Asymmetric total synthesis of (-)-alkaloid 223A and its 6-epimer

Article abstract of DOI:10.1021/jo0341261

The enantiopure γ-amino alcohols 7 and 18 are prepared by using the diastereoselective Michael addition of lithium N-benzyl (R)-α-methylbenzylamide to α,β-unsaturated esters as a key step. The Michael addition of 7 or 18 to an alkynone 8 followed by an in

Full text of DOI:10.1021/jo0341261

Asym m etr ic Tota l Syn th esis of (-)-Alk a loid 223A a n d Its 6-Ep im er
Xiaotao Pu and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
madw@pub.sioc.ac.cn
Received J anuary 29, 2003
The enantiopure γ-amino alcohols 7 and 18 are prepared by using the diastereoselective Michael
addition of lithium N-benzyl (R)-R-methylbenzylamide to R,â-unsaturated esters as a key step.
The Michael addition of 7 or 18 to an alkynone 8 followed by an intramolecular cyclization afford
the cyclic enamine 10 or 20, which are subjected to the diastereoselective hydrogenation, and the
subsequent transformations provide 6-epi-alkaloid 223A and alkaloid 223A, respectively.
In tr od u ction
From the different species of alkaloid-containing
anurans at least 40 indolizidines have been isolated. In
the structural view, most of them are 3,5- or 5,8-di-
substituted indolizidines.1,2 The interesting biological
activities displayed by these alkaloids such as potent and
noncompetitive block action for sodium ion influx, to-
gether with the limited amounts isolated from nature,
have prompted intensive synthetic studies toward these
compounds during the past decades.1,2 In 1997, Daly and
co-workers reported the discovery of alkaloid 223A, the
first trisubstituted indolizidine that was isolated from
1
dendrobatid frogs.1a By GC-MS, GC-FTIR, and H NMR
spectral studies, the structure of this compound was
established as (5R,6S,8R,9S)- or (5S,6R,8S,9R)-6,8-di-
ethyl-5-propylindolizidine 2 (Figure 1).1a Very recently,
its stereochemistry was revised through total synthesis
to the (5R*,6R*,8R*,9S*) form (Figure 1, compound 1).3
During the studies on the synthesis of natural alkaloids
from enantiopure â-amino esters,4 we became interested
in the synthesis of this natural indolizidine. The inves-
tigations thus undertaken are described here.
F IGURE 1. Structures and retrosynthetic analysis of alkaloid
223A and its 6-epimer.
a key step, while the intermediate B could be obtained
through a Michael addition of a γ-amino alcohol 7 to an
alkynone 8 and the subsequent intramolecular cycliza-
tion.
Since our synthetic studies started before the appear-
ance of its structural revision, the proposed structure 2
of the alkaloid 223A was chosen as our target molecule
initially. Our synthetic strategy was illustrated in Figure
1: the indolizidine 2 could be assembled from a cyclic
enamine B using a diastereoselective hydrogenation as
Resu lts a n d Discu ssion s
As shown in Scheme 1, the required γ-amino alcohol 7
was synthesized from tert-butyl 2-hexenoate 3. Diaster-
eoselective Michael addition of lithium amide generated
from N-benzyl (R)-R-methylbenzylamine to this R,â-
unsaturated ester afforded â-amino ester 4.5 After hy-
drogenolysis of 4 the free amino group was reprotected
with PhCOCl to provide the amide 5. Alkylation of 5 with
ethyl iodide produced 6 in greater than 96% de deter-
mined by HPLC.6 Next, treatment of 6 with LAH to
reduce both the ester and the amide moieties followed
by Pd(OH)2/C-catalyzed hydrogenolysis to remove the
newly formed benzyl group yielded the amino alcohol 7.
The Michael addition of 7 to the alkynone 8 worked
well to provide the desired enamine 9 in a mixture of
* Corresponding author.
(1) (a) Garraffo, H. M.; J ain, P.; Spande, T. F.; Daly, J . W. J . Nat.
Prod. 1997, 60, 2-5. (b) Daly, J . W.; Garraffo, H. M.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon Press: New York, 1999; Vol. 13, pp 1-161. (c) Daly, J . W.
Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9-13.
(2) For reviews, see: (a) Mitchinson, A.; Nadin, A. J . Chem. Soc.,
Perkin Trans. 1 2000, 2862-2892. (b) Michael, J . P. Nat. Prod. Rep.
1993, 51-72. (c) Michael, J . P. Nat. Prod. Rep. 1994, 17-39.
(3) Toyooka, N.; Fukutome, A.; Nemoto, H.; Daly, J . W.; Spande, T.
F.; Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4, 1715-1717.
(4) (a) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927-3929. (b) Ma, D.;
Xia, C.; J iang, J .; Zhang, J . Org. Lett. 2001, 3, 2189-2191. (c) Wang,
Y.; Ma, D. Tetrahedron: Asymmetry 2001, 12, 725-729. (d) Ma, D.;
Sun, H. J . Org. Chem. 2000, 65, 6009-6016. (e) Ma, D.; Sun, H. Org.
Lett. 2000, 2, 2503-2505. (f) Ma, D.; Sun, H. Tetrahedron Lett. 2000,
41, 1947-1950. (g) Ma, D.; Sun, H. Tetrahedron Lett. 1999, 40, 3609-
3612. (h) Ma, D.; Zhang, J . Tetrahedron Lett. 1998, 39, 9067-9068.
(5) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183-186.
(6) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28, 3103-
3106.
10.1021/jo0341261 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003
4400
J . Org. Chem. 2003, 68, 4400-4405

Asymmetric Total Synthesis of (-)-Alkaloid 223A
SCHEME 1
SCHEME 3
SCHEME 2
SCHEME 4
acetonitrile and water with the assistance of K2CO3. It
was found that the reaction condition of this step was
very critical, because when other solvents such as ethanol
and DMF or bases were used low yields were observed.7
Treatment of 9 with I2/Ph3P/imidazole in methylene
chloride provided the corresponding iodide,8 which was
refluxed in acetonitrile under the action of triethylamine
to deliver the cyclic enamine 10. Next, Pt2O-catalyzed
hydrogenation of 10 was carried out in acetic acid at room
temperature and gave the tetrasubstituted piperidine 11
as a single isomer! Its stereochemistry was established
by NOE correlations observed as indicated in Scheme 2.
