Total synthesis of (±)-quinolizidine 217A

Article abstract of DOI:10.1021/jo981695d

Several 1,4-disubstituted quinolizidines have been isolated in minute quantities from the skin of certain poisonous frogs and toads. The structures of these alkaloids have been proposed mainly on the basis of MS and IR spectroscopic data. We report the first total synthesis of a naturally occurring alkaloid of this type, quinolizidine 217A. After examination of several azide-based routes, the cyclization of an azide onto an ester- bearing alkene provided a 3,4,5,6-tetrahydropyridine that was reduced in a stereoselective fashion to produce a cis-2,6-disubstituted piperidine (25 → 31 → 32). Transformation of 32 into quinolizidine 217A (2) and its C(1) epimer (41) were accomplished in a straightforward fashion. Synthetic quinolizidine 217A was found to be identical to the natural alkaloid, confirming its stereostructure. Compound 41 has the same stereostructure as that proposed for the alkaloid quinolizidine 207I, a compound whose configuration was recently revised as a result of synthetic studies by Momose et al., who synthesized a 1,4-disubstituted quinolizidine with the configuration previously proposed for quinolizidine 207I and found the synthetic material to be epimeric with the natural material. Compound 41 should provide a useful point of comparison for future studies on the stereostructure of natural or synthetic quinolizidine 207I.

Full text of DOI:10.1021/jo981695d

9
910
J . Org. Chem. 1998, 63, 9910-9918
Tota l Syn th esis of (()-Qu in olizid in e 217A
William H. Pearson* and Hiroyuki Suga
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055
Received August 20, 1998
Several 1,4-disubstituted quinolizidines have been isolated in minute quantities from the skin of
certain poisonous frogs and toads. The structures of these alkaloids have been proposed mainly on
the basis of MS and IR spectroscopic data. We report the first total synthesis of a naturally occurring
alkaloid of this type, quinolizidine 217A. After examination of several azide-based routes, the
cyclization of an azide onto an ester-bearing alkene provided a 3,4,5,6-tetrahydropyridine that was
reduced in a stereoselective fashion to produce a cis-2,6-disubstituted piperidine (25 f 31 f 32).
Transformation of 32 into quinolizidine 217A (2) and its C(1) epimer (41) were accomplished in a
straightforward fashion. Synthetic quinolizidine 217A was found to be identical to the natural
alkaloid, confirming its stereostructure. Compound 41 has the same stereostructure as that proposed
for the alkaloid quinolizidine 207I, a compound whose configuration was recently revised as a result
of synthetic studies by Momose et al., who synthesized a 1,4-disubstituted quinolizidine with the
configuration previously proposed for quinolizidine 207I and found the synthetic material to be
epimeric with the natural material. Compound 41 should provide a useful point of comparison for
future studies on the stereostructure of natural or synthetic quinolizidine 207I.
In tr od u ction
Extracts from the skin of certain poison frogs and toads
have yielded many pharmacologically active alkaloids,
including a variety of azabicyclic compounds of the
“
izidine” type, i.e., pyrrolizidines, indolizidines, and, most
1
recently, quinolizidines. While the structures of the 5,8-
disubstituted indolizidines (1) are well-known and have
in many cases been confirmed by synthesis,2 the 1,4-
disubstituted quinolizidines (e.g., 2-4) are a relatively
-4
F igu r e 1. Representative structures of “izidine” alkaloids
from frogs and toads.
new class of alkaloids isolated from these amphibians
Figure 1).5 GC-FTIR and GC-MS analysis have been
-7
(
used to provide evidence of the structure of the 1,4-
disubstituted quinolizidines due to the minute quantities
involved, and thus there is uncertainty about their exact
structure and stereochemistry. Quinolizidine 217A (2) is
the only 1,4-disubstituted quinolizidine that has been
1
isolated in sufficient quantities to allow H NMR spec-
troscopic analysis, resulting in the proposed structure
7
shown in Figure 1. Although the absolute configuration
F igu r e 2. Retrosynthetic analysis of quinolizidine 217A (2).
of this and other quinolizidines is not known, the relative
configuration is proposed to parallel that of the known
(
1) (a) Daly, J . W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1986;
Vol. 4, pp 1-274. (b) Daly, J . W.; Garraffo, H. M.; Spande, T. F. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1993;
Vol. 43, pp 185-288. (c) Daly, J . In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1997; Vol. 50.
5
,8-disubstituted indolizidines. Only one report of a
synthesis of a 1,4-disubstituted quinolizidine has ap-
peared to date. Momose and co-workers4 reported a
synthesis of 3, originally proposed to be quinolizidine
(
2) Michael, J . P. Nat. Prod. Rep. 1994, 11, 17-39.
