Enantioselective syntheses of two 5, 9E diastereomers of 223V, an alkaloid from the poison frog Dendrobates pumilio

Article abstract of DOI:10.1016/j.tet.2004.11.060

Enantioselective syntheses of two 5, 9E diastereomers (1 and 2) of 223V (3) are described. Neither corresponded on GC-MS and GC-FTIR analyses to alkaloid 223I, previously tentatively proposed to be a 5,8-disubstituted indolizidine of the unusual 5, 9E rel

Full text of DOI:10.1016/j.tet.2004.11.060

Tetrahedron 61 (2005) 1187–1198
Enantioselective syntheses of two 5, 9E diastereomers of 223V,
an alkaloid from the poison frog Dendrobates pumilio
a,
b
c
Naoki Toyooka,a, Hideo Nemoto, Masashi Kawasaki, H. Martin Garraffo,
*
*
Thomas F. Spandec and John W. Dalyc
aFaculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
bDepartment of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, Kurokawa 5180, Kosugi-Machi,
Toyama 939-0398, Japan
cLaboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
DHHS, Bethesda, MD 20892, USA
Received 21 October 2004; accepted 16 November 2004
Available online 8 December 2004
Abstract—Enantioselective syntheses of two 5, 9E diastereomers (1 and 2) of 223V (3) are described. Neither corresponded on GC–MS and
GC-FTIR analyses to alkaloid 223I, previously tentatively proposed to be a 5,8-disubstituted indolizidine of the unusual 5, 9E relative
stereochemistry. Synthetic (K)-(5, 9Z)-5-n-propyl-8-n-butylindolizidine (3) corresponds on GC–MS and GC-FTIR analyses to the natural
indolizidine 223V found in a pumilio from ‘Split Hill’, Panama.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
5,8-Disubstituted indolizidines represent a major class of
alkaloids found in skins of poison frogs.1 Over 60 such
alkaloids have been proposed. Some structures are tentative,
being based only on their GC–MS, dominated by a base
peak due to a-cleavage of the 5-substituent, followed by a
retro-Diels–Alder loss to yield a characteristic fragment at
m/z 96.2 Several of the 5,8-disubstituted indolizidines have
been isolated from frog skin in sufficient quantities to allow
structure confirmation by NMR spectral analysis. These
include (K)-203A,13 (K)-205A,14 (K)-207A,15 233D,13
(K)-235B0 and (C)-235B00 (formerly 235B).14,15 Structures
are shown in Figure 1. The structures of (K)-207A, (K)-
235B0, and (C)-235B00 have been confirmed by enantio-
selective synthesis.3,16,17 The relative stereochemistry of
205A is depicted on the basis of comparison with synthetic
racemic material.18 The structure and absolute stereo-
chemistry of natural 209I15 was confirmed (unpublished
results) by comparison to synthetic racemic material,19 and
the synthetic (K)-unnatural enantiomer.20 Several
laboratories have reported syntheses of (K)-209B.18,21,22
Virtually all alkaloids of this class possess a 5, 9Z structure
as shown by a characteristic sharp and intense Bohlmann
Figure 1. Alkaloids of the 5,8-disubstituted indolizidine class: structures of
203A, 205A, 207A, 233D, 235B0 and 235B00 were established by NMR
Keywords: Enantioselective syntheses; Diastereomers; Alkaloid.
* Corresponding authors. Tel.: C81 764 34 2281; fax: C81 76 434 4656;
e-mail: toyooka@ms.toyama-ac.jp
spectral analysis, while structures indicated by an asterisk have been
synthesized (see text). Absolute configurations have been established for
the indicated alkaloids.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.060

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N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
band near 2790 cmK1 in their GC-FTIR spectra.2 Only two
alkaloids have been tentatively proposed to be (5, 9E)-5,8-
disubstituted indolizidines, based on GC–MS and a weak
absorbance in the Bohlmann band region on GC-IR.1 One of
these is alkaloid 259B from one population of Dendrobates
pumilio with an EI-MS showing the a-cleavage expected of
a 5-C9H13-8-CH3-indolizidine, followed by retro-Diels–
Alder cleavage of the fragment at m/z 138 to yield a
significant diagnostic ion at m/z 96. The second was alkaloid
223I from another population of the poison frog D. pumilio,
tentatively proposed to have a (5, 9) E-5-propyl-8-
butylindolizidine structure even though the diagnostic
peak in EI-MS at m/z 96 was much weaker than expected.
methoxymethyl ether 9 by reduction of the ester moiety of
7 with Super-Hydride, followed by protection of the
resulting alcohol 8 as shown in Schemes 2 and 3.
In this paper, we would like to report the enantioselective
syntheses of two 8-epimers of (5, 9E) 5-propyl-8-butyl-
indolizidine (1, 2) and comparison to alkaloid 223I. In
addition, a previously synthesized (K)-(5, 9Z) 5-propyl-8-
butylindolizidine3 (3) has now been shown to be identical in
GC–MS and GC-FTIR to alkaloid 223V from yet another
population of the same poison frog, D. pumilio from ‘Spilit
Hill’, Panama.
Scheme 2. (a) n-Bu2Culi, K78 to K10 8C (96%); (b) (1) LiOH, MeOH–
H2O, reflux; (2) ClCO2Et, Et3N, THF, 0 8C; (3) CH2N2; (4) PhCO2Ag,
Et3N, MeOH, rt (80% in 4 steps); (c) same as (b) (86% in 4 steps).
Scheme 3. (a) Super-Hydride, THF, 0 8C (88%); (b) MOMCl, Hu¨nig base,
CH2Cl2, rt (87%); (c) (1) 2 M KOH/i-PrOH, 120 8C, sealed tube; (2) CbzCl,
K2CO3, H2O–CH2Cl2, rt (82% in 2 steps).
Hydrolysis of the oxazolizinone ring in 9 with KOH in a
sealed tube, and protection of the resulting amino alcohol
with CbzCl provided the alcohol 10. Two-step oxidation of
the alcohol 10 followed by Arndt–Eistert reaction afforded
the methyl ester 11 (Scheme 4), which was reduced with
DIBAL. Wittig olefination of the resulting aldehyde
intermediate provided the olefin 12. Hydrogenation of the
double bond and hydrogenolysis of the Cbz-protecting
group of 12, and then removal of the methoxymethyl group
with acid followed by indolizidine formation from the
2. Results and discussion
The stereoselective synthesis of 3 has been described.3 The
synthesis of 1 began with the enaminoester 4,4 which was
treated with lithium dibutylcuprate to afford the adduct 5 as
a single isomer.5 The stereoselectivity of this addition
reaction can be explained by the stereoelectronic effect6 and
Cieplak’s hypothesis7 as shown below (Scheme 1).
Scheme 1.
Scheme 4. (a) (1) Swern ox.; (2) NaClO2, H2O–t-BuOH, 0 8C–rt; (3)
ClCO2Et, Et3N, THF, 0 8C; (4) CH2N2; (5) PhCO2Ag, Et3N, MeOH, rt
(54% in 5 steps); (b) (1) DIBAL, CH2Cl2, K78 8C (2) Witting reagent (57%
in 2 steps); (c) (1) 10% Pd–C, H2, EtOAc, 1 atm; (2) conc. HCl, MeOH,
reflux; (3) CBr4, Ph3P, CH2Cl2, rt then Et3N (67% in 3 steps).
The carbon chain at the a-position of 5 was elongated by
two Arndt–Eistert reactions to provide the two-carbon
homologated ester 7, which was converted to the

N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
1189
resulting amino alcohol via an intermediate bromide
furnished the desired indolizidine 1 as shown in Scheme 4.
urethane, the urethane was treated with Comins’ triflating
reagent10 to yield the enoltriflate 21 as shown in Scheme 7.
Synthesis of the indolizidine 2 was as follows: Lipase-
mediated transesterification of the meso-diol 14 afforded the
mono-propanoate 15, which was transformed into the
known 2-methyl-1-hexanol 16 via an intermediate iodide
in a 3-step sequence as shown in Scheme 5. The
enantiomeric excess of 15 was determined to be 95% ee
using a GC chiral column and by comparison of the optical
rotation of synthetic 16 with a reported value for the (C)-
enantiomer.8
Scheme 7. (a) n-BuLi, ClCO2Me, THF, K78–0 8C (98%); (b) LiHMDS,
2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine, THF, K78 to
K40 8C (96%); (c) LiCl, allyltributyltin, Pd(Ph3P)4, THF, rt (92%);
(d) TFA, NaBH3CN, CH2Cl2, K45 8C (65% isolated yield, 2,6-trans/cisZ
11:1).
The triflate 21 was subjected to a Stille-type coupling
reaction11 using allyltributyltin to provide the olefin 22. A
stereoselective reduction of 22 with NaBH3CN under acidic
conditions gave rise to the reduction product as an 11:1
mixture. The major isomer 23 was isolated in 65% yield.
The stereochemistry of 23 was determined to be that of the
desired 2,6-trans piperidine, based on the NOE spectrum of
the corresponding oxazolizinone 24. The stereochemical
course of the attack of the hydride on the iminium salt
generated from 22 under the acidic condition can be
explained by A(1,2) strain and a stereoelectronic effect6 as
shown below (Scheme 8).
Scheme 5. (a) Lipase from Pseudomonas cepacia (Amano PS), vinyl
propanoate MeCN (90%, 95% ee); (b) (1) MsCl, pyridine, CH2Cl2 (99%);
(2) NaI, acetone (94%); (c) LiAlH4, THF (69%).
The mono-propanoate 15 was converted to the olefin 17,
which was subjected to (DHQD)2PYR ligand-induced
Sharpless asymmetric dihydroxylation reaction9 to give
the diol 18 as shown in Scheme 6.
Scheme 8.
The carbon-chain on the 2-position of 23 was elongated by
Swern oxidation followed by Horner–Emmons reaction to
give 25. Hydrogenation of 25 over Pd–C and reduction of
the resulting ester with Super-Hydride afforded the alcohol
26 whose hydroxyl group was protected with methoxy-
methyl chloride in the presence of Hu¨nig base to give 27.
Finally, the ether 27 was subjected to a 3-step indolizidine
ring closure reaction, but no indolizidine formation was
observed (Scheme 9).
Scheme 6. (a) (1) DHP, PPTS, CH2Cl2; (2) K2CO3, MeOH; (3) Swern ox.;
(4) CH3PCPh3IK, n-BuLi, THF (80% in 4 steps) (b) (DHQD)2PYR,
K2OsO4, K3Fe(CN)6, K2CO3, H2O–t-BuOH, 0 8C (84%); (c) (1) TBDPSCl,
Et3N, DMAP, CH2Cl2 (99%); (2) MsCl, Et3N, CH2Cl2, 0 8C; (3) NaN3,
DMF 80 8C (73% in 2 steps); (d) (1) PPTS, EtOH, 60 8C; (2) Swern ox.; (3)
(EtO)2P(O)CH2CO2Et, NaH, THF (88% in 3 steps, 9:1 mixture of
diastereomers); (e) 10% Pd–C, H2, EtOAc, 4 atm (56%) isolated yield);
only major diastereomers of 18, 19, and 20 are shown here.
Protection of the primary hydroxyl group in 18 followed by
substitution of the secondary hydroxyl group with NaN3 via
its mesylate provided azide 19, which was transformed into
the unsaturated ester 20. Hydrogenation of 20 gave rise to
5,6-cis- and trans-piperidones. The desired 5,6-cis-piper-
idone 13 was isolated in 56% yield.
A conversion of 23 to the desired indolizidine 2 was then
attempted via the bicyclic lactam 30 as shown in Scheme 10.
The methyl urethane 23 was converted to Boc-urethane 28
in two-step sequence and the carbon-chain on the 2-
possition of 28 was elongated same as 25 in Scheme 9 to
give rise to 29. Hydrogenation of 29, hydrolysis of the
resulting ester, followed by removal of the Boc group with
After conversion of 13 to the corresponding methyl

