Stereodivergent synthesis of the 2,3,5,6-tetrasubstituted piperidine ring system: An application to the synthesis of alkaloids

Article abstract of DOI:10.1016/j.tet.2004.05.039

Stereodivergent synthesis of the 2,3,5,6-tetrasubstituted piperidine ring system has been achieved by sequential stereocontrolled Michael-type conjugate addition reaction of appropriate enaminoesters. This methodology has been applied to the total synthes

Full text of DOI:10.1016/j.tet.2004.05.039

Tetrahedron 60 (2004) 6197–6216
Stereodivergent synthesis of the 2,3,5,6-tetrasubstituted
piperidine ring system: an application to the synthesis of alkaloids
223A and 205B from poison frogs
*
Naoki Toyooka, Ayako Fukutome, Hiroyuki Shinoda and Hideo Nemoto
*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 5 April 2004; accepted 10 May 2004
Available online 9 June 2004
Abstract—Stereodivergent synthesis of the 2,3,5,6-tetrasubstituted piperidine ring system has been achieved by sequential stereocontrolled
Michael-type conjugate addition reaction of appropriate enaminoesters. This methodology has been applied to the total syntheses of the
poison frog alkaloids 223A and 205B. The relative stereochemistry of natural 223A at the 6-position was revised, and the absolute
stereochemistry of natural 205B was determined by the present synthesis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Our basic strategy for the stereodivergent construction of
the 2,3,5,6-tetrasubstituted piperidine ring core is shown in
Figure 1. The strategy involves the sequential use of
Michael-type conjugate addition reaction to an enamino-
ester. The stereodiversity is a consequence of using an
acyclic or cyclic carbamate functionality to provide total
conformational control of the substrate in the second
addition reaction.
Alkaloids containing a piperidine ring are abundant in
nature. 2,6-Disubstituted piperidine ring systems especially,
are a major structural element found in these natural
products.1 Many of these alkaloids exhibit intriguing
biological activities. Accordingly, numerous efforts to
construct this heterocycle have been reported to date.2 The
2,3,5,6-tetrasubstituted piperidine system, which is found in
some natural products, is generally more difficult to
synthesize and few general methods exist to control the
relative stereochemistry of the four substituents. As part of a
program aimed at developing syntheses of biologically
active alkaloids,3 we present here a full account of the
stereodivergent construction of two 2,3,5,6-tetrasubstituted
piperidine ring systems.4
2. Results and discussion
The synthesis of a 3,5-cis-type 2,3,5,6-tetrasubstituted
piperidine core started with known amide 1.5 Treatment of
1 with n-BuLi and ClCO2Me provided methyl carbamate 2,
which was converted in high yield to enoltriflate 3 using
Figure 1.
Keywords: Alkaloids; Comins’ triflating agent; Piperidones.
*
Corresponding authors. Tel.: þ81-764-34-2281; fax: þ81-76-434-4656; e-mail address: toyooka@ms.toyama-mpu.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.039

6198
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
Scheme 1. (a) n-BuLi, ClCO2Me (98%); (b) LiHMDS, 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (Comins’ reagent) (96%); (c) CO,
Pd(Pl3P)4, Et3N, MeOH (88%); (d) (vinyl)2CuLi (96%); (e) Supper-Hydride (96%); (f) Swern ox. then n-BuLi, EtPþPh3Br2 (79%); (g) 5% Pd–C, H2 then
TBAF (77%); (h) swern ox. then NaClO2 then CH2N2 (90%); (i) LiHMDS, PhSeCl (77%).
Comins’ triflating agent.6 Palladium-catalyzed CO insertion
reaction in the presence of MeOH7 gave rise to enamino-
ester 4. The first Michael-type conjugate addition reaction8
to 4 proceeded smoothly to afford the adduct 5 as a single
isomer. For the key, second Michael-type conjugate
addition reaction of divinyllithium cuprate, the adduct 5
was transformed into the second enaminoester 7 via the
alcohol 6 as shown in Scheme 1.
enaminoester 14. The previously obtained enaminoester 4
was converted to the trisubstituted piperidine 11 using our
original Michael-type conjugate addition reaction, which
was transformed into the oxazolizinone 12. Removal of the
silyl protecting group and a two-step oxidation of the
resulting alcohol followed by esterification with diazo-
methane provided the methyl ester 13. This ester was
converted to 14 using the protocol developed by Matsumura
et al.9 The key, second Michael-type conjugate addition
reaction of 14 proceeded smoothly to give rise to the
tetrasubstituted piperidine 15 in high yield and as a single
isomer. The 3,5-trans-stereochemistry of 15 was confirmed
by the NOE experiment, whose results are shown in
Scheme 3.
With the requisite enaminoester 7 in hand, we next
investigated the second and key conjugate addition reaction.
Accordingly, treatment of 7 with divinyllithium cuprate
provided the tetrasubstituted piperidine 8, again as a single
isomer. The expected 3,5-cis-stereochemistry of 8 was
confirmed by the coupling constants indicated and an NOE
experiment on the corresponding oxazolizinone derivative
10, prepared via the alcohol 9 as shown in Scheme 2.
The observed, remarkable stereoselectivity of the conjugate
addition reactions of 7 and 14 can be rationalized by the
stereoelectronic effect10 and is also consistent with
Cieplak’s hypothesis,11 both illustrated in Figure 2.
From the synthesis of 205B we required the cyclic
Scheme 2.
Scheme 3. (a) (Me)2CuLi (98%); (b) Super-Hydride (92%); (c) NaH (99%); (d) TBAF (99%); (e) Swern ox. then NaClO2 then CH2N2 (86%); (f) LiHMDS,
PhSSPh (99%); (g) m-CPBA, 2,6-lutidine (85%); (h) (Me)2CuLi (93%).

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6199
Figure 2.
Thus, we achieved the stereodivergent synthesis of the
2,3,5,6-tetrasubstituted piperidine ring core with complete
stereoselection. To illustrate the efficacy of our protocol for
the construction of tetrasubstituted piperidines, syntheses of
poison frog alkaloids 223A and 205B were undertaken.
Alkaloid 223A was isolated from a skin extract of a
Panamanian population of the frog Dendrobates pumilio
Schmidt (Dendrobatidae) in 1997, and it was the first
member of a new trialkyl-substituted indolizidine class of
amphibian alkaloids to be characterized.12 In a preliminary
report, the configuration of the ethyl group at C-6 position
was revised.4 The tetrasubstituted piperidine 9 was
converted to the unsaturated ester 16, whose double bonds
were hydrogenated over Pd–C. Reduction of the ester
moiety with Super-Hydride followed by protection of the
resulting alcohol with MOMCl in the presence of Hu¨nig’s
base provided the MOM ether 17. Finally, removal of the
methoxycarbonyl and MOM groups, followed by indolizi-
dine cyclization of the intermediate propyl bromide
furnished the desired indolizidine 18 (Scheme 4).
nicely separated quartet-like signal at d 1.01 with a J of
12.5 Hz for the H-7 axial proton. This observation means
that the quartet-like signal with three large and approxi-
mately equal couplings for the H-7 axial proton must
include two trans-diaxial vicinal couplings with H-6 and
H-8 protons and one geminal coupling with the H-7
equatorial proton, and thus both ethyl-substituents at the
6- and 8-positions should be of the equatorial orientation as
shown in Figure 3. A quartet at this chemical shift was not
seen in the natural material. On the other hand, the H-5
proton in 18 and natural 223A was a doublet of triplet with J
1
values of 11, 2.5 and 11, 4.7 Hz, respectively, in the H
NMR spectrum. We now conclude the hindered rotation at
C-5 in the C-6 epimer 30 of proposed structure for natural
223A (18) leads to a large (11-Hz J5–10) coupling and does
not reflect an originally assumed trans-diaxial J5 – 6
coupling.
Figure 3.
Scheme 4. (a) Swern ox. then (EtO)2P(O)CH2CO2Et, NaH (96%); (b) 10%
Pd–C, H2, then Super-Hydride (89%); (c) MOMCl, Hu¨nig’s base (86%);
(d) n-PrSLi, HMPA; (e) c. HCl, MeOH; (f) CBr4, Ph3P, Et3N (52%).
Therefore, we commenced the synthesis of the 6-epimer
(30) of initially proposed structure for 223A. For the
synthesis of 30, we needed the cis-substituted piperidone 23.
Synthesis of 23 began with the known 2R mono-acetate
19,13 which was converted to the olefin 20. A (DHQD)2-
PYR ligand-induced AD reaction14 of 20 followed by
protection of the primary hydroxyl group gave the
secondary alcohol, which was transformed into the azide
21 via the mesylate. Removal of the THP protecting group
The 1H and 13C NMR and IR spectra of 18 were not
identical with those for the natural product, nor was the GC
retention time. The close similarity of the Bohlmann bands
in the vapor phase FTIR spectra of 18 and natural 223A
indicated the same 5,9-Z configuration for both compounds.
1
In H NMR spectra, our synthetic DCl salt of 18 showed a

6200
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
Scheme 5. (a) DHP, PPTS; (b) K2CO3, MeOH; (c) Swern ox then PH3PþCH3Br2, n-BuLi (76%); (d) AD-mix b-(DHQD)2PYR ligand (80%); (e) TBDPSCl,
Et3N, DMAP (98%); (f) MsCl, Et3N then NaN3 (83%); (g) PPTS, EtOH; (h) Swern ox then NaH, (EtO)2P(O)CH2CO2Et (88%); (i) 10% Pd–C, H2 (73%).
Scheme 6. (a) n-BuLi, ClCO2Me (97%); (b) LiHMDS, Comins’ reagent (97%); (c) CO, Pd(Ph3P)4, Et3N, MeOH (75%); (d) (vinyl)2CuLi (95%); (e) Super-
Hydride (96%); (f) NaH (94%).
with PPTS, and Swern oxidation followed by the Horner–
Emmons reaction provided the unsaturated ester 22.
Hydrogenation of 22 over Pd–C under medium pressure
gave rise to desired piperidone 23 (Scheme 5).
orientation on the conformation 24-A to form 25. The
alternative conformation 24-B is unlikely due to A(1,3)
strain.15
The alcohol 26 was converted to the 2-carbon-homologated
alcohol 28. Protection of the hydroxyl group in 28 followed
by removal of the silyl group provided the alcohol 29. After
carbon-chain elongation of 29 at the a-position, a three-step
indolizidine cyclization reaction gave rise to indolizidine
30,16 whose spectral data were completely in accord with
those for natural 223A (Scheme 7).
This piperidone was transformed into the enaminoester 24
in the same manner as the synthesis of 4. The key Michael-
type conjugate addition reaction to 24 was achieved by
treatment of 24 with divinyllithium cuprate to give the 3,5-
trans-adduct 25 as a single isomer. The stereochemistry of
25 was determined to be that of the desired intermediate for
the synthesis of 30 by the coupling constant indicated and
the NOE cross peaks of the oxazolidinone 27 derived from
the alcohol 26 as shown in Scheme 6.
Thus the structure of natural 223A was revised to 30,4 and
the relative stereochemistry of this natural product was
Stereoselectivity of this conjugate addition reaction can also
be explained as shown in Figure 4. Attack of the vinyl anion
is preferred from the stereoelectronically favored b-axial
Scheme 7. (a) Swern ox. then (EtO)2P(O)CH2CO2Et, NaH (92%); (b) 10%
Pd–C, H2 then Super-Hydride (98%); (c) MOMCl, Hu¨nig base (89%); (d)
TBAF (79%); (e) Swern ox. then n-BuLi, EtPþPh3Br2 (83%); (f) 10% Pd–
C, H2; (g) n-PrSLi, HMPA then c. HCl, MeOH; (h) CBr4, Ph3P, Et3N
(51%).
Figure 4.

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6201
determined to be 5R p,6R p,8R p,9S p by the present
synthesis.
The stereochemical outcome of this cyclization can be
explained as depicted in Figure 6.
Alkaloid 205B, isolated from skin extracts of the
Panamanian frog Dendrobates pumilio, possesses an
unusual and unique 8b-azaacenaphthylene ring system.17
In addition to this unique structure, the alkaloid contains five
asymmetric centers in its compact, fourteen-carbon-atom
tricycle. The structure of alkaloid 205B was first reported to
be A, and recently revised to be B based on FTIR, NMR,
and MS spectral data.18 At present, no synthesis of this
alkaloid has been reported, and the absolute stereochemistry
is still unknown (Fig. 5).
Figure 6.
Regioselective enolization of the ketone precursor to 36 in
the presence of a chiral lithium amide base was performed
to give the enol triflate as a 3:1 mixture of regioisomers, and
major product 38 resulted in 54% yield. The tricyclic ketone
38 was confirmed to have the desired stereochemistry as
shown in Scheme 9. Attempts to convert 38 into final
product 40 under the Takai and Nozaki’s protocol20 or
McMurry’s reaction conditions21 led only to a complex
mixture or recovered starting material, respectively. On the
other hand, the acid-catalyzed isomerization of the exo-
olefin 39, derived from 36 by Wittig olefination was quite
effective,22 and led to the desired endo-olefin 40 in 63%
yield. The spectroscopic data of 40 were identical with those
for the natural product. The absolute sterochemistry of
natural 205B was unambiguously determined to be an
antipode of our synthetic 40 by comparison of optical
rotations.
Figure 5.
We applied our tetrasubstituted piperidine synthesis
illustrated in Figure 1 to the synthesis of alkaloid 205B.
The side chain on the 6-position of 15 was homologated by
the Arndt–Eistert sequence to afford the ester 31, which was
converted to methyl ketone 33 via Weinreb’s amide19 32 in
good yield. After protection of the carbonyl group in 33, the
oxazolizinone ring was hydrolyzed by treatment with 2 M
KOH in i-PrOH at 120 8C in a sealed tube followed by
protection of the resulting amino alcohol with Boc2O in the
presence of NaOH to give rise to 34. Swern oxidation of 34
followed by the Horner–Emmons reaction of the resulting
aldehyde yielded the unsaturated ester 35. Hydrogenation of
the double bond in 35 and reduction of the ester moiety with
DIBAL provided the aldehyde, which was subjected to an
intramolecular Mannich-type cyclization reaction by treat-
ment with pTsOH to provide the tricyclic ketone 36 along
with its acetal 37 (Scheme 8).
3. Conclusion
In summary, we have succeeded in stereodivergent
syntheses of two 2,3,5,6-tetrasubstituted piperidine ring
systems with complete stereoselection by sequential use of
Michael-type conjugate addition reaction to enaminoesters.
Using this methodology, we completed the first total
synthesis of the alkaloids 223A and 205B both of which
possess the above tetrasubstituted piperidine ring structural
element. The original structure for alkaloid 223A has been
Scheme 8. (a) LiOH, MeOH–H2O; (b) ClCO2Et, Et3N: (c) CH2N2; (d) PhCO2Ag, Et3N, MeOH (71%); (e) LiOH, MeOH–H2O; (f) 1,10-carbonyldiimidazole
then E3tN, (MeO)MeNH·HCl (98%); (g) MeMgBr (73%); (h) ethylene glycol p-TsOH (86%); (i) 2 M KOH in i-PrOH, 120 8C then Boc2O, NaOH (74%);
(j) Swern ox.; (k) (EtO)2P(O)CH2CO2Et, NaH (74%); (l) 10% Pd–C, H2 then DIBAL; (m) p-TsOH, benzene–acetone (36; 62%, 37; 15%); n-TsOH, acetone
(80%).