(3) Leading recent references: (a) Bardou, A.; C e´ l e´ rier, J .-P.; Lhom-
2
07I. However, the synthetic material was found to be
met, G. Tetrahedron Lett. 1998, 39, 5189-5192. (b) Michael, J . P.;
Gravestock, D. Pure Appl. Chem. 1997, 69, 583-588. (c) Aehman, J .;
Somfai, P. Tetrahedron 1995, 51, 9747-9756. (d) J efford, C. W.;
Sienkiewicz, K.; Thornton, S. R. Helv. Chim. Acta 1995, 78, 1511-
epimeric with the natural alkaloid, prompting a tentative
reassignment of 207I as 4. The scarcity of 1,4-disubsti-
tuted quinolizidines and the uncertainty surrounding
their structure prompted us to attempt a synthesis of
quinolizidine 217A (2). We report herein the synthesis
of this alkaloid, confirming the structural assignment of
the natural alkaloid to be as shown.
A retrosynthetic analysis of quinolizidine 217A is
shown in Figure 2. Equatorial attack of hydride on the
iminium ion 5 should give the appropriate C(10) config-
uration of 2. We planned to generate the iminium ion 5
by double cyclization of the chloro azidoalkene 6, a one-
1
(
1
124. (e) Momose, T.; Toyooka, N. J . Org. Chem. 1994, 59, 943-945.
f) Aub e´ , J .; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 35, 1141-
147.
4) Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J . W.; Garraffo, H.
M. Tetrahedron 1997, 53, 9553-9574.
5) Garraffo, H. M.; Spande, T. F.; Daly, J . W.; Baldessari, A.; Gros,
E. G. J . Nat. Prod. 1993, 56, 357-373.
6) Garraffo, H. M.; Caceres, J .; Daly, J . W.; Spande, T. F.; An-
driamaharavo, N. R.; Andriantsiferana, M. J . Nat. Prod. 1993, 56,
016-1038.
7) J ain, P.; Garraffo, H. M.; Yeh, H. J . C.; Spande, T. F.; Daly, J .
W.; Andriamaharavo, N. R.; Andriantsiferana, M. J . Nat. Prod. 1996,
9, 1174-1178.
(
(
(
1
(
5
1
0.1021/jo981695d CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/25/1998

Total Synthesis of (()-Quinolizidine 217A
J . Org. Chem., Vol. 63, No. 26, 1998 9911
Sch em e 1. Mod el Stu d y for Qu in olizid in e
Syn th esis
Sch em e 3. Mod el Stu d y for Cycloa d d ition Step
a
On ly
Sch em e 2. Attem p ted syn th esis of a
1
,4-Disu bstitu ted Qu in olizid in ea
tures followed by sodium borohydride reduction led to
highly viscous materials. Chromatography allowed the
isolation of very small amounts (2-10% yield) of a
material that was consistent with 16 by GC-MS. Un-
fortunately, this material was found to be a mixture of
several compounds, presumably diastereomers. Following
1
the progress of the cyclization process by H NMR
spectroscopy indicated that the desired iminium ion was
not being produced cleanly (cf. Scheme 1). While we were
aware that simple homoallylic azides produce resinous
materials upon thermolysis,13 we felt that such decom-
position might be avoided if a second alkene were present
that was capable of a favorable dipolar cycloaddition. The
failure of the cyclization of 15 may be in part due to the
involvement of the homoallylic double bond in the cy-
cloaddition (see, however, Scheme 3 below). We consid-
ered preparing compounds related to 15 that did not have
the terminal vinyl group. However, the observation of
several different diasteromers of 16 was troubling,
indicating nonselectivity in the epimerization (see Figure
pot thermal process we have developed for alkaloid
The configuration of the allylic methyl
group of 6 was not considered to be important, since
synthesis.8
-10
epimerization under the cyclization conditions should
occur to provide the most stable diastereomer of 5.9
2
) and/or hydride reduction step. Hence, we abandoned
Resu lts a n d Discu ssion
the chloro azidoalkene approach in favor of a stepwise
cyclization process.
A simple model cyclization was carried out to test the
ability of the chloro azidoalkene cyclization to generate
quinolizidines (Scheme 1). Reduction of δ-valerolactone
to the lactol followed by a Wittig reaction employing the
Cha has studied the cycloaddition of ester-bearing
1
4
azidoalkenes for the synthesis of indolizidines. To
examine the use of this method for the current applica-
tion, we prepared the ester-bearing azidoalkene 18
(Scheme 3). The allylic methyl group needed for a
synthesis of quinolizidine 217A is purposely missing in
18, since we wished to study the stereochemistry of the
reduction of the imine 19 without complications from a
second stereocenter. Reduction of the lactone 12 and
addition of vinylmagnesium bromide to the resultant
lactol gave a secondary alcohol, which was converted to
8
phosphonium salt 8 and a Mitsunobu reaction with zinc
azide11 afforded the chloro azidoalkene 9. Heating this
azide at 100 °C in a sealed tube cleanly produced the
iminium salt 10 as the sole product as judged by H NMR
1
spectroscopy.
