Facile transformation of 2-azetidinones to 2-piperidones: Application to the synthesis of the indolizidine skeleton and (8S,8aS)-perhydro-8-indolizinol

Article abstract of DOI:10.1021/jo026817n

The highly functionalized bicyclic lactam 7 was prepared from diolefinic-2-piperidone 18 by the use of ruthenium-catalyzed RCM, and in turn, 18 was derived via a two-carbon addition process from readily accessible 4-olefinic-2-azetidinone 13. Bicyclic lac

Full text of DOI:10.1021/jo026817n

F a cile Tr a n sfor m a tion of 2-Azetid in on es to
2-P ip er id on es: Ap p lica tion to th e
Syn th esis of th e In d olizid in e Sk eleton a n d
(8S,8a S)-P er h yd r o-8-in d olizin ol
Hyeon Kyu Lee,* J ong Soo Chun, and
Chwang Siek Pak*
Bio-Organic Science Division,
Korea Research Institute of Chemical Technology,
P.O. Box 107, Yusung, Taejon 305-606, Korea
F IGURE 1.
leehk@krict.re.kr
Among the efforts in this area, we recently reported a
new synthetic methodology for 2-piperidones that may
serve as versatile intermediates for the chiral synthesis
of various piperidine and indolizidine alkaloids from
readily accessible 2-azetidinones.3
Continuing our investigation on the application of this
methodology to indolizidine alkaloids, we describe herein
the efficient construction of potentially useful highly
functionalized indolizidine building block 7 and the
synthesis of (8S,8aS)-perhydro-8-indolizinol 19.
Received December 6, 2002
Abstr a ct: The highly functionalized bicyclic lactam 7 was
prepared from diolefinic-2-piperidone 18 by the use of
ruthenium-catalyzed RCM, and in turn, 18 was derived via
a two-carbon addition process from readily accessible 4-ole-
finic-2-azetidinone 13. Bicyclic lactams 7 and 20 could serve
as potentially valuable intermediates for the chiral synthesis
of various hydroxylated indolizidine alkaloids as exemplified
by the synthesis of (8S,8aS)-perhydro-8-indolizinol 19.
SCHEME 1 a
Indolizidine alkaloids constitute a family of nitrogen-
fused bicyclo[4.3.0]nonanes and have recently received
considerable attention due to their wide range of biologi-
cal activity.1,2 For example, polyhydroxylated indoliz-
idines such as swainsonine, castanospermine, lentigi-
nosine, and certain natural and synthetic analogues
attracted special interest by virtue of their varied and
pharmaceutically useful biological actions as potential
antiviral, antitumor, and immunomodulating agents.
Consequently, the development of efficient synthetic
methods for generating the indolizidine skeleton is the
subject of recent intense research activity.
a
Reaction conditions: (a) ref 3; (b) CH2dCHCH2Br, NaH, cat.
n-Bu4NI, THF, 0 °C, 2 h (88%); (c) n-Bu4NF, THF, 0 °C (95%); (d)
oxidation; (e) Wittig; (f) Grubbs' catalyst [(Cy3P)2Cl2RudCHPh].
(1) For recent reviews of synthesis and biological activity, see: (a)
Nemr, A. E. Tetrahedron 2000, 56, 8579. (b) Asano, N.; Nash, R. J .;
Molyneux, R. J .; Fleet, G. W. J . Tetrahedron: Asymmetry 2000, 11,
1645. (c) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300.
(d) Michael, J . P. Nat. Prod. Rep. 1999, 16, 675. (e) Elbein, A. D.;
Molyneux, R. J . In Iminosugars as Glycosidase Inhibitors; Stutz, A.
E., Ed.; Wiley-VCH: Weinheim, Germany, 1999; p 216. (f) Michael, J .
P. Nat. Prod. Rep. 1997, 14, 619. (g) Takahata, H.; Momose, T. In The
Alkaloids; Cordell, G. A., Ed.; Academic: San Diego, CA, 1993; Vol.
44, Chapter 3. (h) Elbein, A. D.; Molyneux, R. In Alkaloids: Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; Wiley and Sons: New
York, 1987; Vol. 5.
(2) For some representative examples of synthesis, see: (a) Paolucci,
C.; Mattioli, L. J . Org. Chem. 2001, 66, 4787. (b) Park, S. O.; Kang, H.
