Synthesis of Enantiopure Indolizidine Alkaloids from α-Amino Acids: Total Synthesis of (-)-Indolizidine 167B

Full text of DOI:10.1021/jo970591k

J . Org. Chem. 1997, 62, 8549-8552
8549
Sch em e 1. P r op osed Syn th esis of In d olizid in es
Syn th esis of En a n tiop u r e In d olizid in e
Alk a loid s fr om r-Am in o Acid s: Tota l
Syn th esis of (-)-In d olizid in e 167B
Steven R. Angle* and Robert M. Henry
Department of Chemistry, University of
California-Riverside, Riverside, California 92521-0403
Received April 1, 1997
The indolizidine alkaloids display a wide range of
biological activity1 and have been the subject of a
considerable number of synthetic studies.2 The develop-
ment of general methods for the synthesis of racemic and
enantiopure indolizidines remains an area of active
investigation.2 We have developed an enantioselective
synthesis of highly functionalized pipecolic esters that
might find application as part of a general synthetic route
to enantiopure indolizidine alkaloids from readily avail-
able R-amino acids.3 We report here the refinement of
the methodology and implementation of this strategy for
the synthesis of the naturally occurring indolizidine
alkaloid (-)-indolizidine 167B.4
We have previously shown that esters of amino acids
2 could be converted to N-methylpipecolic esters 6a in
good yields (Scheme 1).3a The key step of the synthetic
sequence was a conformationally restricted Claisen rear-
rangement of silyl ketene acetals 5a derived from lac-
tones 4a .9 The extension of this methodology to the
synthesis of indolizidines required removal of the N-
methyl group to allow introduction of the 5-membered
ring of the indolizidine. However, despite considerable
effort, this demethylation could not be achieved.10 Ac-
cordingly, we sought to adapt the methodology to the
synthesis of N-benzylpipecolic esters 6b, since a benzyl
group might be removed under a variety of conditions.
The concise, stereoselective synthesis of N-benzyl lac-
tones 4b from R-amino esters 2 is not straightforward.
We have invested substantial effort in the development
of a stereoselective route to lactones such as 4 from amino
esters 210a and found that the best method for the
conversion of 2 to 3 involves the sequential ester reduc-
tion-diastereoselective addition of vinyl organometallics
to the resulting aldehyde11 (or equivalent).12 This reac-
tion requires an electron-withdrawing group (or alkyli-
dine) on the amine functionality. Whereas, conversion
of amino alcohol 3 to lactone 4 requires an alkyl amine
that can easily be alkylated with R-haloacetyl halides (or
their equivalent) in the presence of the secondary alcohol.
We previously showed that alkylation of the N-BOC
amines 3 with R-haloacetyl halides and their equivalents
(-)-Indolizidine 167B was detected by Daly and co-
workers in the skin secretions of neotropical frogs of the
genera Dendrobates and the family Dendrobatidae.4,5 The
skin secretions of these frogs contain a wide variety of
toxic alkaloids that appear to serve as defensive agents.
Recent work by Daly and co-workers has shown that the
“dendrodaid alkaloids” result from a dietary uptake
system which allows accumulation of these poison alka-
loids in the skin of the frogs.6 There have been several
previous syntheses of indolizidine 167B.7,8
(1) For leading references to the biological activity of indolizidine
alkaloids, see: (a) Michael, J . P. Nat. Prod. Rep. 1997, 14, 21-41. (b)
Takahata, H.; Momose, T. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press, Inc.: San Diego, 1993; Vol. 44, Chapter 3.
(2) For recent examples of and leading references to the synthesis
of indolizidine natural products, see: (a) Angle, S. R.; Breitenbucher,
J . G. In Studies in Natural Products Chemistry; Stereoselective
Synthesis; Atta-ur-Rahman, Ed.; Elsevier: New York, 1995; Vol. 16,
Part J , pp 453-502. (b) Okano, T.; Sakaida, T.; Eguchi, S. Heterocycles
1997, 44, 227-236. (c) Comins, D. L.; Zhang, Y. M. J . Am. Chem. Soc.
1996, 118, 12248-12249. (d) Michael, J . P.; Gravestock, D. Synlett
1996, 981-982. (e) Thanh, G. V.; Ce´le´rier, J .-P.; Lhommet, G.
Tetrahedron: Asymmetry 1996, 7, 2211-2212. (f) Chan, C.; Cocker J .
D.; Davies, H. G.; Gore, A.; Green, R. H. Bioorg. Med. Chem. Lett. 1996,
6, 161-164. (g) Li, Y.; Marks, T. J . J . Am. Chem. Soc. 1996, 118, 707-
708. (h) Takahata, H.; Bandoh, H.; Momose, T. Heterocycles 1996, 42,
39-42. (i) Muraoka, O.; Zheng, B-Z.; Okumura, K.; Tabata, E.;
Tanabe, G.; Kubo, M. J . Chem. Soc., Perkin Trans. 1, 1997, 113-119.