With the piperidine 11 in hand, we finished the total
synthesis of 2 by the following transformations (Scheme
3): (1) hydrogenolysis of 11 followed by cyclization medi-
ated with I2/Ph3P/imidazole provided indolizidine 12; (2)
isomerization of the 8-acteyl group in 12 from R-form to
the thermodynamically stable â-form with sodium meth-
oxide afforded 13; (3) formation of 1,3-dithiolane gave 14;
and (4) hydrogenolysis of 14 with Raney-Ni furnished 2.
During the studies on the synthesis of 2, the structural
revision report for the alkaloid 223A was disclosed.3 This
result prompted us to design a new protocol for synthe-
sizing the alkaloid 223A as illustrated in Figure 1.
Obviously, the first problem for us was how to prepare
the amino alcohol 18. We decided to solve this problem
by using Davies’s procedure.9 Accordingly, esterification
of commercially available acid 15 with 2-methylpropene
provided R,â-unsaturated ester 16 (Scheme 4). After
Michael addition of lithium N-benzyl (R)-R-methylben-
zylamide to 16, the resultant anion was tripped with a
sterically hindered proton source to produce 17 in 67%
yield and greater than 98% de determined by HPLC.9 It
is notable that 3 equiv of lithium amide was necessary
for giving satisfactory yield in this step, probably due to
the poor reactivity of 16. Next, LAH reduction of 17
followed by Pd(OH)2/C-catalyzed hydrogenolysis gave the
γ-amino alcohol 18 in 95% yield. Subjecting 18 to the
Michael addition/cyclization reaction sequence as men-
tioned above provided the cyclic enamine 20. After hydro-
genation of 20, three isomers 21 (34% yield), 22 (33%
yield), and 23 (22% yield) were isolated and their ster-
(7) Kirchanov, A. A.; Zanina, A. S.; Kotlyare-Vskii, L. L. Zh. Org.
Khim. 1984, 21, 1406-1408.
(8) Nicolaou, K. C.; J ung, J .; Yoon, W. H.; Fong, K. C.; Choi, H. S.;
He, Y.; Zhong, Y.; Baron, D. S. J . Am. Chem. Soc. 2002, 124, 2183-
2189.
(9) Davies, S. G.; Ichihara, O.; Walters, I. S. J . Chem. Soc., Perkin
Trans. 1 1994, 1141-1147.
J . Org. Chem, Vol. 68, No. 11, 2003 4401

Pu and Ma
TABLE 1. NMR Sp ectr a l Da ta for DCl Sa lts of th e
Alk a loid 223A 1 a n d Its 6-Ep im er 2 a t 300 MHz (1H)
in D2O
H
1
2
1R
1â
2R
2â
3R
3â
5
1.56 (m)
2.28 (m)
1.97 (m)
1.88 (m)
1.52 (m)
2.16 (m)
1.90 (m)
1.82 (m)
3.58 (dt, J ) 9.6, 2.7 Hz) 3.48 (dt, J ) 9.3, 2.6 Hz)
2.95 (q, J ) 9.1 Hz) 2.87 (q, J ) 9.3 Hz)
3.15 (dt, J ) 11.0, 3.6 Hz) 2.74 (dd, J ) 10.8, 3.9 Hz)
6
1.93 (m)
2.04 (m)
1.20 (m)
1.55 (m)
1.37 (m)
1.78 (m)
0.85 (q, J ) 12.0 Hz)
1.46
7R
7â
8
9
2.86 (dt, J ) 11.5, 6.0 Hz) 2.78 (dt, J ) 11.5, 6.3 Hz)
10
11
13
15
1.68, 1.52
1.34, 1.15
1.44, 1.12
1.39, 1.17
1.60, 1.48
1.28, 1.14
1.36, 1.12
1.37, 1.02
F IGURE 2. Stereochemical course of the hydrogenation of
10 or 20.
12, 14, 16 0.81, 0.84, 0.86
0.68, 0.71, 0.73
SCHEME 5
were assigned. The 1H NMR spectroscopic data for 1 and
2 were summarized in Table 1. As is apparent, marked
differences in chemical shift between the alkaloid 223A
and its 6-epimer at the H-5, H-6, and H-7 positions were
observed.
In summary, we have developed two very efficient
protocols to synthesize the alkaloid 223A (11 linear steps
and 11.5% overall yield) and its 6-epimer (14 linear steps
and 14.4% overall yield). Further application of this
strategy to the synthesis of other related alkaloids is in
hand.
eochemistry was established by NOE correlations ob-
served as indicated in Scheme 4. The piperidine 23 might
result from the isomerization of 22, which was proved
by complete conversion of 22 to 23 upon treatment with
sodium methoxide. This conversion implied that the key
intermediate 23 could be obtained from 20 in 55% total
yield.
The different stereoselectivity displayed by hydrogena-
tion of the cyclic enamines 10 and 20 could be rational-
ized by the stereoelectronic control as outlined in Figure
2. When 10 was subjected to hydrogenation it might be
preferentially reduced via the transition-state conforma-
tion related to conformation B with two alkyl groups both
at the equatorial positions. A stereoelectronic controlled
axial addition of hydrogen from the Re face in conforma-
tion B provided 11 exclusively because in this manner a
kinetically favored chairlike transition state could be
obtained, while the addition from the Si face will be
kinetically disfavored to obtain a boatlike transition
state.10 In the case of hydrogenation of compound 20, two
major conformations C and D with similar stability
existed thereby reducing the stereoselectivity.
Exp er im en ta l Section
Gen er a l P r oced u r es. Analytically pure ethyl acetate and
methanol were used directly without further purification. CH2-
Cl2 and CH3CN were distilled from CaH2, and THF was
distilled from a deep blue ketyl prior to use. All other solvents
were reagent grade quality and used as received. All reactions
were run in flame-dried glassware under nitrogen atmosphere
unless stated otherwise.