1190
N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
NMR spectra were taken on a Varian Gemini 300 or Unity
Plus 500 spectrometer. H NMR spectra were recorded at
1
the indicated field strength as solutions in CDCl3 unless
otherwise indicated. Chemical shifts are given in parts per
million (ppm, d) downfield from TMS and are referenced to
CHCl3 (7.26 ppm) as an internal standard. Splitting patterns
are designated as s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad. 13C NMR spectra were recorded at
the indicated field strength as solutions in CDCl3 unless
otherwise indicated. Chemical shifts are given in ppm, (d)
downfield from TMS and are referenced to the centre line of
CDCl3 (77.0 ppm) as an internal standard. Carbon signals
were assigned by a DEPT pulse sequence, qZmethyl, tZ
methylene, dZmethine, and sZquaternary carbons. Infra-
red spectra (IR) were measured with a Perkin–Elmer 1600
series FT-IR spectrophotometer. Mass spectra (MS) and
high-resolution mass spectra (HRMS) were measured on a
JEOL JMS-AX505HAD mass spectrometer. Optical
rotations were measured on a JASCO DIP-1000 digital
polarimeter. Column chromatography was performed with
Merck silica gel 60 (No 7734-5B) or (No 9385). GC–MS
was performed with a Finnigan GCQ instrument fitted with
a Restek Amine5x column (30 m!0.25 mm) and a program
100 8C (1 min hold time) to 280 8C at 10 8C. GC-FTIR
spectra were obtained with a narrow band HP model 5981
GC-FTIR infrared spectrophotometer interfaced with both
an HP MSD, model 5971 and an HP 5890 gas chromato-
graph using the same temperature program as above and
fitted with the same column except 0.32 mm i.d.
Scheme 9. (a) (1) Swern ox.; (2) NaH, (EtO)2P(O)CH2CO2Et, THF (E/ZZ
4:1, 87% in 2 steps); (b) (1) 10% Pd–C, H2, EtOAc; (2) Super-Hydride,
THF, 0 8C (96% in 2 steps); (c) MOMCl, Hu¨nig base, CH2Cl2, rt (94%);
(d) (1) n-PrSLi, HMPA–THF, 0 8C–rt; (2) conc. HCl, MeOH, reflux; (3)
CBr4, Ph3P, then Et3N, CH2Cl2, 0 8C.
Scheme 10. (a) (1) 2 M KOH/iPrOH, 120 8C sealed tube; (2) Boc2O,
NaOH, dioxane–H2O (70% in 2 steps); (b) (1) Swern ox.; (2) NaH,
(EtO)2P(O)CH2CO2Et, THF (E/ZZ4: 1, 95% in 2 steps) (c) (1) 10% Pd–C,
H2, EtOAc, 1 atm; (2) LiOH, H2O–EtOH, 60 8C; (3) TFA, CH2Cl2, rt; (4)
DEPC, Et3N, DMF, rt (91% in 4 steps); (d) LiAlH4, THF, reflux (81%).
4.1.1. (5S,6S,9S)-(C)-6-Butyl-3-oxohexahydrooxa-
zolo[3,4-a]pyridine-5-carboxylic acid methyl ester (5).
To a stirred solution of the enaminoester 44 (950 mg,
4.82 mmol) in Et2O (150 mL) was added a solution of the
dibutyllithium cuprate, prepared from n-BuLi (1.6 M in
hexane, 24 mL, 38.6 mmol) and CuI (3.44 g, 18.1 mmol) in
Et2O (60 mL) at K50 to K30 8C, and the resulting
suspension was warmed to K10 8C for 1 h. The reaction
was quenched with satd. NH4Cl (aq). The aqueous mixture
was diluted with CH2Cl2 (300 mL), and the resulting
suspension was filtered. The filtrate was separated, and the
aqueous layer was extracted with CH2Cl2 (20 mL!2). The
organic layer and extracts were combined, dried, and
evaporated to give a colorless oil, which was chromato-
graphed on silica gel (40 g, hexane/acetoneZ20:1–10:1) to
give 5 (1.18 g, 96%) as a colorless oil.
CF3CO2H and lactam formation using the Shioiri’s
reagent12 gave rise to 30. Reduction of the lactam moiety
in 30 with LiAlH4 furnished the desired indolizidine 2.
3. Conclusion
The synthesis and properties of indolizidine 3 have been
reported.3 It proved on GC–MS {223 (MC, 1), 222 (1), 180
(100), 166 (1), 138 (1), 136 (1), 126 (1), 124 (2), 110 (2),
108 (1), 96 (12), 70 (9), 55 (4)} and GC-FTIR (2968, 2938,
2880, 2787, 1459, 1377, 1133 cmK1) analysis to be
identical to natural indolizidine 223V.
IR (neat) 2935, 2863, 1745, 1255 cmK1 1H NMR
;
Synthesis of the 5, 9E-indolizidines 1 and 2 provided clear
proof that alkaloid 223I was not a 5, 9E-indolizidine. Both 1
and 2 had an appreciable retro-Diels–Alder fragment at m/z
96, while 223I did not. The structure of natural 223I should
be revised, but further studies are required for the
determination of the structure of natural product and results
will be reported in due course.
(500 MHz) d 0.89 (3H, t-like, JZ6.9 Hz, 1.30–1.39 (5H,
m), 1.46–1.56 (3H, m), 1.63 (1H, m), 1.67 (1H, m), 2.20
(1H, br), 3.74 (3H, s), 3.90 (1H, t, JZ8.5 Hz), 4.06 (1H, m),
4.35 (1H, s), 4.49 (1H, t, JZ8.5 Hz); 13C NMR (125 MHz) d
13.89 (q), 22.38 (t), 23.62 (t), 24.04 (t), 29.50 (t), 30.22 (t),
34.08 (d), 51.66 (d), 52.29 (q), 55.90 (d), 69.00 (t), 157.62
(s), 171.19 (s); MS: 255 (MC); HRMS: Calcd for
C13H21NO4 255.1469; Found 255.1447; [a]2D6 C7.58 (c
0.92, CHCl3).
4. Experimental
4.1. General
4.1.2. (5R,6S,9S)-(K)-(6-Butyl-3-oxohexahydrooxa-
zolo[3,4-a]pyridin-5-yl)acetic acid methyl ester (6). To a
stirred solution of 5 (590 mg, 2.31 mmol) in MeOH (9 mL)
and H2O (3 mL) was added LiOH$H2O (200 mg,
4.73 mmol), and the resulting solution was refluxed for
Melting points were determined with a Yanaco micro
melting point apparatus and are uncorrected. H and 13C
1