(j) Lee, E.; Kang, T.; Chung, C. Bull. Korean Chem. Soc. 1996, 17, 212-
214. (k) Solladie´, G.; Chu, G.-H. Tetrahedron Lett. 1996, 37, 111-114.
(l) Munchhof, M. J .; Meyers, A. I. J . Am. Chem. Soc. 1995, 117, 5399-
5400.
(3) (a) Angle, S. R.; Breitenbucher, J . G.; Arnaiz, D. O. J . Org. Chem.
1992, 57, 5947-5955. (b) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett.
1989, 30, 515-518. (c) Angle, S. R.; Breitenbucher, J . G. Tetrahedron
Lett. 1993, 34, 3985-3988.
(4) For the detection of (-)-indolizidine 167B see: Daly, J . W.
Fortschr. Chem. Org. Naturst. 1982, 41, 205-340.
(5) (a) Daly, J . W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25,
1023-1095. (b) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards,
M. W.; Daly, J . W. Tetrahedron 1986, 42, 3453-3460. (c) Daly, J . W.;
Spanade, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, Chapter 1.
(6) Daly, J . W.; Secunda, S. I.; Garraffo, H. M.; Spande, T. F.;
Wisnieski, A.; Cover J r., J . F. Toxicon 1994, 32, 657-663.
(7) For leading references and previous synthesis of (()-
indolizidine167B see: (a) Holmes, A. B.; Smith, A. L.; Williams, S. F.;
Hughes, L. R.; Lidert, Z.; Swithenbank, C. J . Org. Chem. 1991, 56,
1393-1405. (b) Zeller, E.; Sajus, H.; Grierson, D. S. Synlett 1991, 44-
46. (c) Smith, A. L.; Williams, S. F.; Holmes, A. B.; Hughes, L. R.;
Lidert, Z.; Swithenbank, C. J . Am. Chem. Soc. 1988, 110, 8696-8698.
(8) For previous synthesis of (+)- and (-)-indolizidine167B see: (a)
Lee, E.; Li, K. S.; Lim, J . Tetrahedron Lett. 1996, 37, 1445-1446. (b)
(+)-167B: Takahata, H.; Bandoh, H.; Momose, T. Heterocycles 1995,
41, 1797-1804. (c) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J .
M.; Fang, W. K.; Blickensdorf, J . D. J . Am. Chem. Soc. 1993, 115,
10183-10194. (d) J efford, C. W.; Wang, J . B. Tetrahedron Lett. 1993,
34, 3119-3122. (e) Fleurant, A.; Ce´le´rier, J . P.; Lhommet, G. Tetra-
hedron Asymmetry 1992, 3, 695-696. (f) Polniaszek, R. P.; Belmont,
S. E. J . Org. Chem. 1990, 55, 4688-4693.
(9) For leading references to other examples of conformationally
restricted Claisen rearrangements see: (a) Danishefsky, S. J .; Audia,
J . E. Tetrahedron Lett. 1988, 29, 1371-1374. (b) Burke, S. D.;
Armistead, D. M.; Schoenen, F. J . J . Org. Chem. 1984, 49, 4320-4322.
(c) Burke, S. D.; Schoenen, F. J .; Murtiashaw, C. W. Tetrahedron Lett.
1986, 27, 449-452. (d) Bu¨chi, G.; Powell, J . E., J r. J . Am. Chem. Soc.
1970, 92, 3126-3133. (e) Kang, H.-J .; Paquette, L. A. J . Am. Chem.
Soc. 1990, 112, 3252-3253.
(10) (a) Breitenbucher, J . G., Ph.D. Dissertation, University of
California at Riverside, 1993. (b) Boyce, J . P., Ph.D. Dissertation,
University of California at Riverside, 1994.
(11) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1991, 56, 4370-4382.
(12) Polt, R.; Peterson, M. A.; DeYoung, L. J . Org. Chem. 1992, 57,
5469-5480.