J .; Ko, S.; Park, S.; Chang, S. Tetrahedron: Asymmetry 2001, 12, 2621.
(c) Voigtmann, U.; Blechert, S. Org. Lett. 2000, 2, 3971. (d) Sibi, M.
P.; Christensen, J . W. J . Org. Chem. 1999, 64, 6434. (e) Yoda, H.;
Kawauchi, M.; Takabe, K. Synlett 1998, 137. (f) Pearson, W. H.;
Hembre, E. J . J . Org. Chem. 1996, 61, 7217. (g) Goti, A.; Cardona, F.;
Brandi, A. Synlett 1996, 761. (h) Overkleeft, H. S.; Pandit, U. K.
Tetrahedron Lett. 1996, 37, 547. (i) Kang, S. H.; Kim, G. T. Tetrahedron
Lett. 1995, 36, 5049. (j) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki,
M. J . Org. Chem. 1995, 60, 398. (k) Naruse, M.; Aoyagi, S.; Kibayashi,
C. J . Org. Chem. 1994, 59, 1358. (l) J irousek, M. R.; Cheung, A. W.-
H.; Babine, R. E.; Sass, P. M.; Schow, S. R.; Wick, M. W. Tetrahedron
Lett. 1993, 34, 3671. (m) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna,
L.; Ulgheri, F. J . Org. Chem. 1993, 58, 3397. (n) Chamberlin, A. R.;
Miller, S. A. J . Am. Chem. Soc. 1990, 112, 8100. (o) Ikota, N.; Hanaki,
A Chem. Pharm. Bull. 1990, 38, 2712. (p) Heitz, M.-P.; Overman, L.
E. J . Org. Chem. 1989, 54, 2591. (q) Bennett, R. B., III; Choi, J .-R.;
Montgomery, W. D.; Cha, J . K. J . Am. Chem. Soc. 1989, 111, 2580.
As depicted in Scheme 1, we envisaged that ring-
closing metathesis (RCM)4 of diolefinic 2-piperidone 6
could provide a highly functionalized bicyclic lactam 7
that may serve as a valuable precursor of polyhydroxy-
lated indolizidine alkaloids.
Our initial efforts in the synthesis of diolefinic 2-pip-
eridone 6 started from the known 2-piperidone 2.3 N-
Allylation and desilylation under standard conditions
afforded N-allyl-2-piperidone 4. However, subsequent
oxidation of 4 to aldehyde 5 turned out to be problematic
in our hands. Our attempts to prepare aldehyde 5 from
the oxidation of alcohol 4 with various oxidizing agents
(Swern,5 IBX,6 PCC,7 TEMPO8) were unsuccessful, af-
fording low yields of aldehyde 5.
Next, we thought that the diolefinic 2-piperidone 6
could be derived from 6-vinyl-2-piperidone by N-allylation
and, in turn, 6-vinyl-2-piperidone could be prepared from
(3) Lee, H. K.; Chun, J . S.; Pak, C. S. Tetrahedron Lett. 2001, 42,
3483.
(4) (a) Park, S. O.; Kang, H. J .; Ko, S.; Park, S.; Chang, S.
Tetrahedron: Asymmetry 2001, 12, 2621. For recent reviews of RCM,
see: (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem, Res. 2001, 34, 18. (c)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
10.1021/jo026817n CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
J . Org. Chem. 2003, 68, 2471-2474
2471

SCHEME 2 a
in toluene to give 6-(E)-olefinic-2-piperidone (E)-17 in
excellent yield from (2Z,6E)-16. 6-(Z)-Olefinic-2-piperi-
done (Z)-17 was also prepared from the N-Boc-4-(Z)-
olefinic-2-azetidinone (Z)-13 through essentially the same
procedure for (E)-13 to (E)-17.
N-Allylation of 6-(E)-olefinic-2-piperidone (E)-17 pro-
duced the desired diolefinic-2-piperidone 18. With di-
olefinic-2-piperidone 18 in hand, we were ready to test
the ring-closing metathesis to form the indolizidine
skeleton 7. We were pleased to find that RCM4 of 18 was
indeed successfully effected with Grubbs’ ruthenium
catalyst to generate the highly functionalized bicyclic
lactam 7 despite the steric bulkiness of TBDPSO-CH2
group in 95% yield. (Z)-Diolefinic-2-piperidone (Z)-18 was
also smoothly converted to the same bicyclic lactam 7
under the same RCM reaction conditions with Grubbs’
ruthenium catalyst.