6202
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
Scheme 9. (a) R-(R p, R p)-(þ)-bis(a-methylbenzyl)amine, n-BuLi then Comins’ reagent (54%); (b) Pd(Ph3P)4, Me3Al; (c) (Me)2CuLi; (d) MePþPh3I2, n-BuLi
(84%); (e) p-TsOH, benzene, reflux (63%).
revised to 30, and the absolute stereochemistry of 205B was
determined to be 2aR,5aR,6S,8S,8aR by the present total
synthesis.
mixture was extracted with CH2Cl2 (50 mL£1, 15 mL£2).
The organic extracts were combined, dried, and evaporated
to give colorless oil, which was chromatographed on SiO2
(50 g, hexane:acetone¼30:1–20:1) to give 2 (2.10 g, 98%)
as a colorless solid (mp 97–102 8C).
4. Experimental
4.1. General
1
IR (KBr) 2958, 1718, 1113 cm21; H NMR (500 MHz) d
1.06 (9H, s), 1.69–1.75 (1H, m), 1.86–1.99 (2H, m), 2.12–
2.17 (1H, m), 2.49–2.52 (2H, m), 3.72–3.76 (2H, m), 3.76
(3H, s), 4.41–4.44 (1H, m), 7.37–7.45 (6H, m), 7.63–7.67
(4H, m); 13C NMR (125 MHz) d 17.44 (t), 18.96 (s), 24.18
(t), 26.63 (q), 34.64 (t), 53.52 (q), 56.16 (d), 64.10 (t),
127.60 (d), 129.65 and 129.68 (each d), 132.63 and 132.81
(each s), 135.36 and 135.42 (each d), 154.69 (s), 171.69 (s);
MS: 425 (Mþ), 115 (100); HRMS: Calcd for C24H31NO4Si
425.2022. Found 425.2006. Anal. Calcd for C24H31NO4Si
C, 67.73; H, 7.34; N, 3.29. Found C, 67.73; H, 7.39; N, 3.32;
[a]2D6¼41.6 (c 5.67, CHCl3).
Melting points were determined with a Yanaco micro
1
melting point apparatus and are uncorrected. H and 13C
NMR spectra were taken on a Varian Gemini 300 or Unity
1
Plus 500 spectrometer. H NMR spectra were recorded at
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 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 parts per
million (ppm, d) downfield from TMS and are referenced to
the center line of CDCl3 (77.0 ppm) as internal standard.
Carbon signals were assigned by a DEPT pulse sequence,
q¼methyl, t¼methylene, d¼methyne, and s¼quaternary
carbons. Infrared 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 spec-
trometer. Optical rotations were measured on a JASCO DIP-
1000 digital polarimeter. Column chromatography was
performed on Merck silica gel 60 (No 7734-5B) or (No
9385). Elemental analysis were performed by the micro
analytical laboratory of this University.
4.1.2. Mehtyl (6S)-(2)-2-(tert-butyldiphenylsilyloxy-
methyl)-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-
pyridine-1-carboxylate (3). To a stirred solution of
hexamethyldisilazane (1.5 mL, 6.97 mmol) in THF (5 mL)
was added a solution of n-BuLi (1.6 M in hexane, 4.4 mL,
6.97 mmol) at 0 8C, and the resulting solution was stirred at
0 8C for 30 min. To a stirred solution of 2 (2.47 g,
5.81 mmol) in THF (15 mL) was added a solution of
LiHMDS prepared above at 278 8C, and the reaction
mixture was stirred at 278 8C for 30 min. To the above
reaction mixture was added a solution of 2-[N,N-bis(tri-
fluoromethylsulfonyl)amino]5-chloropyridine
(Comins’
reagent) (97%, 2.73 g, 6.97 mmol) in THF (6 mL) at
278 8C, and the resulting mixture was warned to 240 8C
for 1 h. The reaction was quenched with satd. NH4Cl (aq.),
and the aqueous mixture was extracted with Et2O
(20 mL£4). The organic extracts were combined, dried,
and evaporated to give pale yellow solid, which was
chromatographed on SiO2 (60 g, hexane:acetone¼100:1–
50:1) to give 3 (3.0 g, 96%) as a colorless oil.
4.1.1. Methyl (6S)-(2)-2-(tert-butyldiphenylsilyloxy-
methyl)-6-oxopiperidine-1-carboxylate (2). To a stirred
solution of 1 (1.85 g, 5.40 mmol) in THF (22 mL) was
added a solution of n-BuLi (1.6 m in hexane, 3.5 mL,
5.54 mmol) at 278 8C, and the resulting mixture was stirred
at 278 8C for 30 min. To the reaction mixture was added
ClCO2Me (0.43 mL, 5.54 mmol) at 278 8C, and then the
reaction mixture was warmed to 0 8C for 2 h. The reaction
was quenched with satd. NaHCO3 (aq.), and the aqueous
IR (neat) 2962, 1733, 1423, 1213, 1114 cm21; H NMR
(500 MHz) d 1.06 (9H, s), 1.69–1.76 (1H, m), 1.91–2.04
(2H, br m), 2.13–2.19 (1H, m), 3.57 (2H, dd, J¼10.2,
8.1 Hz), 3.79 (3H, s), 4.64–4.68 (1H, m), 5.17 (1H, t,
1

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6203
J¼3.8 Hz), 7.37–7.46 (6H, m), 7.63–7.67 (4H, m); 13C
NMR (125 MHz) d 19.09 (t), 19.29 (s), 22.22 (t), 26.81 (q),
53.69 (q), 55.63 (d), 60.79 (t), 106.05 (d), 127.63 (d), 129.69
(d), 133.06 and 133.11 (each s), 135.42 and 135.44 (each d),
138.05 (s), 154.69 (s); MS: 557 (Mþ), 422 (100); HRMS:
Calcd for C25H30F3NO6Si 557.1515. Found 557.1518;
[a]2D6¼218.8 (c 1.57, CHCl3).
(1H, br), 4.78 (1H, br), 5.09–5.30 (2H, m), 5.81–5.88 (1H,
m), 7.36–7.44 (6H, m), 7.65–7.67 (4H, m); 13C NMR
(125 MHz) d 18.68 (t), 19.56 (s), 21.03 (t), 27.15(q), 37.06
(d), 52.27 (d), 52.34 (q), 53.19 (q), 56.05 (d), 62.34 (t),
115.56 (t), 127.74 (d), 129.72 (d), 133.76 (s), 135.63 (d),
138.91 (d), 157.63 (s), 172.66 (s); MS: 495 (Mþ); HRMS:
Calcd for C28H37NO5Si 495.2441. Found 495.2464;
[a]2D6¼þ2.1 (c 1.57, CHCl3).
4.1.3. Dimethyl (S)-(2)-6-(tert-butyldiphenylsilyloxy-
methyl)-5,6-dihydro-4H-pyridine-1,2-dicarboxylate (4).
To a stirred solution of the above 3 (5.30 g, 9.52 mmol) in
DMF (25 mL) was added Pd(Ph3P)4 (550 mg, 0.48 mmol),
and the resulting mixture was stirred at room temperature
under CO balloon pressure for 30 min. To the reaction
mixture were added Et3N (5.3 mL, 38.1 mmol) and MeOH
(15.4 mL, 381.0 mmol), and then the reaction mixture was
stirred at 70 8C under CO balloon pressure for 15 h. After
cooling, the reaction mixture was diluted with H2O
(100 mL) and brine (25 mL), and the aqueous mixture was
extracted with Et2O (50 mL£3). The organic extracts were
combined, dried, and evaporated to give pale yellow oil,
4.1.5. Methyl (2R,3S,6S)-(1)-6-(tert-butyldiphenylsilyl-
oxymethyl)-2-hydroxymethyl-3-vinylpiperidine-1-car-
boxylate. To a stirred solution of 5 (2.0 g, 4.04 mmol) in
THF (15 mL) was added Super-Hydride (1 M in THF,
8.9 mL, 8.9 mmol) at 0 8C, and the resulting solution was
stirred at 0 8C for 1 h. The reaction was quenched with
satd. NaHCO3 (aq.), and the aqueous mixture was
extracted with CH2Cl2 (15 mL£6). The organic extracts
were combined, dried, and evaporated to give colorless
oil, which was chromatographed on SiO2 (40 g,
hexane:acetone¼30:1–6:1) to give an alcohol (1.8 g,
96%) as a colorless oil.
which
was
chromatographed
on
SiO2
(80 g,
1
hexane:acetone¼50:1–30:1) to give 4 (3.91 g, 88%) as a
IR (neat) 3449, 3070, 2937, 2862, 1679 cm21; H NMR
colorless oil.
(500 MHz) d 1.05 (9H, s), 1.26–1.39 (2H, m), 1.63–1.70
(1H, m), 1.79–1.86 (1H, br m), 2.35 (1H, br), 2.96 (1H, br),
3.55–3.69 (4H, m), 3.67 (3H, br s), 4.25–4.29 (1H, m), 4.39
(1H, br), 5.06–5.12 (2H, m), 5.79–5.86 (1H, m), 7.39–7.46
(6H, m), 7.66–7.72 (4H, m); 13C NMR (125 MHz) d 19.03
(s), 19.95 (t), 21.27 (t), 26.67 and 26.72 (each q), 36.70 (d),
50.83 (d), 52.72 (q), 56.14 (d), 64.43 (t), 64.88 (t), 115.05
(t), 127.67 and 127.70 (each d), 129.74 (d), 132.93 and
133.02 (each s), 135.44 and 135.49 (each d), 140.18 (d),
157.97 (s); MS: 410 (Mþ257), 378 (100); HRMS: Calcd for
C23H28NO4Si 410.1787. Found 410.1807; [a]2D6¼þ19.7 (c
1.53, CHCl3).
IR (neat) 2968, 1732, 1652, 1240 cm21
;
1H NMR
(500 MHz) d 1.05 (9H, s), 1.77–1.85 (1H, m), 1.91–1.99
(1H, br m), 2.04–2.16 (2H, m), 3.52 (1H, dd, J¼10.2,
8.5 Hz), 3.70 (3H, s), 3.71 (3H, s), 3.77 (1H, dd, J¼10.2,
6.3 Hz), 4.55 (1H, br), 5.96 (1H, t, J¼3.5 Hz), 7.37–7.45
(6H, m), 7.65–7.67 (4H, m); 13C NMR (125 MHz) d 19.43
(t), 19.55 (s), 22.48 (t), 26.95 (q), 52.16 (q), 52.69 (d), 53.30
(q), 61.39 (t), 121.98 (s), 127.72 (d), 129.72 and 129.75
(each d), 130.59 (s), 133.31 and 133.41 (each s), 135.58 (d),
154.52 (s), 165.49 (s); MS: 467 (Mþ, 100); HRMS: Calcd
for C26H33NO5Si 467.2128. Found 467.2134; [a]2D6¼253.3
(c 1.33, CHCl3).
4.1.6. Methyl (2S,3S,6S)-(2)-6-(tert-butyldiphenylsilyl-
oxymethyl)-2-propenyl-3-vinylpiperidine-1-carboxylate.
To a stirred solution of (COCl)2 (0.24 mL, 2.77 mmol) in
CH2Cl2 (5 mL) was added DMSO (0.38 mL, 5.43 mmol) at
278 8C, and the resulting solution was stirred at 278 8C for
10 min. To the mixture was added a solution of the alcohol
prepared above (857 mg, 1.84 mmol) in CH2Cl2 (4 mL) at
278 8C, and the reaction mixture was stirred at 278 8C for
30 min. Triethylamine (1.1 mL, 7.98 mmol) at 278 8C, 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 (10 mL£4). The organic extracts
were combined, dried and evaporated to give pale yellow
oil, which was used directly in the next step.
4.1.4. Dimethyl (2R,3S,6S)-(1)-6-(tert-butyldiphenylsilyl-
oxymethyl)-3-vinylpiperidine-1,2-dicarboxylate (5). To a
stirred suspension of CuI (1.71 g, 9.00 mmol) in Et2O
(15 mL) was added a solution of vinyl lithium, prepared
from tetravinyltin (0.37 mL, 4.50 mmol) and MeLi (1.0 M
in Et2O, 18 mL, 18.0 mmol) in Et2O (15 mL) at 0 8C for
30 min, at 278 8C, and the resulting suspension was
warmed to 235 8C for 20 min. The resulting suspension
was re-cooled to 278 8C, and a solution of 4 (1.05 g,
2.25 mmol) in Et2O (5 mL) was added to the resulting
suspension. The reaction mixture was warmed to 230 8C
for 1 h, and the reaction was quenched with satd. NH4Cl
(aq.). The aqueous mixture was diluted with CH2Cl2
(100 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 colorless oil,
To a stirred suspension of EtPþPh3Br2 (2.73 g, 7.35 mmol)
in THF (15 mL) was added a solution of n-BuLi (1.6 M in
hexane, 4 mL, 6.4 mmol) at 0 8C, and the resulting orange
solution was stirred at 0 8C for 30 min. To the solution was
added a solution of the above oil in THF (6 mL) at 0 8C, and
the reaction mixture was stirred at room temperature for 2 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 pale
yellow oil, which was chromatographed on SiO2 (30 g,
hexane:acetone¼100:1–80:1) to give an olefin (691 mg,
79% in 2 steps) as a colorless oil.
which
was
chromatographed
on
SiO2
(40 g,
hexane:acetone¼40:1–30:1) to give 5 (1.07 g, 96%) as a
colorless oil.
IR (neat) 3071, 2935, 2890, 1750, 1705, 1113 cm21; H
NMR (500 MHz) d 1.05 (9H, s), 1.41–1.43 (1H, m), 1.59
(1H, br), 1.74–1.81 (1H, br m), 1.85–1.88 (1H, m), 3.00
(1H, br), 3.45 (3H, s), 3.65 (3H, s), 3.67–3.70 (1H, m), 4.28
1

6204
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
IR (neat) 3070, 2938, 2860, 1697 cm21
;
1H NMR
The reaction was quenched with satd. NaHSO3 (aq.) and
10% HCl at 0 8C, and the aqueous mixture was extracted
with EtOAc (15 mL£10). The organic extracts were
combined, dried, and evaporated to give colorless oil,
which was used directly in the next step.
(500 MHz) d 1.06 (9H, s), 1.33–1.38 (1H, m), 1.67 (3H,
t-like, J¼6.8 Hz), 1.69–1.75 (2H, br m), 1.81–1.88 (1H,
m), 2.19 (1H, br), 3.58–3.69 (2H, m), 3.63 (3H, br s), 4.35
(1H, m), 4.90 (1H, d-like, J¼9.4 Hz), 5.05–5.10 (2H, m),
5.29–5.33 (1H, m), 5.38–5.43 (1H, m), 5.85–5.91 (1H, m),
7.38–7.45 (6H, m), 7.67–7.68 (4H, m); 13C NMR
(125 MHz) d 13.02 (q), 19.18 (s), 19.47 (t), 20.73 (t),
26.78 (q), 41.73 (d), 51.01 (d), 51.71 (d), 52.46 (q), 64.35
(t), 114.70 (t), 127.62 (d), 129.62 (d), 131.10 (d), 133.50 and
133.64 (each s), 135.56 and 135.59 (each d), 140.22 (d),
156.81 (s); MS: 420 (Mþ257), 423 (100); HRMS: Calcd for
C25H30NO3Si 420.1995. Found 420.2017; [a]2D6¼264.5 (c
2.09, CHCl3).
To a stirred solution of the above oil in EtOAc (20 mL) was
added a solution of CH2N2 in Et2O at 0 8C, and the reaction
mixture was stirred at room temperature for 20 h. The
solvent was evaporated, and the residue was chromato-
graphed on SiO2 (40 g, hexane:acetone¼20:1) to give a
methyl ester (1.008 g, 90% in 3 steps) as a colorless oil.
IR (neat) 2957, 2872, 1740, 1701 cm21
;
1H NMR
(500 MHz) d 0.86 (6H, t-like, J¼6.8 Hz), 1.24–1.42 (7H,
br m), 1.46–1.52 (1H, m), 1.71–1.87 (2H, m), 1.96 (1H, br),
3.66 (3H, s), 3.69 (3H, br s), 3.88–4.05 (1H, br), 4.63 and
4.84 (1H, br); 13C NMR (125 MHz) d 11.87 (q), 13.86 (q),
19.91 (t), 20.31 (t), 25.02 (t), 36.19 (t), 37.75 (d), 51.92 (q),
52.72 (q), 54.79 (d), 157.80 (s), 173.24 (s); MS: 271 (Mþ),
228 (100); HRMS: Calcd for C14H25NO4 271.1784. Found
271.1816; [a]2D6¼265.1 (c 2.17, CHCl3).
4.1.7. Methyl (2S,3R,6S)-(2)-3-ethyl-6-hydroxymethyl-
2-propylpiperidine-1-carboxylate (6). To a solution of the
above olefin (704 mg, 1.48 mmol) in EtOAc (15 mL) was
added 5% Pd–C (50 mg), and the resulting suspension was
hydrogenated under hydrogen atmosphere at 1 atm for 48 h.
The catalyst was removed by filtration, and the filtrate was
evaporated to give colorless oil, which was used directly in
the next step.
4.1.9. Dimethyl (5R,6S)-(1)-5-ethyl-6-propyl-5,6-di-
hydro-4H-pyridine-1,2-dicarboxylate (7). To a stirred
solution of hexamethyldisilazane (0.32 mL, 1.5 mmol) in
THF (3 mL) was added a solution of n-BuLi (1.6 M in
hexane, 0.94 mL, 1.5 mmol) at 0 8C, and the resulting
solution was stirred at 0 8C for 30 min. To a stirred solution
of the above methyl ester (271 mg, 1 mmol) in THF (2 mL)
was added a solution of LiHMDS prepared above at
278 8C, and the reaction mixture was stirred at 278 8C
for 30 min. To a stirred solution of PhSeCl (610 mg,
3 mmol) in THF (5 mL) was added a solution of Li enolate
prepared above at 278 8C, and the resulting suspension was
stirred at room temperature for 20 h. The solvent was
evaporated and the residue was chromatographed on SiO2
(30 g, hexane:acetone¼40:1–35:1) to give 7 (207 mg, 77%)
as a colorless oil.
To a stirred solution of the above oil in THF (10 mL) was
added a solution of TBAF (1 M in THF, 1.9 mL, 1.9 mmol)
at 0 8C, and the resulting solution was stirred at room
temperature for 1 h. The reaction was quenched with satd.
NH4Cl (aq.), and the aqueous mixture was extracted with
CH2Cl2 (10 mL£8). The organic extracts were combined,
dried, and evaporated to give colorless oil, which was
chromatographed on SiO2 (20 g, hexane:acetone¼20:1–
7:1) to give 6 (276 mg, 77% in 2 steps) as a colorless oil.
IR (neat) 3447, 2956, 2872, 2672 cm21
;
1H NMR
(500 MHz) d 0.87–0.91 (6H, m), 1.23–1.59 (9H, br m),
1.71–1.81 (2H, m), 2.94 (1H, br), 3.57–3.64 (2H, m), 3.68
(3H, s), 3.92 (1H, br), 4.25 (1H, br); 13C NMR (125 MHz) d
11.96 (q), 13.98 (q), 19.92 (t), 20.15 (t), 25.73 (t), 37.93 (d),
38.87 (t), 52.67 (q), 52.89 (d), 54.46 (d), 52.46 (q), 65.77 (t),
158.85 (s); MS: 243 (Mþ), 131 (100); HRMS: Calcd for
C13H25NO3 243.1833. Found 243.1821; [a]2D6¼221.8 (c
1.05, CHCl3).
IR (neat) 2958, 2874, 1708, 1646 cm21
;
1H NMR
(500 MHz) d 0.91 and 0.93 (each 3H, each t, J¼7.2 Hz),
1.17–1.34 (4H, br m), 1.42–1.51 (3H, m), 1.99 (1H, dd,
J¼19.2, 3.9 Hz), 2.27 (1H, ddd, J¼19.2, 7.3, 3.9 Hz), 3.70
(3H, br s), 3.76 (3H, s), 4.26 (1H, br), 5.97 (1H, t,
J¼3.9 Hz); 13C NMR (125 MHz) d 11.91 (q), 14.02 (q),
19.30 (t), 25.12 and 26.20 (each t), 33.04 (t), 36.30 (t), 37.99
and 38.66 (each d), 52.10 (q), 53.07 (q), 55.29 (d), 121.05
(d), 129.05 and 129.28 (each s), 155.49 (s), 165.40 (s); MS:
269 (Mþ, 100); HRMS: Calcd for C14H23NO4 269.1627.
Found 269.1604; [a]2D6¼þ63.4 (c 0.68, CHCl3).
4.1.8. Dimethyl (2S,5R,6S)-(2)-5-ethyl-6-propylpiper-
idine-1,2-dicarboxylate. To a stirred solution of (COCl)2
(0.53 mL, 6.12 mmol) in CH2Cl2 (12 mL) was added
DMSO (0.88 mL, 12.38 mmol) at 278 8C, and the resulting
solution was stirred at 278 8C for 10 min. To the mixture
was added a solution of 6 (1 g, 4.12 mmol) in CH2Cl2
(9 mL) at 278 8C, and the reaction mixture was stirred at
278 8C for 30 min. Triethylamine (2.6 mL, 18.47 mmol) at
278 8C, 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 (20 mL£4). The organic
extracts were combined, dried and evaporated to give pale
yellow oil, which was used directly in the next step.
4.1.10. Dimethyl (2S,3R,5R,6S)-(2)-5-ethyl-6-propyl-3-
vinylpiperidine-1,2-dicarboxylate (8). To a stirred suspen-
sion of CuI (622 mg, 3.27 mmol) in Et2O (5 mL) was added
a solution of vinyl lithium, prepared from tetravinyltin
(0.31 mL, 1.63 mmol) and MeLi (1.01 M in Et2O, 6.5 mL,
6.6 mmol) in Et2O (3 mL) at 0 8C for 30 min, at 278 8C,
and the resulting suspension was warmed to 235 8C for
20 min. The resulting suspension was re-cooled to 278 8C,
and a solution of 7 (176 mg, 0.65 mmol) in Et2O (4 mL) was
added to the resulting suspension. The reaction mixture was
warmed to 0 8C for 1 h, and the reaction was quenched with
To a stirred suspension of NaH2PO4 (4.9 g, 40.83 mmol),
2-methyl-2-butene (8.8 mL, 82.5 mmol), and the above oil
in t-BuOH (20 mL) was added a solution of NaClO2 (80%,
2.7 g, 24.3 mmol) in H2O (8 mL), and the resulting
suspension was stirred at room temperature for 45 min.