S0022-3263(97)00591-4 CCC: $14.00 © 1997 American Chemical Society

8550 J . Org. Chem., Vol. 62, No. 24, 1997
Notes
magnesium.14 Lithium aluminum hydride reduction
afforded the desired amine in 82% yield. Alkylation of
the amine with phenyl R-bromoacetate15 followed by
continued stirring of the reaction mixture resulted in
lactonization to afford 10 in 60% yield as an 11:1 mixture
of diastereomers (GC). The stage was now set for the
key Claisen rearrangement. Treatment of 10 with
TIPS-OTf followed by reaction at room-temperature
overnight afforded a solution of TIPS ester 12 which was
immediately treated with lithium aluminum hydride to
afford primary alcohol 13 in 79% overall yield from
lactone 10. The silyl ketene acetal derived from the
minor diastereomer of lactone 10 failed to undergo
Claisen rearrangement, and 13 was obtained as a single
Sch em e 2. Tota l Syn th esis of In d olizid in e
(-)-167B
1
diastereomer by H and 13C NMR analysis. Oxidation
of 13 under Swern conditions16 followed by homologation
with the conjugate base of triethyl phosphonoacetate17
afforded 14 as a 54:46 mixture of E/Z isomers (1H NMR)
in 74% yield. This proved to be superior to homologation
with (carbethoxymethylene)triphenylphosphorane, which
1
afforded 14 as the E-isomer (95:5, E/Z, H NMR) in 37%
yield. Subjection of the ca. 1:1 E/Z mixture or enriched
E-isomer of 14 to hydrogenation/hydrogenolysis condi-
tions (H2, ammonium formate with Pd/C, PtO2, or Pd-
(OH)2/C) resulted in the formation of several different
N-benzylamines resulting from scission of the C-N bond
in the six-membered ring. The reason for this failed
reduction was initially unclear. Corey and Smith18
encountered problems in a hydrogenation due to what
was thought to be sulfur-containing impurities that
poisoned the catalyst. Their solution was to stir a THF
solution of their compound with sodium carbonate and
Pd/C, remove the catalyst, and then carry out the
hydrogenation with fresh catalyst. In our case, sulfur
impurities might arise from the Swern oxidation. It
should be noted that 14 was purified by flash chroma-
tography and homogeneous by NMR and TLC analysis.
However, a slight green tint to 14 led us believe that it
might contain an impurity that was responsible for the
poor behavior in the hydrogenation/hydrogenolysis. Re-
peated flash chromatography failed to remove this green
tint. Accordingly, an ether solution of freshly chromato-
graphed 14 was stirred with potassium carbonate and
Pd/C for 2 h. After two cycles, 14 was a clear, colorless
oil (66% overall yield from 13). Hydrogenation/hydro-
genolysis of 14 (colorless) with Pearlman’s catalyst19 and
hydrogen afforded saturated piperidine-secondary amine
in 74% yield. The enantiomer of this compound was
previously prepared by Momose and co-workers via a
different route.8b Treatment of this amino ester with
trimethylaluminum8b,20 afforded lactam 15 in 74% yield.
Reduction of 15 with lithium aluminum hydride afforded
(-)-indolizidine 167B in 78% yield.21,8b Our synthetic
failed to afford the corresponding lactones (4, R′ )
CO2t-Bu).3,10a Our synthesis of the indolizidine alkaloid
(+)-monomorine3c offered a partial solution to this prob-
lem. N-Benzylpipecolic ester 6b (R ) CH3) was prepared
via removal of the BOC-protecting group in 3 (R ) CH3)
followed by reductive amination of the resulting primary
amine, lactonization to afford 4b (R ) CH3), followed by
enolization and Claisen rearrangement. The underlying
goal of the synthesis of (-)-indolizidine 167B was to
develop a more direct synthesis of N-benzylpipecolic
esters that does not involve a deprotection-reprotection
scheme.
Tota l Syn th esis of (-)-In d olizid in e 167B. In an
effort to circumvent the extra steps required to exchange
the BOC protecting group for a benzyl group, we elected
to examine a benzoyl group in lieu of a BOC group. The
effect of this change on the one-pot DIBAL-H-Grignard
reaction11,12 remained to be seen. If successful, a simple
lithium aluminum hydride reduction of the amide would
then lead to the desired N-benzylamine.
The synthesis of (-)-indolizidine 167B began with the
known13 N-benzoyl ethyl ester of D-norvaline 8 which was
treated with DIBAL-H followed by vinylmagnesium
chloride to afford 9 in 53% yield as an 8:1 mixture of
diastereomers (Scheme 2). The yield of this reaction was
clearly dependent upon the quality of the Grignard
reagent. Reproducible results were obtained with Grig-
nard reagent freshly prepared from vinyl chloride and
(14) Ramsden, H. E.; Leebrick, J . R.; Sanders, D.; Rosenberg, S. D.;
Miller, E. H.; Walburn, J . J .; Balint, A. E.; Cserr, R. J . Org. Chem.
1957, 22, 1602-1607.
(15) Dellaria, J . F., J r.; Santarsiero, B. D. J . Org. Chem. 1989, 54,
3916-3926.
(16) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(17) D’Incan, E.; Seyden-Penne, J . Synthesis 1975, 516-517.
(18) Corey, E. J .; Smith, J . G.; J . Am. Chem. Soc. 1979, 101, 1038-
1039. Similar problems with a palladium-catalyzed hydrogenation
following a Swern oxidation have been reported: Kocienski, P. J .
Protecting Groups; George Thieme Verlag: New York, 1994; p 137.
(19) Pearlman, W. M. Tetrahedron Lett. 1967, 1663-1664.