N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
1191
2 h. After cooling, the MeOH was evaporated and the
residue was acidified with 10% HCl solution (aq). The
aqueous mixture was extracted with EtOAc (10 mL!5).
The organic extracts were combined, dried, and evaporated
to give a colorless paste, which was used directly in the next
step. To a stirred solution of the above paste in THF (6 mL)
were added ClCO2Et (0.29 mL, 3.03 mmol) and Et3N
(0.42 mL, 3.03 mmol) at 0 8C, and the resulting suspension
was stirred at 0 8C for 1 h. The reaction mixture was diluted
with Et2O (20 mL) and Et3N$HCl was removed by
filtration. The filtrate was evaporated to give a colorless
oil, which was used directly in the next step. To a stirred
solution of the above oil in Et2O (10 mL) was added a
solution of CH2N2 in Et2O at 0 8C, and the reaction was
stirred at room temperature for 20 h. The solvent was
evaporated to give a pale yellow oil, which was dissolved in
MeOH (10 mL). To the MeOH solution were added
PhCO2Ag (53 mg, 0.23 mmol) and Et3N (0.64 mL,
4.63 mmol), and the resulting suspension was stirred at
room temperature for 18 h. The reaction mixture was diluted
with EtOAc and the insoluble material was removed by
filtration. The filtrate was evaporated to give a pale yellow
oil, which was chromatographed on silica gel (20 g, hexane/
acetoneZ30:1–10:1) to give 6 (500 mg, 80%) as a colorless
oil.
the insoluble material was removed by filtration. The filtrate
was evaporated to give a pale yellow oil, which was
chromatographed on silica gel (20 g, hexane/acetoneZ
15:1–12:1) to give 7 (405 mg, 86%) as a colorless oil.
IR (neat) 2932, 2864, 1743, 1253 cmK1
;
1H NMR
(500 MHz) d 0.87 (3H, t, JZ6.8 Hz), 1.22–1.34 (5H, m),
1.41–1.46 (1H, m), 1.48–1.63 (4H, br m), 1.70–1.80 (2H,
m), 2.09–2.17 (1H, m), 2.33–2.43 (2H, m), 3.65 (3H, s),
3.69 (1H, dd, JZ10.7, 4.5 Hz), 3.76–3.82 (1H, m), 3.89
(1H, dd, JZ8.6, 5.6 Hz), 4.37 (1H, t-like, JZ8.6 Hz); 13C
NMR (125 MHz) d 13.94 (q), 22.42 (t), 22.55 (t), 25.27 (t),
26.39 (t), 29.73 (t), 30.90 (t), 31.07 (t), 36.13 (d), 50.06 (d),
51.62 (q), 53.67 (d), 68.36 (t), 157.79 (s), 173.73 (s); MS:
283 (MC); HRMS: Calcd for C15H25NO4 283.1782; Found
283.1759; [a]2D6 K32.48 (c 0.87, CHCl3).
4.1.4. (5R,6S,9S)-(K)-6-Butyl-5-(3-hydroxypropyl)hexa-
hydrooxazolo[3,4-a]pyridin-3-one (8). To a stirred sol-
ution of 7 (558 mg, 1.97 mmol) in THF (12 mL) was added
a solution of Super-Hydride (1 M in THF, 4.4 mL,
4.4 mmol) at 0 8C, and the reaction mixture was stirred at
0 8C for 2 h. The reaction was quenched with satd. NaHCO3
(aq), and the aqueous mixture was extracted with CH2Cl2
(10 mL!5). The organic extracts were combined, dried,
and evaporated to give a colorless oil, which was
chromatographed on silica gel (25 g, hexane/acetoneZ
10:1–2:1) to give 8 (444 mg, 88%) as a colorless oil.
1
IR (neat) 2932, 2864, 1746, 1417, 1256 cmK1; H NMR
(500 MHz) d 0.88 (3H, t, JZ7 Hz), 1.25–1.38 (5H, br m),
1.46–1.51 (2H, m), 1.53–1.66 (3H, m), 1.69–1.76 (1H, m),
2.57 (1H, dd, JZ14.5, 7.7 Hz), 2.65 (1H, dd, JZ14.5,
8.1 Hz), 3.67 (3H, s), 3.76–3.82 (1H, m), 3.88 (1H, dd, JZ
8.1, 6.9 Hz), 4.19 (1H, t-like, JZ6.1 Hz), 4.40 (1H, t-like,
JZ8.1 Hz); 13C NMR (125 MHz) d 13.91 (q), 22.28 (t),
22.52 (t), 24.91 (t), 29.56 (t), 30.85 (t), 35.29 (d), 36.11 (t),
50.39 (d), 51.84 (q), 68.43 (t), 157.19 (s), 170.95 (s); MS:
269 (MC); HRMS: Calcd for C14H23NO4 269.1626; Found
269.1648; [a]2D6 K12.78 (c 1.07, CHCl3).
1
IR (neat) 3427, 2931, 2864, 1733, 1063 cmK1; H NMR
(500 MHz) d 0.82 (3H, t-like, JZ6.4 Hz), 1.17–1.27 (6H, br
m), 1.35–1.54 (7H, br m), 1.68–1.79 (2H, m), 2.90 (1H, br),
3.58 (2H, br), 3.64 (1H, m), 3.74 (1H, m), 3.83 (1H, m), 4.36
(1H, m); 13C NMR (125 MHz) d 13.87 (q), 22.12 (t), 22.49
(t), 25.31 (t), 27.37 (t), 29.04 (t), 29.65 (t), 30.86 (t), 35.61
(d), 50.09 (d), 53.51 (d), 61.89 (t), 68.44 (t), 157.88 (s); MS:
255 (MC); HRMS: Calcd for C14H25NO3 255.1833; Found
255.1855; [a]2D6 K17.28 (c 1.05, CHCl3).
4.1.3. (5R,6S,9S)-(K)-3-(6-Butyl-3-oxohexahydrooxa-
zolo[3,4-a]pyridin-5-yl)propionic acid methyl ester (7).
To a stirred solution of 6 (445 mg, 1.65 mmol) in MeOH
(6 mL) and H2O (2 mL) was added LiOH$H2O (141 mg,
3.33 mmol), and the resulting solution was refluxed for 2 h.
After cooling, the MeOH was evaporated and the residue
was acidified with 10% HCl solution (aq). The aqueous
mixture was extracted with EtOAc (10 mL!5). The
organic extracts were combined, dried, and evaporated to
give a colorless paste, which was used directly in the next
step. To a stirred solution of the above oil in THF (6 mL)
were added ClCO2Et (0.21 mL, 2.19 mmol) and Et3N
(0.30 mL, 2.19 mmol) at 0 8C, and the resulting suspension
was stirred at 0 8C for 1 h. The reaction mixture was diluted
with Et2O (20 mL) and Et3N$HCl was removed by
filtration. The filtrate was evaporated to give a colorless
oil, which was used directly in the next step. To a stirred
solution of the above oil in Et2O (8 mL) was added a
solution of CH2N2 in Et2O at 0 8C, and the reaction was
stirred at room temperature for 25 h. The solvent was
evaporated to give a pale yellow oil, which was dissolved in
MeOH (8 mL). To the MeOH solution were added PhCO2-
Ag (48 mg, 0.21 mmol) and Et3N (0.46 mL, 3.33 mmol),
and the resulting suspension was stirred at room temperature
for 20 h. The reaction mixture was diluted with EtOAc and
4.1.5. (5R,6S,9S)-(K)-6-Butyl-5-(3-methoxymethoxy-
propyl)hexahydrooxazolo[3,4-a]pyridin-3-one (9). To a
stirred solution of 8 (444 mg, 1.74 mmol) in CH2Cl2 (5 mL)
were added MOMCl (0.29 mL, 3.83 mmol) and Hu¨nig base
(0.87 mL, 5 mmol), and the reaction mixture was stirred at
room temperature for 48 h. The volatiles were evaporated
and the residue was chromatographed on silica gel (25 g,
hexane/acetoneZ10:1–7:1) to give 9 (438 mg, 87%) as a
colorless oil.
IR (neat) 2931, 2868, 1746, 1040 cmK1
;
1H NMR
(500 MHz) d 0.80 (3H, t-like, JZ6.8 Hz), 1.17–1.25 (6H,
br m), 1.35–1.58 (7H, br m), 1.67–1.74 (2H, m), 3.26 (3H,
s), 3.46 (2H, br), 3.62 (1H, br), 3.70 (1H, br), 3.79–3.80 (1H,
m), 4.30–4.33 (1H, m), 4.52 (2H, s); 13C NMR (125 MHz) d
13.83 (q), 22.30 (t), 22.45 (t), 25.30 (t), 26.44 (t), 27.69 (t),
29.66 (t), 30.82 (t), 35.58 (d), 50.03 (d), 53.36 (d), 54.89 (q),
67.00 (t), 68.21 (t), 96.14 (t), 157.53 (s); MS: 299 (MC);
HRMS: Calcd for C16H29NO4 299.2095; Found 299.2098;
[a]2D6 K18.48 (c 7.56, CHCl3).
4.1.6. (2R,3S,6S)-(K)-3-Butyl-6-hydroxymethyl-2-(3-
methoxymethoxypropyl)piperidine-1-carboxylic acid
benzyl ester (10). A solution of 2 M KOH in i-PrOH