(3R,1′R)-3-[Ben zyl(1-ph en yleth yl)am in o]h exan oic Acid
ter t-Bu tyl Ester (4). To a stirred solution of (+)-N-benzyl-
N-R-methylbenzylamine (14.9 g, 71 mmol) in 140 mL of dry
THF at 0 °C was slowly added n-BuLi (1.6 M, 44.38 mL, 71
mmol). After the mixture was stirred for 1 h, the system was
put into a dry ice/acetone bath, and a solution of tert-butyl
2-hexenoate 3 (10.5 g) in 20 mL of dry THF was added by a
syringe for about 40 min. The mixture was stirred for 30 min
at -78 °C before saturated aqueous ammonium chloride (60
mL) was added to quench the reaction. The organic layer was
separated and the aqueous layer was extracted with diethyl
ether. The combined organic layers were dried over MgSO4
and concentrated in vacuo. The residue was purified by
chromatography eluting with 1/40 ethyl acetate/petroleum
ether to give 20 g (85%) of 4 as a colorless oil. [R]15 +6 (c 0.6,
D
Transformation of 23 to the alkaloid 223A was dem-
onstrated in Scheme 5. Hydrogenolysis of 23 and subse-
quent I2/Ph3P/imidazole-mediated cyclization gave the
indolizidine 24. Finally, reduction of the ketone moiety
of 24 through the 1,3-dithiolane by Raney-Ni catalyzed
hydrogenolysis produced 1. Its analytical data were all
identical with those reported.3 On the basis of the COSY
1
EtOH); H NMR (300 MHz, CDCl3) δ 7.31 (m, 10H), 3.81 (m,
2H), 3.41 (d, J ) 14 Hz, 1H), 3.31 (m, 1H), 1.91 (ABX, J ) 9.3,
3.9 Hz, 2H), 1.22-1.59 (m, 4H), 1.39 (s, 9H), 1.30 (d, J ) 7.2
Hz, 3H), 0.89 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 172.2, 143.2, 142.1, 128.16, 128.11, 128.04, 127.92, 126.47,
126.82, 79.81, 58.39, 53.98, 50.09, 37.84, 33.43, 22.65, 28.08,
20.47, 14.06; IR (neat) 2959, 1723 cm-1; EI-MS m/z 381 (M+),
290, 238. HRMS calcd for C25H35NO2 381.2933, found 381.2981.
(3R)-3-Ben zoyla m in oh exa n oic Acid ter t-Bu t yl E st er
(5). A solution of 4 (18 g 47.3 mmol) in methanol (250 mL)
was hydrogenated over 20% palladium on charcoal (3.6 g) at
50 °C and 50 atm for 12 h. After the mixture was filtered
1
studies of 1 and 2, some signals in their H NMR spectra
(10) (a) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289-296. (b)
Deslongchamps, P. Stereoelectronic effects in organic chemistry; Per-
gamon Press: Oxford, UK, 1983.
4402 J . Org. Chem., Vol. 68, No. 11, 2003

Asymmetric Total Synthesis of (-)-Alkaloid 223A
through Celite, the filtrate was concentrated to give a colorless
oil. This residue was dried in vacuo for 5 h before it was
dissolved in 120 mL of CH2Cl2 and 27 mL of Et3N at 0 °C. To
this stirring solution was slowly added benzoyl chloride (7 mL,
60 mmol). After the resulting mixture was stirred at room
temperature for 5 h, it was washed with aqueous KOH, dried
over MgSO4, and concentrated. The residue was purified by
chromatography eluting with 1/10 ethyl acetate/petroleum
(t, J ) 8.1 Hz, 2H), 1.98 (s, 3H), 1.82 (m, 2H), 1.21-1.42 (m,
13C NMR (75 MHz, CDCl3) δ
9H), 0.89 (dt, J ) 7.0 Hz, 6H);
12.03, 13.99, 19.44, 19.98, 28.14, 28.24, 28.61, 34.73, 46.90,
53.29, 61.08, 68.99, 72.77, 93.64, 127.52, 127.59, 128.251,
138.01, 166.88, 194.16; IR (neat) 3368, 2960, 1600, 1519 cm-1
;
EI-MS m/z 361 (M+), 288, 270, 105; HRMS calcd for C22H35
-
NO3 361.2594, found 361.2570.
(5S,6R)-2-(3′-Ben zyloxy)p r op yl-3-a cyl-5-eth yl-6-p r op yl-
1,4,5,6-tetr a h yd r op yr id in e (10). To a stirred solution of 9
(542 mg, 1.5 mmol) in 15 mL of dry CH2Cl2 were added
triphenylphospine (1.18 g, 4.5 mmol), imidazole (306 mg, 4.5
mmol), and iodine (762 mg, 3 mmol) at 0 °C. After the mixture
was warmed to room temperature in about 2 h, it was diluted
with petroleum ether, and then filtered through Celite. The
filtrate was concentrated to give the corresponding iodide
compound, which was dissolved in 30 mL of dry CH3CN. After
0.23 mL of Et3N was added the resulting solution was refluxed
for about 15 h. The mixture was evaporated in vacuo and the
residue was purified via chromatography eluting with 4/1 ethyl
acetate/petroleum ether to give 410 mg (80%) of 10 as an
ether to give 12.6 g (92%) of 5. [R]15 +36.7 (c 1.35, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 7.71 (d, J ) 7.2 Hz, 2H), 7.40
(m, 3H), 7.21 (br d, J ) 7.1 Hz, 1H), 4.57 (m, 1H), 2.5 (ABX,
J ) 9.3, 3.9 Hz, 2H), 1.20-1.61 (m, 4H), 1.49 (s, 9H), 0.89 (t,
J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.46, 166.52,
134.51, 131.16, 128.32, 126.78, 81.05, 46.22, 39.53, 36.30,
27.89, 19.34, 13.76; IR (neat) 3360, 2962, 2847, 1714, 1639,
1166, 718 cm-1; EI-MS m/z 291 (M+), 248, 235, 192, 105. HRMS
calcd for C17H25NO3 291.3851, found 291.3821.