(20) Weinreb, S. M.; Lipton, M. F.; Basha, A. Org. Synth. 1980, 59,
49-53.
(13) (a) Synthesis of norvaline ethyl ester: Titouani, S. L.; Lavergne,
J . P.; Viallefont, PH. Tetrahedron 1980, 36, 2961-2965. (b) Rotation
and alternative synthesis of L-(+)-norvaline ethyl ester: Fu, S.-C. J .;
Birnbaum, S. M.; Greenstein, J . P. J . Am. Chem. Soc. 1954, 76, 6054-
6058. (c) Synthesis of N-benzoyl D-norvaline ethyl ester: Karrer, V.
P.; Schneider, H. Helv. Chim Acta 1930, 13, 1281-1291.
(21) The synthetic material showed identical 1H NMR and 13C NMR
spectra, MS data, and rotation to that reported for the natural product.

Notes
J . Org. Chem., Vol. 62, No. 24, 1997 8551
material showed spectral characteristics (1H NMR,8d,f 13
C
rate of addition was adjusted as needed to maintain a temper-
ature of -75 °C. The resulting solution was stirred for 20 min.
Freshly prepared vinylmagnesium chloride14 (7.0 mL of a 0.88
M solution in THF, 6.16 mmol) was then added slowly, again
the rate of addition was continuously adjusted to maintain a
temperature of -75 °C. Immediately after the addition was
complete, the reaction flask was placed in an ice bath and
allowed to slowly warm to rt. After stirring for 18 h, the reaction
mixture was slowly poured into stirring 1 N HCl (25 mL) at 0
°C. Aqueous workup (ether, K2CO3) afforded 530 mg of crude
product. Flash chromatography (1:1 hexanes/ethyl acetate)
afforded 9 (255 mg, 53%, 8:1 mixture of diastereomers, 1H NMR)
as a white solid: mp 87-89 °C; 1H NMR (300 MHz, CDCl3, major
diastereomer) δ 7.75 (d, J ) 7.1 Hz, 2H), 7.45 (m, 3H), 6.31 (d,
J ) 8.3 Hz, 1H), 5.93 (ddd, J ) 17.2, 10.5, 5.7 Hz, 1H), 5.32 (d,
J ) 17.2 Hz, 1H), 5.19 (d, J ) 10.5 Hz, 1H), 4.28 (m, 1H), 4.22-
4.12 (m, 1H), 2.05 (bs, 1H), 1.73-1.58 (m, 2H), 1.51-1.39 (m,
2H), 0.96 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, major
diastereomer) δ 168.0, 138.4, 134.6, 131.4, 128.5, 127.0, 116.0,
74.2, 53.7, 34.1, 19.5, 14.0; IR (CCl4) 3616, 3443, 2962, 2934,
1655, 1516, 1274 cm-1; MS (Cl, NH3) m/z 234 (MH+, 100), 216
(50), 176 (55), 122 (56), 105 (95); HRMS calcd for C14H20NO2 (M
+ H) 234.1494, found 234.1487; [R]25D + 33.5° (c ) 0.0498, CH2-
Cl2).
NMR,8d,f and EI mass spectrum8d) identical with those
reported by other workers.
Con clu sion
The synthesis of (-)-indolizidine 167B was accom-
plished in nine steps (5.8% overall yield) from amino ester
8. This synthesis demonstrates the utility of our Claisen
rearrangement strategy for the synthesis of enantiopure
indolizidine alkaloids from readily available R-amino
acids. In addition, the synthesis of (-)-indolizidine 167B
illustrates the concise route to N-benzylpipecolic esters
that we have developed. Work is currently ongoing to
apply this methodology to the synthesis of other natural
products.
Exp er im en ta l Section
Gen er a l In for m a tion . Capillary GC was carried out using
an FID detector on a 25 m HP-101 (methyl silicone) column.
The following standard GC parameters were used unless
indicated otherwise: flow rate ) 60 mL/min; injector tempera-
ture ) 200 °C; detector temperature ) 280 °C; temperature
program ) 40 to 280 °C at 18 °C/min, initial time ) 1 min. The
molarity indicated for vinylmagnesium chloride was established
by titration with 2,2′-dipyridyl/sec-butyl alcohol in methylene
chloride.22 In cases where synthetic intermediates or products
were isolated by “aqueous workup (aqueous solution, organic
solvent, drying agent)”, the procedure was to quench the reaction
mixture with the indicated aqueous solution, dilute with the
indicated organic solvent, separate the organic layer, extract the
aqueous layer several times with the organic solvent, dry the
combined organic extracts over the indicated drying agent, and
remove the solvent under reduced pressure (water aspirator)
with a rotary evaporator. All reactions were run under an
atmosphere of nitrogen in flame dried glassware.