It should be noted that the highly functionalized
bicyclic lactam 7 could serve as a potentially valuable
intermediate for chiral synthesis of various hydroxylated
indolizidine alkaloids.13 For example, bicyclic lactam 7
was easily converted to (8S,8aS)-perhydro-8-indolizinol
1914 through hydrogenation and amide reduction in good
overall yield. On the other hand, regioselective reduction
of the 6,7-double bond of the bicyclic lactam 7 with
K-selectride2j afforded the mono-unsaturated bicyclic
lactam 20, which could be used for the synthesis of
swainsonine analogues.
a
Reaction conditions: (a) Ph3PdCHCHO, PhH, reflux, 24 h;
(b) NaBH4, THF, 0 °C, 1 h (68% from 8); (c) TBDPSCl, imidazole,
DMF, cat. DMAP (94%, E:Z ) 1.7:1); (d) (NH4)2Ce(NO3)6, CH3CN-
H2O, 0 °C, 30 min (E-12:61%; Z-12:47%); (e) (Boc)2O, cat. DMAP,
CH3CN, 10 min (E-13:97%; Z-13:84%)
4-vinyl-2-azetidinone by our reported methodology.3 How-
ever, treatment of 2-azetidinone-4-aldehyde 8 with
Ph3PdCH2 (Ph3PCH3Br/n-BuLi) gave a low yield of
4-vinyl-2-azetidinone. We then tried to synthesize 4-sub-
stituted vinyl-2-azetidinone 13 as the starting material
for preparing 6-olefinic-2-piperidone 17 from the known
optically pure 2-azetidinone-4-aldehyde 89 as shown in
Schemes 2 and 3.
Thus, treatment of 8 with (triphenylphosphoranylide-
ne)acetaldehyde afforded the R,â-unsaturated aldehyde
9 as an E and Z mixture. Since it was difficult to separate
the (E)- and (Z)-isomers at this stage, the unsaturated
aldehyde (E)- and (Z)-9 mixture was subjected to reduc-
tion and subsequent protection with TBDPSCl of the
resulting alcohol afforded a 1.7:1 mixture of (E)-isomer
(E)-11 as the major product and (Z)-isomer (Z)-11 in 64%
overall yield from 8. Oxidative removal of the PMP
protecting group10 in (E)-11 with CAN and subsequent
treatment with (t-Boc)2O furnished the N-Boc-4-olefinic-
2-azetidinone (E)-13 in good yields.
The applications of bicyclic lactams 7 and 20 to the
synthesis of various more complex indolizidine alkaloids
are under investigation.
In summary, the bicyclic lactam 7 was prepared from
diolefinic-2-piperidone 18 by the use of ruthenium-
catalyzed RCM and, in turn, 18 was derived via a two-
carbon addition process from readily accessible 4-olefinic-
2-azetidinone 13. Bicyclic lactams 7 and 20 could serve
as potentially valuable intermediates for the chiral
synthesis of various hydroxylated indolizidine alkaloids
as exemplified by the synthesis of (8S,8aS)-perhydro-8-
indolizinol 19.
Transformation of the N-Boc-4-olefinic-2-azetidinone
13 to 6-olefinic-2-piperidone 17 was straightforward
using our published two-carbon addition process3 as
shown in Scheme 3.
Thus, (E)-13 was reduced to 3-N-Boc-amino alcohol (E)-
14 in 95% yield by LiAlH4 in THF at 0 °C for 10 min.
Oxidation of 3-N-Boc-amino alcohol (E)-14 by IBX (2-
iodoxybenzoic acid)6 in DMSO for 5 h at room tempera-
ture cleanly produced highly pure 3-N-Boc-amino alde-
hyde (E)-15, which was used in the next step without
further purification. Aldehyde (E)-15 was dissolved in dry
MeOH11 and treated with methyl (triphenylphosphora-
nylidene)acetate at room temperature to give an 8:1
mixture of the (Z)-R,â-unsaturated ester of (2Z,6E)-16 as
the major product and its (E)-isomer (2E,6E)-16 in 86%
overall yield from (E)-14. After separation by flash
chromatography, the (Z)-N-Boc amino ester (2Z,6E)-16
was subjected to removal of N-Boc protection under mild
conditions12 and in turn cyclized with catalytic DMAP
Exp er im en ta l Section
Flash column chromatography was performed on silica gel
(230-400 mesh). THF and Et2O were refluxed over sodium in
the presence of benzophenone and distilled prior to use. CH2Cl2
was distilled from calcium hydride. DMF, benzene, CH3CN,
MeOH, and toluene were dried, distilled, and stored under
nitrogen prior to use.16 All other reagent-grade chemicals
obtained from commercial sources were used as received.