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6205
satd. NH4Cl (aq.). The aqueous mixture was diluted with
CH2Cl2 (50 mL), and the resulting suspension was filtered.
The filtrate was separated, and the aqueous layer was
extracted with CH2Cl2 (10 mL£2). The organic layer and
extracts were combined, dried, and evaporated to give
colorless oil, which was chromatographed on SiO2 (20 g,
hexane:acetone¼70:1–40:1) to give 8 (174 mg, 90%) as a
colorless oil.
J¼11 Hz), 2.21–2.29 (1H, m), 2.82 (1H, td, J¼10, 3.5 Hz),
3.24 (1H, ddd, J¼13, 7, 3 Hz), 3.96 (1H, dd, J¼8, 3 Hz),
4.16 (1H, dd, J¼8, 7 Hz), 5.10–5.14 (2H, m), 5.52 (1H, ddd,
J¼16.5, 10, 8 Hz); 13C NMR (125 MHz) d 10.20 (q), 14.01
(q), 19.49 (t), 24.19 (t), 29.34 (t), 35.98 (t), 39.97 (d), 44.78
(d), 61.16 (d), 61.20 (d), 64.87 (t), 117.44 (t), 137.61 (d),
155.82 (s); MS: 237 (Mþ, 100); HRMS: Calcd for
C14H23NO2, 237.1728. Found 237.1740; [a]2D6¼231.9 (c
1.52, CHCl3).
IR (neat) 2957, 2873, 1747, 1702 cm21
;
1H NMR
(500 MHz) d 0.88 and 0.89 (each 3H, each t, J¼7.3 Hz),
0.96 (1H, q, J¼12 Hz), 1.24–1.46 (6H, br m), 1.62–1.70
(1H, m), 1.70–1.77 (1H, m), 2.64 (1H, q-like, J¼8 Hz),
3.67 (3H, s), 3.69 (3H, s), 3.92 (1H, br), 4.29 (1H, br), 5.00–
5.08 (2H, m), 5.71–5.78 (1H, m); 13C NMR (125 MHz) d
11.31 (q), 13.98 (q), 19.86 (t), 29.56 (t), 31.76 (t), 39.68 (d),
40.50 (t), 40.86 (d), 51.73 (q), 52.81 (q), 55.40 (d), 59.78
(d), 115.31 (t), 139.95 (d), 157.35 (s), 173.20 (s); MS: 254
(Mþ243, 100); HRMS: Calcd for C13H20NO4 (Mþ2C3H7)
254.1392. Found 254.1353; [a]2D6¼265.9 (c 0.91, CHCl3).
4.1.13. Dimethyl (2R,3R,6S)-(1)-6-(tert-butyldiphenyl-
silyloxymethyl)-3-methylpiperidine-1,2-dicarboxylate
(11). To a stirred suspension of CuI (5.95 g, 31.25 mmol) in
Et2O (20 mL) was added a solution of MeLi (1.14 M in
Et2O, 55 mL, 62.5 mmol) at 278 8C, and the resulting
suspension was stirred at 278 to 235 8C for 20 min. The
resulting solution was cooled to 278 8C, and a solution of 4
(2.92 g, 6.25 mmol) in Et2O (10 mL) was added to the
above reaction mixture at 278 8C. The temperature was
gradually raised to 235 8C, and then the reaction
was quenched with satd. NH4Cl (aq.). The reaction mixture
was diluted with CH2Cl2, and the insoluble material was
removed through a celite pad. The filtrate was separated and
the aqueous layer was extracted with CH2Cl2. The filtrate
and organic layers were combined, dried, and evaporated to
give a pale yellow oil, which was chromatographed on SiO2
(60 g, hexane:acetone¼30:1–20:1) to give 11 (2.96 g, 98%)
as a colorless oil.
4.1.11. Methyl (2S,3R,5R,6S)-(2)-5-ethyl-2-hydroxy-
methyl-6-propyl-3-vinylpiperidine-1-carboxylate (9). To
a stirred solution of 8 (45 mg, 0.15 mmol) in THF (1 mL)
was added a solution of Super-Hydride (1 M in THF,
0.4 mL, 0.4 mmol) at 0 8C, and the resulting mixture was
stirred at 0 8C for 1 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 colorless oil, which was
chromatographed on SiO2 (10 g, hexane:acetone¼30:1–
15:1) to give 9 (41 mg, 99%) as a colorless oil.
1
IR (neat) 2955, 1861, 1708 cm21; H NMR (500 MHz) d
1.05 (9H, s), 1.07 (3H, d, J¼6.8 Hz), 1.18–1.25 (1H, m),
1.54–1.57 (1H, br), 1.81–1.85 (2H, m), 2.45 (1H, br), 3.45
(3H, s), 3.49 (1H, t-like, J¼9.9 Hz), 3.65 (3H, s), 3.68 (1H,
dd, J¼9.9, 4.3 Hz), 4.28 (1H, br), 4.44 (1H, br), 7.35–7.44
(6H, m), 7.64–7.68 (4H, m); 13C NMR (125 MHz) d 17.98
(q), 18.13 (t), 19.19 (s), 21.87 (t), 26.78 (q), 28.02 (d), 51.77
(q), 52.06 (d), 52.80 (q), 58.48 (d), 127.53 and 127.56 (each
d), 129.53 and 129.54 (each d), 133.58 and 133.63 (each s),
135.47 (d), 157.36 (s), 172.82 (s); MS: 483 (Mþ), 426 (100);
HRMS: Calcd for C23H28NO5Si (Mþ2C4H9) 426.1736.
Found 426.1744; [a]2D6¼þ13.6 (c 5.12, CHCl3).
1
IR (neat) 3456, 3078, 2958, 2873, 1672 cm21; H NMR
(500 MHz) d 0.88 and 0.92 (each 3H, each t, J¼7.3 Hz),
1.00 (1H, q, J¼10.7 Hz), 1.28–1.47 (6H, br m), 1.53–1.59
(1H, m), 1.62–1.66 (2H, m), 2.12 (1H, br q-like, J¼9.8 Hz),
3.54–3.59 (1H, m), 3.71 (3H, s), 3.72–3.85 (1H, br), 3.97
(2H, br), 5.03–5.29 (2H, m), 5.69 (1H, ddd, J¼17.1, 9.8,
8.1 Hz); 13C NMR (125 MHz) d 11.22 (q), 13.88 (q), 19.65
(t), 29.56 (t), 32.50 (t), 40.51 (d), 41.63 (t), 41.74 (d), 52.98
(q), 55.65 (d), 60.40 (d), 67.09 (t), 115.63 (t), 141.02 (d);
MS: 238 (Mþ231), 117 (100); HRMS: Calcd for
C14H24NO2 (Mþ2MeO), 238.1808. Found 238.1792;
[a]2D6¼293.4 (c 1.86, CHCl3).
4.1.14. Methyl (2R,3R,6S)-(1)-6-(tert-butyldiphenylsilyl-
oxymethyl)-2-hydroxymethyl-3-methylpiperidine-1-car-
boxylate. To a stirred solution of 11 (2.96 g, 6.13 mmol) in
THF (15 mL) was added a solution of Super-Hydride (1 M
in THF, 13.5 mL, 13.48 mmol) at 0 8C, and the resulting
mixture was stirred at 0 8C for 1 h. The reaction was
quenched with satd. NaHCO3 (aq.), and the aqueous mixture
was extracted with CH2Cl2. The organic extracts were
combined, dried, and evaporated to give a pale yellow oil,
4.1.12. (5S,6R,8R,9S)-(2)-6-Ethyl-5-propyl-8-vinylhexa-
hydrooxazolo[3,4-a]pyridin-3-one (10). To
a stirred
solution of 9 (41 mg, 0.15 mmol) in THF (1 mL) was
added NaH (60%, 7.9 mg, 0.20 mmol) at 0 8C, and the
resulting suspension was stirred at 0 8C for 1 h. The reaction
was quenched with 10% AcOH, and the aqueous mixture
was extracted with CH2Cl2 (5 mL£4). The organic extracts
were combined, dried, and evaporated to give colorless oil,
which
was
chromatographed
on
SiO2
(45 g,
hexane:acetone¼30:1–6:1) to give an alcohol (2.58 g,
92%) as a colorless oil.
which
was
chromatographed
on
SiO2
(10 g,
hexane:acetone¼20:1) to give 10 (30.3 mg, 84%) as a
IR (neat) 3450, 3070, 2956, 1680 cm21 1H NMR
;
colorless oil.
(500 MHz) d 1.04 (9H, s), 1.05 (3H, d, J¼7.7 Hz), 1.15–
1.18 (1H, m), 1.43 (1H, br), 1.58–1.64 (1H, m), 1.78–1.90
(2H, m), 2.99 (1H, br), 3.53–3.64 (4H, m), 3.67 (3H, s),
4.01–4.04 (1H, m), 4.39 (1H, br), 7.37–7.46 (6H, m), 7.66–
7.72 (4H, m); 13C NMR (125 MHz) d 18.98 (q), 19.14 (s),
19.49 (t), 22.37 (t), 26.63 (q), 27.28 (d), 50.81 (d), 52.63 (q),
58.79 (d), 64.89 (t), 127.62 and 127.65 (each d), 129.68 and
IR (neat) 3078, 2962, 2872, 1751 cm21
;
1H NMR
(500 MHz) d 0.87 (3H, t, J¼7.5 Hz), 0.93 (3H, t,
J¼7.3 Hz), 1.06–1.16 (2H, m), 1.26–1.33 (1H, br m),
1.51 (1H, qm, J¼11.5 Hz), 1.54–1.62 (2H, m), 1.73–1.80
(1H, m), 1.97 (1H, dt, J¼13, 3.5 Hz), 2.17 (1H, qm,

6206
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
129.69 (each d), 133.03 (s), 135.39 and 135.45 (each d),
158.32 (s); MS: 398, 366 (100); HRMS: Calcd for
C22H28NO4Si (Mþ2C4H9) 398.1787. Found 398.1787;
[a]2D6¼þ19.8 (c 1.89, CHCl3).
the reaction mixture was added Et3N (3.1 mL, 22.62 mmol)
at 278 8C, and the temperature was gradually raised to 0 8C.
The reaction mixture was diluted with Et2O and water, and
the organic layer was separated. The aqueous layer was
extracted with Et2O and 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
solution of the above oil in t-BuOH (21 mL) were added
NaHPO4 (5.9 g, 49.17 mmol) and 2-methyl-2-butene
(21 mL, 192.92 mmol) at room temperature, and then a
solution of NaClO2 (80%, 3.3 g, 29.18 mmol) in water
(8 mL) was added dropwise to the reaction mixture at 0 8C.
The resulting suspension was stirred at room temperature
for 30 min, and the reaction was quenched with satd.
NaHSO3 (aq.) at 0 8C. To the mixture was added 10% HCl
(aq.), and the aqueous mixture was saturated with NaCl. The
aqueous mixture was extracted with EtOAc, and the organic
extracts were combined, dried, and evaporated to give a pale
yellow oil, which was used direcly in the next step.
4.1.15. (5S,8R,9R)-(2)-5-(tert-Butyldiphenylsilyloxy-
methyl)-8-methylhexahydrooxazolo[3,4-a]pyridin-3-one
(12). To a stirred solution of the above alcohol (493 mg,
1.08 mmol) in THF (8 mL) was added NaH (60%, 48 mg,
1.19 mmol) at 0 8C, and the resulting suspension was stirred
at 0 8C for 1 h. The reaction was quenched with 10% AcOH
(aq.), and the aqueous mixture was extracted with CH2Cl2.
The organic extracts were combined, dried, and evaporated
to give a pale yellow oil, which was chromatographed on
SiO2 (15 g, hexane:acetone¼30:1–15:1) to give 12
(456 mg, 99%) as a colorless solid (mp 81–83 8C).
IR (KBr) 2958, 2859, 1751, 757 cm21; 1H NMR (500 MHz)
d 0.88 (3H, d, J¼6.4 Hz), 1.03 (9H, s), 1.11–1.20 (1H, m),
1.41–1.48 (2H, m), 1.90 (1H, dq, J¼13.7, 3.4 Hz), 2.07
(1H, dq, J¼13.4, 3.4 Hz), 3.12–3.20 (2H, m), 3.89 (1H, dd,
J¼8.6, 7.3 Hz), 4.18 (1H, dd, J¼10.2, 8.1 Hz), 4.33 (1H, dd,
J¼8.6, 7.7 Hz), 4.48 (1H, dd, J¼10.2, 4.3 Hz), 7.36–7.43
(6H, m), 7.66–7.69 (4H, m); 13C NMR (125 MHz) d 16.87
(q), 19.14 (s), 26.75 (q), 28.39 (t), 31.72 (t), 35.09 (t), 56.93
(d), 62.38 (d), 63.16 (t), 66.64 (t), 127.48 (d), 129.45 (d),
133.38 and 133.50 (each s), 135.40 and 135.46 (each d),
156.20 (s); MS: 366 (100); HRMS: Calcd for C21H24NO3Si
(Mþ2C4H9) 366.1526. Found 366.1526. Anal. Calcd for
C25H33NO3Si C, 70.88; H, 7.85; N, 3.31. Found C, 70.71;
H, 7.92; N, 3.39; [a]2D6¼243.5 (c 1.46, CHCl3).
To a stirred solution of the above pale yellow oil in EtOAc
(10 mL) was added a solution of CH2N2 in Et2O (10 mL) at
0 8C, and then the resulting solution was stirred at room
temparature for 23 h. The solvent was evaporated and the
residue was chromatographed on SiO2 (40 g,
hexane:acetone¼15:1–12:1) to give 13 (1.06 g, 86% in 2
steps) as a colorless solid (mp 74–76 8C).
IR (KBr) 2960, 2932, 1762, 1205 cm21
;
1H NMR
(500 MHz) d 0.90 (3H, d, J¼6.4 Hz), 1.13 (1H, qd,
J¼12.8, 3.4 Hz), 1.54–1.60 (1H, m), 1.71–1.80 (1H, m),
1.88–1.98 (2H, m), 3.14–3.20 (1H, m), 3.67 (1H, dd, J¼11,
3.5 Hz), 3.77 (3H, s), 3.95 (1H, t-like, J¼8.5 Hz), 4.41 (1H,
t-like, J¼8.5 Hz); 13C NMR (125 MHz) d 16.88 (q), 27.70
(t), 30.66 (t), 34.08 (d), 52.44 (q), 55.82 (d), 61.40 (d), 67.97
(t), 156.79 (s), 170.36 (s); MS: 213 (Mþ), 211 (100);
HRMS: Calcd for C10H15NO4 213.0101. Found 213.0991;
[a]2D6¼296.7 (c 1.08, CHCl3).
4.1.16. (5S,8R,9R)-(2)-5-Hydroxymethyl-8-methylhexa-
hydrooxazolo[3,4-a]pyridin-3-one. To a stirred solution of
12 (1.49 g, 3.51 mmol) in THF (20 mL) was added a
solution of TBAF (1 M in THF, 4.6 mL, 4.6 mmol) at 0 8C,
and the reaction mixture was stirred at room temperature for
1 h. The reaction was quenched with satd. NH4Cl (aq.), and
the aqueous mixture was extracted with CHCl3. The organic
extracts were combined, dried, and evaporated to give a pale
yellow oil, which was chromatographed on SiO2 (18 g,
hexane:acetone¼10:1–4:1) to give an alcohol (648 mg,
99%) as a colorless oil.
4.1.18. Methyl (8R,9R)-(2)-8-methyl-3-oxo-5-phenyl-
sulfanylhexahydrooxazolo[3,4-a]pyridine-5-carboxylate.
To a stirred solution of hexamethyldisilazane (1.01 mL,
4.73 mmol) in THF (6 mL) was added n-BuLi (1 M in
hexane, 3.0 mL, 4.73 mmol) at 0 8C, and the resulting
mixture was stirred at 0 8C for 30 min. To a stirred solution
of 7 (871 mg, 4.09 mmol) in THF (6 mL) was added a
solution of LiHMDS in THF prepared above at 278 8C, and
the reaction mixture was stirred at 278 8C for 30 min. To
the reaction mixture was added a solution of (PhS)2 in THF
(4 mL) via canule at 278 8C, and the temperature was
gradually raised to 0 8C. The volatiles were removed and the
residue was chromatographed on SiO2 (50 g,
hexane:acetone¼10:1) to give a phenylthio ether (1.3 g,
99%) as a colorless oil.
IR (neat) 3420, 2930, 2875, 1723 cm21
;
1H NMR
(500 MHz) d 0.78–0.83 (3H, m), 1.06–1.16 (1H, m),
1.26–1.37 (2H, m), 1.51–1.57 (1H, m), 1.76–1.82 (1H, m),
3.04–3.13 (1H, m), 3.13–3.21 (1H, m), 3.66–3.71 (1H, m),
3.73–3.84 (1H, m), 3.86–3.91 (1H, m), 4.37–4.41 (1H, m),
4.57–4.62 (1H, m); 13C NMR (125 MHz) d 16.52 (q), 27.46
(t), 31.40 (t), 35.70 (d), 58.44 (d), 62.02 (d), 63.23 (t), 67.52
(t), 157.40 (s); MS: 185 (Mþ), 155 (100); HRMS: Calcd for
C9H15NO3 185.1052. Found 185.1050; [a]2D6¼239.7 (c
1.32, CHCl3).
4.1.17. Methyl (5S,8R,9R)-(2)-8-methyl-3-oxohexa-
hydrooxazolo[3,4-a]pyridine-5-carboxylate (13). To a
stirred solution of (COCl)2 (0.65 mL, 7.47 mmol) in
CH2Cl2 (10 mL) was added DMSO (1.1 mL, 15.41 mmol)
at 278 8C, and the resulting mixture was stirred at 278 8C
for 5 min. To the mixture was added a solution of the above
alcohol (923 mg, 4.99 mmol) in CH2Cl2 (5 mL) via canule
at 278 8C, and then stirring was continued for 30 min. To
IR (neat) 2956, 1762, 1269, 1202, 758 cm21 1H NMR
;
(500 MHz) d 0.94 (3H, d, J¼6.4 Hz), 1.52–1.59 (1H, m),
1.65–1.73 (2H, m), 1.87 (1H, dt-like, J¼14.5, 3 Hz), 2.05–
2.11 (1H, m), 3.65–3.70 (1H, m), 3.74 (3H, s), 3.88 (1H,
t-like, J¼8.5 Hz), 4.40 (1H, t-like, J¼8.5 Hz), 7.25–7.29
(2H, m), 7.31–7.33 (1H, m), 7.66–7.68 (2H, m); 13C NMR
(125 MHz) d 16.74 (q), 27.93 (t), 32.82 (t), 34.59 (d), 53.08
(q), 57.42 (d), 67.96 (t), 71.98 (s), 128.57 (d), 129.25 (s),