(5R,6R)-6-Eth en yl-4-(p h en ylm eth yl)-5-p r op yl-3,4,5,6-tet-
r a h yd r o-2H-1,4-oxa zin -2-on e (10). A solution of 9 (8:1 mix-
ture of diastereomers, 1.90 g, 8.13 mmol) in THF (25 mL) was
added dropwise to a stirring suspension of LiAlH4 (1.24 g, 32.5
mmol) in THF (40 mL) at 0 °C. The resulting suspension was
refluxed for 3 h and cooled to 0 °C, and H2O (1.25 mL), 15%
NaOH (1.25 mL), and H2O (3.75 mL) were sequentially added.
The resulting suspension was allowed to warm to rt, stirred for
1 h, filtered through Celite, and concentrated to afford 2.21 g of
crude product as a yellow oil. Flash chromatography (1:3
hexanes/ethyl acetate, 4% triethylamine) afforded (3R,4R)-3-
hydroxy-4-[N-(phenylmethyl)amino]-1-heptene (1.47 g, 82%, 8:1
mixture of diastereomers, 1H NMR) as a pale yellow oil: 1H NMR
(300 MHz, CDCl3, major diastereomer) δ 7.41-7.25 (m, 5H), 5.84
(ddd, J ) 16.9, 10.4, 6.2 Hz, 1H), 5.35 (d, J ) 17.1 Hz, 1H), 5.20
(d, J ) 10.4 Hz, 1H), 3.86-3.79 (m, 2H), 3.80 (partially obscured
ABq, J ) 12.7 Hz, ∆ν ) 27.1 Hz, 2H), 2.54 (dt, J ) 6.6, 5.1 Hz,
1H), 1.61-1.22 (m, 5H), 0.94 (t, J ) 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3, major diastereomer) δ 140.1, 139.4, 128.4, 128.0,
127.1, 116.3, 73.6, 61.2, 51.5, 33.0, 19.0, 14.3; IR (neat) 3612,
3363, 3030, 3007, 2961, 2874, 1455, 1089, 1029 cm-1. Freshly
distilled phenyl R-bromoacetate (1.86 g, 8.59 mmol) in CH3CN,
(25 mL) was added to a stirred solution of the above N-
benzylamine (1.56 g, 7.16 mmol) and diisopropylethylamine (5.1
mL, 29 mmol) in CH3CN (75 mL) at 0 °C.15 The resulting
solution was warmed to rt and stirred for 12 h. Diethylamine
(0.296 mL, 2.86 mmol) was then added to remove excess phenyl
R-bromoacetate and the resulting solution was allowed to stir
for 1 h. The reaction mixture was concentrated (0.01 mmHg,
30 min) and the resulting oil was diluted with ether (30 mL)
and stirred for 5 min to precipitate amine salts. The organic
layer was then decanted away from the precipitate. The
precipitate was washed with ether (4 × 30 mL) and the combined
ether solutions were concentrated to afford crude lactone. Flash
chromatography (8:1 hexanes/ethyl acetate) afforded 2.95 g of
lactone 10 contaminated with phenol. The phenol was insepa-
rable from 10 by chromatography but could be removed by
conversion to phenyl acetate followed by flash chromatography.
Acetic anhydride (0.600 mL, 6.33 mmol) was added to a stirred
solution of the above crude lactone (2.95 g) in pyridine (10 mL)
at rt. The resulting solution was allowed to stir for 4 h and then
concentrated. Flash chromatography (4:1 hexanes/ethyl acetate)
afforded lactone 10 (1.10 g, 60%) as a clear oil (11:1 mixture of
diastereomers by capillary GC analysis, major tR ) 37.3 min,
minor tR ) 37.7 min): 1H NMR (300 MHz, CDCl3, major
diastereomer) δ 7.31 (m, 5H), 5.98 (ddd, J ) 17.1, 10.4, 6.7 Hz,
1H), 5.42 (d, J ) 16.8 Hz, 1H), 5.34 (d, J ) 10.1 Hz, 1H), 4.72 (t,
J ) 6.2 Hz, 1H), 3.67 (ABq, J ) 13.1 Hz, ∆ν ) 21.8 Hz, 2H),
3.36 (ABq, J ) 18.0 Hz, ∆ν ) 24.6 Hz, 2H), 2.72 (q, J ) 5.9 Hz,
1H), 1.65-1.38 (m, 4H), 0.94 (t, J ) 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3, major diastereomer) δ 168.6, 137.2, 135.1, 128.7,
128.5, 127.6, 118.9, 81.8, 59.6, 57.3, 50.9, 28.0, 19.1, 14.1 IR
(neat) 2960, 2933, 1748, 1212 cm-1; MS (EI, 50 eV) m/z 259 (M+,
N-P h en ylca r bon yl-D-Nor va lin e Eth yl Ester (8). Thionyl
chloride (28.9 mL, 388 mmol) was added dropwise over 10 min
to absolute ethanol (325 mL) at 0 °C.13a D-Norvaline (6.49 g,
10.2 mmol) was added and the resulting solution was refluxed
for 10 h. The solution was then concentrated in vacuo. Aqueous
workup (saturated aqueous NaHCO3/NH4OH, 5/1, v/v, 50 mL;
benzene, K2CO3) afforded D-norvaline ethyl ester (7.85 g, 98%)
as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 4.17 (q, J ) 7.1
Hz, 2H), 3.42 (t, J ) 5.6 Hz, 1H), 1.85-1.36 (m, 6H), 1.26 (t, J
) 7.1 Hz, 3H), 0.90 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 176.3, 60.7, 54.3, 37.1, 18.9, 14.3, 13.8; IR (neat) 3383,
3317, 2962, 2875, 1733 cm-1; [R]25D -10.0° (c ) 0.0245, 5 N HCl),
lit.13b [R]25 +9.5° (c ) 2, 5 N HCl) for L-norvaline ethyl ester.