(-)-(4E)-(2R,3S)-3-(t-Bu tyloxyca r bon yl)a m in o-2-(ben zy-
loxy)-6-(t-bu tyld ip h en ylsilyloxy)-4-h exen -1-ol ((E)-14). To
a suspension of LiAlH4 (0.16 g, 4.09 mmol) in THF (10 mL) was
added dropwise a solution of (E)-13 (2.34 g, 4.09 mmol) in THF
(10 mL) at 0 °C. After the mixture was stirred at that temper-
ature for 20 min, ice-water (20 mL) and Rochelle salt (20 mL)
was added and the reaction mixture was stirred for additional
1 h. The reaction mixture was extracted with CH2Cl2 (3 × 40
(5) Tidwell, T. T. Synthesis 1990, 857.
(6) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J . Org.
Chem. 1995, 60, 7272.
(7) Hijfte, L. V.; Heydt, V.; Kolb, M. Tetrahedron Lett. 1993, 34, 4793.
(8) Leanna, M. R.; Sowin, T. J .; Morton, H. E. Tetrahedron Lett.
1992, 33, 5029.
(9) Alcaide, B.; Martin-Cantalejo, Y.; Perez-Castells, J .; Sierra, M.
J . Org. Chem. 1996, 61, 9156.
(13) For synthesis and functionalization of similar bicyclic lactams,
see: Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J . Org. Chem.
1995, 60, 398.
(14) Rader, C. P.; Young, R. L., J r.; Aaron, H. J . Org. Chem. 1965,
30, 1536.
(10) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J . Org. Chem. 1982,
47, 2765.
(11) Sanchez-Sancho, F.; Valverde, S.; Herradon, B. Tetrahedron:
Asymmetry 1996, 7, 3209.
(15) Wagle, D. R.; Garai, C.; Chiang, J .; Monteleone, M. G.; Kurys,
B. E.; Strohmeyer, T. W.; Hegde, V. R.; Manhas, M. S.; Bose, A. K. J .
Org. Chem. 1988, 53, 4227.
(16) Perrin, D. D.; Armarego, W. L. P.; Perrin, D. R. In Purification
of Laboratory Chemicals, 2nd ed.; Pergamon: New York, 1980.
(12) Sakaitani, M.; Ohfune, Y. J . Org. Chem. 1990, 55, 870.
2472 J . Org. Chem., Vol. 68, No. 6, 2003

SCHEME 3 a
a
Reaction conditions: (a) LiAlH4, THF, 0 °C, 10 min (E-14:97%; Z-14:95%); (b) IBX, DMSO, rt, 5 h (E-15:97%; Z-15:95%); (c)
Ph3PdCHCO2Me, MeOH, rt, 12 h (E-16:89% (E:Z )1:8); Z-16:86% (E:Z ) 1:7)); (d) TMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 1 h, then cat.
DMAP, toluene, reflux, 1 h (E-17:95%; Z-17:82%); (e) CH2dCHCH2Br, NaH, cat. n-Bu4NI, THF, 0 °C, 2 h (E-18:88%; Z-18:73%); (f) 3 mol
% (Cy3P)2Cl2RudCHPh, PhH, reflux, 1 h (95%).
SCHEME 4 a
MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.45-7.25 (m, 12H), 6.88 (dd,
1H, J ) 6.0, 15.7 Hz), 6.07 (dd, 1H, J ) 1.3, 15.7 Hz), 5.87-5.69
(m, 2H), 4.83-4.78 (m, 1H), 4.59 (d, 1H, J ) 11.6 Hz), 4.40 (d,
1H, J ) 11.6 Hz), 4.31 (m, 1H), 4.20-4.19 (m, 2H), 4.09-4.06
(m, 1H), 3.74 (s, 3H), 1.42 (s, 9H), 1.05 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 166.23, 155.31, 144.88, 137.42, 135.47, 133.49,
131.07, 129.64, 128.39, 128.06, 127.85, 127.79, 127.65, 123.36,
79.70, 77.20, 71.72, 63.60, 51.92, 51.64, 28.27, 26.77, 19.19; MS
m/z 632 (M+ + 3), 572, 516, 450, 394, 368, 350, 324, 316, 272;
HRMS (CI, methane) calcd for C37H47NO6Si 630.3250 (MH+),
found 630.3248.
a
Reaction conditions: (a) (i) H2/Pd(OH)2, EtOH, 3 days (98%);
(ii) BH3SMe2, THF, 0 °C, 4 h (68%). (b) K-Selectride, Et2O, -78
°C, 30 min (51 %).