1192
N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
(25 mL) was added to 9 (432 mg, 1.44 mmol), and the
resulting mixture was heated at 120 8C in a sealed tube for
48 h. After cooling, the solvent was evaporated, and the
residue was dissolved in H2O. The aqueous mixture was
extracted with CHCl3 (10 mL!8). The organic extracts
were combined, dried over K2CO3, and evaporated to give a
pale yellow oil, which was used directly in the next step. To
a stirred solution of the above oil in H2O (6 mL) and CHCl3
(15 mL) were added CbzCl (0.42 mL, 2.89 mmol) and
K2CO3 (800 mg, 5.78 mmol) at 0 8C, and the resulting
mixture was stirred at room temperature for 3 h. The organic
layer was separated, and the aqueous layer was extracted
with CHCl3 (10 mL!5). The organic layer and extracts
were combined, dried, and evaporated to give a pale yellow
oil, which was chromatographed on silica gel (30 g, hexane/
acetoneZ18:1–13:1) to give 10 (483 mg, 82%) as a
colorless oil.
Et2O at 0 8C, and the reaction solution was stirred at room
temperature for 20 h. The solvent was evaporated to give a
pale yellow oil, which was dissolved in MeOH (6 mL). To
the MeOH solution were added PhCO2Ag (54 mg,
0.24 mmol) and Et3N (0.33 mL, 2.34 mmol), and the
resulting suspension was stirred at room temperature for
16 h. The reaction mixture was diluted with EtOAc and the
insoluble material was removed by filtration. The filtrate
was evaporated to give a pale yellow oil, which was
chromatographed on silica gel (20 g, hexane/acetoneZ
35:1–30:1) to give 11 (278 mg, 54%) as a colorless oil.
1
IR (neat) 2931, 1740, 1039 cmK1; H NMR (500 MHz) d
0.83–0.86 (3H, m), 1.22–1.95 (16H, br m), 2.58–2.62 (1H,
m), 3.35 (3H, s), 3.49–3.59 (2H, m), 3.64 (3H, s), 3.78 (1H,
br), 4.00 (1H, br), 4.60 (2H, s), 5.07 (2H, s), 7.28–7.36 (5H,
m); 13C NMR (125 MHz) d 13.98 (q), 22.64 (t), 22.72 (t),
24.40 (t), 26.37 (t), 26.94 (t), 28.12 (t), 29.71 (t), 32.58 (t),
37.50 (d), 38.68 (t), 49.02 (d), 51.40 (q), 54.99 (q), 66.56 (t),
67.33 (t), 67.37 (t), 96.22 (t), 127.78 (d), 127.83 (d), 127.92
(d), 128.30 (d), 136.73 (s), 156.40 (s), 172.21 (s); MS: 449
(MC); HRMS: Calcd for C25H39NO6 449.2775; Found
449.2759; [a]2D6 K15.58 (c 4.27, CHCl3).
1
IR (neat) 3456, 2931, 1680, 1112, 1040 cmK1; H NMR
(500 MHz) d 0.82 (3H, t-like, JZ6.9 Hz), 1.20 (5H, br),
1.34–1.38 (3H, m), 1.45–1.57 (4H, br m), 1.74–1.90 (3H, br
m), 3.28 (1H, br), 3.33 (3H, s), 3.46–3.51 (2H, m), 3.81
(3.89 (2H, m), 4.19–4.23 (1H, m), 4.52 (1H, br), 4.57 (2H,
s), 5.05 (2H, ABq, JZ12 Hz), 7.29–7.38 (5H, m); 13C NMR
(125 MHz) d 14.09 (q), 22.80 (t), 23.72 (t), 24.29 (t), 26.47
(t), 27.54 (t), 29.95 (t), 31.67 (t), 37.10 (d), 55.08 (q), 55.74
(d), 57.36 (d), 64.27 (t), 67.08 (t), 67.24 (t), 96.29 (t), 127.85
(d), 127.89 (d), 128.31 (d), 136.28 (s), 156.17 (s); MS: 407
(MC); HRMS: Calcd for C23H37NO5 407.2670; Found
407.2659; [a]2D6 K24.78 (c 1.22, CHCl3).
4.1.8. (2R,3S,6S)-(C)-6-Allyl-3-butyl-2-(3-methoxy-
methoxypropyl)piperidine-1-carboxylic acid benzyl
ester (12). To a stirred solution of 11 (83 mg, 0.18 mmol)
in CH2Cl2 (1 mL) was added a solution of DIBAL (0.93 M
in hexane, 0.2 mL, 0.18 mmol) at K78 8C, and the reaction
mixture was stirred at K78 8C for 30 min. The reaction was
quenched with MeOH (0.3 mL) and with satd. potassium
sodium tartrate solution (aq). The aqueous mixture was
extracted with CH2Cl2 (5 mL!3). The organic extracts
were combined, dried, and evaporated to give a colorless oil,
which was used directly in the next step. To a stirred
suspension of CH3PCPh3IK (374 mg, 0.92 mmol) in THF
(2 mL) was added a solution of n-BuLi (1.6 M in hexane,
0.52 mL, 0.83 mmol) at 0 8C, and the reaction mixture was
stirred at 0 8C for 30 min. To the mixture was added a
solution of the above aldehyde in THF (2 mL) at 0 8C, and
the orange suspension was stirred at room temperature for
22 h. The reaction was quenched with H2O, and the aqueous
mixture was extracted with Et2O (10 mL!3). The organic
extracts were combined, dried, and evaporated to give a pale
yellow oil, which was chromatographed on silica gel (15 g,
hexane/acetoneZ80:1–30:1) to give 12 (44 mg, 57%) as a
colorless oil.
4.1.7. (2R,3S,6S)-(K)-3-Butyl-6-methoxycarbonyl-
methyl-2-(3-methoxymethoxypropyl)-piperidine-1-car-
boxylic acid benzyl ester (11). To a stirred solution of
(COCl)2 (0.16 mL, 1.78 mmol) in CH2Cl2 (3 mL) was
added DMSO (0.26 mL, 3.56 mmol) at K78 8C, and the
resulting solution was stirred for 10 min. To the mixture was
added a solution of 10 (483 mg, 1.19 mmol) in CH2Cl2
(1 mL!2) at K78 8C, and the reaction mixture was stirred
for 30 min. Triethylamine (0.74 mL, 5.34 mmol) was added
and the reaction mixture was warmed to 0 8C for 1 h. The
reaction was quenched with H2O, and the aqueous mixture
was extracted with Et2O (15 mL!3). The organic extracts
were combined, dried, and evaporated to give a pale yellow
oil, which was used directly in the next step. To a stirred
suspension of NaH2PO4$2H2O (1.85 g, 11.86 mmol),
2-methyl-2-butene (2.5 mL, 23.6 mmol), and the above oil
in t-BuOH (10 mL) was added a solution of NaClO2 (80%,
810 mg, 7.16 mmol) in H2O (5 mL), and the resulting
suspension was stirred at room temperature for 45 min. The
reaction was quenched with satd. NaHSO3 (aq) and 10%
HCl (aq) at 0 8C, and the aqueous mixture was extracted
with EtOAc (10 mL!10). The organic extracts were
combined, dried, and evaporated to give a pale yellow oil,
which was used directly in the next step. To a stirred
solution of the above oil in THF (3 mL) were added
ClCO2Et (0.15 mL, 1.54 mmol) and Et3N (0.21 mL,
1.54 mmol) at 0 8C, and the resulting suspension was stirred
at 0 8C for 1 h. The reaction mixture was diluted with Et2O
(10 mL) and Et3N$HCl was removed by filtration. The
filtrate was evaporated to give a pale yellow oil, which was
used directly in the next step. To a stirred solution of the
above oil in Et2O (5 mL) was added a solution of CH2N2 in
1
IR (neat) 3070, 2930, 2869, 1699, 1110, 1042 cmK1; H
NMR (500 MHz) d 0.87 (3H, t-like, JZ6.8 Hz), 1.18–1.82
(15H, br m), 2.39 (1H, br), 2.78 (1H, br), 3.36 (3H, s), 3.44–
3.55 (3H, br m), 3.73 (1H, br), 4.60 (2H, s), 5.00–5.15 (4H,
m), 5.73–5.81 (1H, m), 7.28–7.39 (5H, m); 13C NMR
(125 MHz) d 14.03 (q), 22.80 (t), 24.44 (t), 26.74 (t), 28.49
(t), 29.62 (t), 33.04 (t), 37.51 (t), 37.94 (d), 53.16 (d), 55.04
(q), 58.40 (d), 66.56 (t), 67.48 (t), 96.27 (t), 116.40 (t),
127.79 (d), 127.86 (d), 128.36 (d), 136.24 (d), 136.92 (s),
156.80 (s); MS: 417 (MC); HRMS: Calcd for C25H39NO4
417.2877; Found 417.2883; [a]2D6 C2.98 (c 2.24, CHCl3).
4.1.9. (5R,8S,9R)-(C)-8-Butyl-5-propyloctahydroindol-
izine (1). To a solution of 12 (135 mg, 0.32 mmol) in
EtOAc (15 mL) was added 10% Pd–C (100 mg), and the