D
D-Norvaline ethyl ester (1.48 g, 10.2 mmol) was dissolved in CH2-
Cl2 (20 mL) and the resulting solution was cooled to 0 °C.
Triethylamine (4.20 mL, 33.1 mmol) and benzoyl chloride (2.97
mL, 25.6 mmol) were added sequentially, and the resulting
solution was warmed to rt and stirred for 24 h. The reaction
mixture was then poured into pH 7 phosphate buffer (50 mL).
Aqueous workup (CH2Cl2, K2CO3) afforded 2.45 g of crude
product. Flash chromatography (3:1 hexanes/ethyl acetate)
followed by crystallization from hexanes (200 mL, stirred 2 h at
-25 °C) afforded 8 (2.36 g, 94%) as white needles: mp 58-59
°C, (lit.13c mp 59 °C); 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J )
7.0, Hz, 2H), 7.48 (m, 3H), 6.68 (d, J ) 6.8 Hz, 1H), 4.90-4.80
(m, 1H), 4.25 (q, J ) 7.1 Hz, 2H), 2.05-1.35 (m, 4H), 1.30 (t, J
) 7.1 Hz, 3H), 0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 172.8, 167.0, 134.1, 131.7, 128.6, 127.0, 61.5, 52.5, 34.8,
18.6, 14.2, 13.7; IR (CCl4) 3694, 3437, 2965, 1732, 1662, 1516,
1485 cm-1; [R]25 +15.9 ° (c ) 0.014, abs EtOH), lit.13c [R]19
D
D
+7.98 ° (c ) 0.0138, “alcoholic solution, d ) 0.8”).
(3R,4R)-3-Hyd r oxy-4-[(N-p h en ylca r bon yl)a m in o]-1-h ep -
ten e (9). A solution of DIBAL-H (0.73 mL, 4.1 mmol) in hexanes
(0.73 mL) was added dropwise over 10 min to a stirried -78 °C
solution of ester 8 (510 mg, 2.05 mmol) in CH2Cl2 (7 mL). The
(22) Ellison, R. A.; Griffin, R.; Kotsonis, F. N. J . Organomet. Chem.
1972, 36, 209-213.

8552 J . Org. Chem., Vol. 62, No. 24, 1997
Notes
26), 175 (17), 160 (14), 146 (11), 91 (100); HRMS calcd for C16H21
-
1454, 1180 cm-1; MS (DCI/NH3) m/z 314 (MH+, 100), 270 (45),
91 (44); HRMS calcd for C20H28NO2 (M + H) 314.2110, found
NO2 259.1572, found 259.1579; [R]25 +59.46° (c ) 0.0124,
D
CHCl3).
314.2120; [R]25 -97.3° (c ) 0.0203, CH2Cl2).