(2R,3R)-3-Ben zoyla m in o-2-eth ylh exa n oic Acid ter t-Bu -
tyl Ester (6). To a stirred solution of 5 (10 g, 34.36 mmol) in
110 mL of dry THF was slowly added LDA (2 M in THF, 38
mL, 76 mmol) by syringe at -78 °C. After the mixture was
warmed to -45 °C in about 2 h, the system was cooled to -78
°C again, and then ethyl iodide was added slowly. The
resulting mixture was stirred overnight, while warming up to
room temperature. The reaction was quenched by adding 20
mL of saturated aqueous ammonium chloride. The organic
layer was separated and the aqueous layer was extracted
several times with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated. The residue was purified
by chromatography eluting with 1/10 ethyl acetate/petroleum
ether to give 8.8 g (85%) of 6 as a white gum. The diaster-
1
unstable pale yellow oil. [R]15 +62 (c 1.68, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.31 (m, 5H), 4.72 (br s, 1H), 4.50 (d, J )
3.3 Hz, 2H), 3.5 (m, 2H), 2.9 (m, 1H), 2.8 (m, 2H), 2.5 (dd, J )
13.5, 5.7 Hz, 1H), 2.11 (s, 3H), 1.81 (m, 2H), 1.40-1.12 (m,
8H), 0.89 (dt, J ) 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
11.41, 13.94, 18.41, 24.95, 26.83, 28.25, 29.08, 31.44, 35.99,
37.05, 54.34, 69.56, 72.68, 99.06, 127.45, 127.56, 128.25,
138.336, 156.32, 195.24; IR (neat) 3316, 2962, 1648 cm-1; EI-
MS m/z 343 (M+), 328, 252, 166. HRMS calcd for C22H33NO2
343.2464, found 343.2418.
(2S,3S,5S,6R)-2-(3′-Ben zyloxy)p r op yl-3-a cyl-5-eth yl-6-
p r op ylp ip er id in e (11). Compound 10 (208 mg, 0.6 mmol) was
dissolved in glacial acid (40 mL) and hydrogenated over
platinum dioxide (10 mg) at room temperature and 1 atm for
1 h. It was then filtered through Celite, and the filtrate was
concentrated and diluted with saturated aqueous NaHCO3.
The aqueous layer was extracted several times with ethyl
acetate and the combined organic layers were dried over
MgSO4. The solution was concentrated and the residue was
purified via chromatography eluting with 4/1 ethyl acetate/
eoisomeric excess was about 96% determined by HPLC. [R]15
D
1
+57.8 (c 1.2, CHCl3); H NMR (300 MHz, CDCl3) δ 7.81 (d, J
) 6.9 Hz, 2H), 7.40 (m, 3H), 7.33 (br d, J ) 7.0 Hz, 1H), 4.41
(m, 1H), 2.40 (m, 1H), 1.41-1.62 (m, 6H), 1.46 (s, 9H), 0.89 (t,
J ) 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 175.37, 166.68,
134.46, 131.15, 128.36, 126.75, 81.23, 50.45, 49.61, 36.66,
27.97, 23.63, 19.34, 13.83, 11.83; IR (neat) 3277, 2959, 2875,
1722, 1636, 1129, 694 cm-1; EI-MS m/z 319 (M+), 276. Anal.
Calcd for C19H29NO3: C, 71.47; H, 9.1; N, 4.38. Found: C,
71.45; H, 9.26; N, 4.23.
petroleum ether to give 180 mg (86%) of 11 as a colorless oil.
(2R,3R)-3-Am in o-2-eth ylh exa n ol (7). A mixture of 6 (8.4
g, 26.3 mmol) and LiAlH4 (3.2 g) in 110 mL of dry THF was
refluxed for 12 h. The reaction was quenched by adding ethyl
acetate at room temperature. After water was added, the
organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and evaporated in vacuo to give a colorless oil.
This compound was dissolved in methanol (100 mL) and
hydrogenated over 20% palladium hydroxide on charcoal (1.5
g) at 50 °C and 50 atm for 12 h. The mixture was filtered
through Celite, and the filtrate was concentrated and purified
by a short silica column eluting with 1/5 methanol/ethyl
1
[R]15 -3.0 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) δ 7.31
D
(m, 5H), 4.48 (s, 2H), 3.44 (m, 2H), 2.72 (m, 1H), 2.51 (dt, J )
7.2, 2.9 Hz, 1H), 2.17 (dt, J ) 7.5, 3.0 Hz, 1H), 2.15 (s, 3H),
2.01 (dt, J ) 11.4, 2.1 Hz, 1H), 1.12-1.72 (m, 13H), 0.89 (dt,
J ) 7.2, 6H); 13C NMR (75 MHz, CDCl3) δ 10.33, 14.31, 18.16,
24.61, 27.07, 30.62, 31.23, 32.40, 35.26, 36.74, 49.09, 58.07,
60.20, 70.25, 72.74, 127.35, 127.50, 128.18, 138.40, 212.67; IR
(neat) 2959, 2870, 1702, 1455, 1354 cm-1; EI-MS m/z 344 (M+
- H+), 302, 254, 196; HRMS calcd for C22H35NO2 345.2630,
found 345.2591.
(5R,6S,8S,9S)-8-Acyl-6-eth yl-5-p r op ylocta h yd r oin d oli-
zin e (12). Compound 11 (180 mg, 0.52 mmol) was dissolved
in 10 mL of methanol and then hydrogenated over 20% pal-
ladium hydroxide on charcoal (60 mg) at ordinary temperature
and pressure for 12 h. The mixture was then filtered through
Celite, and the filtrate was concentrated to give a colorless
oil. To a stirred solution of the above compound in 15 mL of
dry CH2Cl2 were added triphenylphospine (352 mg), imidazole
(92 mg), and iodine (228 mg) at 0 °C. After the solution was
warmed to room temperature in about 2 h, the mixture was
washed with saturated aqueous NaHCO3. The aqueous layer
was extracted with ethyl acetate. The combined organic layers
were dried over MgSO4, and evaporated in vacuo. The residue
was purified by chromatography eluting with 4/1 ethyl acetate/
petroleum ether containing a drop of ethylamine to give 90
acetate to give 3.6 g (95%) of 7 as a colorless oil. [R]15 +25 (c
D
1.28, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.61 (br s, 3H),
3.88 (dd, J ) 11.1, 2.1 Hz, 1H), 3.58 (dd, J ) 11.1, 5.1 Hz,
1H), 3.01 (q, J ) 6.9 Hz, 1H), 1.2-1.6 (m, 7H), 0.89 (dt, J )
7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 11.79, 13.86, 18.9,
21.68, 35.75, 44.5, 54.48, 63.48; IR (neat) 3315, 2960, 1465,
1049 cm-1; EI-MS m/z 144 (M+ - H+), 128, 102, 72; HRMS
calcd for C8H19NO 145.1505, found 145.1543.