N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
1193
resulting suspension was hydrogenated under a hydrogen
atmosphere at 4 atm for 40 h. The catalyst was removed by
filtration, and the filtrate was evaporated to give a colorless
oil, which was used directly in the next step. To a stirred
solution of the oil above in MeOH (6 mL) was added conc.
HCl (aq) (4 drops), and the reaction mixture was refluxed
for 1 h. After cooling, the solvent was evaporated and the
residue was washed with Et2O. To the hydrochloride salt
was added NH3 (aq), and the aqueous mixture was extracted
with CHCl3 (5 mL!10). The organic extracts were
combined, dried over K2CO3, and evaporated to give a
colorless oil, which was used directly in the next step.
Carbon tetrachloride (150 mg, 0.45 mmol) and Ph3P
(127 mg, 0.49 mmol) were added to a solution of the
above oil in CH2Cl2 (4 mL) at 0 8C, and the reaction mixture
was stirred at 0 8C for 2 h. To the reaction mixture was
added Et3N (0.72 mL, 5.18 mmol) at 0 8C, and the resulting
suspension was stirred for 30 min. The volatiles were
evaporated, and the residue was extracted with n-pentane
(10 mL!4). The organic extracts were combined and
evaporated to give a pale orange solid, which was
chromatographed on silica gel (10 g, hexane/acetone/
Et3NZ50:1:5 drops-20:1:5 drops) to give 1 (48 mg, 67%)
as a pale yellow oil.
stirred at room temperature for 1 h. The solvent was
evaporated and the residue was chromatographed on Silica
gel (10 g, hexane/acetoneZ12:1–8:1) to give the mesylate
(265 mg, 99%) as a colorless oil.
1
IR (neat) 2938, 2867, 1738, 1355, 1178 cmK1; H NMR
(500 MHz) d 0.89 (3H, t, JZ7.2 Hz), 1.13 (3H, t, JZ
7.7 Hz), 1.30–1.40 (6H, br m), 2.04–2.09 (1H, m), 2.34 (2H,
q, JZ7.7 Hz), 3.01 (3H, s), 4.03 (1H, dd, JZ11.1, 6.8 Hz),
4.13 (1H, dd, JZ11.1, 4.7 Hz), 4.16–4.23 (2H, m); 13C
NMR (125 MHz) d 8.97 (q), 13.77 (q), 22.54 (t), 27.15 (t),
27.35 (t), 28.63 (t), 37.09 (q), 37.61 (d), 63.00 (t), 69.16 (t),
174.19 (s); MS: 266 (MC); HRMS: Calcd for C11H22O5S
266.1187; Found 266.1199; [a]2D6 C3.98 (c 4.74, CHCl3).
To a stirred solution of the mesylate obtained above
(265 mg, 1 mmol) in acetone (10 mL) was added NaI
(1.5 g, 9.96 mmol), and the resulting solution was stirred at
room temperature for 14 h and at reflux for 2 h. After
cooling, the reaction mixture was diluted with Et2O. The
ethereal layer was washed with 10% Na2S2O3 in satd.
NaHCO3 (aq), dried and evaporated to give a colorless oil,
which was chromatographed on silica gel (10 g, hexane/
acetoneZ100:1–80:1) to give the iodide (280 mg, 94%) as a
colorless oil.
IR (neat) 2928, 2865, 2803, 1657, 1460, 1376, 1259, 1219,
1170, 1142, 1101, 905, 754 cmK1; H NMR (500 MHz) d
1
IR (neat) 2956, 2931, 2863, 1740 cmK1 1H NMR
;
0.89 (3H, t, JZ6.8 Hz), 0.92 (3H, t, JZ6.8 Hz), 1.01–1.67
(14H, br m), 1.56–1.70 (3H, m), 1.72–1.82 (1H, m), 1.87–
1.94 (1H, m), 2.07–2.11 (1H, m), 2.63 (1H, q, JZ8.5 Hz),
2.80 (1H, td, JZ8.6, 2.9 Hz), 2.95–2.99 (1H, m); 13C NMR
(125 MHz) d 14.06 (q), 14.40 (q), 20.65 (t), 20.94 (t), 23.00
(t), 24.28 (t), 24.83 (t), 27.88 (t), 28.88 (t), 29.68 (t), 33.06
(t), 42.45 (d), 48.92 (t), 54.94 (d), 60.29 (d); MS: 223 (MC);
HRMS: Calcd for C15H29N 223.2299; Found 223.2290;
[a]2D6 C31.08 (c 2.14, CHCl3).
(500 MHz) d 0.88 (3H, t, JZ7.2 Hz), 1.12 (3H, t, JZ
7.4 Hz), 1.26–1.35 (6H, br), 1.52–1.58 (1H, m), 2.30 (2H, q,
JZ7.4 Hz), 3.23 (1H, dd, JZ9.9, 5.2 Hz), 3.29 (1H, dd, JZ
9.9, 6.6 Hz), 3.89 (1H, dd, JZ11, 7.1 Hz), 4.08 (1H, dd, JZ
11, 4.6 Hz); 13C NMR (125 MHz) d 9.18 (q), 11.10 (t),
13.95 (q), 22.62 (t), 27.52 (t), 28.61 (t), 30.97 (t), 38.49 (d),
66.44 (t), 173.90 (s); MS: 298 (MC); HRMS: Calcd for
C10H19IO2 298.0430; Found 298.0442; [a]2D6 C5.38 (c 2.00,
CHCl3).
4.1.10. (R)-(C)-Propionic acid 2-hydroxymethylhexyl
ester (15). To a stirred solution of 14 (3 g, 22 mmol) in
MeCN (300 mL) were added vinyl propanoate (4.55 g,
45 mmol) and lipase PCL (Amano PS) (1.5 g), and the
resulting suspension was stirred at room temperature for
20 h. The lipase catalyst was removed by filtration, and the
volatiles were evaporated to give a colorless oil, which was
chromatographed on silica gel (60 g, hexane/EtOAcZ3:1)
to give 15 (3.72 g, 90%) as a colorless oil. The enantiomeric
excess was determined to be 95% ee by the GC analysis
using a cyclodextrin-b-236M-19 chiral column.
4.1.12. (S)-(C)-2-Methylhexan-1-ol (16). To a stirred
solution of the iodide (280 mg, 0.94 mmol) in Et2O
(20 mL) was added LiAlH4 (380 mg, 10 mmol), and the
resulting suspension was refluxed for 16 h. After cooling,
the reaction was quenched with 10% NaOH (aq), and the
aqueous mixture was extracted with Et2O (10 mL!4). The
organic extracts were combined, dried, and evaporated to
give a colorless oil, which was chromatographed on silica
gel (10 g, hexane/acetoneZ15:1–10:1) to give 16 (75 mg,
69%) as a colorless oil.
1
IR (neat) 3445, 2935, 2862 cmK1; H NMR (500 MHz) d
1
IR (neat) 3449, 2931, 2868, 1736, 1193 cmK1; H NMR
0.89–0.92 (6H, m), 1.06–1.13 (1H, m), 1.20–1.43 (5H, m),
1.57–1.64 (1H, m), 1.91 (1H, br), 3.39–3.42 (1H, m), 3.48–
3.81 (1H, m); 13C NMR (125 MHz) d 14.04 (q), 16.52 (q),
22.93 (t), 29.15 (t), 32.79 (t), 35.66 (d), 68.28 (t); [a]D26
K10.58 (c 2.01, CHCl3), lit.8 [a]D26 C118 (c 2.5, CHCl3).
(500 MHz) d 0.88 (3H, t, JZ6.6 Hz), 1.13 (3H, t, JZ
7.6 Hz), 1.26–1.34 (6H, br), 1.76–1.81 (1H, m), 2.21–2.27
(1H, m), 2.33 (2H, q, JZ7.6 Hz), 3.44–3.61 (2H, m), 4.07
(1H, dd, JZ11, 6.6 Hz), 4.19 (1H, dd, JZ11, 4.7 Hz); 13C
NMR (125 MHz) d 9.24 (q), 14.00 (q), 22.90 (t), 27.56 (t),
27.64 (t), 29.17 (t), 40.52 (d), 62.71 (t), 64.51 (t), 174.87 (s);
MS: 188 (MC); HRMS: Calcd for C10H20O3 188.1411;
Found 188.1432; [a]2D6 C10.68 (c 1.96, CHCl3).
4.1.13. (S)-(C)-2-(2-Butylbut-3-enyloxy)tetrahydro-
pyran (17). To a stirred solution of 15 (1.814 g,
9.65 mmol) in CH2Cl2 (20 mL) were added DHP
(1.32 mL, 14.5 mmol) and PPTS (485 mg, 1.93 mmol),
and the reaction mixture was stirred at room temperature for
6 h. The reaction was quenched with satd. NaHCO3 (aq),
and the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (20 mL!3). The organic layer and
4.1.11. (S)-(C)-Propionic acid 2-iodomethylhexyl ester.
To a stirred solution of 15 (188 mg, 1 mmol) in CH2Cl2
(5 mL) were added MsCl (0.12 mL, 1.5 mmol) and pyridine
(0.15 mL, 1.8 mmol) at 0 8C, and the reaction mixture was

1194
N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
extracts were combined, dried, and evaporated to give a
colorless oil, which was used directly in the next step. To a
stirred solution of the above oil in MeOH (12 mL) was
added K2CO3 (803 mg, 5.82 mmol), and the resulting
suspension was stirred at room temperature for 19 h. The
reaction mixture was diluted with H2O, and the aqueous
mixture was extracts with CH2Cl2 (15 mL!6). The organic
extracts were combined, dried, and evaporated to give a
colorless oil, which was used directly in the next step. To a
stirred solution of (COCl)2 (1.25 mL, 14.33 mmol) in
CH2Cl2 (15 mL) was added DMSO (2.05 mL,
28.89 mmol) at K78 8C, and the reaction mixture was
stirred for 5 min. To the reaction mixture was added a
solution of the alcohol obtained above in CH2Cl2 (3 mL!2)
at K78 8C, and the reaction mixture was stirred for 30 min.
Triethylamine (6 mL, 43.37 mmol) was added to the
reaction mixture at K78 8C, and the reaction was warmed
to 0 8C for 1 h. The reaction mixture was diluted with H2O
and Et2O, and the organic layer was separated. The aqueous
layer was extracted with Et2O (20 mL!2). The organic
layer and extracts were combined, dried, and evaporated to
give a pale yellow oil, which was used directly in the next
step. To a stirred suspension of CH3PCPh3IK (15.7 g,
38.8 mmol) in THF (35 mL) was added a solution of n-BuLi
(1.6 M in hexane, 22.9 mL, 36.6 mmol) at 0 8C, and the
resulting orange suspension was stirred at 0 8C for 30 min.
To the suspension was added a solution of the aldehyde
obtained above in THF (10 mL) at 0 8C, and the reaction
mixture was stirred at room temperature for 22 h. The
reaction was quenched with H2O, and the aqueous mixture
was extracted with Et2O (20 mL!3). The organic extracts
were combined, dried, and evaporated to give a pale yellow
oil, which was chromatographed on silica gel (30 g, hexane/
acetoneZ100:1–80:1) to give 17 (1.63 g, 80%) as a
colorless oil.
1.49 (5H, m), 1.55–1.63 (4H, m), 1.72–1.86 (4H, m), 2.56–
2.63 (1H, m), 3.40–3.98 (8H, br m), 4.58–4.62 (1H, m).
4.1.15. 2-Azido-1-(tert-butyldiphenylsilanyloxy)-3-
(tetrahydropyran-2-yloxymethyl)heptane (19). To a stir-
red solution of 18 (700 mg, 2.85 mmol) in CH2Cl2 (5 mL)
were added Et3N (0.51 mL, 3.7 mmol), DMAP (69 mg,
0.57 mmol), and TBDPSCl (0.82 mL, 3.13 mmol) at 0 8C,
and the reaction mixture was stirred at room temperature for
45 h. The volatiles were evaporated and the residue was
chromatographed on silica gel (30 g, hexane/acetoneZ
50:1–30:1) to give the silyl ether (1.37 g, 99%) as a
colorless oil consisting of a diastereomeric mixture.
1H NMR (500 MHz) d 0.91 (3H, t-like, JZ6 Hz), 1.09 (9H,
s), 1.22–1.83 (14H, br m), 3.01–3.04 (1H, m), 3.38–3.56
(2H, m), 3.70–3.94 (4H, m), 4.51–4.53 (1H, m), 7.38–7.47
(6H, m), 7.70–7.76 (4H, m).
To a stirred solution of the silyl ether obtained above
(1.37 g, 2.83 mmol) in CH2Cl2 (5 mL) were added MsCl
(0.24 mL, 3.11 mmol) and Et3N (0.59 mL, 4.25 mmol) at
0 8C, and the reaction mixture was stirred at 0 8C for 1 h.
The reaction was quenched with satd. NaHCO3 (aq), and the
organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (10 mL!2). The organic layer and
extracts were combined, dried, and evaporated to give the
mesylate, which was used directly in the next step. To a
stirred solution of the mesylate obtained above in DMF
(5 mL) was added NaN3 (1.84 g, 28.31 mmol), and the
resulting suspension was heated at 80 8C for 15 h. After
cooling, the insoluble material was removed by filtration,
and the solvent was evaporated to give a pale yellow oil,
which was chromatographed on silica gel (25 g, hexane/
acetoneZ50:1–40:1) to give 19 (1.05 g, 73%) as a colorless
oil containing a diastereomeric mixture.
IR (neat) 3075, 2934, 2866, 1642, 1127, 1071, 1032 cmK1
;
1H NMR (500 MHz) d 0.87–0.91 (3H, m), 1.10 (9H, s),
1.10–1.75 (13H, br m), 3.22–3.29 (1H, m), 3.46–3.56 (1H,
m), 3.64–3.84 (5H, m), 4.48–4.52 (1H, m), 7.40–7.48 (6H,
m), 7.71–7.74 (4H, m).
1H NMR (500 MHz) d 0.88 (3H, t, JZ7.3 Hz), 1.20–1.33
(5H, m), 1.44–1.61 (5H, m), 1.66–1.72 (1H, m), 1.78–1.85
(1H, m), 2.26–2.33 (1H, m), 3.28–3.32 (1H, m), 3.47–3.52
(1H, m), 3.65 (1H, dd, JZ9.4, 6.8 Hz), 3.83–3.88 (1H, m),
4.56–4.59 (1H, m), 5.02–5.07 (2H, m), 5.62–5.70 (1H, m);
13C NMR (125 MHz) d 13.98 (q), 19.37 (t), 19.43 (t), 22.71
(t), 25.44 (t), 29.12 (t), 29.14 (t), 30.55 (t), 30.90 (t), 43.83
(d), 44.04 (d), 61.96 (t), 62.03 (t), 70.86 (t), 70.95 (t), 98.57
(d), 98.77 (d), 115.20 (t), 115.27 (t), 140.29 (d), 140.44 (d);
MS: 212 (MC); HRMS: Calcd for C13H24O2 212.1775;
Found 212.1784; [a]2D6 C8.88 (c 16.20, CHCl3).
4.1.16. 5-Azido-6-(tert-butyldiphenylsilanyloxy)-4-butyl-
2-hexenoic acid ethyl ester (20). To a stirred solution of 19
(1.05 g, 2.06 mmol) in EtOH (5 mL) was added PPTS
(104 mg, 0.41 mmol), and the reaction mixture was stirred
at 60 8C for 2 h. After cooling, the reaction was quenched
with satd. NaHCO3 (aq), and the aqueous mixture was
extracted with CH2Cl2 (10 mL!5). The organic extracts
were combined, dried, and evaporated to give a colorless oil,
which was used directly in the next step. To a stirred
solution of (COCl)2 (0.27 mL, 3.09 mmol) in CH2Cl2
(6 mL) was added DMSO (0.44 mL, 6.19 mmol) at
K78 8C, and the reaction mixture was stirred for 5 min.
To the reaction mixture was added a solution of the oil
obtained above in CH2Cl2 (2 mL) at K78 8C, and the
resulting mixture was stirred at K78 8C for 30 min.
Triethylamine (1.3 mL) was added to the reaction mixture,
and the reaction was warmed to 0 8C for 1 h. The reaction
mixture was then diluted with H2O and Et2O, and the
organic layer was separated. The aqueous layer was
extracted with Et2O (20 mL!2). The organic layer and
extracts were combined, dried, and evaporated to give a pale
4.1.14. 3-(Tetrahydropyran-2-yloxymethyl)heptane-1,2-
diol (18). To a stirred solution of 17 (1.63 g, 7.69 mmol) in
t-BuOH (30 mL) and H2O (30 mL) was added AD-mix with
(DHQD)2PYR (14 g) at 0 8C, and the resulting suspension
was stirred at 0 8C for 17 h. The reaction was quenched with
Na2SO3 (10 g), and the reaction mixture was extracted with
EtOAc (30 mL!5). The organic extracts were combined,
dried, and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (40 g, hexane/acetoneZ
10:1–4:1) to give 18 (1.58 g, 84%) a colorless oil consisting
of a diastereomeric mixture.
1H NMR (500 MHz) d 0.91 (3H, t-like, JZ6.8 Hz), 1.27–