Our first attempt at using the chloro azidoalkene
cyclization to synthesize a 1,4-disubstituted quinolizidine
is outlined in Scheme 2. An allyl group was chosen for
the eventual C(4) substituent, since several quinolizidines
have such a substituent (e.g., 3/4 above) and other
quinolizidines might be accessible by manipulation of the
1
5
1
7 by a J ohnson ortho ester Claisen rearrangement.
Transformation of 17 to the azide 18 followed by heating
afforded the imine 19 in 41% yield after considerable
optimization. Unfortunately, reduction of 19 with a
variety of hydridic reagents gave complex mixtures of
amino alcohols. Nonetheless, the cyclization of 18 shows
that a homoallylic azide may indeed be used for a
cycloaddition with a second double bond with moderate
efficiency (cf. Scheme 2). However, the low overall yield
of 19 and the potential problems inherent in transforming
the terminal vinyl group into the desired enyne side chain
of quinolizidine 217A led us to consider a less problematic
substituent.
allyl group. Addition of allyltrimethylsilane to the alde-
hyde 1112 followed by cyclization of the resultant hydroxy-
ester gave the lactone 12. Methylation of the enolate of
2 afforded a 1:1 mixture of diastereomeric lactones 13,
which were subjected to the same sequence of reactions
used in Scheme 1 to produce the chloro azidoalkene 15
as an inseparable mixture of diastereomers. Cyclization
of 15 in a variety of solvents and at different tempera-
1
(
8) Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990, 31, 7571-
7
6
1
574.
(
783-6789.
(
After considerable experimentation, we settled on a
,3-dioxolane group as a masked aldehyde. The synthesis
9) Pearson, W. H.; Schkeryantz, J . M. J . Org. Chem. 1992, 57,
1
10) Pearson, W. H.; Walavalkar, R. Tetrahedron 1994, 50, 12293-
2304.
(13) Logothetis, A. L. J . Am. Chem. Soc. 1965, 87, 749-754.
(14) Bennett, R. B., III; Choi, J .-R.; Montgomery, W. D.; Cha, J . K.
(
11) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
12) (a) Huckstep, M.; Taylor, R. J . K. Synthesis 1982, 881-882.
b) Corey, E. J .; Niwa, H.; Knolle, J . J . Am. Chem. Soc. 1978, 100,
942-1943. (c) Burgstahler, A. W.; Weigel, L. O.; Shaefer, C. G.
Synthesis 1976, 767-768.
(
J . Am. Chem. Soc. 1989, 111, 2580-2582.
(
(15) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J .; Li, T.; Faulkner, D. J .; Petersen, M. R. J . Am. Chem. Soc. 1970,
92, 741-743.
1

9
912 J . Org. Chem., Vol. 63, No. 26, 1998
Pearson and Suga
Sch em e 6. Cycliza tion of Azid e 25
Sch em e 4. Syn th esis of Cycloa d d ition
a
P r ecu r sor s
Sch em e 5. Cycliza tion of Mod el Azid e 23
2
,6-disubstituted piperidines 32, but the overall yield
from 25 could not be optimized above 27%. Fortunately,
work by Lhommet18 and co-workers on the stereoselective
reduction of pyrrolines to 2,5-disubstituted pyrrolidines
provided us with a solution to this problem. Thus,
4 2
reduction of the crude imine 31 with NaBH /PdCl
provided 32 efficiently (vide infra) as an inseparable 1:1.3
mixture of the two possible cis-2,6-disubstituted pip-
eridines, which were best used without purification.
Surprisingly, we were not able to induce the cyclization
of 32 to the lactams under a variety of conditions. For
example, heating 32 with sodium cyanide or freshly
prepared sodium ethoxide in anhydrous ethanol produced
the acids 33 and 34 rather than the lactams. Ultimately,
we found it convenient to simply saponify 32 to 33 and
of the key cycloaddition precursors 25 and 23 (with and
without the allylic methyl group) are shown in Scheme
4
. The lactones 12 and 13 were subjected to ozonolysis
and protection to give 20 and 21, which were reduced to
the lactols and converted to the alkenes 22 and 24 with
the ylide derived from the phosphonium salt 26.14 Stan-
3
4 and close the second ring using other nonacylative
dard displacement chemistry was used to install the azido
groups, producing 23 and 25.
The cyclization of 23 was studied first (Scheme 5), since
the absence of the allylic methyl group simplifies devel-
opment of a stereoselective hydride reduction of the imine
chemistry (see Scheme 7). Fortunately, the crystalline
acids 33 and 34 were easily separated and were formed
in 34 and 26% overall yield, respectively, from the azide
2
5. Thus, the three-step sequence (cycloaddition, reduc-
tion, and saponification) had been quite efficient, i.e., a
0% overall yield of 33/34 after separation. Assignment
2
7. Heating 23 in a sealed tube produced 27, which was
then treated with a variety of hydride reagents. Following
literature precedent,16 we found that LiAlH
/AlMe and
6
of the relative configurations of 33 and 34 was made at
a later stage (vide infra).
4
3
DIBAL-H were the most diastereoselective reagents,
The acids 33 and 34 were converted to quinolizidine
217A (2) and its C(1) epimer 41 as shown in Scheme 7.