(1′R,2′R)-7-Ben zyloxy-4-[(2′-h yd r oxym eth yl-1′-p r op yl)-
bu tyl]a m in oh ep t-3-en -2-on e (9). To a mixture of 7 (993 mg,
6.85 mmol), compound 8 (1.78 g 8.22 mmol), and K2CO3 (900
mg, 6.5 mmol) in 14 mL of CH3CN was slowly added 15 drops
of water to make the system turbid, then the solution was
stirred vigorously at 50 °C for 10 h. After the mixture was
dried over MgSO4 the solvent was removed in vacuo. The
residue was purified via chromatography eluting with 3/1 ethyl
acetate/petroleum ether to give 2.1 g (88%) of 9 as a colorless
mg (73%) of 12. [R]15 -45.2 (c 0.25, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 3.15 (dt, J ) 9.0, 3.3 Hz, 1H), 2.74 (br d, J )
3.2 Hz, 1H), 2.28 (s, 3H), 2.17 (m, 1H), 2.01 (dt, J ) 13.0, 3.6
Hz, 1H), 1.91 (q, J ) 8.4 Hz, 1H), 1.21-1.50 (m, 13H), 0.89
oil. [R]15 -47.8 (c 0.85, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.31 (m, 5H), 4.92 (s, 1H), 4.51 (s, 2H), 3.50-3.61 (m, 5H), 2.31
(dt, J ) 7.2 Hz, 6H); IR (neat) 2959, 1697, 1460, 1351 cm-1
;
J . Org. Chem, Vol. 68, No. 11, 2003 4403

Pu and Ma
EI-MS m/z 238 (M+ + H+), 194; HRMS calcd for C15H27NO
(2S,3R,1′R)-3-[Ben zyl(1′-p h en ylet h yl)a m in o]-2-et h yl-
h exa n oic Acid ter t-Bu tyl Ester (17). To a stirred solution
of (+)-N-benzyl-N-R-methylbenzylamine (10.5 g, 50 mmol) in
30 mL of dry toluene was slowly added n-BuLi (1.6 M, 31 mL,
50 mmol) at 0 °C. After the mixture was stirred for 1 h, the
system was put into a dry ice/acetone bath. To this solution
was added tert-butyl 2-ethyl-2-hexenoate 16 (3.96 g 20 mmol)
in dry toluene (20 mL) by syringe over about 40 min. The
mixture was stirred for 1 h at -78 °C and then warmed to
-40 °C over 1 h. The solution was maintained at this
temperature for 1 h before it was recooled to -78 °C. Precooled
THF (-78 °C, 200 mL) was added swiftly by cannula to the
reaction mixture, which was then stirred for a further 30 min
at -78 °C. Finally, a precooled solution of 2,6-di-tert-butyl-4-
methylphenol (18 g, 100 mmol) in THF (-78 °C, 20 mL) was
added swiftly by cannula to the reaction mixture, which was
then stirred for a further 10 min at -78 °C, and warmed to
room temperature over 1 h. Evaporation of the mixture in
vacuo left a residue that was partitioned between brine and
diethyl ether and the combined organic layers were dried over
MgSO4 and the solvent removed in vacuo. The residue was
purified via chromatography eluting with 1/100 ethyl acetate/
petroleum ether to yield 5.5 g (67%) of 17 as a colorless oil.
The diastereoisomeric excess was about 98% determined by
237.2133, found 237.2174.
(5R,6S,8R,9S)-8-Acyl-6-eth yl-5-p r op ylocta h yd r oin d oli-
zin e (13). To 2 mL of dry methanol were added 2.5 mg of
sodium and a solution of 12 (25 mg) in 1 mL of dry MeOH at
room temperature. After the mixture was refluxed for about
3 h, the solvent was evaporated off. The residue was triturated
with water and extracted with ethyl acetate. The organic layer
was dried over MgSO4, and evaporated in vacuo. The residue
was purified via chromatography eluting with 1/3 to 1/1 ethyl
acetate/petroleum ether to give 20 mg (87%) of 13. [R]15D -48.7
(c 0.75, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.11 (dt, J )
8.5, 3.2 Hz, 1H), 2.41 (dt, J ) 11.0, 3.2 Hz, 1H), 2.16 (s, 3H),
2.02-1.81 (m, 4H), 1.71-1.12 (m, 12H), 0.89 (t, J ) 6.9 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 10.89, 14.64, 17.22, 22.08,
24.30, 28.73, 29.68, 32.50, 33.02, 39.15, 51.00, 55.14, 65.10,
66.52, 211.07; IR (neat) 2959 1709, 1460 cm-1; EI-MS m/z 237
(M+), 194; HRMS calcd for C15H27NO 237.2112, found 237.2130.
(5R,6S,8R,9S)-8-(2-Meth yl-[1,3]-d ith iola n -2-yl)-6-eth yl-
5-p r op ylocta h yd r oin d olizin e (14). A solution of compound
13 (10 mg, 0.042 mmol) and ethane-1,2-dithiol (0.07 mL, 0.84
mmol) in 2 mL of CH2Cl2 was cooled to 0 °C before BF3‚OEt2
(0.03 mL, 0.21 mmol) was added. After the mixture was stirred
for 30 min it was warmed to rt, and then stirred for an
additional 12 h. The suspension was diluted with 10 mL of
CH2Cl2, washed with saturated aqueous NaHCO3, and dried
over MgSO4. The solution was concentrated in vacuo and the
residue was purified via chromatography eluting with 1/5 ethyl
acetate/petroleum ether to yield 10.6 mg (81%) of 14 as a pale
HPLC. [R]15 +43 (c 1.25, CHCl3); 1H NMR (300 MHz, CDCl3)
D
δ 7.35-7.21 (m, 10H), 3.91 (dq, J ) 14, 3.5 Hz, 3H), 2.82 (m,
1H), 2.21 (m, 1H), 1.52-1.23 (m, 4H), 1.41 (s, 9H), 1.26 (d, J
) 6.9 Hz, 3H), 0.94 (m, 2H), 0.81 (t, J ) 7.2 Hz, 3H), 0.66 (t,
J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.10, 144.82,
142.65, 128.23, 128.03, 128.00, 127.95, 127.88, 126.99, 126.66,
126.28, 79.83, 60.06, 51.16, 32.76, 28.04, 24.97, 21.08, 19.95,
14.29. 11.89; IR (neat) 2966, 2874, 1725, 1455 cm-1. EI-MS
m/z 409 (M+), 366, 319, 192, 91. HRMS calcd for C27H39NO2
409.2474, found 409.2455.