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6207
129.57 (d), 137.10 (d), 155.17 (s), 169.56 (s); MS: 321
(Mþ), 213 (100); HRMS: Calcd for C16H19NO4S 321.1035.
Found 321.1038; [a]2D6¼213.3 (c 1.38, CHCl3).
in CH2Cl2 (2 mL) was added DMSO (0.18 mL, 2.52 mmol)
at 278 8C, and the resulting solution was stirred at 278 8C
for 10 min. To the mixture was added a solution of 9
(150 mg, 0.56 mmol) in CH2Cl2 (3 mL) at 278 8C, and the
reaction mixture was stirred at 278 8C for 30 min.
Triethylamine (0.52 mL, 3.78 mmol) at 278 8C, 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 (10 mL£4). The organic extracts were
combined, dried and evaporated to give pale yellow oil,
which was used directly in the next step.
4.1.19. Methyl (8R,9R)-(2)-8-methyl-3-oxo-1,7,8,8a-
tetrahydrooxazolo[3,4-a]pyridine-5-carboxylate
(14).
To a stirred solution of the above phenylthio ether
(160 mg, 0.50 mmol) in CH2Cl2 (2 mL) was added 2,6-
lutidine (0.15 mL, 1.29 mmol), and then mCPBA (65%,
320 mg, 1.20 mmol) was added to the resulting mixture in
four portions in 15 min interval at room temperature. The
reaction was quenched with 10% Na2S2O3 in satd. NaHCO3
(aq.), and the aqueous mixture was diluted with EtOAc. The
layers were separated and the aqueous layer was extracted
with EtOAc. The organic layer and extracts were combined,
washed with brine, 10% HCl, and brine, successively, dried
and evaporated to give a colorless oil, which was
chromatographed on SiO2 (15 g, hexane:acetone¼10:1) to
give 14 (89 mg, 85%) as a colorless solid (mp 101–103 8C).
To a stirred suspension of NaH (60%, 25 mg, 0.61 mmol) in
THF (2 mL) was added (EtO)2P(O)CH2CO2Et (0.12 mL,
0.59 mmol) at 0 8C, and the resulting solution was stirred at
0 8C for 15 min. To the reaction mixture was added a
slolution of the above oil in THF (4 mL) at 0 8C, and 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 (10 mL£3). The organic
extracts were combined, dried, and evaporated to give pale
yellow oil, which was chromatographed on SiO2 (12 g,
hexane:acetone¼80:1) to give 16 (181 mg, 96%) as a
colorless oil.
IR (KBr) 2989, 2956, 1763, 1730, 1411, 1249, 1214 cm21
;
1H NMR (500 MHz) d 1.01 (3H, d, J¼6.4 Hz), 1.85–1.87
(1H, m), 1.89–1.96 (1H, m), 2.48 (1H, dt, J¼19.7, 5.1 Hz),
3.39–3.44 (1H, m), 3.83 (3H, s), 4.23 (1H, dd, J¼9.0,
3.0 Hz), 4.55 (1H, t-like, J¼8.5 Hz), 6.25 (1H, dd, J¼4.9,
2.8 Hz); 13C NMR (125 MHz) d 16.43 (q), 30.64 (d), 31.42
(t), 52.44 (q), 57.98 (d), 123.56 (d), 154.76 (s), 163.25 (s);
MS:211 (Mþ); HRMS: Calcd for C10H13NO4 211.0844.
Found 211.0870; [a]2D6¼234.4 (c 0.46, CHCl3).
IR (neat) 3078, 2958, 2873, 1697 cm21
;
1H NMR
(500 MHz) 0.86–0.92 (6H, m), 1.00 (1H, q,
d
J¼11.1 Hz), 1.25 (3H, t, J¼7.3 Hz), 1.29–1.45 (7H, br
m), 1.51–1.58 (1H, m), 1.68–1.72 (1H, m), 2.30 (1H,
q-like, J¼11.1 Hz), 3.67 (3H, s), 4.16 (2H, q, J¼7.3 Hz),
4.18 (1H, br), 5.03–5.07 (2H, m), 5.59–5.66 (1H, m), 5.79–
5.87 (1H, m), 6.77 (1H, dd, J¼15.8, 6.9 Hz); 13C NMR
(125 MHz) d 11.20 (q), 13.80 (q), 14.15 (q), 19.76 (t), 29.70
(t), 32.23 (t), 41.17 (t), 41.51 (d), 41.82 (d), 52.69 (q), 55.37
(d), 58.29 (d), 60.35 (t), 116.19 (t), 122.33 (d), 139.72 (d),
147.09 (d), 157.17 (s), 166.42 (s); MS: 337 (Mþ), 294 (100);
HRMS: Calcd for C19H31NO4, 337.2253. Found 337.2231;
[a]2D6¼242.1 (c 1.08, CHCl3).
4.1.20. Methyl (5R,6R,8R,9R)-(2)-6,8-dimethyl-3-oxo-
hexahydrooxazolo[3,4-a]pyridine-5-carboxylate (15). To
a stirred suspension of CuI (744 mg, 3.91 mmol) in Et2O
(25 mL) was added a solution of MeLi (1.18 M in Et2O,
6.6 mL, 7.82 mmol) at 278 8C, and the reaction mixture
was warmed to 235 8C for 30 min. To a solution of 14
(165 mg, 0.78 mmol) in Et2O (70 mL) was added a solution
of (Me)2CuLi, prepared above, at 278 8C, and the reaction
mixture was warmed to 210 8C for 1 h. The reaction was
quenched with satd. NH4Cl (aq.), and the aqueous mixture
was diluted with CH2Cl2 (300 mL). The resulting suspen-
sion was filtered, and the filtrate was separated. The aqueous
layer was extracted with CH2Cl2 (10 mL£2), and the filtrate
and organic extracts were combined, dried, and evaporated
to give a colorless oil, which was chromatographed on SiO2
(15 g, hexane:acetone¼14:1) to give 15 (165 mg, 93%) as a
colorless oil.
4.1.22. Methyl (2R,3S,5R,6S)-(2)-3,5-diethyl-2-(3-
hydroxypropyl)-6-propylpiperidine-1-carboxylate. To a
solution of 16 (200 mg, 0.59 mmol) in EtOAc (10 mL) was
added 5% Pd–C (50 mg), and the resulting suspension was
hydrogenated under hydrogen atmosphere at 1 atm for 72 h.
The catalyst was removed by filtration, and the filtrate was
evaporated to give colorless oil, which was used directly in
the next step.
1
IR (neat) 2961, 1748, 1420, 1272, 1243 cm21; H NMR
To a stirred solution of the above in THF (8 mL) was added
a solution of Super-Hydride (1 M in THF, 1.3 mL,
1.3 mmol) at 0 8C, and the resulting mixture was stirred at
0 8C for 1 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 colorless oil, which was chromato-
graphed on SiO2 (20 g, hexane:acetone¼30:1–8:1) to give
an alcohol (157 mg, 89%) as a colorless oil.
(500 MHz) d 0.84 (3H, d, J¼6.4 Hz), 1.13 (3H, d,
J¼7.3 Hz), 1.28 (1H, td, J¼13, 4.3 Hz), 1.53 (1H, dt,
J¼14, 3 Hz), 1.65–1.72 (1H, m), 2.49–2.51 (1H, m), 3.59
(1H, dt, J¼10, 8 Hz), 3.74 (3H, s), 3.97 (1H, t-like,
J¼8.5 Hz), 4.26 (1H, br), 4.52 (1H, t-like, J¼8.5 Hz); 13C
NMR (125 MHz) d 17.18 (q), 18.17 (q), 29.51 (d), 29.73 (d),
34.82 (t), 52.39 (q), 57.21 (d), 57.67 (d), 68.12 (t), 157.68
(s), 170.97 (s); MS: 227 (Mþ), 169 (100); HRMS: Calcd for
C11H17NO4 227.1158. Found 227.1168; [a]2D6¼236.4 (c
0.96, CHCl3).
IR (neat) 3448, 2957, 2872, 1674 cm21
;
1H NMR
(500 MHz) d 0.63 (1H, q-like, J¼11.1 Hz), 0.86–0.89
(9H, m), 1.18–1.66 (15H, br m), 2.60 (1H, br), 3.59–3.65
(2H, br), 3.63 (3H, s), 3.76 (1H, br), 3.92 (1H, br); 13C NMR
(125 MHz) d 11.46 (q), 14.02 (q), 20.09 (t), 28.45 (t), 28.82
4.1.21. Methyl (2S,3R,5R,6S)-(2)-2-(2-ethoxycarbonyl-
vinyl)-5-ethyl-6-propyl-3-vinylpiperidine-1-carboxylate
(16). To a stirred solution of (COCl)2 (0.11 mL, 1.26 mmol)

6208
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
(t), 29.73 (t), 30.60 (t), 34.41 (t), 40.46 (t), 42.12 (d), 52.43
(q), 55.23 (d), 56.74 (d), 62.70 (t), 158.40 (s); MS: 299
(Mþ), 256 (100); HRMS: Calcd for C17H33NO3, 299.2460.
Found 299.2459; [a]2D6¼27.2 (c 3.00, CHCl3).
(1H, br); 13C NMR (75 MHz) d 11.08 (q), 14.76 (q), 18.00
(t), 20.71 (t), 24.71 (t), 26.03 (t), 28.80 (t), 32.98 (t), 35.23
(t), 39.94 (d), 52.06 (t), 67.49 (d); MS: 223 (Mþ), 190 (100);
[a]2D6¼þ60.4 (c 0.25, CHCl3).
1
4.1.23. Methyl (2R,3S,5R,6S)-(1)-3,5-diethyl-2-(3-meth-
oxymethoxypropyl)-6-propylpiperidine-1-carboxylate
(17). To a stirred solution of the above alcohol (217 mg,
0.73 mmol) in CHCl3 (5 mL) were added MOMCl
(0.22 mL, 2.9 mmol) and Hu¨nig base (0.56 mL, 3.19 mmol),
and the resulting mixture was refluxed for 2 h. After cooling,
the solvent was evaporated and the residue was chromato-
graphed on SiO2 (15 g, hexane:acetone¼30:1) to give 17
(215 mg, 86%) as a colorless oil.
DCl salt. H NMR (500 MHz, D2O) d 0.84–0.91 (9H, m),
1.01 (1H, q-like, J¼12.5 Hz), 1.23 (3H, m), 1.39 (1H, m),
1.55 (3H, br m), 1.65 (2H, m), 1.75 (2H, m), 1.94 (1H, quint-
like, J¼11 Hz), 2.05 (2H, dm, J¼14 Hz), 2.33 (1H, m), 2.89
(1H, dt-like, J¼12, 2.5 Hz), 2.93 (1H, m), 3.03 (1H, q-like,
J¼10 Hz), 3.65 (1H, td-like, J¼10, 3 Hz); 13C NMR
(75 MHz, D2O) d 9.79 (q), 9.99 (q), 13.79 (q), 16.49 (t),
19.45 (t), 23.74 (t), 25.13 (t), 27.12 (t), 30.15 (t), 33.20 (t),
38.53 (d), 40.21 (d), 51.42 (t), 67.89 (d), 71.87 (d);
[a]2D6¼þ17.2 (c 0.3, CHCl3).
IR (neat) 2955, 2873, 1693, 1110 cm21
;
1H NMR
(500 MHz) d 0.60 (1H, q-like, J¼8.8 Hz), 0.83–0.86 (9H,
m), 1.19–1.62 (15H, br m), 3.30 (3H, br s), 3.46 (2H, br),
3.60 (3H, br s), 3.71 (1H, br), 3.91 (1H, br), 4.55 (2H, br s);
13C NMR (125 MHz) d 11.42 (q), 14.00 (q), 20.10 (t), 27.17
(t), 28.60 (t), 30.60 (t), 34.38 (t), 40.21 (t), 42.08 (d), 52.22
(q), 54.91 (q), 56.76 (d), 67.52 (t), 96.20 (t), 158.13 (s); MS:
343 (Mþ), 300 (100); HRMS: Calcd for C19H37NO4,
343.2721. Found 343.2709; [a]2D6¼þ0.126 (c 6.28, CHCl3).
4.1.25. (2S)-2-(2-Ethylbut-3-enyloxy)tetrahydropyran
(20). To a stirred solution of (2R)-2-(hydroxymethyl)butyl
acetate (19, 730 mg, 5 mmol) in CH2Cl2 (5 mL) were added
3,4-dihydro-2H-pyran (0.55 mL, 6 mmol) and PPTS
(251 mg, 1 mmol), and the resulting mixture was stirred at
room temperature for 2 h. The reaction was quenched with
satd NaHCO3 (a), and the aqueous mixture was extracted
with CH2Cl2 (10 mL£4). The organic extracts were
combined, dried, and evaporated to give colorless oil,
which was used directly in the next step.
4.1.24. (5S,6R,8S,9R)-(1)-6,8-Diethyl-5-propylocta-
hydroindolizine (18). To a stirred solution of n-PrSLi,
prepared from n-PrSH (0.11 mL, 1.17 mmol) and n-BuLi
(1.6 M in hexane, 0.69 mL, 1.13 mmol) in HMPA (0.5 mL)
at 0 8C for 30 min. To the reaction mixture was added a
solution of 17 (40 mg, 0.17 mmol) in THF (2 mL) at 0 8C,
and the resulting solution was stirred at room temperature
for 48 h. The reaction was quenched with NH3 (aq.), and the
aqueous mixture was extracted with Et2O (5 mL£10). The
organic extracts were combined, dried over K2CO3, and
evaporated to give pale yellow oil, which was used directly
in the next step.
To a stirred solution of the above oil in MeOH (5 mL) was
added solid K2CO3 (414 mg, 3 mmol) at 0 8C, and the
resulting suspension was stirred at room temperature for 3 h.
The reaction was quenched with 10% AcOH, and the
aqueous mixture was extracted with CHCl3 (10 mL£6). The
organic extracts were combined, dried, and evaporated to
give colorless oil, which was used directly in the next step.
To a stirred solution of (COCl)2 (0.65 mL, 7.5 mmol) in
CH2Cl2 (7 mL) was added DMSO (1.06 mL, 15.0 mmol) at
278 8C, and the resulting solution was stirred at 278 8C for
10 min. To the mixture was added a solution of the above oil
in CH2Cl2 (6 mL) at 278 8C, and the reaction mixture was
stirred at 278 8C for 30 min. Triethylamine (3.1 mL,
22.5 mmol) at 278 8C, 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£4). The organic extracts were combined, dried and
evaporated to give pale yellow oil, which was used directly
in the next step.
To a stirred solution of the above oil in MeOH (4 mL) was
added c. HCl (3 drops), and the resulting mixture was
refluxed for 1 h. After cooling, the solvent was evaporated,
and the residue was washed with Et2O. To the residue was
added NH3 (aq.), and the aqueous mixture was extracted
with CHCl3 (5 mL£8). The organic extracts were combined,
dried over K2CO3, and evaporated to give colorless oil,
which was used directly in the next step.
Carbontetrabromide (55 mg, 0.16 mmol) and Ph3P (46 mg,
0.17 mmol) were added to a solution of the above oil in
CH2Cl2 (1 mL) at 0 8C, and the reaction mixture was stirred
at 0 8C for 2 h. To the reaction mixture was added Et3N
(0.26 mL, 1.87 mmol) at 0 8C, and the resulting suspension
was stirred at 0 8C for 10 min. The solvent was evaporated,
and the residue was extracted with n-pentane (5 mL£5). The
organic extracts were combined and evaporated to give
colorless solid, which was chromatographed on SiO2 (7 g,
hexane:acetone:Et3N¼50:1:5 drops) to give 18 (14 mg,
52%) as a pale yellow oil.
To a stirred suspension of MePþPh3Br2 (8.08 g,
20.0 mmol) in THF (20 mL) was added a solution of
n-BuLi (1.6 M ih hexane, 12 mL, 19.0 mmol) at 0 8C, and
the resulting orange solution was stirred at 0 8C for 30 min.
To the solution was added a solution of the above oil in THF
(10 mL) at 0 8C, and the reaction mixture was stirred at
room temperature for 1.5 h. The reaction was quenched with
H2O, and the aqueous mixture was extracted with Et2O
(25 mL£3). The organic extracts were combined, dried, and
evaporated to give pale yellow oil, which was chromato-
graphed on SiO2 (40 g, hexane:acetone¼100:1–80:1) to
give 20 (695 mg, 76% in 4 steps) as a colorless oil.
IR (neat) 2959, 2872, 2778, 1461, 1379, 1324, 1247, 1172,
934, 901, 733 cm21 1H NMR (500 MHz) d 0.61 (1H,
;
q-like, J¼12 Hz), 0.89 (9H, t, J¼7 Hz), 1.07 (2H, m), 1.20–
1H NMR (500 MHz) d 0.88 (3H, t, J¼7.3 Hz), 1.22–1.35
1.80 (13H, br m), 1.93 (3H, br dt-like, J¼13, 3.5 Hz), 3.18
(1H, m), 1.46–1.62 (5H, br m), 1.69 (1H, m), 1.80 (1H, m),