Reduction of the acids produced the alcohols 35 and 36.
At this point, we were able to use the stereochemical
assignments of the simpler piperidines 28 and 29 along
with literature precedent and coupling constant analysis
to assign the stereostructures of 35 and 36 and thus 33
and 34. A full discussion of these assignments may be
found in the Experimental Section. Cyclization of 35 and
producing the trans- and cis-piperidines 28 and 29 as
single diastereomers as judged by H NMR spectroscopy
in good to modest overall yield (unoptimized). The as-
1
signment of the relative configurations of these two
piperidines relies on close literature precedent17 (see
Experimental Section).
With the model piperidines 28 and 29 assigned and in
hand, we turned our attention to the more complex
cyclization of the azide 25, which bears the allylic methyl
group necessary for a synthesis of quinolizidine 217A
3
6 to the quinolizidines 37 and 38 using phosphorus-
based methods proceeded without difficulty. Hydrolysis
of the dioxolanes to the aldehydes and olefination using
Yamamoto’s method19 afforded the silyl enynes 39 and
(Scheme 6). Heating the azide 25 (an inseparable 1:1.2
mixture of diastereomers) produced the triazoline 30
initially, which decomposed as planned to the imine 31,
which was found to be a 1:1.3 mixture of diastereomers
4
0. Desilylation afforded racemic quinolizidine 217A (2)
1
1
and its C(1) epimer 41. The H NMR spectroscopic and
mass spectrometric data for 2 matched the literature
values (see Supporting Information),7 as did the IR
by H NMR spectroscopy. Reduction of 31 with DIBAL-H
(see above) gave a 1:2 mixture of the two possible cis-
(
16) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane,
S.; Hattori, K.; Yamamoto, H. J . Am. Chem. Soc. 1983, 105, 2831-
(18) Bacos, D.; C e` l e` rier, J . P.; Marx, E.; Saliou, C.; Lhommet, G.
Tetrahedron Lett. 1989, 30, 1081-1082.
(19) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto, H.
Bull. Chem. Soc. J pn. 1984, 57, 2768-2776.
2
843.
(17) Taber, D. F.; Deker, P. B.; Silverberg, L. J . J . Org. Chem. 1992,
5
7, 5990-5994.

Total Synthesis of (()-Quinolizidine 217A
J . Org. Chem., Vol. 63, No. 26, 1998 9913
Sch em e 7. Syn th esis of Qu in olizid in e 217A (2)
Con clu sion
a
a n d Ep im er (41).
In summary, our synthesis of quinolizidine 217A (2)
represents the first synthesis of a naturally occurring 1,4-
disubstituted quinolizidine alkaloid and confirms the
literature assignment of the relative configuration of this
substance. The C(1) epimeric compound 41 represents
the first synthetic 1,4-disubstituted quinolizidine with the
same relative configuration as that recently proposed for
quinolizidine 207I (4).
Exp er im en ta l Section
Gen er a l. Meth od s. Reagents and starting materials were
obtained from commercial suppliers and used without further
purification unless otherwise noted. Methylene chloride (CH
2
-
Cl ), triethylamine, dimethyl sulfoxide (DMSO), N,N-dimeth-
2
ylformamide (DMF), and benzene were distilled from calcium
hydride under a nitrogen atmosphere. Methanol (MeOH) was
distilled from magnesium turnings under a nitrogen atmo-
sphere. Tetrahydrofuran (THF) and ether were distilled from
sodium/benzophenone ketyl under a nitrogen atmosphere.
Chloroform was filtered through basic alumina. Alkyllithiums
2
2
were titrated by the method of Gilman and Haubein or
Ronald et al.23 All reactions were conducted in oven- or flame-
dried glassware under an anhydrous nitrogen atmosphere with
standard precautions taken to exclude moisture. Chromatog-
raphy refers to flash chromatography on silica gel (230-400
mesh) unless otherwise noted.
6
-Allyltetr a h yd r op yr a n -2-on e (12). This is a known
2
4
compound but was prepared by an alternative procedure.