21
(Z)-Isom er ((2Z,6E)-16): colorless oil; [R]D +10.2 (c 0.53,
mL), washed with NaHCO3 and brine, and dried (MgSO4). After
evaporation of the solvent in vacuo, the crude product was
purified by flash chromatography (from 7:1 to 5:1 hexane-
EtOAc): yield 2.28 g (97%); colorless oil; Rf 0.34 (3:1 hexane-
CHCl3); IR (NaCl, cm-1) ν 3070, 2931, 1722; 1H NMR (300 MHz,
CDCl3) δ 7.70-7.65 (m, 3H), 7.46-7.25 (m, 12H), 6.25 (dd, 1H,
J ) 8.4, 11.7 Hz), 5.97 (dd, 1H, J ) 1.1, 11.7 Hz), 5.88-5.79 (m,
2H), 5.14-4.97 (m, 2H), 4.53 (d, 1H, J ) 11.6 Hz), 4.42 (d, 1H,
J ) 11.6 Hz), 4.39 (m, 1H), 4.22-4.20 (m, 2H), 3.71 (s, 3H), 1.43
(s, 9H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 166.03,
155.48, 148.09, 137.91, 135.50, 133.63, 133.61, 130.41, 129.60,
127.95, 127.77, 127.70, 127.64, 122.28, 79.29, 71.87, 63.71, 60.38,
55.69, 51.46, 28.36, 26.79, 19.22; MS m/z 630 (M+ + 1), 572, 530,
516, 408, 368, 318, 266, 246; HRMS (CI, methane) calcd for
21
EtOAc); [R]D -21.8 (c 1.59, CHCl3); IR (NaCl, cm-1) ν 3445,
1716, 1698; 1H NMR (300 MHz, CDCl3) δ 7.69-7.65 (m, 3H),
7.45-7.24 (m, 12H), 5.84-5.73 (m, 2H), 4.86 (d, 1H, J ) 9.6 Hz),
4.55 (m, 3H), 4.21 (m, 2H), 3.67-3.45 (m, 3H), 3.24 (br s, 1H),
1.45 (s, 9H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.69,
137.89, 135.48, 133.52, 133.48, 130.54, 129.68, 128.42, 127.94,
127.68, 111.49, 81.27, 80.08, 73.50, 63.69, 60.93, 51.87, 28.29,
26.80, 19.22; MS m/z 462 (M+ - 113), 444, 418, 401, 384, 368,
340; HRMS (CI, methane) calcd for C34H45NO5Si 576.3145
(MH+), found 576.3148.
C
37H47NO6Si 630.3250 (MH+), found 630.3250.
(+)-(5S,6S)-5-(Ben zyloxy)-6-[(E)-3-(t-bu tyld ip h en ylsily-
loxy)-1-p r op en -yl]-1,2,5,6-tetr a h yd r o-2-p yr id in on e ((E)-17).