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6209
2.22 (1H, br), 3.31 (1H, m), 3.50 (1H, br), 3.68 (1H, m), 3.80
(1H, m), 4.59 (1H, br), 5.07 (2H, m), 5.63 (1H, m).
sion was stirred at 80 8C for 15 h. After cooling, the
insoluble material was filtered, washed with CH2Cl2, and
filtrate was evaporated to give pale yellow oil, which was
chromatographed on SiO2 (30 g, hexane:acetone¼50:1–
40:1) to give 21 (1.3 g, 83%) as a colorless oil.
4.1.26. (2R,3R)-3-(Tetrahydropyran-2-yloxymethyl)-
pentane-1,2-diol. To a stirred solution of 20 (690 mg,
3.75 mmol) in t-BuOH (10 mL) and H2O (10 mL) was
added AD-mix b (4 g), prepared from (DHQD)2PYR
(0.5 g), K2OsO4·2H2O (40.5 mg), K3Fe(CN)6 (54.7 g), and
K2CO3 (22.9 g), at 0 8C, and the resulting suspension was
stirred at 0 8C for 24 h. The reaction was quenched with
Na2SO3 (4 g), and the reaction mixture was extracted with
EtOAc (20 mL£5). The organic extracts were combined,
dried, and evaporated to give pale yellow oil, which was
chromatographed on SiO2 (20 g, hexane:acetone¼10:1–
4:1) to give a diol (654 mg, 80%) as a colorless oil.
1
IR (neat) 3070, 2936, 2098, 1112, 1032 cm21; H NMR
(500 MHz) d 0.88 and 0.90 (3H, each t, each J¼7.3 Hz),
1.10 (9H, s), 1.44–1.75 (9H, br m), 3.22–3.29 (1H, m),
3.44–3.52 (1H, m), 3.66–3.83 (5H, br m), 4.46 and 4.51
(1H, each br), 7.39–7.47 (6H, m), 7.70–7.74 (4H, m); 13C
NMR (125 MHz) d 11.82 and 11.91 (each q), 19.06 and
19.14 (each t), 19.42 (s), 20.09 and 20.26 (each t), 25.35
and 25.38 (each t), 26.66 (q), 30.45 and 30.49 (each t), 41.26
and 41.32 (each d), 61.76 and 62.22 (each t), 65.49 and
65.55 (each d), 65.68 (t), 66.19 (t), 66.83 (t), 98.32 and
99.35 (each d), 127.70 (d), 129.70 and 129.72 (each d),
133.03 and 133.14 (each s), 135.58 and 135.60 (each d).
IR (neat) 3405, 2940, 2877, 1124 cm21
;
1H NMR
(500 MHz) d 0.91–0.94 (3H, m), 1.31–1.78 (9H, br m),
2.22 and 2.28 (1H, each br), 3.46–3.65 (3H, m), 3.66–3.72
(3H, m), 3.78 (1H, br), 3.82–3.93 (2H, br m), 4.52 and 4.57
(1H, each br), 3.91 (1H, br); 13C NMR (125 MHz) d 11.60
and 11.61 (each q), 19.37 and 19.76 (each t), 21.22 and
21.43 (each t), 25.13 (t), 30.41 and 30.55 (each t), 42.13 and
42.27 (each d), 62.38 and 62.99 (each t), 65.11 (t), 67.74 and
68.15 (each t), 73.61 and 73.59 (each d), 98.88 and 99.74
(each d).
4.1.29. Ethyl (4R,5S)-5-azide-6-(tert-butyldiphenylsilyl-
oxy)-4-ethyl-2-hexenoate (22). To a stirred solution of 21
(1.1 g, 2.29 mmol) in EtOH (5 mL) was added PPTS
(115 mg, 0.46 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 (20 mL£4). The organic extracts
were combined, dried, and evaporated to give colorless oil,
which was used directly in the next step.
4.1.27. (2R,3R)-1-(tert-Butyldiphenylsilyloxy)-3-(tetra-
hydropyran-2-yloxymethyl)-pentan-2-ol. To a stirred
solution of the above diol (590 mg, 2.71 mmol) in CH2Cl2
(5 mL) were added TBDPSCl (0.8 mL, 2.98 mmol), Et3N
(0.5 mL, 3.52 mmol), and DMAP (70 mg, 0.54 mmol) at
0 8C, and the reaction mixture was stirred at room
temperature for 20 h. The solvent was evaporated and the
redisue was chromatographed on SiO2 (30 g,
hexane:acetone¼50:1–30:1) to give a silyl ether (1.21 g,
98%) as a colorless oil.
To a stirred solution of (COCl)2 (0.3 mL, 3.43 mmol) in
CH2Cl2 (6 mL) was added DMSO (0.5 mL, 6.86 mmol) at
278 8C, and the resulting solution was stirred at 278 8C for
10 min. To the mixture was added a solution of the above
alcohol in CH2Cl2 (8 mL) at 278 8C, and the reaction
mixture was stirred at 278 8C for 30 min. Triethylamine
(1.4 mL, 10.29 mmol) at 278 8C, 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£4). The organic extracts were combined, dried and
evaporated to give pale yellow oil, which was used directly
in the next step.
1
IR (neat) 3486, 3069, 2935, 2864, 1113 cm21; H NMR
(500 MHz) d 0.95 and 0.96 (3H, each t, each J¼7.7 Hz),
1.06 (9H, s), 1.42–1.76 (9H, br m), 3.01–3.05 (1H, m),
3.44–3.52 (2H, m), 3.72–3.95 (5H, br m), 4.52 (1H, br),
7.40–7.46 (6H, m), 7.69–7.72 (4H, m); 13C NMR
(125 MHz) d 11.62 and 11.76 (each q), 19.12 and 19.14
(each t), 19.32 (s), 21.02 and 21.08 (each t), 25.24 and 25.27
(each t), 26.77 (q), 30.38 and 30.41 (each t), 41.57 (d), 61.77
and 61.82 (each t), 66.33 (t), 66.97 (t), 73.18 and 73.24
(each d), 98.55 and 99.12 (each d), 127.61 (d), 129.61 and
129.62 (each d), 133.27 and 133.28 (each s), 135.47 (d).
To a stirred suspension of NaH (60%, 100 mg, 2.52 mmol)
in THF (5 mL) was added (EtO)2P(O)CH2CO2Et (0.5 mL,
2.52 mmol) at 0 8C, and the resulting solution was stirred at
0 8C for 15 min. To the reaction mixture was added a
solution of the above aldehyde in THF (6 mL) at 0 8C, and
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£3). The organic
extracts were combined, dried, and evaporated to give pale
yellow oil, which was chromatographed on SiO2 (25 g,
hexane:acetone¼80:1) to give 22 (935 mg, 88% in 3 steps)
as a colorless oil.
4.1.28. (2S,3S)-1-(tert-Butyldiphenylsilyloxy)-3-(tetra-
hydropyran-2-yloxymethyl)pentan-2-azide (21). To a
stirred solution of the above silyl ether (1.49 g,
3.27 mmol) in CH2Cl2 (4 mL) were added MsCl
(0.28 mL) and Et3N (0.68 mL) at 0 8C, and the resulting
suspension was stirred at 0 8C for 1 h. The reaction was
quenched with satd NaHCO3 (aq.), and aqueous mixture
was extracted with CH2Cl2 (10 mL£4). The organic extracts
were combined, dried, and evaporated to give pale yellow
oil, which was used directly in the next step.
1
IR (neat) 3070, 2962, 2934, 2861, 1720, 1110 cm21; H
NMR (500 MHz) d 0.84–0.92 (3H, m), 1.11 (9H, s), 1.31
(3H, t, J¼6.0 Hz), 1.33–1.40 (1H, m), 1.69–1.77 (1H, m),
2.30–2.44 (1H, m), 3.36–3.40 (1H, m), 3.56–3.74 (1H, m),
3.78–3.81 (1H, m), 4.21 (2H, q, J¼6.0 Hz),5.83 (1H, d,
J¼15.4 Hz), 6.63 (1H, dd, J¼15.4, 7.7 Hz), 7.40–7.48 (6H,
m), 7.69–7.73 (4H, m); 13C NMR (125 MHz) d 11.35 (q),
14.17 (q), 19.00 (s), 23.36 (t), 26.62 (q), 44.97 (d), 60.28 (t),
To a stirred solution of the above oil in DMF (10 mL) was
added NaN3 (2.1 g, 32.65 mmol), and the resulting suspen-

6210
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
65.37 (t), 66.12 (d), 123.73 (d), 127.71 and 127.75 (each d),
129.78 and 129.80 (each d), 132.64 and 132.66 (each s),
135.47 and 135.50 (each d), 139.33 (d), 147.35 (d), 165.79
(s).
stirred at 0 8C for 30 min. To a stirred solution of the above
imide (1.84 g, 4.06 mmol) in THF (10 mL) was added a
solution of LiHMDS prepared above at 278 8C, and the
reaction mixture was stirred at 278 8C for 30 min. To the
above reaction mixture was added a solution of 2-[N,N-
bis(trifluoromethylsulfonyl)amino]5-chloropyridine (Comins’
reagent) (97%, 1.96 g, 4.85 mmol) in THF (6 mL) at
278 8C, and the resulting mixture was warned to 245 8C
for 1 h. The reaction was quenched with satd. NH4Cl (aq.),
and the aqueous mixture was extracted with Et2O
(20 mL£4). The organic extracts were combined, dried,
and evaporated to give pale yellow solid, which was
chromatographed on SiO2 (40 g, hexane:acetone¼50:1–
40:1) to give an enol triflate (2.3 g, 97%) as a colorless oil.
4.1.30. (5R,6S)-(1)-6-(tert-Butyldiphenylsilyloxy-
methyl)-5-ethylpiperidin-2-one (23). To a solution of 22
(3.88 g, 8.34 mmol) in EtOAc (100 mL) was added 10%
Pd–C (800 mg), and the resulting suspension was hydro-
genated under hydrogen atmosphere at 4 atm for 72 h. The
catalyst was removed by filtration, and the filtrate was
evaporated to give colorless oil, which was chromato-
graphed on SiO2 (80 g, hexane:acetone¼40:1–8:1) to give
23 (2.4 g, 73%) as a colorless oil.
1
IR (neat) 3402, 3206, 2933, 1666, 1108 cm21; H NMR
IR (neat) 3070, 2959, 2933, 2887, 2860, 1733, 1684, 1213,
1111 cm21; 1H NMR (300 MHz) d 0.83 (3H, t, J¼7.4 Hz),
1.06 (9H, s), 1.13–1.30 (2H, m), 1.60–1.81 (2H, m), 2.32
(1H, dm, J¼16.4 Hz), 3.57–3.63 (1H, m), 3.71–3.78 (1H,
m), 3.85 (3H, s), 4.61–4.67 (1H, m), 5.23 (1H, t, J¼3.4 Hz),
7.38–7.48 (6H, m), 7.67–7.75 (4H, m); 13C NMR
(75 MHz) d 11.89 (q), 19.11 (s), 25.44 (t), 26.49 (t), 26.59
(q), 37.62 (d), 53.46 (q), 59.25 (d), 58.43 (t), 59.75 (d),
105.51 (d), 127.51 and 127.56 (each d), 129.52 and 129.60
(each d), 133.09 and 133.14 (each s), 135.42 and 135.51
(each d), 138.13 (s), 153.80 (s); MS: 528 (Mþ257), 308
(100); HRMS: Calcd for C23H25NO6F3SiS (Mþ2C4H9)
528.1124. Found 528.1115; [a]2D6¼243.8 (c 5.73, CHCl3).
(500 MHz) d 0.81 (3H, t, J¼7.5 Hz), 1.05 (9H, s), 1.17–
1.26 (2H, m), 1.66–1.70 (2H, m), 1.72–1.76 (1H, m), 2.30–
2.39 (2H, m), 3.53–3.57 (1H, m), 3.58 (1H, t-like, J¼9 Hz),
3.63 (1H, dd, J¼9, 3 Hz), 6.20 (1H, br), 7.37–7.46 (6H, m),
7.62–7.65 (4H, m); 13C NMR (125 MHz) d 11.57 (q), 19.05
(s), 21.19 (t), 23.00 (t), 26.73 (q), 29.48 (t), 35.73 (d), 56.78
(d), 64.42 (t), 127.79 and 127.81 (each d), 129.85 and
129.88 (each d), 132.79 (s), 135.44 and 135.46 (each d),
171.89 (s); MS: 338 (Mþ257), 199 (100); HRMS: Calcd for
C20H24NO2Si (Mþ2C4H9) 338.1577. Found 338.1592;
[a]2D6¼þ28.2 (c 2.94, CHCl3).
4.1.31. Methyl (2S,3R)-(2)-2-(tert-butyldiphenylsilyl-
oxymethyl)-3-ethyl-6-oxopiperidine-1-carboxylate. To a
stirred solution of 23 (1.7 g, 4.30 mmol) in THF (15 mL)
was added a solution of n-BuLi (1.6 M in hexane, 3.0 mL,
4.80 mmol) at 278 8C, and the reaction mixture was stirred
at 278 8C for 30 min. To the reaction mixture was added
ClCO2Me (0.5 mL, 6.33 mmol) at 278 8C, and the resulting
mixture 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£4). The organic
extracts were combined, dried, and evaporated to give
colorless oil, which was chromatographed on SiO2 (30 g,
hexane:acetone¼20:1–15:1) to give an imide (1.88 g, 97%)
as a colorless oil.
4.1.33. Dimethyl (5R,6S)-(2)-6-(tert-butyldiphenylsilyl-
oxymethyl)-5-ethyl-5,6-dihydro-4H-pyridine-1,2-dicar-
boxylate (24). To a stirred solution of the above enol triflate
(2.3 g, 3.93 mmol) in DMF (15 mL) was added Pd(Ph3P)4
(230 mg, 0.20 mmol), and the resulting mixture was stirred
at room temperature under CO balloon pressure for 30 min.
To the reaction mixture were added Et3N (2.2 mL,
15.73 mmol) and MeOH (6.4 mL, 157.26 mmol), and then
the reaction mixture was stirred at 70 8C under CO balloon
pressure for 14 h. After cooling, the reaction mixture was
diluted with H2O (50 mL) and brine (10 mL), and the
aqueous mixture was extracted with Et2O (50 mL£4). The
organic extracts were combined, dried, and evaporated to
give pale yellow oil, which was chromatographed on SiO2
(40 g, hexane:acetone¼40:1–20:1) to give 24 (1.46 g, 75%)
as a colorless oil.
IR (neat) 3069, 3049, 2957, 2883, 2860, 1774, 1719,
1108 cm21; 1H NMR (300 MHz) d 0.93 (3H, t, J¼7.4 Hz),
1.02 (9H, s), 1.23–1.44 (2H, m), 1.81–1.88 (2H, m), 1.99–
2.06 (1H, m), 2.49–2.70 (2H, m), 3.73 (1H, dd, J¼11,
3.3 Hz), 3.80 (3H, s), 3.83 (1H, dd, J¼11, 4.4 Hz), 4.28 (1H,
br), 7.35–7.47 (6H, m), 7.61–7.68 (4H, m); 13C NMR
(75 MHz) d 12.02 (q), 18.96 (s), 24.53 (t), 25.68 (t), 26.71
(q), 34.38 (t), 39.11 (d), 53.69 (q), 59.25 (d), 61.48 (t),
127.55 and 127.58 (each d), 129.62 (d), 132.08 and 132.63
(each s), 135.41 and 135.52 (each d), 154.82 (s), 171.78 (s);
MS: 396 (Mþ257), 84 (100); HRMS: Calcd for
C22H26NO4Si (Mþ2C4H9) 396.1631. Found 396.1631;
[a]2D6¼234.9 (c 3.38, CHCl3).
1
IR (neat) 3048, 2955, 2882, 2859, 1919, 1650 cm21; H
NMR (500 MHz) d 0.87 (3H, t, J¼7.5 Hz), 1.04 (9H, s),
1.18–1.32 (2H, m), 1.66–1.72 (1H, m), 1.82–1.86 (1H, m),
2.27–2.33 (1H, m), 3.59–3.71 (2H, m), 3.74 (3H, s), 3.75
(3H, s), 4.54 (1H, br), 6.01 (1H, br), 7.36–7.45 (6H, m),
7.66–7.73 (4H, m); 13C NMR (125 MHz) d 11.80 (q), 19.14
(s), 26.02 (t), 26.55 (q), 27.43 (t), 37.51 (d), 51.89 (q), 53.04
(q), 56.29 (d), 59.14 (t), 121.34 (d), 127.43 and 127.46 (each
d), 129.41 and 129.47 (each d), 133.28 (s), 133.26 (s),
135.44 and 135.47 (each d), 154.42 (s), 165.58 (s); MS: 438
(Mþ257), 68 (100); HRMS: Calcd for C24H28NO5Si
(Mþ2C4H9) 438.1736. Found 438.1741; [a]2D6¼247.1 (c
4.22, CHCl3).
4.1.32. Methyl (2S,3R)-(2)-2-(tert-butyldiphenylsilyloxy-
methyl)-3-ethyl-6-trifluoromethanesulfonyl-oxy-3,4-
dihydro-2H-pyridine-1-carboxylate. To a stirred solution
of hexamethyldisilazane (1.03 mL, 4.87 mmol) in THF
(8 mL) was added a solution of n-BuLi (1.6 M in hexane,
3.03 mL, 4.86 mmol) at 0 8C, and the resulting solution was
4.1.34. Dimethyl (2R,3S,5R,6S)-(1)-6-(tert-butyldi-
phenylsilyloxymethyl)-5-ethyl-3-vinylpiperidine-1,2-
dicarboxylate (25). To a stirred suspension of CuI (2.69 g,