yellow oil. [R]15 -41.4 (c 0.4, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 3.31-3.20 (m, 5H), 2.15 (dt, J ) 12.1, 3.2 Hz, 1H),
2.01-1.89 (m, 5H), 1.71 (s, 3H), 1.62-1.11 (m, 10H), 1.01 (q,
J ) 12.0 Hz, 1H), 0.89 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 11.01, 14.74, 17.39, 20.74, 24.54, 29.62, 30.34, 32.84,
36.05, 37.49, 39.71, 51.66, 52.17, 67.16, 67.71, 70.83; IR (neat)
2958, 2874, 2786, 1458 cm-1; EI-MS m/z 313 (M+), 270; HRMS
calcd for C17H31NS2 313.1887, found 313.1892.
(2S,3R)-3-Am in o-2-et h ylh exa n ol (18). A mixture of 17
(5.5 g 13.4 mmol) and LiAlH4 (1.5 g) in dry THF (60 mL) was
refluxed for 12 h. The reaction was quenched by adding ethyl
acetate at room temperature. After water was added, the
organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and evaporated in vacuo to give a colorless oil.
This compound was dissolved in methanol (50 mL) and
hydrogenated over 20% palladium hydroxide on charcoal (600
mg) at 50 °C and 50 atm for 12 h. The mixture was filtered
through Celite, and the filtrate was concentrated and purified
by a short silica column eluting with 1/5 methanol/ethyl
(5R,6S,8R,9S)-6,8-Diet h yl-5-p r op yloct a h yd r oin d oli-
zin e (2). To a solution of dithioacetal 14 (8 mg, 0.026 mmol)
in i-PrOH (3 mL) was added Raney nickel (1 g). The resulting
mixture was vigorously stirred under hydrogen atmosphere
(1 atm) at 70 °C. After completion of the reaction monitored
by TLC, the mixture was filtered through Celite. The filtrate
was concentrated and purified by a short silica column (EA:
MeOH 100:1) to give 4.5 mg (78%) 2 as a volatile colorless oil.
1
Data for its DCl salt: [R]15 -19.7 (c 0.26, CHCl3); H NMR
D
(300 MHz, D2O) δ 3.48 (dt, J ) 9.3, 2.6 Hz, 1H), 2.87 (q, J )
9.3 Hz, 1H), 2.78 (dt, J ) 11.5, 6.3 Hz, 1H), 2.74 (dd, J ) 10.8,
3.9 Hz, 1H), 2.16 (m, 1H), 1.89 (m, 2H), 1.78 (m, 1H), 1.68-
1.48 (m, 4H), 1.46-1.32 (m, 3H), 1.23 (m, 1H), 1.18-0.95 (m,
3H), (m, 11H), 0.85 (q, J ) 12.0 Hz, 1H), 0.75-0.69 (m, 9H);
13C NMR (75 MHz, D2O) δ 9.10, 9.30, 13.12, 15.19, 18.71, 22.97,
24.37, 26.37, 29.39, 32.40, 37.69, 39.34, 50.71, 67.15, 71.19;
IR (neat) 2960, 2875, 2781, 1459 cm-1; EI-MS m/z 223 (M+),
180; HRMS calcd for C15H29N 223.3975, found 223.3991.
acetate to give 1.8 g (95%) of 18 as a colorless oil. [R]15 -1.5
D
1
(c 1.8, CHCl3); H NMR (300 MHz, CDCl3) δ 5.61 (br s, 3H),
3.71 (dd, J ) 12.1, 3.4 Hz, 1H), 3.50 (dd, J ) 12.1, 5.6 Hz,
1H), 3.12 (m, 1H), 1.61-1.22 (m, 7H), 0.89 (dt, J ) 7.1 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 12.24, 13.93, 18.03, 19.74,
35.27, 44.53, 55.07, 64.55; IR (neat) 3325, 2962, 1569, 1069
cm-1; EI-MS m/z 144 (M+ - H+), 126, 114, 102, 72; HRMS
calcd for C8H19NO 145.1462, found 145.1458.
(1′R,2′S)-7-Ben zyloxy-4-[(2′-h yd r oxym eth yl-1′-p r op yl)-
bu tyl]a m in oh ep t-3-en -2-on e (19). To a mixture of 18 (990
mg, 6.85 mmol), compound 8 (1.78 g, 8.22 mmol), and K2CO3
(900 mg, 6.5 mmol) in CH3CN (14 mL) was slowly added 15
drops of water to make the system turbid, then the mixture
was stirred vigorously at 50 °C for 10 h. After the mixture
was dried over MgSO4 it was concentrated in vacuo. The
residue was purified via chromatography eluting with 3/1 ethyl
2-Eth ylh ex-2-en oic Acid ter t-Bu tyl Ester (16). Isobutyl-
ene (40 mL) was condensed into a Schlenk tube containing
acid 15 (14.2 g, 0.1 mol) at -70 °C. After sulfuric acid (0.5
mL) was added, the vessel was sealed and warmed to room
temperature slowly. After 3 days at room temperature, the
vessel was cooled to -70 °C before opening and excessive
isobutylene was released by slowly warming the solution to
room temperature. The crude product was directly purified via
chromatography eluting with 1/5 ethyl acetate/petroleum ether
acetate/petroleum ether to yield 2.1 g (88%) of 19 as a colorless
1
oil. [R]15 -50.4 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ
1
D
to yield 16.8 g (85%) of 16 as a volatile colorless oil. H NMR
7.27 (m, 5H), 4.88 (s, 1H), 4.47 (s, 2H), 3.82 (m, 1H), 3.61 (dd,
J ) 8.4, 3.3 Hz, 1H), 3.40 (m, 3H), 2.31 (d, J ) 7.6 Hz, 2H),
1.90 (s, 3H), 1.81 (m, 3H), 1.52-1.23 (m, 8H), 0.89 (dt, J ) 7.4
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 12.51, 13.99, 18.74,
19.78, 27.95, 28.19, 28.65, 35.86, 46.78, 52.35, 61.31, 69.00,
72.80, 93.58, 127.50, 127.59, 128.28, 137.99, 167.181, 194.19;
(300 MHz, CDCl3) δ 6.6 (t, J ) 7.5 Hz, 1H), 2.28 (q, J ) 7.8
Hz, 2H), 2.12 (q, J ) 7.2 Hz, 2H), 1.46 (s and m, 11H), 0.91
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 166.78, 140.213, 135.17,
79.27, 30.05, 27.86, 27.58, 21.93, 19.77, 13.63; IR (neat) 2968,
2876, 1707, 1458 cm-1; EI-MS m/z 198 (M+), 155, 143; HRMS
calcd for C12H22O2 198.1644, found 198.1668.