To a solution of (2Z)-N-Boc amino ester (2Z,6E)-16 (1.86 g, 2.95
mmol) and 2,6-lutidine (0.64 g, 5.95 mmol) in CH2Cl2 (30 mL)
was added TMSOTf (0.8 mL, 4.43 mmol) dropwise at 0 °C. After
the reaction mixture was stirred for 1 h at room temperature,
the reaction was quenched by addition of saturated NaHCO3
solution (30 mL) and the organic layer was separated and dried
over MgSO4. After evaporation of the solvent in vacuo, the
resulting oil was dissolved in toluene (20 mL) and DMAP (0.01
g, 0.09 mmol) was added; the reaction mixture was refluxed for
1 h. The reaction mixture was cooled to room temperature and
washed with 1 N HCl solution, saturated NaHCO3 (20 mL), and
brine (20 mL) successively. After drying (MgSO4) and evapora-
tion of the solvent in vacuo, the crude product was purified by
flash chromatography (from 3:1 to 1:1 hexane-EtOAc): yield
(4E)-(2R,3S)-3-(t-Bu tyloxycar bon yl)am in o-2-(ben zyloxy)-
6-(t-bu tyld ip h en ylsilyloxy)-4-h exen a l ((E)-15). To a solution
of 3-N-Boc-amino alcohol (E)-14 (2.81 g, 4.88 mmol) in DMSO
(20 mL) was added 2-iodoxybenzoic acid (2.1 g, 7.33 mmol). After
stirring at room temperature for 5 h, the reaction mixture was
diluted with water (40 mL), filtered over Celite, and extracted
with Et2O (3 × 30 mL). The combined organic layers were
washed with saturated NaHCO3 and brine, dried (MgSO4), and
evaporated in vacuo. The crude aldehyde was sufficiently pure
to be used in the next step without further purification: yield
2.72 g (97%); pale yellow oil; IR (NaCl, cm-1) ν 2930, 2857, 1720;
1H NMR (300 MHz, CDCl3) δ 9.65 (s, 1H), 7.69-7.64 (m, 3H),
7.47-7.25 (m, 12H), 5.82-5.72 (m, 2H), 5.01 (d, 1H, J ) 9.4 Hz),
4.74 (d, 1H, J ) 11.6 Hz), 4.75-4.73 (m, 1H), 4.58 (d, 1H, J )
11.6 Hz), 4.22-4.20 (m, 2H), 3.89 (br s, 1H), 1.42 (s, 9H), 1.06
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.49, 155.03, 135.47,
133.49, 133.45, 131.43, 129.69, 128.53, 128.21, 128.12, 127.69,
127.68, 84.70, 79.87, 73.19, 63.49, 60.39, 28.27, 26.79, 19.23; MS
m/z 574 (M+ + 1), 518, 460, 416, 382, 368; HRMS (CI, methane)
calcd for C34H43NO5Si 574.2988 (MH+), found 574.2997.
21
1.39 g (95%); colorless oil; Rf 0.05 (3:1 hexane-EtOAc 3:1); [R]D
+27.9 (c 0.61, CHCl3); IR (NaCl, cm-1) ν 3222, 1682, 1615; 1H
NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.47-7.25 (m,
12H), 6.57 (dd, 1H, J ) 3.5, 10.0 Hz), 6.07-5.94 (m, 2H), 5.84
(tt, 1H, J ) 4.1, 4.3 Hz), 5.52 (br s, 1H), 4.65-4.53 (m, 2H), 4.25-
4.10 (m, 4H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 164.88,
140.30, 137.48, 135.50, 133.54, 133.42, 133.38, 129.74, 128.48,
127.95, 127.70, 125.50, 124.75, 71.50, 71.36, 63.54, 26.78, 19.19;
MS m/z 497 (M+), 440, 406, 332, 289, 272, 254, 211, 199; HRMS
(EI) calcd for C31H35NO3Si 497.2386, found 497.2390.
Met h yl
(6E)-(4S,5S)-5-(t-Bu t yloxyca r b on yl)a m in o-4-
(b en zyloxy)-8-(t-b u t yld ip h en ylsilyloxy)-2,6-oct a d ien oa t e
((2E,6E)- a n d (2Z,6E)-16). To a solution of aldehyde (E)-15 (2.48
g, 4.33 mmol) in dry methanol (40 mL) was added Ph3PdCHCO2-
Me (1.74 g, 5.19 mmol). The reaction mixture was stirred for 18
h at room temperature, and the solvent was evaporated in vacuo.
The crude product was separated to pure (E)- and (Z)-isomers
by flash chromatography (from 15:1 to 10:1 hexane-EtOAc):
yield 2.43 g (89%, 2E:2Z ) 1:8).
