.
Acknowledgment. Dedicated to the memory of Dr. Christian
ꢀ
Marazano. We thank the Universite Paris-Sud 11 and the CNRS
for financial support.
Supporting Information Available: Experimental proce-
1
dures, characterization of compounds, and H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
4336 J. Org. Chem. Vol. 75, No. 12, 2010