D
(2R,6R)-6-(Hyd r oxym eth yl)-N-(p h en ylm eth yl)-2-p r op yl-
1,2,5,6-tetr a h yd r op yr id in e (13). Triisopropylsilyl trifluoro-
methanesulfonate (1.45 mL, 5.37 mmol) was added to a stirred
solution of lactone 10 (1.10 g, 4.24 mmol) and triethylamine (1.4
mL, 9.9 mmol) in benzene (20 mL) at rt. The mixture was
allowed to stir for 18 h. The reaction flask was immersed in an
ice bath, and ether (5 mL) and LiAlH4 (434 mg, 1.14 mmol) were
added. The mixture was then warmed to rt, stirred for 2 h, and
cooled to 0 °C, and H2O (0.45 mL), 15% NaOH (0.45 mL), H2O
(1.35 mL) were sequentially added. The resulting suspension
was stirred for 2 h, filtered through Celite, and concentrated to
afford 1.90 g of a pale yellow oil. Flash chromatography (4:1
hexanes/ethyl acetate) afforded 13 (819 mg, 79%) as a clear oil:
1H NMR (300 MHz, CDCl3) δ 7.50-7.35 (m, 5H), 5.81-5.73 (m,
1H), 5.69 (m, 1H), 3.81 (s, 2H), 3.44 (partially obscured q, J )
10.1 Hz, 1H), 3.38 (m, 1H), 3.12-3.00 (m, 2H), 2.90 (bs, 1H),
2.33 (dm, J ) 17.8, 1H), 1.74 (dm, J ) 17.7 Hz, 1H), 1.55-1.21
(m, 4H), 0.82 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
140.1, 128.9, 128.8, 128.4, 127.2, 122.6, 63.0, 60.4, 57.3, 56.4,
39.0, 22.2, 20.1, 14.0; IR (neat) 3027, 2956, 2931, 2872, 1453,
1027 cm-1; MS (CI/NH3) m/z 246 (MH+, 49), 214 (91), 202 (71),
91 (100); HRMS calcd for C16H24NO (M + H) 246.1858, found
(5R,9R)-5-P r op ylin d olizid in -3-on e (15). To a solution of
14 (100 mg, 0.318 mmol) in absolute ethanol (3 mL) was added
Pearlman’s catalyst19 Pd(OH)2/C (10%, 60.0 mg). The mixture
was pressurized in a Parr hydrogenator to 30 PSI, heated to 60
°C, and shaken for 1.5 h. After cooling, the reaction mixture
was diluted with CHCl3 (10 mL) and saturated aqueous Na2-
CO3 (10 mL). Aqueous workup (CHCl3, K2CO3) afforded (2R,6R)-
6-[(3-ethoxycarbonyl)propyl]-2-propylpiperidine (53.3 mg, 74%)
as a clear oil: 1H NMR (300 MHz, CDCl3) δ 4.10 (q, J ) 7.1 Hz,
2H), 2.51-2.39 (m, 2H), 2.34 (t, J ) 7.7 Hz, 2H), 1.80-1.56 (m,
6H), 1.40-1.27 (m, 5H), 1.23 (t, J ) 7.1 Hz, 3H), 1.07-0.93 (m,
2H), 0.88 (t, J ) 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6,
60.3, 56.7, 56.3, 39.6, 32.6, 32.4, 32.3, 31.0, 24.7, 19.1, 14.2; IR
(CCl4) 2930, 2873, 1737, 1300, 1190, 1110 cm-1; [R]25D -1.09° (c
) 0.0128, CH2Cl2). Trimethylaluminum20 (0.14 mL of a 2.0 M
solution in benzene, 0.28 mmol) was added dropwise to a stirred
solution of the above secondary amine (53 mg, 0.23 mmol) in
benzene (12 mL) at 0 °C. The resulting solution was refluxed
for 43 h, cooled to rt, and poured into stirring 1 N HCl (25 mL).
Aqueous workup (CH2Cl2, K2CO3) afforded crude product (50.6
mg) as an oil. Flash chromatography (2:3 hexanes/ethyl acetate)
afforded 15 (31.0 mg, 74%) as a clear, colorless oil: 1H NMR
(300 MHz, CDCl3) δ 3.42-3.31 (m, 1H), 3.22-3.11 (m, 1H), 2.40-
2.26 (m, 3H), 2.14-2.00 (m, 1H), 1.85-1.58 (m, 4H), 1.57-1.19
(m, 6H), 0.91 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
174.2, 59.6, 57.3, 34.5, 31.9, 31.8, 29.5, 25.1, 22.7, 20.1, 14.1; IR
(CCl4) 2935, 2873, 2861, 1693, 1423, 1251 cm-1; MS (EI+, 20
eV) m/z 181 (M+, 7), 139 (16), 138 (100), 110 (6); HRMS calcd
for C11H19NO 181.1467, found 181.1465; [R]25D -27.6° (c ) 0.021,
246.1862; [R]25 -76.1° (c ) 0.0117, CHCl3). Anal. Calcd for
D
C
16H23NO: C, 78.00; H, 9.82; N, 5.69. Found: C, 77.98; H, 9.53;
N, 5.58.
E- a n d Z-(2R,6R)-6-[(3-Eth oxyca r bon yl)p r op en -1-yl]-1-
(p h en ylm eth yl)-2-p r op yl-1,4,5,6-tetr a h yd r op yr id in e (14).
A solution of DMSO (0.27 mL, 3.9 mmol) in CH2Cl2 (2 mL) was
added to a stirred solution of oxalyl chloride (0.20 mL, 2.3 mmol)
in CH2Cl2 (4 mL) at -78 °C over 5 min.16 A solution of alcohol
13 (189 mg, 0.770 mmol) in CH2Cl2 (4 mL) was added and the
resulting solution was stirred for 30 min at -78 °C. Triethyl-
amine (0.75 mL, 5.4 mmol) in CH2Cl2 (2 mL) was then added,
and the reaction mixture was allowed to warm to rt over 20 min
and then poured into stirring H2O (10 mL). Aqueous workup
(CH2Cl2, K2CO3) and concentration afforded the unstable alde-
hyde, which was immediatly diluted with THF (5 mL). KH (177
mg of a 35% w/w solution in mineral oil, 1.54 mmol) was washed
with hexanes (2 × 10 mL) and then diluted with THF (25 mL).