(-)-(5S,6S)-1-Allyl-5-(ben zyloxy)-6-[(E)-3-(t-bu tyld ip h e-
n ylsilyloxy)-1-p r op en yl]-1,2,5,6-t et r a h yd r o-2-p yr id in on e
((E)-18). To a slurry of NaH (60% in mineral oil, 64 mg, 1.607
mmol) in THF (7 mL) was added a solution of (E)-17 (400 mg,
0.803 mmol) in THF (10 mL) at 0 °C. After the mixture was
stirred for 20 min at this temperature, allyl bromide (0.14 mL,
1.607 mmol) and n-Bu4NI (12 mg, 0.032 mmol) were added. The
21
(E)-Isom er ((2E,6E)-16): colorless oil; [R]D -2.0 (c 0.7,
CHCl3); IR (NaCl, cm-1) ν 3070, 3031, 2931, 1724; 1H NMR (300
J . Org. Chem, Vol. 68, No. 6, 2003 2473

reaction mixture was stirred for 1 h at room temperature, and
the reaction was quenched with saturated NH4Cl (20 mL). The
aqueous layer was extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified
by flash chromatography (from 5:1 to 3:1 hexane-EtOAc): yield
155.0946. Borane-methyl sulfide complex (1.13 mL of 2 M
solution in THF, 2.268 mmol) was added dropwise over a period
of 10 min at 0 °C to a solution of (-)-(8S,8a S)-8-h yd r oxy-5-
in d olizid in on e (88 mg, 0.567 mmol) in THF (5 mL). After 30
min, the solution was warmed to room temperature and stirred
for another 4 h at that temperature. The reaction was quenched
by slow addition of ethanol. Evaporation of the solvent gave a
viscous oil, which was redissolved in ethanol (5 mL) and heated
to reflux for 2 h. After cooling to room temperature and
evaporation under reduced pressure, the residue was purified
by flash chromatography (3:1 hexane-EtOAc) giving 19 as a
white solid: yield 54 mg (68%); Rf 0.18 (2:1 hexane-EtOAc);
21
378 mg (88%); colorless oil; Rf 0.35 (3:1 hexane-EtOAc); [R]D
-26.5 (c 2.02, CHCl3); IR (NaCl, cm-1) ν 3070, 1673, 1615; 1H
NMR (300 MHz, CDCl3) δ 7.68-7.63 (m, 3H), 7.45-7.25 (m,
12H), 6.38 (tt, 1H, J ) 1.7, 10.2 Hz), 5.85 (dd, 1H, J ) 2.4, 10.2
Hz), 5.81-5.61 (m, 3H), 5.20-5.12 (m, 2H), 4.76-4.65 (m, 1H),
4.59-4.51 (m, 3H), 4.23-4.21 (m, 2H), 4.12-4.05 (m, 1H), 3.16
(q, 1H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 163.18,
140.37, 137.20, 135.49, 133.83, 133.51, 133.43, 129.66, 128.50,
128.00, 127.76, 127.66, 123.99, 122.70, 117.39, 73.95, 71.37,
63.67, 58.91, 46.29, 26.74, 19.18; MS m/z 537 (M+), 480, 450,
402, 374, 312, 289, 259; HRMS (EI) calcd for C34H39NO3Si
537.2699, found 537.2696.
21
mp 101-102 °C; [R]D -17.4 (c 1.15, CHCl3); IR (KBr, cm-1) ν
3430, 2962, 2372, 1471, 1452; 1H NMR (500 MHz, CDCl3) δ
4.46-4.42 (m, 1H), 3.36-3.32 (m, 1H), 3.25-3.19 (m, 1H), 3.12-
3.08 (m, 1H), 2.79-2.75 (m, 1H), 2.58 (ddd, 1H, J ) 3.3, 12.2,
12.2 Hz), 2.18-2.05 (m, 3H), 1.99-1.93 (m, 3H), 1.84-1.81 (m,
1H), 1.68-1.63 (m, 1H), 1.56-1.48 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 68.73, 65.23, 64.16, 51.74, 26.30, 22.32, 19.90, 18.91;
MS m/z 141 (M+), 140, 123, 96, 84, 69, 55, 41; HRMS (EI) calcd
for C8H15NO 141.1153, found 141.1152.