N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
1195
yellow oil, which was used directly in the next step. To a
stirred suspension of NaH (60%, 99 mg, 2.48 mmol) in THF
(5 mL) was added (EtO) 2P(O)CH2CO2Et (0.5 mL,
2.48 mmol) at 0 8C, and the reaction mixture was stirred
at 0 8C for 30 min. To the mixture was added a solution of
the aldehyde obtained above in THF (4 mL) at 0 8C, and
then the reaction mixture was stirred at room temperature
for 2 h. The reaction was quenched with H2O, and the
aqueous mixture was extracted with CH2Cl2 (15 mL!4).
The organic extracts were combined, dried, and evaporated
to give a pale yellow oil, which was chromatographed on
silica gel (25 g, hexane/acetoneZ100:1–50:1) to give 20
(890 mg, 88%) as a colorless oil as a 9:1 mixture of
diastereomers.
1.98 (1H, m), 2.01–2.08 (1H, m), 2.54–2.61 (1H, m), 2.64–
2.66 (1H, m), 3.76 (1H, dd, JZ11.1, 2.9 Hz), 3.82 (3H, s),
3.86 (1H, dd, JZ11.1, 3.9 Hz), 4.28 (1H, br), 7.39–7.48
(6H, m), 7.64–7.71 (4H, m); 13C NMR (125 MHz) d 13.84
(q), 18.85 (s), 22.61 (t), 24.79 (t), 26.61 (q), 29.33 (t), 32.33
(t), 34.31 (t), 37.16 (d), 53.66 (q), 59.42 (d), 61.50 (t),
127.64 (d), 127.67 (d), 129.73 (d), 132.16 (s), 132.73 (s),
135.53 (d), 135.64 (d), 154.99 (s), 172.03 (s); MS: 424
(MCK57); HRMS: Calcd for C24H30NO4Si 424.1942;
Found 424.1961; [a]2D6 K27.48 (c 3.02, CHCl3).
To a stirred solution of the methyl urethane obtained above
(633 mg, 1.32 mmol) in THF (2 mL) was added a solution
of LiHMDS, prepared from hexamethyldisilazane
(0.33 mL, 1.6 mmol) and n-BuLi (1.6 M in hexane, 1 mL,
1.6 mmol) in THF (2 mL) at 0 8C for 30 min, at K78 8C,
and the reaction mixture was stirred at the same temperature
for 30 min. To the resulting mixture was added a solution of
2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyri-
dine (Comins’ reagent, 640 mg, 1.6 mmol) in THF (2 mL)
at K78 8C, and the reaction temperature was warmed to
K40 8C for 30 min. The reaction was quenched with satd.
NH4Cl (aq), and the organic layer was separated. The
aqueous layer was extracted with Et2O (10 mL!3), and the
organic layer and extracts were combined, dried, and
evaporated to give a pale yellow oil, which was chromato-
graphed on silica gel (30 g, hexane/acetoneZ50:1–40:1) to
give 21 (772 mg, 96%) as a colorless oil.
1H NMR (500 MHz) d 0.89 (3H, t-like, JZ7.2 Hz), 1.10
(9H, s), 1.11–1.38 9H, m, including at d 1.32, 3H, t, JZ
7.3 Hz), 2.36–2.42 (1H, m), 3.34–3.38 (1H, m), 3.50–3.67
(1H, m), 3.68–3.80 (1H, m), 4.20 (2H, q, JZ7.3 Hz), 5.81
(1H, d, JZ15.4 Hz), 6.63 (1H, dd, JZ15.4, 9.4 Hz), 7.40–
7.48 (6H, m), 7.68–7.72 (4H, m).
4.1.17. (5R,6S)-(C)-5-Butyl-6-(tert-butyldiphenylsilanyl-
oxymethyl)piperidin-2-one (13). To a solution of 20
(1.77 g, 3.59 mmol) in EtOAc (60 mL) was added 10%
Pd–C (400 mg), and the resulting suspension was hydro-
genated with 4 atm of hydrogen for 48 h. The catalyst was
removed by filtration, and the filtrate was evaporated to give
a colorless oil, which was chromatographed on silica gel
(30 g, hexane/acetoneZ12:1–7:1) to give 13 (852 mg, 56%)
as a colorless oil.
IR (neat) 3069, 2956, 2932, 2860, 1733, 1424, 1328, 1272,
1
1215, 1114 cmK1; H NMR (500 MHz) d 0.91 (3H, t, JZ
6.9 Hz), 1.13 (9H, s), 1.15–1.36 (6H, br m), 1.68–1.75 (1H,
m), 1.89 (1H, br), 2.31–2.37 (1H, m), 3.68 (1H, d-like, JZ
8.9 Hz), 3.85 (1H, t-like, JZ6.8 Hz), 3.90 (3H, s), 4.70 (1H,
br), 5.29 (1H, t, JZ3.4 Hz), 7.45–7.51 (6H, m), 7.74–7.84
(4H, m); 13C NMR (125 MHz) d 13.67 (q), 18.89 (s), 22.42
(t), 26.41 (q), 26.59 (t), 29.22 (t), 31.97 (t), 35.64 (d), 53.27
(q), 58.26 (t), 59.87 (d), 105.64 (d), 117.01 (s), 119.55 (s),
127.56 (d), 127.59 (d), 129.56 (d), 129.67 (d), 133.14 (s),
133.17 (s), 135.45 (d), 135.59 (d), 138.13 (s), 153.89 (s);
MS: 613 (MC); HRMS: Calcd for C29H38NO6F3SSi
613.2139; Found 613.2118; [a]2D6 K30.58 (c 8.45, CHCl3).
1
IR (neat) 3206, 3070, 2931, 2860, 1666 cmK1; H NMR
(500 MHz) d 0.84 (3H, t, JZ7.3 Hz), 1.07 (9H, s), 1.08–
1.27 (7H, m), 1.68 (2H, q-like, JZ6.4 Hz), 2.33–2.39 (2H,
m), 3.53–3.67 (3H, br m), 6.27 (1H, br), 7.39–7.48 (6H, m),
7.66–7.67 (4H, m); 13C NMR (125 MHz) d 13.82 (q), 19.00
(s), 22.54 (t), 23.50 (t), 26.69 (q), 28.05 (t), 29.11 (t), 29.56
(t), 33.97 (d), 56.76 (d), 64.34 (t), 127.74 (d), 127.75 (d),
129.80 (d), 129.83 (d), 132.68 (s), 132.73 (s), 135.40 (d),
135.42 (d), 171.88 (s); MS: 423 (MC); HRMS: Calcd for
C26H37NO2Si 423.2591; Found 423.2597; [a]2D6 C25.48 (c
1.04, CHCl3).
4.1.19. (2S,3R)-(K)-6-Allyl-3-butyl-2-(tert-butyldi-
phenylsilanyloxymethyl)-3,4-dihydro-2H-pyridine-1-
carboxylic acid methyl ester (22). To a stirred solution of
21 (1.18 g, 1.92 mmol) in THF (20 mL) were added
allyltributyltin (1.2 mL, 3.8 mmol), Pd(PPh3)4 (222 mg,
0.19 mmol), and LiCl (480 mg, 11.32 mmol), and the
resulting mixture was heated at 70 8C for 4 h. After cooling,
the reaction mixture was diluted with Et2O. The insoluble
materials were removed by filtration, and the filtrate was
evaporated to give a pale brown oil, which was chromato-
graphed on silica gel (30 g, hexane/acetoneZ100:1) to give
22 (900 mg, 92%) as a pale yellow oil.
4.1.18. (2S,3R)-(K)-3-Butyl-2-(tert-butyldiphenylsilanyl-
oxymethyl)-6-trifluoromethane-sulfonyloxy-3,4-di-
hydro-2H-pyridine-1-carboxylic acid methyl ester (21).
To a stirred solution of 13 (1.06 g, 2.50 mmol) in THF
(7 mL) was added a solution of n-BuLi (1.6 M in hexane,
1.72 mL, 2.75 mmol) at K78 8C, and the reaction mixture
stirred at K78 8C for 30 min. To the reaction mixture was
added ClCO2Me (0.22 mL, 2.75 mmol), and the solution
was warmed to 0 8C for 1 h. The reaction was quenched with
satd. NaHCO3 (aq), and the aqueous mixture was extracted
with CH2Cl2 (20 mL!3). The organic extracts were
combined, dried, and evaporated to give a pale yellow oil,
which was chromatographed on silica gel (30 g, hexane/
acetoneZ30:1–10:1) to give the methyl urethane (1.17 g,
98%) as a colorless oil.
IR (neat) 3070, 2954, 2928, 2858, 1709, 1660, 1111 cmK1
;
1H NMR (500 MHz) d 0.87 (3H, t, JZ6.8 Hz), 1.09 (9H, s),
1.12–1.50 (6H, m), 1.51–1.56 (1H, m), 1.82–1.91 (1H, m),
2.11–2.16 (1H, m), 3.13–3.17 (1H, m), 3.56 (1H, br), 3.60–
3.63 (1H, m), 3.73 (1H, t-like, JZ9.4 Hz), 3.78 (3H, s), 4.58
(1H, br), 5.00–5.08 (2H, br), 5.13 (1H, t-like, JZ17 Hz),
5.85–5.94 (1H, m), 7.42–7.49 (6H, m), 7.71–7.78 (4H, m);
IR (neat) 1743, 1641, 3017, 2954, 2932, 2860, 1773, 1719,
1284 cmK1; 1H NMR (500 MHz) d 0.89 (3H, t, JZ6.9 Hz),
1.04 (9H, s), 1.25–1.37 (6H, m), 1.81–1.87 (1H, m), 1.95–