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6211
14.14 mmol) in Et2O (15 mL) was added a solution of vinyl
lithium, (prepared from tetravinyltin (1.2 mL, 7.07 mmol)
and MeLi (1.0 M in Et2O, 28 mL, 28.0 mmol) in Et2O
(10 mL) at 0 8C for 30 min), at 278 8C, and the resulting
suspension was warmed to 235 8C for 20 min. The resulting
suspension was re-cooled to 278 8C, and a solution of 24
(1.4 g, 2.82 mmol) in Et2O (8 mL) was added to the
resulting suspension. The reaction mixture was warmed to
220 8C for 1 h, and the reaction was quenched with satd.
NH4Cl (aq.). The aqueous mixture was diluted with CH2Cl2
(100 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
colorless oil, which was chromatographed on SiO2 (30 g,
hexane:acetone¼50:1–30:1) to give 25 (1.41 g, 95%) as a
colorless oil.
0.10 mmol) in THF (0.5 mL) was added NaH (60%,
4.8 mg, 0.12 mmol) at 0 8C, and the resulting suspension
was stirred at 0 8C for 1 h. The reaction was quenched with
10% AcOH, and the aqueous mixture was extracted with
CH2Cl2 (10 mL£4). The organic extracts were combined,
dried, and evaporated to give colorless oil, which was
chromatographed on SiO2 (10 g, hexane:acetone¼40:1–
25:1) to give 27 (44 mg, 94%) as a colorless oil.
1
IR (neat) 3070, 2958, 2933, 1753, 1110 cm21; H NMR
(500 MHz) d 0.92 (3H, t, J¼7.4 Hz), 1.09 (9H, s), 1.25–
1.32 (1H, m), 1.41 (1H, ddd, J¼15, 12, 5 Hz), 1.49–1.57
(1H, m), 2.01–2.05 (2H, m), 2.27 (1H, ddd, J¼12, 10,
5 Hz), 3.35 (1H, ddd, J¼10.5, 8.5, 5 Hz), 3.42 (1H, ddd,
J¼8.5, 5.5, 3 Hz), 3.94 (1H, dd, J¼8.5, 5 Hz), 4.25 (1H, t,
J¼8.5 Hz), 4.32 (1H, dd, J¼10.5, 8.5 Hz), 4.35 (1H, dd,
J¼10.5, 5.5 Hz), 5.05–5.16 (2H, m), 5.48–5.55 (1H, m),
7.37–7.45 (6H, m), 7.65–7.73 (4H, m); 13C NMR
(75 MHz) d 11.89 (q), 18.25 (t), 19.34 (s), 26.99 (q),
32.81 (t), 35.42 (d), 40.53 (d), 59.77 (d), 60.11 (d), 60.42 (t),
66.44 (t), 117.09 (t), 127.55 (d), 129.55 (d), 133.35 and
133.42 (each s), 135.41 and 135.44 (each d), 137.46 (d),
156.38 (s); MS: 406 (Mþ257, 100); HRMS: Calcd for
C24H28NO3Si (Mþ2C4H9) 406.1839. Found 406.1841;
[a]2D6¼232.8 (c 2.03, CHCl3).
1
IR (neat) 3070, 2954, 2860, 1704, 1112 cm21; H NMR
(500 MHz) d 0.80 (3H, t-like, J¼7 Hz), 1.05 (9H, s), 1.11–
1.18 (1H, m), 1.36 (1H, quint-like, J¼7.2 Hz), 1.52 (1H,
d-like, J¼13.7 Hz), 1.64 (1H, td, J¼13.2, 4.7 Hz), 1.72–
1.77 (1H, m), 3.09 (1H, br), 3.45 (3H, s), 3.63 (2H, d,
J¼6.8 Hz), 3.70 (3H, br s), 4.40 (1H, br), 4.98 (1H, br),
5.07–5.13 (2H, m), 5.79–5.85 (1H, m), 7.36–7.45 (6H, m),
7.68–7.69 (4H, br); 13C NMR (75 MHz) d 11.91 (q), 19.21
(s), 25.70 (t), 26.83 (q), 27.81 (t), 34.63 (d), 36.99 (d), 52.00
(q), 52.97 (q), 54.80 (d), 61.18 (t), 115.07 (t), 127.46 (d),
129.49 (d), 133.34 and 133.39 (each s), 135.42 (d), 139.15
(d), 156.91 (s), 172.52 (s); MS: 466 (Mþ257, 100); HRMS:
Calcd for C26H32NO5Si (Mþ2C4H9) 466.2050. Found
466.2035; [a]2D6¼þ26.6 (c 5.52, CHCl3).
4.1.37. Methyl (2S,3R,5S,6R)-(2)-2-(tert-butyldiphenyl-
silyloxymethyl)-3,5-diethyl-6-(2-ethoxycarbonylvinyl)-
piperidine-1-carboxylate. To a stirred solution of (COCl)2
(0.26 mL, 3.03 mmol) in CH2Cl2 (8 mL) was added DMSO
(0.43 mL, 6.06 mmol) at 278 8C, and the resulting solution
was stirred at 278 8C for 10 min. To the mixture was added
a solution of 26 (1.0 g, 2.02 mmol) in CH2Cl2 (10 mL) at
278 8C, and the reaction mixture was stirred at 278 8C for
30 min. Triethylamine (1.26 mL, 9.09 mmol) at 278 8C,
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 (20 mL£4). The organic extracts
were combined, dried and evaporated to give pale yellow
oil, which was used directly in the next step.
4.1.35. Methyl (2S,3R,5S,6R)-(1)-2-(tert-butyldiphenyl-
silyloxymethyl)-3-ethyl-6-hydroxymethyl-5-vinylpiper-
idine-1-carboxylate (26). To a stirred solution of 25
(1.38 g, 2.64 mmol) in THF (15 mL) was added a solution
of Super-Hydride (1 M in THF, 6 mL, 6.0 mmol) at 0 8C,
and the resulting mixture was stirred at 0 8C for 1 h. The
reaction was quenched with satd. NaHCO3 (aq.), and the
aqueous mixture was extracted with CH2Cl2 (15 mL£6).
The organic extracts were combined, dried, and evaporated
to give a colorless oil, which was chromatographed on SiO2
(25 g, hexane:acetone¼40:1–15:1) to give 26 (1.26 g, 96%)
as a colorless oil.
To a stirred suspension of NaH (60%, 90 mg, 2.22 mmol) in
THF (10 mL) was added (EtO)2P(O)CH2CO2Et (0.44 mL,
2.22 mmol) at 0 8C, and the resulting solution was stirred at
0 8C for 15 min. To the reaction mixture was added a
solution of the above oil in THF (10 mL) at 0 8C, and 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 (30 mL£3). The organic
extracts were combined, dried, and evaporated to give pale
yellow oil, which was chromatographed on SiO2 (30 g,
hexane:acetone¼80:1–40:1) to give an a,b-unsaturated
ester (1.05 g, 92%) as a colorless oil.
1
IR (neat) 3459, 3071, 2957, 2932, 1692, 1111 cm21; H
NMR (500 MHz) d 0.53 and 0.64 (3H, br), 0.90–0.99 (2H,
br), 1.02 (9H, s), 1.40–1.44 (1H, br), 1.56 (1H, td, J¼13.7,
4.7 Hz), 1.71–1.77 (1H, br), 2.30 and 2.41 (1H, br), 3.61–
3.91 (8H, br), 4.44–4.69 (2H, br), 5.00–5.14 (2H, m),
5.83–5.90 (1H, m), 7.39–7.46 (6H, m), 7.65–7.88 (4H, m);
13C NMR (75 MHz) d 11.04 (q), 18.95 (s), 25.11 (t), 26.65
(q), 27.43 (t), 33.67 (d), 36.62 (d), 52.81 (q), 54.61 (d),
61.95 (t), 64.36 (t), 114.75 (t), 127.58 and 127.69 (each d),
129.68 and 129.78 (each d), 132.66 (s), 135.21 (d), 140.12
(d), 157.90 (s); MS: 438 (Mþ257), 407 (100); HRMS:
Calcd for C25H32NO4Si (Mþ2C4H9) 438.2101. Found
438.2099; [a]2D6¼þ22.7 (c 2.37, CHCl3).
1
IR (neat) 3070, 2957, 2932, 1703, 1111 cm21; H NMR
(500 MHz) d 0.62 (3H, br t-like, J¼7 Hz), 0.95 (2H, quint-
like, J¼7.5 Hz), 1.07 (9H, s), 1.20 (3H, t, J¼7.5 Hz), 1.44
(1H, d-like, J¼14 Hz), 1.60 (1H, td, J¼13, 4.7 Hz), 1.76
(1H, br), 2.71 (1H, br), 3.49 (1H, dd, J¼11, 5.2 Hz), 3.64–
3.76 (5H, br m), 4.10–4.24 (2H, m), 4.40–4.65 (1H, br),
5.09–5.28 (2H, m), 5.88–5.94 (1H, m), 6.16 (1H, d-like,
J¼16 Hz), 7.26 (1H, d-like, J¼16 Hz), 7.36–7.45 (6H, m),
7.67–7.81 (4H, m); 13C NMR (75 MHz) d 11.30 (q), 14.27
4.1.36. (5S,6R,8R,9R)-(2)-5-(tert-Butyldiphenylsilyloxy-
methyl)-6-ethyl-8-vinyl-hexahydrooxazolo[3,4-a]pyri-
din-3-one (27). To a stirred solution of 26 (50 mg,

6212
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
(q), 19.01 (s), 25.29 (t), 26.71 (q), 27.46 (t), 33.70 (d), 39.16
(d), 52.81 (q), 53.41 (d), 54.32 (d), 60.16 (t), 60.37 (t),
115.15 (t), 121.36 (d), 129.42 and 129.50 (each d), 133.35
(s), 135.38 (d), 139.62 (d), 149.26 (d), 157.15 (s), 166.12 (s);
MS: 506 (Mþ257), 69 (100); HRMS: Calcd for
C29H36NO5Si (Mþ2C4H9) 506.2363. Found 506.2363;
[a]2D6¼210.8 (c 4.43, CHCl3).
129.41 (d), 133.27 and 133.37 (each s), 135.28 and 135.33
(each d), 157.53 (s); MS: 512 (Mþ257, 100); HRMS: Calcd
for C29H42NO5Si (Mþ2C4H9) 512.2832. Found 512.2829;
[a]2D6¼20.98 (c 3.37, CHCl3).
4.1.40. Methyl (2S,3R,5R,6S)-(1)-3,5-diethyl-2-hydroxy-
methyl-6-(3-methoxymethoxypropyl)-piperidine-1-car-
boxylate (29). To a stirred solution of the above MOM ether
(240 mg, 0.42 mmol) in THF (8 mL) was added a solution
of TBAF (1 M in THF, 1.5 mL, 1.5 mmol) at 0 8C, and the
reaction mixture was stirred at room temperature for 22 h.
The reaction was quenched with satd. NH4Cl (aq.), and the
aqueous mixture was extracted with CHCl3 (10 mL£5). The
organic extracts were combined, dried, and evaporated to
give a colorless oil, which was chromatographed on SiO2
(15 g, hexane:acetone¼30:1–6:1) to give 29 (110 mg, 79%)
as a colorless oil.
4.1.38. Methyl (2S,3R,5R,6S)-(1)-2-(tert-butyldiphenyl-
silyloxymethyl)-3,5-diethyl-6-(3-hydroxypropyl)piper-
idine-1-carboxylate (28). To a solution of the above a,b-
unsaturated ester (1.0 g, 1.78 mmol) in EtOAc (30 mL) was
added 5% Pd–C (100 mg), and the resulting suspension was
hydrogenated under hydrogen atmosphere at 1 atm for 72 h.
The catalyst was removed by filtration, and the filtrate was
evaporated to give colorless oil, which was used directly in
the next step.
1
To a stirred solution of the above in THF (12 mL) was added
a solution of Super-Hydride (1 M in THF, 4.0 mL,
4.0 mmol) at 0 8C, and the resulting mixture was stirred at
0 8C for 1 h. The reaction was quenched with satd NaHCO3
(aq.), and the aqueous mixture was extracted with CH2Cl2
(15 mL£5). The organic extracts were combined, dried, and
evaporated to give colorless oil, which was chromato-
graphed on SiO2 (25 g, hexane:acetone¼40:1–12:1) to give
28 (913 mg, 98%) as a colorless oil.
IR (neat) 3461, 2955, 2878, 1680, 1114, 1042 cm21; H
NMR (500 MHz) d 0.86 (3H, t-like, J¼7.3 Hz), 0.90 (3H, t,
J¼7.2 Hz), 1.12 (1H, m), 1.22–1.38 (2H, m), 11.40–1.59
(3H, m), 1.61–1.72 (5H, m), 2.17 (1H, br), 2.46 (1H, br),
3.32 (3H, s), 3.50 (2H, m), 3.57–3.66 (1H, m), 3.67 (3H, s),
3.69–3.76 (1H, br), 3.93–4.14 (1H, br), 4.31–4.46 (1H, br),
4.58 (2H, s); 13C NMR (75 MHz) d 11.93 (q), 12.30 (q),
25.29 (t), 25.50 (t), 27.43 (t), 32.15 (t), 33.28 (d), 37.94 (d),
52.84 (q), 54.43 (d), 55.11 (q), 55.21 (d), 62.12 (t), 67.47 (t),
96.25 (t), 159.39 (s); MS: 330 (Mþ21), 300 (100); HRMS:
Calcd for C17H32NO5 (Mþ2H) 330.2279. Found 330.2291;
[a]2D6¼þ3.6 (c 4.85, CHCl3).
1
IR (neat) 3448, 2998, 2962, 2839, 1738, 1240 cm21; H
NMR (500 MHz) d 0.76–0.95 (6H, m), 1.04 (9H, s), 1.15–
1.86 (11H, br m), 1.98–2.23 (1H, br), 2.72 (1H, br), 3.58–
3.71 (4H, br m), 3.62 (3H, s), 3.91–4.08 (1H, br), 4.41–4.45
(1H, br), 7.39–7.41 (6H, m), 7.63–7.69 (4H, m); 13C NMR
(75 MHz) d 11.89 (q), 12.38 and 12.54 (each q), 19.16 (s),
22.67 (t), 25.53 (t), 25.71 (t), 26.78 (q), 29.53 (t), 31.16 (t),
33.51 (d), 33.67 (d), 52.59 (q), 53.54 (d), 54.74 (d), 59.25
(t), 61.99 (t), 127.50 and 127.56 (each d), 129.49 and 129.58
(each d), 133.21 and 133.35 (each s), 135.33 and 135.41
(each d), 158.23 (s); MS: 468 (Mþ257), 256 (100); HRMS:
Calcd for C27H38NO4Si (Mþ2C4H9) 468.2570. Found
468.2568; [a]2D6¼þ10.6 (c 1.57, CHCl3).
4.1.41. Methyl (2S,3R,5R,6S)-(1)-3,5-diethyl-2-(3-meth-
oxymethoxypropyl)-6-propenylpiperidine-1-carboxyl-
ate. To a stirred solution of (COCl)2 (0.12 mL, 1.41 mmol)
in CH2Cl2 (4 mL) was added DMSO (0.2 mL, 2.82 mmol)
at 278 8C, and the resulting solution was stirred at 278 8C
for 10 min. To the mixture was added a solution of 29
(311 mg, 0.94 mmol) in CH2Cl2 (4 mL) at 278 8C, and the
reaction mixture was stirred at 278 8C for 30 min.
Triethylamine (0.58 mL, 4.23 mmol) at 278 8C, 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 (10 mL£4). The organic extracts were
combined, dried and evaporated to give pale yellow oil,
which was used directly in the next step.
4.1.39. Methyl (2S,3R,5R,6S)-(2)-2-(tert-butyldiphenyl-
silyloxymethyl)-3,5-diethyl-6-(3-methoxymethoxy-
propyl)piperidine-1-carboxylate. To a stirred soultion of
28 (913 mg, 1.74 mmol) in CHCl3 (12 mL) were added
MOMCl (0.52 mL, 6.96 mmol) and Hu¨nig base (1.4 mL,
7.66 mmol), and the resulting mixture was refluxed for 2 h.
After cooling, the solvent was evaporated and the residue
was chromatographed on SiO2 (25 g, hexane:acetone¼40:1)
to a MOM ether (878 mg, 89%) as a colorless oil.
To a stirred suspension of EtPþPh3Br2 (1.7 g, 4.70 mmol)
in THF (15 mL) was added a solution of n-BuLi (1.6 M ih
hexane, 2.6 mL, 4.22 mmol) at 0 8C, and the resulting
orange solution was stirred at 0 8C for 30 min. To the
solution was added a solution of the above oil in THF
(6 mL) at 0 8C, and the reaction mixture was stirred at room
temperature for 2 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 pale yellow oil, which was
chromatographed on SiO2 (20 g, hexane:acetone¼100:1–
30:1) to give an olefin (266 mg, 83% in 2 steps) as a
colorless oil.
1
IR (neat) 2932, 1692, 1111 cm21; H NMR (500 MHz) d
0.73 and 0.79 (3H, each t, each J¼7.3 Hz), 0.90 (3H, t-like,
J¼7.3 Hz), 1.02 (9H, s), 1.14–1.77 (12H, br m), 3.30 (3H,
s), 3.41–3.45 (1H, m), 3.49–3.58 (1H, m), 3.64 (3H, s),
3.61–3.69 (2H, m), 3.93 and 4.12 (1H, m), 4.42 and 4.68
(1H, m), 4.57 (2H, s), 7.37–7.44 (6H, m), 7.67–7.78 (4H,
m); 13C NMR (75 MHz) d 11.70 and 11.86 (each q), 12.36
and 12.48 (each q), 19.09 (s), 25.47 (t), 25.66 (t), 26.70 (q),
27.81 (t), 31.81 (t), 33.41 and 33.77 (each d), 37.59 and
38.01 (each d), 52.39 (q), 54.38 (d), 54.75 (d), 54.98 (q),
62.12 (t), 67.70 (t), 96.27 (t), 127.43 and 127.48 (each d),
IR (neat) 2929, 1693 cm21; H NMR (500 MHz) d 0.80
1
(3H, t, J¼7.3 Hz), 0.86 (3H, m), 1.01–1.08 (1H, m), 1.09–
1.15 (1H, m), 1.22–1.74 (12H, br m), 1.77 (1H, d-like,