(-)-(8S,8a S)-8-(Ben zyloxy)-3,5,6,7,8,8a -h exa h yd r o-5-in -
d olizid in on e (20). To a stirred solution of 7 (80 mg, 0.331 mmol)
in Et2O (3 mL) was added a solution of K-selectride (0.83 mL of
a 1 M solution in THF, 0.827 mmol) at -78 °C. After gradual
warming to 0 °C and further stirring for 30 min at that
temperature, the reaction was quenched by the addition of
saturated NaHCO3, and extracted with CH2Cl2. The organic
layers were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (EtOAc) to give 20 as a colorless oil: yield 41
mg (51%); Rf 0.24 (EtOAc); [R]D21 -8.4 (c 1.31, CHCl3); IR (NaCl,
cm-1) ν 1651, 1460, 1409, 1361; 1H NMR (300 MHz, CDCl3) δ
7.37-7.26 (m, 5H), 5.98-5.95 (m, 1H), 5.80-5.76 (m, 1H), 4.62
(d, 1H, J ) 12.4 Hz), 4.56-4.53 (m, 1H), 4.49 (d, 1H, J ) 12.4
Hz), 4.46-4.43 (m, 1H), 4.09-3.95 (m, 2H), 2.57-2.44 (m, 2H),
2.26-2.09 (m, 1H), 1.98-1.77 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 169.18, 138.08, 128.38, 127.67, 127.35, 127.14, 126.97,
70.51, 70.20, 67.96, 53.04, 26.80, 24.63; MS m/z 243 (M+), 190,
152, 134, 120, 106, 91, 68; HRMS (EI) calcd for C15H17NO2
243.1259, found 243.1252.
(+)-(8S,8a S)-8-(Ben zyloxy)-3,5,8,8a -tetr a h yd r o-5-in d oliz-
id in on e (7). A mixture of N-allyl-2-pyridone (E)-18 or (Z)-18
(786 mg, 1.46 mmol) and (Cy3P)2Cl2RudCHPh [Grubbs’ catalyst
(33 mg, 0.04 mmol)] in benzene (30 mL) was heated to reflux
for 1 h. After the mixture was cooled to room temperature,
DMSO (0.15 mL, 2 mmol) was added and stirred for 12 h. The
reaction mixture was filtered over Celite, and the filtrate was
concentrated under reduced pressure. The residue was purified
by flash chromatography (from 3:1 to 1:1 hexane-EtOAc) to give
7 as a colorless oil: yield 335 mg (95%); Rf 0.17 (1:1 hexane-
21
EtOAc); [R]D +135.6 (c 1.86, CHCl3); IR (NaCl, cm-1) ν 1665,
1598; 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 5H), 6.61 (dd,
1H, J ) 5.7, 9.8 Hz), 6.21 (dd, 1H, J ) 3.0, 9.8 Hz), 6.07-6.00
(m, 1H), 5.90-5.84 (m, 1H), 4.65-4.61 (m, 1H), 4.56-4.44 (m,
3H), 4.28-4.16 (m, 1H), 4.06 (dd, 1H, J ) 3.7, 5.7 Hz); 13C NMR
(125 MHz, CDCl3) δ 161.27, 137.76, 135.74, 129.46, 128.45,
127.90, 127.66, 127.61, 125.78, 70.46, 67.17, 66.63, 51.81; MS
m/z 241 (M+), 214, 174, 150, 133, 104, 91; HRMS (EI) calcd for
C
15H15NO2 241.1102, found 241.1102.
(-)-(8S,8a S)-8-Hyd r oxyin d olizid in e (19). A mixture of 7
(175 mg, 0.725 mmol) and 20% Pd(OH)2 (88 mg, 50% w/w) in
EtOH (8 mL) was shaken for 3 days under 60 psi of hydrogen
pressure using a Parr hydrogenator. The mixture was filtered
over Celite, and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography
(10:1 EtOAc-MeOH) to give (-)-(8S,8a S)-8-h yd r oxy-5-in -
d olizid in on e as a white solid: yield 100 mg (98%); Rf 0.11 (10:1
Ack n ow led gm en t. We thank the Ministry of Sci-
ence and Technology of Korea for financial support.
21
EtOAc-MeOH); mp 98-100 °C; [R]D -30.6 (c 2, CHCl3); IR
1
(KBr, cm-1) ν 3397, 1602; H NMR (500 MHz, CDCl3) δ 4.14-
Su p p or tin g In for m a tion Ava ila ble: Full experimental
1
procedures and copies of H and 13C NMR spectra for 7, 11-
4.13 (m, 1H), 3.52-3.47 (m, 3H), 2.52-2.45 (m, 1H), 2.38-2.32
(m, 1H), 2.09-2.04 (m, 1H), 1.94-1.85 (m, 5H), 1.75-7.71 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 168.89, 63.85, 62.44, 45.27,
28.42, 27.63, 26.01, 22.03; MS m/z 155 (M+), 138, 127, 111, 98,
83, 70, 55, 41; HRMS (EI) calcd for C8H13NO2 155.0946, found
14, and 16-20. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O026817N
2474 J . Org. Chem., Vol. 68, No. 6, 2003