1196
N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
13C NMR (125 MHz) d 13.98 (q), 19.16 (s), 22.70 (t), 26.65
(q), 27.73 (t), 29.29 (t), 33.02 (t), 36.02 (d), 39.43 (t), 52.44
(q), 57.60 (d), 58.78 (t), 112.11 (d), 115.70 (t), 127.43 (d),
129.37 (d), 129.47 (d), 133.40 (s), 133.56 (s), 135.36 (d),
135.51 (d), 136.22 (d), 154.78 (s); MS: 505 (MC); HRMS:
Calcd for C31H43NO3Si 505.3010; Found 505.3025; [a]D26
K62.68 (c 2.91, CHCl3).
mixture was added a solution of 23 (253 mg, 0.94 mmol) in
CH2Cl2 (2 mL), at K78 8C, and the reaction was stirred for
30 min. Triethylamine (0.59 mL) was added at K78 8C, and
the reaction was warmed to 0 8C for 1 h. The reaction was
quenched with H2O, and the mixture was extracted with
Et2O (15 mL!3). The organic extracts were combined,
dried, and evaporated to give a pale yellow oil, which was
used directly in the next step. To a stirred suspension of NaH
(60%, 45 mg, 1.13 mmol) in THF (4 mL) was added (EtO)
2P(O)CH2CO2Et (0.23 mL, 1.13 mmol) at 0 8C, and the
reaction mixture was stirred at 0 8C for 30 min. To the
reaction mixture was added a solution of the aldehyde
obtained above in THF (2 mL) at 0 8C, and the resulting
mixture was stirred at room temperature for 10 h. The
reaction was quenched with H2O, and the aqueous mixture
was extracted with CH2Cl2 (10 mL!4). The organic
extracts were combined, dried, and evaporated to give a
pale yellow oil, which was chromatographed on Silica gel
(10 g, hexane/acetoneZ50:1) to give 25 (276 mg, 87%) as a
colorless oil.consisting of a 4:1 mixture of E- and Z-isomers.
4.1.20.
(2S,3R,6S)-(K)-6-Allyl-3-butyl-2-hydroxy-
methylpiperidine-1-carboxylic acid methyl ester (23).
To a stirred solution of 22 (700 mg, 1.39 mmol) in CH2Cl2
(15 mL) were added NaBH3CN (95%, 460 mg, 6.95 mmol)
at K78 8C, and then TFA (1.07 mL, 13.9 mmol) at
K78 8C, and the resulting suspension was stirred at K78
to K45 8C for 3 h. The reaction was quenched with satd.
NaHCO3 (aq), and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (15 mL!5). The
organic layer and extracts were combined, dried, and
evaporated to give a colorless oil, which was chromato-
graphed on silica gel (20 g, hexane/acetoneZ30:1–10:1) to
give 23 (242 mg, 65%) as a colorless oil.
4.1.23. (2R,3R,6R)-(K)-3-Butyl-2-(3-hydroxypropyl)-6-
propylpiperidine-1-carboxylic acid methyl ester (26).
To a stirred solution of 25 (270 mg, 0.8 mmol) in EtOAc
(20 mL) was added 10%Pd–C (250 mg), and the resulting
suspension was hydrogenated at 1 atm for 20 h. The catalyst
was removed by filtration, and the filtrate evaporated to give
a colorless oil, which was used directly in the next step. To a
stirred solution of the ester obtained above in THF (10 mL)
was added a solution of Super-Hydride (1 M in THF,
1.8 mL, 1.8 mmol) at 0 8C, and the reaction mixture was
stirred at 0 8C for 1 h. The reaction was quenched with H2O,
and the aqueous mixture was extracted with CH2Cl2
(10 mL!5). The organic extracts were combined, dried,
and evaporated to give a colorless oil, which was
chromatographed on Silica gel (15 g, hexane/acetoneZ
30:1–8:1) to give 26 (229 mg, 96%) as a colorless oil.
1
IR (neat) 3447, 3074, 1678 cmK1; H NMR (500 MHz) d
0.91 (3H, t-like, JZ6.8 Hz), 1.21–1.41 (7H, br m), 1.73–
1.89 (3H, m), 1.93–1.97 (1H, br), 2.18–2.24 (1H, m), 2.50–
2.55 (1H, m), 3.18 (1H, br), 3.69–3.73 (1H, m), 3.74 (3H, s),
3.80–3.88 (2H, m), 4.06–4.09 (1H, m), 5.05–5.11 (2H, m),
5.71–5.78 (1H, m); 13C NMR (125 MHz) d 14.11 (q), 21.49
(t), 22.25 (t), 22.85 (t), 29.50 (t), 32.73 (t), 34.69 (d), 38.87
(t), 51.79 (d), 52.76 (q), 57.71 (d), 64.27 (t), 116.93 (t),
135.39 (d), 158.27 (s); MS: 269 (MC); HRMS: Calcd for
C15H27NO3 269.1989; Found 269.1999; [a]2D6 K25.68 (c
1.72, CHCl3).
4.1.21. (5S,8R,9S)-(K)-5-Allyl-8-butylhexahydrooxa-
zolo[3,4-a]pyridin-3-one (24). To a stirred solution of 23
(54 mg, 0.2 mmol) in THF (2 mL) was added NaH (60%,
8.8 mg, 0.22 mmol) at 0 8C, and the reaction mixture was
stirred at room temperature for 1 h. The reaction was
quenched with 10% AcOH (aq), and the aqueous mixture
was extracted with CH2Cl2 (5 mL!3). The organic extracts
were combined, dried, and evaporated to give a colorless oil,
which was chromatographed on silica gel (10 g, hexane/
acetoneZ30:1–10:1) to give 24 (42 mg, 89%) as a colorless
oil.
IR (neat) 3447, 2931, 2865, 11689 cmK1 1H NMR
;
(500 MHz) d 0.87–0.93 (6H, m), 1.15–1.35 (9H, br m),
1.44–1.81 (10H, br m), 2.48 (1H, br), 3.52 (1H, br), 3.67
(3H, s), 3.62–3.71 (2H, br), 4.02 (1H, br); 13C NMR
(125 MHz) d 14.14 (q), 20.58 (t), 22.91 (t), 23.14 (t), 25.10
(t), 25.92 (t), 29.40 (t), 33.23 (t), 36.60 (t), 37.20 (d), 52.07
(q), 52.44 (d), 55.17 (d), 62.50 (t), 156.81 (s); MS: 299
(MC); HRMS: Calcd for C17H33NO3 299.2459; Found
299.2434; [a]2D6 K28.28 (c 2.33, CHCl3).
IR (neat) 3075, 2933, 2866, 1746 cmK1
;
1H NMR
(500 MHz) d 0.90 (3H, t-like, JZ6.8 Hz), 1.15–1.17 (1H,
m), 1.20–1.40 (6H, br m), 1.62–1.81 (4H, m), 2.25–2.30
(1H, m), 2.40–2.45 (1H, m), 3.93–3.96 (1H, m), 3.98–4.01
(1H, m), 4.14–4.19 (1H, m), 4.23–4.27 (1H, m), 5.05–5.10
(2H, m), 5.71–5.80 (1H, m); 13C NMR (125 MHz) d 13.96
(q), 20.38 (t), 21.07 (t), 22.69 (t), 22.87 (t), 29.31 (t), 34.43
(d), 34.99 (t), 48.41 (d), 53.95 (d), 64.34 (t), 117.38 (t),
134.57 (d), 157.20 (s); MS: 237 (MC); HRMS: Calcd for
C14H23NO2 237.1728; Found 237.1724; [a]2D6 K45.98 (c
2.58, CHCl3).
4.1.24. (2R,3R,6R)-(K)-3-Butyl-2-(3-methoxymethoxy-
propyl)-6-propylpiperidine-1-carboxylic acid methyl
ester (27). To a stirred solution of 26 (55 mg, 0.18 mmol)
in CH2Cl2 (2 mL) were added MOMCl (0.084 mL,
1.10 mmol) and Hu¨nig base (0.26 mL, 1.47 mmol) at 0 8C,
and the reaction mixture was stirred at room temperature for
28 h. The volatiles were evaporated, and the residue was
chromatographed on silica gel (10 g, hexane/acetoneZ
30:1–20:1) to give 27 (59 mg, 94%) as a colorless oil.
1
4.1.22. (2S,3R,6S)-6-Allyl-3-butyl-2-(2-ethoxycarbonyl-
vinyl)piperidine-1-carboxylic acid methyl ester (25). To
a stirred solution of (COCl)2 (0.12 mL, 1.41 mmol) in
CH2Cl2 (3 mL) was added DMSO (0.2 mL) at K78 8C, and
the reaction mixture was stirred for 5 min. To the reaction
IR (neat) 2930, 2867, 1699 cmK1; H NMR (500 MHz) d
0.87–0.92 (6H, m), 1.15–1.38 (9H, br m), 1.46–1.83 (10H,
br m), 3.35 (3H, s), 3.39 (1H, br), 3.52 (2H, br), 3.65 (3H, s),
4.03 (1H, br), 4.61 (2H, s); 13C NMR (125 MHz) d 14.11
(q), 14.16 (q), 20.63 (t), 22.90 (t), 24.01 (t), 25.08 (t), 26.03