Thus, a solution of TiCl (45.6 mL, 45.6 mmol, 1.0 M solution
2
in CH Cl ) in dry CH Cl (120 mL) was added to a solution of
4
2
2
2
1
2
methyl 5-oxopentanoate (11) (4.94 g, 38.0 mmol) and allyl-
trimethylsilane (5.21 g, 7.24 mL, 45.6 mmol) in dry CH Cl
2
2
(
70 mL) over a period of 1.5 h at -78 °C. The mixture was
allowed to warm to -20 °C over a period of 3 h, where it was
held another 30 min. Water (100 mL) was added, the layers
were separated, and the organic layer was extracted with CH
Cl
(100 mL × 2). The combined organic layers were dried
(MgSO ) and concentrated. The residue was chromatographed
3:1 hexane/ethyl acetate) to give 4.43 g of pale yellow oil,
which was dissolved in benzene (450 mL) and heated at reflux
O (0.53 g), removing water
2
-
2
spectal data.6 Both 2 and 41 show the presence of
Bohlmann bands in their infrared spectra, consistent
4
(
with trans-decalin-like structures with a cis relationship
for 3 h in the presence of p-TsOH‚H
2
2
0
of the C(10) and C(4) methine hydrogens. A sample of
our synthetic quinolizidine 217A was provided to Daly
and Spande,21 who found an exact match with natural
quinolizidine 217A by GC-FTIR. Further, analysis of our
synthetic material by GC on a chiral column resolved the
racemate into two enantiomers. The most highly retained
enantiomer cochromatographed with natural quinolizi-
dine 217A.21 The H NMR spectrum of 2 is also similar
to that of synthetic (1R,4S,10S)-4-allyl-1-ethylquinolizi-
with a Dean-Stark trap. The mixture was cooled and concen-
trated to about 30 mL and chromatographed (3:1 hexane/ethyl
acetate) to give 3.90 g (73%) of the title compound as pale
1
yellow oil. R
CDCl
4
7
f
) 0.20 (3:1 hexane/ethyl acetate); H NMR
(
3
, 300 MHz) δ 1.48-1.98 (m, 4H), 2.34-2.65 (m, 4H),
.30-4.39 (m, 1H), 5.12-5.18 (m, 2H), 5.82 (ddt, J ) 17.1, 10.2,
.3, Hz, 1H). These spectral data matched the literature data.
-Allyl-3-m eth yltetr a h yd r op yr a n -2-on e (13). n-Butyl-
2
4
6
1
lithium (7.44 mL, 17.1 mmol, 2.3 M solution in hexane) was
added to a solution of diisopropylamine (1.73 g, 2.40 mL, 17.1
mmol) in dry THF (25 mL) at -78 °C. After 30 min at 0 °C,
the solution was cooled to -78 °C and a solution of 12 (2.00 g,
14.3 mmol) in dry THF (25 mL) was added. After 1 h,
iodomethane (6.08 g, 2.67 mL, 42.8 mmol) was added. After
stirring at -78 °C for 1 h, the mixture was quenched with
4
1
dine (3, Figure 1). The quinolizidine 41 exhibited
H
NMR resonances that were clearly different from those
7
reported for natural quinolizidine 217A. Note that 41
has the same relative configuration as that proposed for
the newly revised structure of quinolizidine 207I (4,
Figure 1). Unfortunately, due to the miniscule amounts
THF/H
3). The organic extracts were dried (MgSO
trated. Chromatography (10:1 hexane/ethyl acetate) provided
.73 g of the title compound as colorless oil. The aqueous
washes from the extraction were treated with 1 M HCl (15
mL) and extracted with CH Cl
(100 mL × 3). The organic
extract was dried (MgSO ) and concentrated. The resulting oil
2
O (1:1, 100 mL) and extracted with CH
2 2
Cl (100 mL
×
4
) and concen-
6
of natural quinolizidine 207I isolated from frogs, NMR
spectroscopic data are not available for comparison with
synthetic 41. However, should such material become
available, either by isolation or synthesis, our synthetic
1
2
2
4
1 will serve as a useful point of comparison.
4
(
20) Bohlmann, F. Chem. Ber. 1958, 91, 2157-2167.
(22) Gilman, H.; Haubein, R. H. J . Am. Chem. Soc. 1955, 77, 1515.
(23) Winkle, M. R.; Lansinger, J . M.; Ronald, R. C. J . Chem. Soc.,
Chem. Commun. 1980, 87.
(24) (a) Utaka, M.; Kuriki, H.; Sakai, T.; Takeda, A. Chem. Lett.
1983, 911-912. (b) Matsubara, B.; Utaka, M.; Kuriki, H.; Sakai, T.;
Takeda, A. J . Org. Chem. 1986, 51, 935-938. (c) Takai, K.; Nozaki, H.
Bull. Chem. Soc. J pn. 1983, 56, 2029-2032.
(21) Personal communication with J ohn W. Daly and T. Spande,
NIDDK (National Institutes of Health). The GC-FTIR data was
obtained on an HP-5 fused silica-bonded capillary column (25 m × 0.32
mm). The chiral GC analysis was performed using a Supelco Beta-
DEX 120 fused silica capillary column (30 m, 0.25 mm i.d., 0.25 µm
film thickness).