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6213
1
J¼6 Hz), 3.31 (3H, s), 3.44–3.48 (2H, br), 3.63 and 3.66
(3H, each s), 3.94 and 4.27 (1H, each br), 4.56 (2H, s), 4.93
and 5.11 (1H, each br), 5.48 (1H, q-like, J¼9.4 Hz), 5.54
(1H, br); 13C NMR (75 MHz) d 11.44 (q), 12.38 (q), 13.19
and 13.63 (each q), 25.37 and 25.42 (each t), 25.76 (t), 26.99
and 27.20 (each t), 32.60 (t), 34.14 (d), 38.07 and 38.65
(each d), 49.96 (d), 52.38 (q), 54.15 (d), 55.01 (q), 67.54 (t),
96.17 (t), 126.28 and 126.51 (each d), 127.37 and 128.42
(each d), 156.83 (s); MS: 341 (Mþ), 239 (100); HRMS:
Calcd for C19H35NO4 341.2564. Found 341.2583;
[a]2D6¼þ34.7 (c 1.50, CHCl3).
DCl salt. H NMR (500 MHz, D2O) d 0.83–0.89 (9H, m),
1.10–1.23 (4H, m), 1.32–1.39 (1H, m), 1.42–1.51 (2H, br
m), 1.53–1.62 (3H, m), 1.66–1.74 (1H, m), 1.85–2.01 (3H,
m), 2.07 (1H, dm, J¼13.5 Hz), 2.27–2.34 (1H, m), 2.85
(1H, td-like, J¼11, 6 Hz), 2.94 (1H, q-like, J¼10 Hz), 3.14
(1H, dm, J¼11 Hz), 3.58 (1H, tm, J¼10 Hz); 13C NMR
(75 MHz, D2O) d 9.47 (q), 11.10 (q), 12.77 (q), 16.57 (t),
17.35 (t), 18.27 (t), 24.06 (t), 26.39 (t), 29.43 (t), 29.48 (t),
34.92 (d), 35.00 (d), 51.08 (t), 66.13 (d), 71.82 (d);
[a]2D6¼240.9 (c 0.25, CHCl3).
4.1.43. Methyl (5S,6R,8R,9R)-(2)-(6,8-dimethyl-3-oxo-
hexahydrooxazolo[3,4-a]pyridin-5-yl)acetate (31). To a
stirred solution of 15 (211 mg, 0.93 mmol) in MeOH (3 mL)
and H2O (1 mL) was added LiOH·H2O (84 mg, 1.99 mmol),
and the resulting solution was refluxed for 2 h. After
cooling, the MeOH was evaporated, and the aqueous residue
was acidified with 10% HCl and saturated with NaCl. The
aqueous layer was extracted with EtOAc (10 mL£7), and
the organic extracts were combined, dried, and evaporated
to give a colorless oil, which was used directly in the next
step.
4.1.42. (5R,6R,8R,9S)-(2)-6,8-Diethyl-5-propylocta-
hydroindolizine (30). To a solution of the above olefin
(120 mg, 0.35 mmol) in EtOAc (12 mL) was added 5% Pd–
C (100 mg), and the resulting suspension was hydrogenated
under hydrogen atmosphere at 1 atm for 84 h. The catalyst
was removed by filtration, and the filtrate was evaporated to
give colorless oil, which was used directly in the next step.
To a stirred solution of n-PrSLi, prepared from n-PrSH
(0.32 mL, 3.50 mmol) and n-BuLi (1.6 M in hexane,
2.1 mL, 3.33 mmol) in HMPA (3 mL) at 0 8C for 30 min.
To the reaction mixture was added a solution of the above
oil in THF (3 mL) at 0 8C, and the resulting solution
was stirred at room temperature for 60 h. The reaction was
quenched with NH3 (aq.), and the aqueous mixture was
extracted with Et2O (10 mL£10). The organic extracts were
combined, dried over K2CO3, and evaporated to give pale
yellow oil, which was used directly in the next step.
To a stirred solution of the above oil in THF (8 mL) were
added ClCO2Et (0.15 mL, 1.56 mmol) and Et3N (0.23 mL,
1.66 mmol) at 0 8C, and the resulting suspension was stirred
at 0 8C for 1 h. The insoluble material was filtered off, and
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 (15 mL) was
added a solution of CH2N2 in Et2O at 0 8C, and the resulting
mixture was stirred at room temperature for 19 h. The
solvent 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 MeOH (10 mL) was
added c. HCl (8 drops), and the resulting mixture was
refluxed for 2 h. After cooling, the solvent was evaporated,
and the residue was washed with Et2O. To the residue was
added NH3 (aq.), and the aqueous mixture was extracted
with CHCl3 (10 mL£8). The organic extracts were com-
bined, dried over K2CO3, and evaporated to give colorless
oil, which was used directly in the next step.
To a stirred solution of the above oil in MeOH (10 mL) were
added PhCO2Ag (48 mg, 0.21 mmol) and Et3N (0.3 mL,
2.17 mmol) at 0 8C, and the resulting suspension was stirred
in the dark at room temperature for 27 h. The insoluble
material was filtered, and the filtrate was evaporated to give
a pale yellow oil, which was chromatographed on SiO2
(15 g, hexane:acetone¼14:1) to give 31 (160 mg, 71% in 4
steps) as a colorless oil.
Carbontetrabromide (163 mg, 0.49 mmol) and Ph3P
(138 mg, 0.53 mmol) were added to a solution of the
above oil in CH2Cl2 (6 mL) at 0 8C, and the reaction mixture
was stirred at 0 8C for 2 h. To the reaction mixture was
added Et3N (0.77 mL, 5.60 mmol) at 0 8C, and the resulting
suspension was stirred at 0 8C for 30 min. The solvent was
evaporated, and the residue was extracted with n-pentane
(10 mL£5). The organic extracts were combined and
evaporated to give colorless solid, which was chromato-
graphed on SiO2 (15 g, hexane:acetone:Et3N¼50:1:5 drops)
to give 30 (40 mg, 51%) as a pale yellow oil.
1
IR (neat) 2960, 2923, 1750 cm21; H NMR (500 MHz) d
0.85 (3H, d, J¼6.8 Hz), 1.08 (3H, d, J¼7.3 Hz), 1.42–1.53
(2H, m), 1.64–1.70 (1H, m), 1.84–1.89 (1H, m), 2.53 (1H,
dd, J¼14.5, 7.7 Hz), 2.61 (1H, dd, J¼14.5, 8.2 Hz), 3.28–
3.34 (1H, m), 3.66 (3H, s), 3.95 (1H, dd, J¼8.5, 6.4 Hz),
4.09 (1H, t-like, J¼7.9 Hz), 4.41 (1H, t-like, J¼8.5 Hz); 13C
NMR (125 MHz) d 17.25 (q), 18.56 (q), 29.95 (d), 30.85 (d),
33.46 (t), 36.15 (t), 51.70 (d), 51.94 (q), 56.32 (d), 67.34 (t),
157.16 (s), 170.96 (s); MS: 241 (Mþ), 197 (100); HRMS:
Calcd for C12H19NO4 241.1314. Found 241.1312;
[a]2D6¼237.7 (c 1.01, CHCl3).
IR (neat) 2958, 2874, 2776, 1460, 1378, 1316, 1180, 1112,
928, 888 cm21 1H NMR (500 MHz) d 0.86 (3H, t,
;
J¼7.5 Hz), 0.87 (3H, t, J¼7.5 Hz), 0.91 (3H, t, J¼7 Hz),
0.97–1.06 (1H, m), 1.13–1.21 (1H, m), 1.21–1.52 (11H, br
m), 1.55–1.62 (1H, m), 1.70–1.77 (1H, m), 1.86 (1H, q,
J¼9 Hz), 1.86–1.92 (1H, m), 1.94 (1H, dt, J¼13, 3 Hz),
1.95–1.99 (1H, m), 3.12 (1H, td, J¼8, 2 Hz); 13C NMR
(75 MHz) d 11.23 (q), 12.56 (q), 14.68 (q), 18.45 (t), 19.17
(t), 20.49 (t), 26.00 (t), 29.29 (t), 32.49 (t), 33.51 (t), 37.28
(d), 37.86 (d), 52.13 (t), 66.82 (d), 71.34 (d); MS: 223 (Mþ,
100); [a]2D6¼2100.9 (c 1.76, CHCl3).
4.1.44. (5S,6R,8R,9R)-(2)-2-(6,8-Dimethyl-3-oxohexa-
hydrooxazolo[3,4-a]pyridin-5-yl)-N-methoxy-N-methyl-
acetamide (32). To a stirred solution of 31 (267 mg,
1.11 mmol) in MeOH (3 mL) and H2O (1 mL) was added
LiOH·H2O (94 mg, 2.22 mmol), and the resulting solution
was refluxed for 1 h. After cooling, the MeOH was

6214
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
evaporated, and the aqueous residue was acidified with 10%
HCl and saturated with NaCl. The aqueous layer was
extracted with EtOAc (10 mL£8), and the organic extracts
were combined, dried, and evaporated to give a colorless oil,
which was used directly in the next step.
separated. The aqueous layer was extracted with benzene
(10 mL£3), and the organic layer and extracts were
combined, dried, and evaporated to give a colorless oil,
which
was
chromatographed
on
SiO2
(20 g,
hexane:acetone¼10:1–7:1) to give an acetal (166 mg,
86%) as a colorless solid (mp 82–84 8C).
To a stirred solution of the above oil in CH2Cl2 (5 mL) was
added 1,10-carbonyldiimidazole (234 mg, 1.44 mmol) at
0 8C, and the resulting mixture was stirred at room
temperature for 30 min. To the reaction mixture were
added Me(MeO)NH·HCl (141 mg, 1.44 mmol) and Et3N
(0.2 mL, 1.44 mmol) at 0 8C, and the reaction mixture was
stirred at room temperature for 22 h. The solvent was
evaporated and the rsidue was chromatographed on SiO2
(15 g, hexane:acetone¼10:1–4:1) to give 32 (292 mg, 98%)
as a colorless oil.
IR (KBr) 2961, 2922, 1740, 1060 cm21
;
1H NMR
(500 MHz) d 0.82 (3H, d, J¼6.5 Hz), 1.04 (3H, d,
J¼7.3 Hz), 1.33 (3H, s), 1.45–1.47 (2H, m), 1.63–1.69
(1H, m), 1.76 (1H, dd, J¼14.5, 4.7 Hz), 1.83–1.88 (1H, m),
2.06 (1H, dd, J¼14.5, 9 Hz), 3.28–3.33 (1H, m), 3.87–3.99
(6H, m), 4.36 (1H, t-like, J¼8.5 Hz); 13C NMR (125 MHz)
d 17.35 (q), 18.34 (q), 23.76 (q), 30.16 (d), 32.20 (d), 33.75
(t), 39.65 (t), 50.72 (d), 56.25 (d), 64.26 (t), 66.91 (t), 109.03
(s), 157.09 (s); MS: 269 (Mþ), 254 (100); HRMS: Calcd for
C14H23NO4 269.1627. Found 269.1641. Anal. Calcd for
C14H23NO4 C, 62.43; H, 8.61; N, 5.20. Found C, 62.59; H,
8.67; N, 5.14; [a]2D6¼220.4 (c 1.59, CHCl3).
1
IR (neat) 2961, 2926, 1746, 1656, 1416 cm21; H NMR
(500 MHz) d 0.86 (3H, d, J¼6.4 Hz), 1.09 (3H, d,
J¼7.3 Hz), 1.49–1.50 (2H, m), 1.64–1.68 (1H, m), 1.93–
1.95 (1H, m), 2.62 (1H, dd, J¼13.7, 7.6 Hz), 2.73 (1H, dd,
J¼13.7, 7.7 Hz), 3.15 (3H, s), 3.39 (1H, q-like, J¼8.1 Hz),
3.72 (3H, s), 3.92 (1H, t-like, J¼7.3 Hz), 4.10 (1H, t-like,
J¼7.2 Hz), 4.42 (1H, t-like, J¼7.3 Hz; 13C NMR
(125 MHz) d 17.26 (q), 18.65 (q), 30.07 (d), 30.74 (d),
32.14 (q), 33.56 (t), 34.31 (t), 51.36 (d), 56.60 (d), 61.41 (d),
67.52 (t), 157.27 (s), 171.23 (s); MS: 270 (Mþ), HRMS:
Calcd for C13H22N2O4 270.1578. Found 270.1563;
[a]2D6¼253.3 (c 1.28, CHCl3).
4.1.47. 2-Methyl-2-propyl (2R,3R,5R,6S)-(1)-2-hydroxy-
methyl-3,5-dimethyl-6-(2-methyl-[1,3]dioxolan-2-
ylmethyl)piperidine-1-carboxylate (34). A solution of
2 M KOH in i-PrOH (50 mL) was added to the above
acetal (1.9 g, 7.06 mmol), and the resulting mixture was
heated at 120 8C in the sealed tube for 2 days. After cooling,
the solvent was evaporated, and the residue was dissolved in
H2O. The aqueous mixture was extracted with CHCl3
(20 mL£10), and the organic extracts were combined, dried
over K2CO3, and evaporated to give pale yellow oil, which
was used directly in the next step.
4.1.45. (5S,6R,8R,9R)-(2)-6,8-Dimethyl-5-(2-oxopropyl)-
hexahydrooxazolo[3,4-a]pyridin-3-one (33). To a stirred
solution of 32 (51 mg, 0.19 mmol) in THF (2 mL) was
added a solution of MeMgBr (0.9 m in THF, 0.31 mL,
0.28 mL) at 0 8C, and the reaction mixture was stirred at
room temperature for 1 h. The reaction was quenched with
satd. NH4Cl (aq.), and the aqueous mixture was extracted
with CH2Cl2 (10 mL£3). The organic extracts were
combined, dried, and evaporated to give a colorless oil,
To a stirred solution of the above oil in H2O (24 mL) and
dioxane (48 mL) were added NaOH (950 mg, 23.75 mmol)
and Boc2O (4.8 g, 21.99 mmol) at 0 8C, and the resulting
solution was stirred at room temperature for 18 h. The
aqueous layer was extracted with CHCl3 (10 mL£5). The
organic extracts were combined, dried, and evaporated to
give a pale yellow oil, which was chromatographed on SiO2
(50 g, hexane:acetone¼20:1) to give 34 (1.8 g, 74% in 2
steps) as a colorless oil.
which
was
chromatographed
on
SiO2
(10 g,
hexane:acetone¼10:1–7:1) to give 33 (31 mg, 73%) as a
colorless solid (mp 53–56 8C).
IR (neat) 3425, 2963, 2928, 1669 cm21
;
1H NMR
1
IR (KBr) 2962, 1748 cm21; H NMR (500 MHz) d 0.83
(500 MHz) d 0.91 (3H, d, J¼6.4 Hz), 0.98 (3H, d,
J¼6.8 Hz), 1.33 (3H, s), 1.38–1.42 (2H, br), 1.44 (9H, s),
1.72 (1H, br), 1.76 (1H, dd, J¼14.5, 4.1 Hz), 2.00–2.16
(2H, br), 2.83 (1H, br), 3.89 (2H, br), 3.92 (4H, m), 4.19
(1H, br), 5.29 (1H, br); 13C NMR (125 MHz) d 18.34 (q),
18.95 (q), 23.88 (q), 26.58 (d), 28.37 (q), 33.42 (d), 36.36
(t), 41.79 (t), 55.75 (d), 60.60 (t), 61.31 (d), 64.31 (t), 64.51
(t), 79.92 (s), 109.53 (s), 157.60 (s); MS: 343 (Mþ), 212
(100); HRMS: Calcd for C18H33NO5 343.2357. Found
343.2345; [a]2D6¼þ22.8 (c 9.84, CHCl3).
(3H, d, J¼6.4 Hz), 1.07 (3H, d, J¼7.3 Hz), 1.40–1.50 (2H,
m), 1.62–1.69 (1H, m), 1.82–1.84 (1H, br), 2.13 (3H, s),
2.63 (1H, dd, J¼15.4, 7.6 Hz), 2.68 (1H, dd, J¼15.4,
7.7 Hz), 3.23–3.28 (1H, m), 3.95 (1H, dd, J¼8.5, 6.4 Hz),
4.12 (1H, t-like, J¼7.7 Hz), 4.36 (1H, dd, J¼8.5, 6.4 Hz);
13C NMR (125 MHz) d 17.22 (q), 18.52 (q), 29.68 (q), 29.77
(d), 30.86 (d), 33.40 (t), 45.30 (t), 50.99 (d), 56.41 (d), 67.25
(t), 157.24 (s), 206.19 (s); MS: 225 (Mþ), 182 (100);
HRMS: Calcd for C12H19NO3 225.1364. Found 225.1364;
[a]2D6¼213.9 (c 1.48, CHCl3).
4.1.48. (2R,3R,5R,6S)-(1)-2-Methyl-2-propyl 2(2-
ethoxycarbonylvinyl)-3,5-dimethyl-6-(2-methyl-[1,3]-
dioxolan-2-ylmethyl)piperidine-1-carboxylate (35). To a
stirred solution of (COCl)2 (0.7 mL, 8.06 mmol) in CH2Cl2
(20 mL) was added DMSO (1.2 mL, 17.0 mmol) at 278 8C,
and the resulting solution was stirred at 278 8C for 10 min.
To the mixture was added a solution of 12 (1.8 g,
5.25 mmol) in CH2Cl2 (10 mL) at 278 8C, and the reaction
mixture was stirred at 278 8C for 30 min. Triethylamine
4.1.46. (5S,6R,8R,9R)-(2)-6,8-Dimethyl-5-(2-methyl-
[1,3]dioxolan-2-ylmethyl)hexahydrooxazolo[3,4-a]pyri-
din-3-one. To a stirred solution of 33 (161 mg, 0.72 mmol)
in benzene (15 mL) were added p-TsOH·H2O (30 mg,
0.16 mmol) and ethyleneglycol (0.3 mL, 5.39 mmol), and
the reaction mixture was refluxed using Dean–Stark
apparatus for 18 h. After cooling, the reaction was quenched
with satd. NaHCO3 (aq.) and the organic layer was