4404 J . Org. Chem., Vol. 68, No. 11, 2003

Asymmetric Total Synthesis of (-)-Alkaloid 223A
IR (neat) 3369, 2961, 1600, 1567 cm-1; EI-MS m/z 361 (M+),
288, 270, 91; HRMS calcd for C22H35NO3 361.2662, found
361.2697.
charcoal (60 mg) at ordinary temperature and pressure for 12
h. It was then filtered through Celite, and the filtrate was
concentrated to give a colorless oil.
(5R,6R)-2-(3′-Ben zyloxy)p r op yl-3-a cyl-5-eth yl-6-p r op yl-
1,4,5,6-tetr a h yd r op yr id in e (20). To a stirred solution of 19
(300 mg, 0.83 mmol) in dry CH2Cl2 (8 mL) were added
triphenylphospine (654 mg, 2.48 mmol), imidazole (168 mg,
2.48 mmol), and iodine (419 mg, 1.66 mmol) at 0 °C. After the
solution was warmed to room temperature in about 2 h, the
mixture was diluted with petroleum ether and then filtered
through Celite. The filtrate was concentrated to give the
corresponding iodide compound, which was dissolved in dry
CH3CN (15 mL). After Et3N (0.115 mL) was added the mixture
was refluxed for about 15 h. The solution was evaporated in
vacuo and the residue was purified via chromatography eluting
with 4/1 ethyl acetate/petroleum ether to yield 263 mg (94%)
of 20 as an unstable pale yellow oil. [R]15D +48 (c 1.95, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.31 (m, 5H), 4.72 (br s, 1H),
4.50 (d, J ) 6.9 Hz, 2H), 3.52 (t, J ) 6.1 Hz, 2H), 3.11 (m, J )
3.1 Hz, 1H), 2.70 (t, J ) 7.2 Hz, 2H), 2.41 (dd, J ) 10, 3.6 Hz,
1H), 2.12 (s, 3H), 1.81 (m, 2H), 1.73-1.12 (m, 8H), 0.89 (dt, J
) 7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 12.30, 14.33, 19.55,
23.12, 28.50, 28.70, 29.44, 31.89, 32.00, 37.12, 53.72, 70.01,
73.12, 100.33, 127.84, 127.98, 128.62, 138.68, 157.01, 195.55;
IR (KBr) 3295, 2961, 1717, 1619 cm-1; EI-MS m/z 343 (M+),
328, 252, 166; HRMS calcd for C22H33NO2 343.2458, found
343.2432.
To a stirred solution of the above compound in dry CH2Cl2
(15 mL) were added triphenylphospine (282 mg), imidazole (75
mg), and iodine (182 mg) at 0 °C. After the mixture was
warmed to room temperature in about 2 h, it was washed with
saturated aqueous NaHCO3. The aqueous layer was extracted
with ethyl acetate and the combined organic layers were dried
over MgSO4. The solution was evaporated in vacuo and the
residue was purified via chromatography eluting with 4/1 ethyl
acetate/petroleum ether containing a drop of ethylamine to
give 54 mg (74%) of 24 as a colorless oil: [R]15 -79.2 (c 0.98,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.11 (dt, J ) 9.1, 2.0
Hz, 1H), 2.50 (dt, J ) 9.6, 3.2 Hz, 1H), 2.16 (s, 3H), 2.11-1.82
(m, 5H), 1.70-1.13 (m, 11H), 0.89 (dt, J ) 7.0 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 12.59, 14.72, 18.02, 19.21, 20.64,
29.26, 29.66, 30.87, 33.43, 36.77, 51.14, 51.35, 66.34, 66.55,
211.67; IR (neat) 2959, 2873, 2783, 1714, 1463 cm-1; EI-MS
m/z 237 (M+), 194; HRMS calcd for C15H27NO 237.2102, found
237.2138.
(5R,6R,8R,9S)-6-Eth yl-8-(2-m eth yl-[1,3]-d ith iola n -2-yl)-
5-p r op ylocta h yd r oin d olizin e (25). To a solution of com-
pound 24 (30 mg, 0.126 mmol) and ethane-1,2-dithiol (0.21 mL,
2.5 mmol) in CH2Cl2 (2 mL) was added BF3‚OEt2 (0.09 mL,
0.63 mmol) at 0 °C. After the mixture was stirred for 30 min
it was warmed to rt, and then stirred for an additional 12 h.
The suspension was diluted with CH2Cl2 (10 mL), washed with
saturated aqueous NaHCO3, dried over MgSO4, and concen-
trated in vacuo. The residue was purified via chromatography
eluting with 1/5 ethyl acetate/petroleum ether to afford 31 mg
(81%) of 25 as a pale yellow oil. [R]15D -67.8 (c 0.6, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 3.32-3.12 (m, 5H), 2.15 (dt, J )
11.1, 3.2 Hz, 1H), 1.68 (s, 3H), 2.01-1.73 (m, 6H), 1.61-1.23
(m, 10H), 0.89 (dt, J ) 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 12.2, 14.5, 17.9, 18.9, 20.4, 29.4, 30.5, 33.3, 33.5, 37.2, 37.3,
39.8, 47.6, 51.7, 66.8, 68.9, 70.9; IR (neat) 2960, 2875, 2785,
Com p ou n d s 21, 22, a n d 23. The cyclic enamine 20 (332
mg, 0.97 mmol) was dissolved in glacial acid (40 mL) and then
hydrogenated over platinum dioxide (12 mg) at ordinary
temperature and pressure for 1 h. After the mixture was
filtered through Celite, the filtrate was concentrated and
diluted with saturated aqueous NaHCO3. EtOAc-extract work-
up followed by chromatography eluting with 5/1 ethyl acetate/
petroleum ether and 100/1 ethyl acetate/methanol to give 116
mg (34%) of 21, 110 mg (33%) of 22, and 72 mg (22%) of 23.