9
914 J . Org. Chem., Vol. 63, No. 26, 1998
Pearson and Suga
was heated for 3 h with p-TsOH‚H O (45 mg) in benzene (40
2
compound (35% from 13) as colorless oil, which was found to
mL) at reflux with water removal using a Dean -Stark trap
for 3 h to cyclize the hydroxy acid to the lactone. The solution
was cooled and concentrated, and the resultant oil was
chromatographed (10:1 hexane/ethyl acetate) to give 0.295 g
of additional product for a combined yield of 2.021 g (93%) of
be an inseparable 1:1.1 mixture of diastereomers as deter-
mined by 1H NMR analysis. R
) 0.12 (3:1 hexane/ethyl
1
f
-
1
3
acetate); IR (neat) 1731 (s) cm ; H NMR (CDCl , 300 MHz)
δ 1.22 (d, J ) 6.7 Hz, 3H × 1/2.1), 1.30 (d, J ) 7.1 Hz, 3H ×
1.1/2.1), 1.47-2.19 (m, 6H), 2.40-2.68 (m, 1H), 3.82-4.03 (m,
the title compound as an inseparable 1:1 mixture of diaster-
4H), 4.49-4.58 (m, 1H), 5.04-5.09 (m, 1H); 13C NMR (CDCl
,
3
1
eomers as determined by H NMR analysis. R
f
) 0.33 (4:1
100 MHz) δ 16.25, 17.57, 25.64, 27.29, 28.64, 29.76, 33.23,
-1 1
hexane/ethyl acetate); IR (neat) 1732 (s) cm ; H NMR (CDCl
3
,
36.21, 39.82, 40.76, 64.93, 65.06, 74.69, 78.48, 101.25, 101.29,
1
+
3
3
(
1
2
1
00 MHz) δ 1.22 (d, J ) 6.7 Hz, 3H × /
2
), 1.30 (d, J ) 7.1 Hz,
174.08, 176.07; MS (CI, NH
3
) m/z (rel intense) 201 [(M + H) ,
1
H × /
2
), 1.47-1.72 (m, 2H), 1.88-2.15 (m, 2H), 2.30-2.64
100], 200 (0.3) 199 (2), 183 (4), 157 (4); HRMS (CI, NH
3
) calcd
H [(M + H) ] 201.1127, found 201.1123. Anal.
: C, 59.98; H, 8.08. Found: C, 59.66; H,
+
m, 3H), 4.31-4.39 (m, 1H), 5.11-5.18 (m, 2H), 5.75-5.90 (m,
16 4
for C10H O
1
3
H); C NMR (CDCl
8.46, 28.58, 33.26, 36.18, 39.63, 40.54, 77.51, 81.04, 118.42,
18.56, 132.73, 132.91, 174.32, 176.17; MS (CI, NH ) m/z (rel
3
, 100 MHz) δ 16.30, 17.45, 25.59, 26.16,
Calcd for C10
8.15.
16 4
H O
3
Eth yl (Z)-10-(1,3-Dioxola n -2-yl)-9-h yd r oxy-4-d ecen oa te
(22). DIBALH (0.09 mL, 0.131 mmol, 1.5 M solution in toluene)
was added to a cold (-78 °C) solution of 20 (20.3 mg, 0.109
+
intense) 155 [(M + H) , 100], 137 (21), 130 (5); HRMS (CI,
+
NH
3
) calcd for C
9 14 2
H O H [(M + H) ] 155.1072, found 155.1066.
6
-[(1,3-Dioxolan -2-yl)m eth yl]tetr ah ydr opyan -2-on e (20).
2 2
mmol) in dry CH Cl (1 mL). After 1 h, methanol (0.05 mL)
Osmium tetraoxide (0.85 mL of a 2.5 wt % solution in tert-
butyl alcohol) was added to a solution of 12 (0.794 g, 5.66
mmol) and N-methylmorpholine-N-oxide (NMO, 0.995 g, 8.49
mmol) in THF/t-BuOH (5:2, 11.2 mL). After 73 h, additional
portions of osmium tetraoxide (0.20 mL of a 2.5 wt % solution
in t-BuOH) and NMO (0.498 g, 4.25 mmol) were added. After
and water (0.05 mL) were added sequentially. After being
warmed to room temperature, the mixture was diluted with
ether (5 mL) and MgSO was added. After stirring vigorously
4
for 1 h, the mixture was filtered and the filter cake was washed
with ether (20 mL). The filtrate was concentrated to give 24.0
mg of the crude lactol as colorless oil. Potassium bis(tri-
methysilyl)amide (0.52 mL, 0.262 mmol, 0.5 M solution in
9
3
0 h, 10% aqueous NaHSO
0 min, brine (50 mL) was added and the mixture was
Cl (50 mL
) and concentrated.