N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
6215
(3.3 mL, 23.92 mmol) was added to the reaction mixture at
278 8C, 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 (20 mL£5). The organic
extracts were combined, dried, and evaporated to give a pale
yellow oil, which was used directly in the next step.
steps) as a colorless solid (mp 57–58 8C) and its acetal 37
(15 mg, 15% in 3 steps) as a pale yellow oil.
1
Ketone 36. IR (KBr) 2959, 2920, 2867, 1707 cm21; H
NMR (500 MHz) d 0.91 (3H, d, J¼6.3 Hz), 1.18 (3H, d,
J¼7 Hz), 1.38–1.53 (4H, m), 1.63 (1H, m), 1.75 (1H, m),
2.02–2.08 (2H, m), 2.13–2.20 (2H, m), 2.29 (1H, dd,
J¼13.5, 11 Hz), 2.58 (1H, td, J¼10, 6.4 Hz), 2.64 (1H, t,
J¼13 Hz), 3.08 (1H, dt, J¼12, 2.5 Hz), 3.39 (1H, m); 13C
NMR (125 MHz) d 18.74 (q), 20.42 (q), 28.88 (t), 29.00 (t),
32.13 (d), 33.23 (d), 35.68 (t), 42.67 (t), 45.14 (t), 59.59 (d),
61.05 (d), 61.55 (d), 210.34 (s); MS: 207 (Mþ), 91 (100);
HRMS: Calcd for C13H21NO 207.1622. Found 207.1642;
[a]2D6¼þ27.1 (c 2.29, CHCl3).
Acetal 37. IR (neat) 2951, 2921, 2878, 1152 cm21; 1H NMR
(500 MHz) d 0.84 (3H, d, J¼6.4 Hz), 1.15 (3H, d,
J¼7.3 Hz), 1.27–1.39 (5H, m), 1.42–1.44 (1H, m), 1.51–
1.56 (2H, m), 1.68 (1H, br), 1.83 (1H, t, J¼12.8 Hz), 1.94
(1H, m), 2.04 (1H, m), 2.44 (1H, m), 3.00 (1H, d-like,
J¼12.7 Hz), 3.26 (1H, m), 3.96 (4H, s-like); 13C NMR
(125 MHz) d 18.82 (q), 20.42 (q), 28.07 (t), 28.95 (t), 32.18
(d), 32.93 (d), 34.19 (t), 36.36 (t), 36.57 (t), 57.33 (d), 57.73
(d), 58.96 (d), 63.83 (t), 64.41 (t), 109.17 (s); MS: 251 (Mþ),
250 (100); HRMS: Calcd for C15H25NO2 251.1884. Found
251.1889; [a]2D6¼24.6 (c 1.48, CHCl3).
To a stirred suspension of NaH (60%, 330 mg, 8.05 mmol)
in THF (20 mL) was added (EtO)2P(O)CH2CO2Et (1.6 mL,
7.87 mmol) at 0 8C, and the resulting solution was stirred at
0 8C for 30 min. To the mixture was added a solution of the
above aldehyde in THF (9 mL) at 0 8C, and the reaction
mixture was stirred at room temperature for 6 h. The
reaction was quenched with H2O, and the aqueous mixture
was extracted with CH2Cl2 (20 mL£4). The organic extracts
were combined, dried, and evaporated to give pale yellow
oil, which was chromatographed on SiO2 (50 g,
hexane:acetone¼20:1) to give 35 (2.16 g, 73% in 2 steps)
as a colorless oil.
1
IR (neat) 2972, 2929, 2881, 1716, 1690 cm21; H NMR
(500 MHz) d 0.81 (3H, d, J¼6.4 Hz), 0.98 (3H, d,
J¼6.8 Hz), 1.26 (3H, t, J¼7.2 Hz), 1.33 (3H, s), 1.35–
1.42 (1H, m), 1.40 (9H, s), 1.80–1.86 (4H, m), 2.14–2.18
(1H, m), 3.46 (1H, t-like, J¼8.5 Hz), 3.88–3.95 (5H, m),
4.18 (2H, q, J¼7.2 Hz), 5.80 (1H, d, J¼15.8 Hz), 7.10 (1H,
dd, J¼15.8, 7.7 Hz); 13C NMR (125 MHz) d 14.18 (q),
18.67 (q), 18.85 (q), 23.82 (q), 28.28 (q), 29.28 (d), 31.70
(d), 35.36 (t), 39.46 (t), 55.18 (d), 60.06 (t), 64.24 (t), 64.34
(t), 79.87 (s), 109.32 (s), 120.12 (d), 148.59 (d), 155.75 (s),
166.58 (s); MS: 411 (Mþ), 253 (100); HRMS: Calcd for
C22H37NO6 411.2619. Found 411.2932; [a]2D6¼þ37.0 (c
1.39, CHCl3).
Deprotection of 37 with acid. To a stirred solution of 37
(179 mg, 0.71 mmol) in acetone (20 mL) was added
p-TsOH·H2O (1 g, 5.71 mmol), and the reaction mixture
was heated at reflux for 20 h. After cooling, the reaction was
quenched with satd. NaHCO3 (aq.), and the aqueous mixture
was extracted with CH2Cl2 (20 mL£4). The organic extracts
were combined, dried over K2CO3, and evaporated to give
pale yellow oil, which was chromatographed on SiO2 (15 g,
hexane:acetone¼30:1–15:1) to give 36 (118 mg, 80%) as a
colorless solid, whose spectral data were identical with
those of the authentic sample.
4.1.49. (2aS,5aS,6R,8R,8aS)-(1)-6,8-Dimethyldeca-
hydropyrrolo[2,1,5-de]quinolizin-4-one (14) and its
acetal (36). To a stirred solution of 35 (165 mg,
0.40 mmol) in EtOAc (20 mL) was added 10% Pd–C
(50 mg), and the resulting suspension was hydrogenated
under hydrogen atmosphere at 1 atm for 45 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.
4.1.50. (2aS,5aS,6R,8R,8aR)-(2)-6,8-Dimethyl-2,2a,
5,5a,6,7,8,8a-octahydro-1H-pyrrolo[2,1,5-de]-quino-
lizin-4-yl trifluoromethanesulfonate (38). To a stirred
solution of R-(R p,R p)-(þ)-bis(a-methylbenzyl)amine
(110 mg, 0.49 mmol) in THF (1 mL) was added n-BuLi
(1.6 M in hexane, 0.3 mL, 0.49 mmol) at 0 8C, and the
resulting solution was stirred at 0 8 C for 30 min. To the above
solution was added a solution of 36 (66 mg, 0.32 mmol) in
THF (2 mL) at 278 8C, and the reaction mixture was stirred at
278 8C for 30 min. To the reaction mixture was added a
solution of 2[N,N-bis(trifluoromethylsulfonyl)amino]-5-
chloropyridie (Comins’ reagent) (194 mg, 0.49 mmol) at
278 8C, and the reaction mixture was warmed to 240 8C
for 30 min. The reaction was quenched with satd. NaHCO3
(aq.), and the aqueous mixture was extracted with CH2Cl2
(15 mL£5). The organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was
chromatographed on SiO2 (20 g, hexane:acetone¼150:1) to
give 38 (58 mg, 54%) as a colorless oil.
To a stirred solution of the above oil in CH2Cl2 (2 mL) was
added a solution of DIBAL (0.93 M in hexane, 0.43 mL,
0.4 mmol) at 278 8C, and the resulting mixture was stirred
at 278 8C for 30 min. The reaction was quenched with
MeOH (1 mL) and satd. Rochelle solution in H2O (1 mL).
The organic layer was seperated, and the aqueous layer was
extracted with CH2Cl2 (10 mL£3). The organic layer and
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 benzene (24 mL) and
acetone (4 mL) was added p-TsOH·H2O (228 mg,
1.2 mmol), and the reaction mixture was heated at reflux
using Dean–Stark apparatus for 5 h. After cooling, the
reaction was quenched with satd. NaHCO3 (aq.), and the
organic layer was separated. The aqueous layer was extracted
with CH2Cl2 (10 mL£5), and the organic layer and extracts
were combined, dried over K2CO3, and evaporated to give
pale yellow oil, which was chromatographed on SiO2 (20 g,
hexane:acetone¼30:1–15:1) to give 36 (52 mg, 62% in 3
IR (neat) 2947, 2926, 2875, 1283 cm21
;
1H NMR
(500 MHz) d 0.88 (3H, d, J¼6.4 Hz), 1.20 (3H, d,
J¼7.3 Hz), 1.34–1.46 (4H, m), 1.52 (1H, m), 1.78 (1H,
m), 1.99 (2H, m), 2.10 (1H, td, J¼10, 5 Hz), 2.20 (1H, m),

6216
N. Toyooka et al. / Tetrahedron 60 (2004) 6197–6216
2.59 (1H, m), 3.11 (1H, dd, J¼11, 5 Hz), 3.99 (1H, dd-like,
J¼7, 2.5 Hz), 5.62 (1H, t-like, J¼2.5 Hz); 13C NMR
(125 MHz) d 18.77 (q), 20.03 (q), 26.65 (t), 27.86 (t),
29.19 (t), 32.22 (d), 35.19 (t), 57.23 (d), 57.46 (d), 60.79 (d),
100.57 (s), 121.95 (d), 144.71 (s); MS: 339 (Mþ), 69 (100);
HRMS: Calcd for C14H20F3NO3S 339.1115. Found
339.1137; [a]2D6¼213.8 (c 1.84, CHCl3).
Spande, and H. Martin Garraffo, NIH, for very valuable
suggestions and discussions about this paper. We are also
grateful to Dr. Yoshihiko Hirose, Amano Pharmaceutical
Co., Ltd., for the generous gift of lipase AK used in the
synthesis of 19. We also thank Professors Shigetoshi Kadota
and Yasuhiro Tezuka for recording the NOE spectra of 38.
4.1.51. (2aS,5aS,6R,8R,8aS)-(1)-3,5-Dimethyl-7-methyl-
enedecahydropyrrolo[2,1,5-de]quinolizine (39). To a
stirred suspension of MePþPh3Br2 (1.22 g, 3.01 mmol) in
THF (5 mL) was added n-BuLi (1.6 M in hexane, 1.65 mL,
2.63 mmol) at 0 8C, and the resulting yellow suspension was
stirred at 0 8C for 15 min. To the suspension was added a
solution of 36 (78 mg, 0.38 mmol) in THF (2 mL) at 0 8C,
and the resulting suspension was stirred at room temperature
for 21 h. The reaction was quenched with H2O, and the
aqueous mixture was extracted with Et2O (15 mL£4). The
organic extracts were combined, dried over K2CO3, and
evaporated to give a pale yellow oil, which was chromato-
graphed on SiO2 (15 g, hexane:acetone¼100:1) to give 39
(65 mg, 84%) as a colorless oil.
References and notes
1. Michael, J. P. The Alkaloids; Cordell, G. A., Ed.; Academic:
San Diego, 2001; Vol. 55. Pinder, A. R. Nat. Prod. Rep.; 1992,
9, 491–504.
2. Laschat, S.; Dickerner, T. Synthesis 2000, 1781–1813.
Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1
2000, 2862–2892.
3. Toyooka, N.; Nemoto, H. Drugs Future 2002, 27, 143–158.
Toyooka, N.; Nemoto, H. Recent Res. Dev. Org. Chem. 2002,
6, 611–624. Toyooka, N.; Nemoto, H. Trends Heterocycl.
Chem. 2002, 8, 145–154. Toyooka, N.; Nemoto, H. Stud. Nat.
Prod. Chem. 2003, 419, 448.
4. For complete synthetic details: Toyooka, N.; Fukutome, A.;
Nemoto, H.; Daly, J. W.; Spande, T. F.; Garraffo, H. M.;
Kaneko, T. Org. Lett. 2002, 4, 1715–1717. Toyooka, N.;
Fukutome, A.; Shinoda, H.; Nemoto, H. Angew. Chem., Int.
Ed. 2003, 42, 3808–3810.
IR (neat) 3070, 2954, 2927, 2791 cm21
;
1H NMR
(500 MHz) d 0.86 (3H, d, J¼6.9 Hz), 1.14 (3H, d,
J¼7.3 Hz), 1.34–1.38 (4H, m), 1.54 (1H, m), 1.74 (1H,
br), 1.85 (1H, d, J¼11.5 Hz), 1.96–2.07 (4H, m), 2.32 (1H,
t, J¼12.4 Hz), 2.59 (1H, q-like, J¼6.9 Hz), 2.74 (1H, dm,
J¼12.4 Hz), 3.05 (1H, br), 4.66 (2H, br); 13C NMR
(125 MHz) d 18.79 (q), 20.49 (q), 28.54 (t), 29.11 (t),
32.31 (d), 33.25 (d), 35.13 (t), 36.52 (t), 37.60 (t), 59.45 (d),
61.58 (d), 61.92 (d), 106.48 (t), 148.42 (s); MS: 205 (Mþ),
150 (100); HRMS: Calcd for C14H23N 205.1829. Found
205.1844; [a]2D6¼þ12.4 (c 3.01, CHCl3).
5. Hodgkinson, T. J.; Shipman, M. Synthesis 1998, 1141–1144.
6. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299–6302.
7. Cacchi, S.; Morera, E.; Orter, G. Tetrahedron Lett. 1985, 26,
1109–1112.
8. Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943–945.
Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J. W.; Garraffo,
H. M. Tetrahedron 1997, 53, 9553–9574.
4.1.52. (2aS,5aS,6R,8R,8aS)-(1)-3,5,7-Trimethyl-2,2a,
3,4,5,5a,6,8a-octahydro-1H-pyrrolo[2,1,5-de]-quinolizi-
dine (205B, 40). To a stirred solution of 39 (60 mg,
0.29 mmol) in benzene (6 mL) was added p-TsOH·H2O
(167 mg, 0.88 mmol), and the reaction mixture was heated at
reflux for 24 h. After cooling, the reaction was quenched with
satd. NaHCO3 (aq.), and the organic layer was separated. The
aqueouslayerwasextractedwithEt2O(10 mL£4), theorganic
layer and extracts were combined, dried over K2CO3, and
evaporated to give a pale yellow oil, which was chromato-
graphed on SiO2 (15 g, hexane:acetone¼100:1) to give 40
(38 mg, 63%) as a pale yellow oil.
9. Matsumura, Y.; Inoue, M.; Nakamura, Y.; Talib, I. L.; Maki,
T.; Onomura, O. Tetrahedron Lett. 2000, 41, 4619–4622.
10. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983; pp 209–290.
11. Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540–4552.
12. Garraffo, H. M.; Jain, P.; Spande, T. F.; Daly, J. W. J. Nat.
Prod. 1997, 60, 2–5.
13. Izquierdo, I.; Plaza, M. P.; Rodriguez, M.; Tamayo, J.
Tetrahedron: Asymmetry 1999, 10, 449–455.
14. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.
15. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1873.
16. For another synthesis of 223A and 6-epimer; see: Harris, J. A.;
Padwa, A. J. Org. Chem. 2003, 68, 4371–4381. Pu, X.; Ma, D.
J. Org. Chem. 2003, 68, 4400–4405.
IR (neat) 2956, 2905, 2790, 1660, 1458, 1375, 1317, 1216,
1169 cm21; 1H NMR (500 MHz) d 0.86 (3H, d, J¼6.4 Hz),
1.19 (3H, d, J¼7.3 Hz), 1.27–1.52 (6H, br m), 1.64 (3H, s),
1.72 (1H, m), 1.92 (1H, m), 2.12–2.18 (3H, m), 3.00 (1H,
dd, J¼11.2, 4.5 Hz), 3.80 (1H, br), 5.20 (1H, br); 13C NMR
(125 MHz) d 18.83 (q), 20.19 (q), 23.56 (q), 28.35 (t), 28.38
(t), 29.22 (t), 32.44 (d), 32.55 (d), 35.42 (d), 56.49 (d), 58.04
(d), 60.46 (d), 125.52 (d), 129.52 (d); MS: 205 (Mþ), 71
(100); HRMS: Calcd for C14H23N 205.1829. Found
205.1828; [a]2D6¼þ8.1 (c 1.05, CHCl3).
17. Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.;
Daly, J. W. Tetrahedron 1987, 43, 643–657.
18. Tokuyama, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. An.
Asoc. Quim. Argent. 1998, 86, 291–298.
19. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815–3818.
20. Takai, K.; Sato, M.; Oshima, K.; Nozaki, H. Bull. Chem. Soc.
Jpn 1984, 57, 108–115.
21. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21,
4313–4316.
Acknowledgements
22. Calculations were performed by using the B3LYP method in
Gaussian98 with the 6-31þGp p basis set. The desired isomer
We would like to thank Drs. John W. Daly, Thomas F.
40 is more stable than the other by 2.01 kcal/mol21
.