Triethyl phosphonoacetate (0.46 mL, 2.3 mmol) was added and
the mixture stirred at rt for 30 min and then cooled to -78 °C.
The THF solution of the above aldehyde was slowly added and
the reaction mixture was allowed to warm to rt and stirred for
7 h. The mixture was poured into stirring H2O (25 mL).
Aqueous workup (ethyl acetate, K2CO3) afforded crude product
(579 mg) as a brown oil. Flash chromatography (95:5 hexanes/
ethyl acetate) afforded 14 (179 mg, 74%) as a bright green oil.
This material contained a minor impurity that poisoned the Pd
catalyst in the next step.18 The impurity was removed by
stirring a solution of 14 (bright green oil, 179 mg, 0.570 mmol),
K2CO3, (100 mg), and Pd/C (5%, 100 mg) in ether (12 mL) for 2
h. The reaction mixture was filtered and the solids were rinsed
with CHCl3 (6 × 25 mL). The combined washings were
concentrated and the procedure was repeated one additional
CH2Cl2), lit.8b [R]25 +28.1° (c ) 1.125, CH2Cl2) for (+)-enanti-
D
omer.
(-)-In d olizid in e 167B (1). LiAlH4 (11.3 mg, 0.29 mmol) was
added to a solution of 20 (14 mg, 0.077 mmol) in ether at 0 °C.
The resulting suspension was refluxed for 3 h, and cooled to 0
°C, and H2O (0.011 mL), 15% NaOH (0.011 mL), H2O (0.033 mL)
were sequentially added. The resulting suspension was stirred
for 20 min, filtered through Celite, and concentrated to afford 1
(10.0 mg, 78%) as a gold oil: 1H NMR (300 MHz, CDCl3) δ 3.26
(dt, J ) 1.8, 8.6 Hz, 1H), 1.95 (q, J ) 9.0 Hz, 1H), 1.88-1.52 (m,
8H), 1.50-1.06 (m, 8H), 0.90 (t, J ) 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 65.0, 63.7, 51.6, 36.9, 31.0, 30.9, 30.6, 24.7, 20.4,
19.1, 14.5; IR (CCl4) 2933, 2873, 2859, 1458, 1381, 1177, 1127
cm-1; MS (EI, 20 eV) m/z 167 (M+, 9), 166 (5), 125 (25), 124 (100),
96 (26), 70 (8); HRMS calcd for
C11H21N 167.1674, found
167.1671; [R]25D -116.6° (c ) 0.0042, CH2Cl2), lit.13f [R]D -111.3°
(c ) 1.3, CH2Cl2).
Ack n ow led gm en t. We would like to thank Dr.
J ames Guy Breitenbucher for early work on this project.
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society, for partial support of this research and
S.R.A. acknowledges an A. P. Sloan Foundation Re-
search Fellowship (1993-1997).
1
time to afford ester 14 (159 mg, 66%; 46:54, Z/E by H NMR) as
a clear oil: 1H NMR (300 MHz, CDCl3, 46:54 Z/E mixture of
isomers) δ 7.30 (m, 10H), 6.83 (dd, J ) 15.8, 8.3 Hz, 1H), 6.11
(dd, J ) 11.4, 9.6 Hz, 1H), 5.70 (m, 5H), 4.45 (m, 1H), 4.12 (q, J
) 7.1 Hz, 4H), 3.76 (s, 4H), 3.45 (br dd J ) 13.9, 7.01 Hz, 1H),
3.38 (br dd J ) 13.6, 6.0 Hz, 1H) 3.13 (bs, 2H), 2.10 (bs, 4H),
1.65-1.19 (m, 14H), 1.25 (m, 6H); 13C NMR (75 MHz, CDCl3,
46:54 Z/E mixture of isomers) δ 166.3, 166.1, 152.6, 151.3, 141.0,
140.1, 130.1, 129.8, 128.6, 128.3, 128.1, 127.9, 126.6, 126.4, 122.7,
122.3, 120.9, 119.1, 60.2, 60.0, 59.3, 58.7, 58.1, 57.3, 56.7, 36.4,
31.3, 29.9, 18.7, 18.1, 14.3; IR (neat) 3029, 2957, 1720, 1650,
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for compounds 1 (-)-indolizidine 167B, 8, 9, 10, 13,
1
14, and 15, a procedure for the synthesis of E-14, and H NMR
spectral data (16 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O970591K