The residue was purified by passing through a short plug of
silica gel (9:1 CHCl /MeOH) to give 0.385 g of colorless oil,
which was immediately dissolved in ether/H O (9 mL, 2:1) and
was treated with NaIO (0.637 g, 2.98 mmol) at 0 °C. After 15
4
(5 mL) was added at 0 °C. After
3 2 3 2
toluene) was added to a suspension of [Ph P(CH ) CO Et]Br
extracted with ethyl acetate (50 mL × 5) and CH
3). The organic layers were dried (MgSO
2
2
(26, 126 mg, 0.273 mmol)14 in dry THF (2.0 mL) at 0 °C. After
30 min, the mixture was cooled to -78 °C and the lactol in
dry THF (2.0 mL) was added. After 30 min at -78 °C, the
mixture was warmed to 0 °C, stirred for 1 h, then quenched
×
4
3
2
with saturated aqueous NH
4
Cl (5 mL), and extracted with
4
SO )
4
ether (10 mL × 3). The organic extracts were dried (Na
2
min, the mixture was warmed to room temperature and stirred
for 2 h. Brine (10 mL) was added to the mixture, and the
product was extracted with ethyl acetate (20 mL × 5). The
and concentrated. The residue was purified chromatographed
(3:1 hexane/ethyl acetate) to give 12.1 mg (39%) of the title
compound as colorless oil, which was found to be only the
1
organic layer was dried (MgSO
4
) and concentrated to give 0.277
Z-isomer by H NMR spectroscopy. R
f
) 0.40 (1:1 hexane/ethyl
-
1 1
g of colorless oil, which was dissolved in dry CH
2
Cl
2
(12 mL)
3
acetate); IR (neat) 3511 (br), 1734 (s) cm ; H NMR (CDCl ,
and stirred with ethylene glycol (0.133 g, 0.12 mL, 2.15 mmol)
and (TMS)Cl (TMS ) trimethylsilyl (0.466 g, 0.54 mL, 4.29
mmol) at room temperature for 6 h. The solution was diluted
400 MHz) δ 1.26 (t, J ) 7.3 Hz, 3H), 1.36-1.57 (m, 4H), 1.78
(ddd, J ) 5.1, 9.2, 14.3 Hz, 1H), 1.88 (ddd, J ) 2.2, 3.7, 14.3
Hz, 1H), 2.05-2.13 (m, 2H), 2.30-2.40 (m, 4H), 2.94 (br, 1H),
3.83-3.94 (m, 3H), 3.98-4.05 (m, 2H), 4.13 (q, J ) 7.3 Hz,
with CH
the organic phase was dried (MgSO
Chromatography (3:1 hexane/ethyl acetate) provided 0.157 g
2
Cl
2
(100 mL) and washed with brine (50 mL), and
1
3
4
) and concentrated.
2H), 5.04 (dd, J ) 3.7, 5.1 Hz, 1H), 5.31-5.45 (m, 2H);
NMR (CDCl , 100 MHz) δ 14.46, 23.04, 25.65, 27.26, 34.59,
37.06, 40.37, 60.51, 64.95, 65.15, 67.89, 103.84, 127.96, 131.26,
C
3
(
(
(
2
1
15% from 12) of the title compound as colorless oil. R ) 0.17
f
-
1
1
+
1:1 hexane/ethyl acetate); IR (neat) 1734 (s) cm ; H NMR
CDCl , 400 MHz) δ 1.55-1.67 (m, 1H), 1.81-2.05 (m, 4H),
.16 (ddd, J ) 3.3, 7.7, 13.9 Hz, 1H), 2.45 (ddd, J ) 7.0, 8.4,
7.6 Hz, 1H), 2.60 (ddd, J ) 1.1, 6.6, 17.6 Hz, 1H), 3.82-3.91
173.46; MS (CI, NH
269 (12), 216 (35), 297 (11), 199 (100); HRMS (CI, NH
for C15H O
26 5
3
) m/z (rel intense) 287 [(M + H) , 30],
) calcd
H [(M + H) ] 287.1858, found 287.1858. Anal.
: C, 62.91; H, 9.15. Found: C, 62.72; H,
3
3
+
Calcd for C15
9.12.
26 5
H O
(
m, 2H), 3.93-4.02 (m, 2H), 4.53 (dddd, J ) 2.9, 4.8, 7.7, 11.0
13
Hz, 1H), 5.08 (dd, J ) 3.7, 6.6 Hz, 1H); C NMR (CDCl
MHz) δ 18.62, 28.42, 29.54, 40.36, 65.00, 65.12, 77.23, 101.29,
3
, 90
Eth yl (Z)-9-Azido-10-(1,3-dioxolan -2-yl)-4-decen oate (23).
Methanesulfonyl chloride (166 mg, 0.11 mL, 1.45 mmol) was
added to a cold (-40 °C) solution of 22 (83 mg g, 0.290 mmol)
+
1
1
71.66; MS (CI, NH
3
) m/z (rel intense) 187 [(M + H) , 100],
) calcd for C H [(M +
85 (4), 169 (3); HRMS (CI, NH
3
9
H
14
O
4
and triethylamine (162 mg, 0.22 mL, 1.60 mmol) in dry CH
Cl (4.0 mL). After 1 h at room temperature, ether (20 mL)
was added and the mixture was washed with ice-cold 2% HCl
(20 mL) and then saturated NaHCO (20 mL). The organic
phase was dried (MgSO ) and concentrated to give pale yellow
2
-
+
H) ] 187.0970, found 187.0961.