(2R,3R,5R,6R)-2-(3′-Ben zyloxy)p r op yl-3-a cyl-5-eth yl-6-
1
p r op ylp ip er id in e (21). [R]15 +12 (c 0.2, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.31 (m, 5H), 4.48 (s, 2H), 3.45 (m, 2H),
2.79 (br m, 2H), 2.12 (s, 3H), 1.72-1.11 (m, 15H), 0.89 (dt, J
1425 cm-1; EI-MS m/z 313 (M+), 270; HRMS calcd for C17H31
-
NS2 313.1887, found 313.1875.
) 7.0 Hz, 6H); IR (neat) 2958, 2879, 1705, 1455, 1154 cm-1
;
(5R,6R,8R,9S)-6,8-Diet h yl-5-p r op yloct a h yd r oin d oli-
zin e (1). To a solution of dithioacetal 25 (16 mg, 0.052 mmol)
in i-PrOH (3 mL) was added Raney nickel (1.5 g). The resulting
mixture was vigorously stirred under hydrogen atmosphere
(1 atm) at 70 °C. After completion of the reaction monitored
by TLC, the mixture was filtered through Celite. The filtrate
was concentrated and purified by a short silica column (EA:
MeOH 100:1) to give 9 mg (78%) of 1 as a volatile colorless
oil. Data for its DCl salt: [R]15D -38.4 (c 0.3, CHCl3); 1H NMR
(300 MHz, D2O) δ 3.58 (dt, J ) 9.6, 2.7 Hz, 1H), 3.15 (dt, J )
11.0, 3.6 Hz, 1H), 2.95 (q, J ) 9.1 Hz, 1H), 2.86 (dt, J ) 11.5,
6.0 Hz, 1H), 2.28 (m, 1H), 2.05 (dd, J ) 13.2, 2.5 Hz, 1H), 1.97-
1.88 (m, 3H), 1.74-1.37 (m, 7H), 1.22-1.12 (m, 4H), 0.88-
0.80 (m, 9H); 13C NMR (75 MHz, D2O) δ 11.4, 13.0, 14.7, 18.5,
19.3, 20.2, 26.0, 27.7, 31.3, 31.4, 36.9, 36.8, 52.7, 68.1, 73.8;
IR (neat) 2960, 2871, 2781, 1456 cm-1; EI-MS m/z 223 (M+),
180; HRMS calcd for C15H29N 223.3976, found 223.3958.
ESI-MS m/z 346 (M+ + H+); HRMS calcd for C22H35NO2
345.2730, found 345.2740.
(2S,3S,5R,6R)-2-(3′-Ben zyloxy)p r op yl-3-a cyl-5-eth yl-6-
p r op ylp ip er id in e (22). [R]15D -20.5 (c 0.95, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.31 (m, 5H), 4.52 (s, 2H), 3.41 (m, 2H),
2.66 (m, 1H), 2.59 (m, 1H), 2.49 (m, 1H), 2.30 (dt, J ) 14.5,
2.6 Hz, 1H), 2.17 (s, 3H), 1.79-1.11 (m, 13H), 0.89 (dt, J )
7.2 Hz, 6H); IR (neat) 2959, 2871, 1707, 1455, 1354 cm-1; EI-
MS m/z 344 (M+ - H+), 302, 254, 196; ESI-HRMS calcd for
C
22H36NO2 346.2732 (M+ + H+), found 346.2740.
(2S,3R,5R,6R)-2-(3′-Ben zyloxy)p r op yl-3-a cyl-5-eth yl-6-
p r op ylp ip er id in e (23). [R]15D -23.6 (c 0.25, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.31 (m, 5H), 4.52 (s, 2H), 3.41 (t, J ) 6.2
Hz, 2H), 2.80 (dt, J ) 9.0, 2.7 Hz, 1H), 2.62 (m, 1H), 2.41 (dt,
J ) 11.0, 3.0 Hz, 1H), 1.90 (dd, J ) 11.1, 3.3 Hz, 1H), 2.11 (s,
3H), 1.63-1.24 (m, 13H), 0.89 (dt, J ) 7.2, 6H); IR (neat) 2959,
2871, 1705, 1455, 1361 cm-1; ESI-MS m/z 346 (M+ + H+). ESI-
HRMS calcd for
346.2741.
C
22H36NO2 346.2751 (M+ + H+), found
Ack n ow led gm en t. The authors are grateful to the
Chinese Academy of Sciences, National Natural Science
Foundation of China (grant 29972049), and the Qiu Shi
Science & Technologies Foundation for their financial
support.
Ep im er iza tion of Com p ou n d 22. To a freshly prepared
solution of sodium methoxide (1 mmol) in methanol was added
a solution of 22 (1 mmol) in dry MeOH at room temperature.
The mixture was refluxed for about 3 h before the solvent was
evaporated off. The residue was triturated with water and
extracted with ethyl acetate. The combined organic layers were
dried over MgSO4. After removal of solvents, the residue was
subjected to a short FC (PE:EA 1:1) to afford 23 in quantitative
yield.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR or 13C
NMR spectra for compounds 1, 2, 9-11, 13, 14, 19, 20, and
23-25. This material is available free of charge via the
Internet at http://pubs.acs.org.
(5R,6R,8R,9S)-8-Acyl-6-eth yl-5-p r op ylocta h yd r oin d oli-
zin e (24). A mixture of 23 (110 mg, 0.31 mmol) and 10 mL of
methanol was hydrogenated over 20% palladium hydroxide on
J O0341261
J . Org. Chem, Vol. 68, No. 11, 2003 4405