N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
1197
(t), 26.81 (t), 29.37 (t), 33.02 (t), 36.54 (t), 37.64 (d), 51.87
(q), 52.68 (d), 55.04 (q), 55.79 (d), 67.70 (t), 96.25 (t),
156.68 (s); MS: 343 (MC); HRMS: Calcd for C19H37NO4
343.2721; Found 343.2749; [a]2D6 K23.18 (c 2.86, CHCl3).
and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (20 g, hexane/acetoneZ
80:1–70:1) to give 29 (150 mg, 95%) as a colorless oil
consisting of a 4:1 mixture of E- and Z-isomers.
4.1.25.
(2S,3R,6S)-(K)-6-Allyl-3-butyl-2-hydroxy-
4.1.27. (5R,8R,9R)-(K)-8-Butyl-5-propylhexahydroindo-
lizin-3-one (30). To a stirred solution of 29 (150 mg,
0.40 mmol) in EtOAc (10 mL) was added 10% Pd–C
(100 mg), and the resulting suspension hydrogenated at
1 atm for 20 h. The catalyst was removed by filtration, and
the filtrate was evaporated to give a colorless oil, which was
used directly in the next step. To a stirred solution of the
ester obtained above in EtOH (3 mL) and H2O (1 mL) was
added LiOH$H2O (33 mg, 0.79 mmol), and the reaction
mixture was heated at 60 8C for 2 h. After cooling, the
solvent was evaporated, and the residue was extracted with
EtOAc (5 mL!10). The organic extracts were combined,
dried, and evaporated to give a colorless oil, which was used
directly in the next step. To a stirred solution of the
carboxylic acid obtained above in CH2Cl2 (2 mL) was
added TFA (0.18 mL, 2.37 mmol) at 0 8C, and the reaction
mixture was stirred at room temperature for 5 h. The
volatiles were evaporated to give a pale yellow oil, which
was used directly in the next step. To a stirred solution of the
amine obtained above in DMF (2 mL) were added Et3N
(0.16 mL, 1.19 mmol) and DEPC (0.09 mL, 0.59 mmol) at
0 8C, and the resulting mixture was stirred at room
temperature for 1 h. The volatiles were evaporated, and
the residue was chromatographed on silica gel (15 g,
hexane/acetoneZ30:1–10:1) to give 30 (86 mg, 90%) as a
pale yellow oil.
methylpiperidine-1-carboxylic acid tert-butyl ester (28).
2 M Potassium hydroxide in i-PrOH (25 mL) was added to
23 (429 mg, 1.59 mmol), and the resulting solution was
heated at 120 8C in a sealed tube for 48 h. After cooling, the
solvent was evaporated, and the residue was dissolved in
H2O. The aqueous mixture was saturated with K2CO3, and
extracted with CHCl3 (10 mL!10). The organic extracts
were combined, dried over K2CO3, and evaporated to give a
pale yellow oil, which was used directly in the next step.
To a stirred solution of the oil obtained above in dioxane
(20 mL) and H2O (10 mL) were added NaOH (270 mg,
6.75 mmol) at 0 8C, and then Boc2O (1.1 g, 5.04 mmol) at
the same temperature. The reaction mixture was stirred at
room temperature for 12 h, then it was extracted with
CH2Cl2 (15 mL!5), and the organic extracts were
combined, dried, and evaporated to give a pale yellow oil,
which was chromatographed on silica gel (20 g, hexane/
acetoneZ40:1–30:1) to give 28 (350 mg, 70%) as a
colorless oil.
IR (neat) 3446, 3074, 2931, 2867, 1665, 1173 cmK1; H
1
NMR (500 MHz) d 0.92 (3H, t-like, JZ6.9 Hz), 1.18–1.23
(1H, m), 1.27–1.39 (6H, m), 1.50 (9H, s), 1.74–1.84 (3H,
m), 1.92–1.97 (1H, m), 2.16–2.22 (1H, m), 2.49–2.53 (1H,
m), 3.45 (1H, br), 3.62–3.67 (1H, m), 3.78–3.86 (2H, m),
4.08–4.11 (1H, m), 5.05–5.11 (2H, m), 5.73–5.81 (1H, m);
13C NMR (125 MHz) d 14.11 (q), 21.28 (t), 21.97 (t), 22.88
(t), 28.54 (q), 29.53 (t), 33.36 (t), 34.59 (d), 39.29 (t), 51.86
(d), 57.08 (d), 64.69 (t), 80.24 (s), 116.75 (t), 135.68 (d),
157.45 (s); MS: 311 (MC); HRMS: Calcd for C18H33NO3
311.2459; Found 311.2463; [a]2D6 K35.48 (c 1.52, CHCl3).
1
IR (neat) 2933, 2867, 1682 cmK1; H NMR (500 MHz) d
0.83–0.90 (6H, m), 1.10–1.42 (10H, br m), 1.55–1.67 (5H,
m), 1.72–1.83 (1H, m), 1.94–1.99 (1H, m), 2.22–2.34 (2H,
m), 3.76–3.81 (1H, m), 4.12–4.19 (1H, br); 13C NMR
(125 MHz) d 14.10 (q), 14.19 (q), 19.71 (t), 20.44 (t), 21.46
(t), 22.25 (t), 22.98 (t), 23.09 (t), 29.58 (t), 30.68 (t), 32.59
(t), 37.25 (d), 47.49 (d), 56.61 (d), 173.48 (s); MS: 237
(MC); HRMS: Calcd for C15H27NO 237.2091; Found
237.2076; [a]2D6 K38.48 (c 3.96, CHCl3).
4.1.26. (2S,3R,6S)-6-Allyl-3-butyl-2-(2-ethoxycarbonyl-
vinyl)piperidine-1-carboxylic acid tert-butyl ester (29).
To a stirred solution of (COCl)2 (0.055 mL, 0.63 mmol) in
CH2Cl2 (2 mL) was added DMSO (0.089 mL, 1.25 mmol)
at K78 8C, and the reaction mixture was stirred at K78 8C
for 5 min. To the reaction mixture was added a solution of
18 (130 mg, 0.42 mmol) in CH2Cl2 (2 mL), and the
resulting mixture was stirred at K78 8C for 30 min.
Triethylamine was added to the reaction mixture, and the
reaction mixture was warmed to 0 8C for 1 h. The reaction
was quenched with H2O and Et2O was added. The organic
layer was separated, and the aqueous layer was extracted
with Et2O (10 mL!2). The organic layer and extracts were
combined, dried, and evaporated to give a pale yellow oil,
which was used directly in the next step. To a stirred
suspension of NaH (60%, 22 mg, 0.54 mmol) in THF
(5 mL) was added (EtO)2P(O)CH2CO2Et (0.11 mL,
0.54 mmol) at 0 8C, and the reaction mixture was stirred
at 0 8C for 30 min. To the reaction mixture was added a
solution of the aldehyde obtained above in THF (2 mL) at
0 8C, and the reaction mixture was stirred at room
temperature for 12 h. The reaction was quenched with
H2O, and the aqueous layer was extracted with CH2Cl2
(10 mL!3). The organic extracts were combined, dried,
4.1.28. (5R,8R,9R)-(K)-8-Butyl-5-propyloctahydroindo-
lizine (2). To a stirred solution of 30 (79 mg, 0.33 mmol) in
THF (10 mL) was added LiAlH4 (126 mg, 3.33 mmol), and
the resulting suspension was refluxed for 15 h. After
cooling, the reaction was quenched with 10% NaOH (aq),
and the aqueous mixture was extracted with Et2O
(10 mL!5). The organic extracts were combined, dried
over K2CO3, and evaporated to give a colorless oil, which
was chromatographed on Silica gel (15 g, hexane/acetone/
Et3NZ450:15:10 drops) to give 2 (60 mg, 81%) as a
colorless oil.
IR (neat) 2954, 2927, 2868, 2796, 1461, 1375, 1268, 1187,
1059, 899 cmK1; 1H NMR (500 MHz) d 0.88–0.93 (6H, m),
1.12–1.31 (10H, br m), 1.35–1.47 (1H, m), 1.48–1.66 (5H,
br m), 1.78–1.84 (2H, m), 1.94 (1H, br), 2.11–2.15 (1H, m),
2.66–2.72 (1H, m), 3.00–3.05 (1H, m), 3.15–3.19 (1H, m);
13C NMR (125 MHz) d 14.19 (q), 14.63 (q), 19.40 (t), 20.95
(t), 21.44 (t), 23.01 (t), 25.29 (t), 29.48 (t), 31.29 (t), 33.35
(t), 36.78 (d), 37.00 (t), 50.43 (t), 54.19 (d), 64.17 (d) (s);

1198
N. Toyooka et al. / Tetrahedron 61 (2005) 1187–1198
MS: 223 (MC); HRMS: Calcd for C15H29N 223.2299;
9. Smith, A. L.; Williams, S. F.; Holmes, A. B.; Hughes, L. R.;
Lidert, Z.; Swithenbank, C. J. Am. Chem. Soc. 1998, 110,
8696. Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes,
L. R.; Lidert, Z.; Swithenbank, C. J. Org. Chem. 1991, 56,
1393.
Found 223.2292; [a]2D6 K29.08 (c 2.99, CHCl3).
Acknowledgements
10. Michel, P.; Rassatt, A.; Daly, J. W.; Spande, T. F. J. Org.
Chem. 2000, 65, 8908.
This work was supported in part by The Research
Foundation for Pharmaceutical Sciences.
11. Enders, D.; Theibes, C. Synlett 2000, 1745.
˚
12. Ahman, J.; Somfai, P. Tetrahedron 1995, 35, 9747.
13. Song, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43,
8635.
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