-[(1,3-Dioxolan -2-yl)m eth yl]-3-m eth yltetr ah ydr opyr an -
-on e (21). Osmium tetraoxide (3.53 mL of a 2.5 wt % solution
2
6
2
3
in tert-butyl alcohol) was added to a solution of 13 (3.30 g, 21.68
mmol) and N-methylmorpholine-N-oxide (NMO, 7.26 g, 65.04
mmol) in THF/t-BuOH (5:2, 55 mL). After 20.5 h, ethyl acetate
4
oil that was dissolved in dry THF (1.4 mL) and treated with
tetra-n-butylammonium azide (1.16 mL, 1 M solution in THF,
1.16 mmol). After stirring for 17 h at room temperature, the
mixture was diluted with dichloromethane and washed with
(
200 mL) was added to the mixture and the organic layer was
separated and washed with 10% NaHSO solution (40 mL).
The aqueous layer was extracted with ethyl acetate (100 mL
5) and CH Cl
(100 mL × 5). The combined organic phases
were dried (MgSO ) and concentrated to give pale yellow oil,
which was dissolved in ether/H O (162 mL, 2:1) and was
treated with NaIO (6.03 g, 28.2 mmol) at 0 °C. After 15 min,
3
water (20 mL) and then the organic phase was dried (Na
SO ) and concentrated. The residue was chromatographed
(10:1 hexane/ethyl acetate) to give 76.2 g (84%) of the title
compound as colorless oil. R ) 0.50 (3:1 hexane/ethyl acetate);
IR (neat) 2103 (s), 1732 (s) cm ; H NMR (CDCl
2
-
×
2
2
4
4
2
f
-
1 1
4
3
, 400 MHz)
the mixture was warmed to room temperature, stirred for 1
h, then diluted with water (60 mL), and extracted with ethyl
δ 1.26 (t, J ) 7.3 Hz, 3H), 1.38-1.61 (m, 4H), 1.79 (ddd, J )
4.4, 5.9, 14.3 Hz, 1H), 1.91 (ddd, J ) 3.6, 8.8, 14.3 Hz, 1H),
2.06-2.13 (m, 2H), 2.34-2.37 (m, 4H), 3.52 (m, 1H), 3.85-
3.92 (m, 2H), 3.95-4.01 (m, 2H), 4.13 (q, J ) 7.3 Hz, 2H), 4.99
acetate (100 mL × 5). The organic phase was dried (MgSO
4
)
and concentrated to give colorless oil, which was dissolved in
benzene (108 mL) and heated with ethylene glycol (1.35 g, 1.21
(dd, J ) 3.7, 5.9 Hz, 1H), 5.33-5.45 (m, 2H); 13C NMR (CDCl
,
3
mL, 21.68 mmol) and p-TsOH‚H
2
O (0.325 g) at reflux for 30
90 MHz) δ 14.48, 23.05, 26.10, 27.00, 34.52, 34.70, 38.92, 59.20,
min using a Dean-Stark trap for water removal. The solution
was cooled and concentrated. The residue was chromato-
graphed (3:1 hexane/ethyl acetate) to give 1.54 g of the title
60.55, 65.06, 65.18, 102.23, 128.45, 130.67, 173.41; MS (CI,
+
NH
3
) m/z (rel intense) 284 [(M + H - N
2
) , 100], 212 (56), 198
3
(28), 196 (61), 182 (24), 156 (25); HRMS (CI, NH ) calcd for

Total Synthesis of (()-Quinolizidine 217A
H-N [(M + H - N
)+] 284.1862, found 284.1875.
J . Org. Chem., Vol. 63, No. 26, 1998 9915
C
15
H
25
O
4
N
3
2
2
tr a n s-2-[(1,3-Dioxolan -2-yl)m eth yl]-6-(4-h ydr oxybu tyl)-
p ip er id in e (28). A solution of 23 (26.8 mg, 0.0860 mmol) in
Anal. Calcd for C15 3: C, 57.86; H, 8.09; N, 13.49.
25 4
H O N
Found: C, 57.83; H, 8.03; N, 13.20.
6 6
C D (1.0 mL) in a sealable NMR tube was degassed using
three freeze/thaw cycles and then sealed under vacuum. The
tube were heated in an oil bath to 120 °C for 68.5 h, when
NMR spectroscopic analysis showed complete formation of the
Eth yl (Z)-10-(1,3-Dioxola n -2-yl)-9-h yd r oxy-6-m eth yl-4-
d ecen oa te (24). DIBALH (0.63 mL, 0.941 mmol, 1.5 M
solution in toluene) was added to a cold (-78 °C) solution of
1
tetrahydropyridine 27 [ H NMR (C
)
(
1
2
1
6
D
6
, 300 MHz) δ 0.95 (t, J
2
2 2
1 (0.157 g, 0.784 mmol) in dry CH Cl (3.7 mL). After 1 h,
7.1 Hz, 3H), 1.10-2.40 (m, 14H), 3.34-3.65 (m, 4H), 3.67
methanol (0.1 mL) and water (0.1 mL) were added sequen-
tially. After being warmed to room temperature, the mixture
was diluted with ether (5 mL) and MgSO was added. After
4
br, 1H), 3.96 (q, J ) 7.1 Hz, 2H), 5.48 (dd, J ) 3.7, 6.6 Hz,
H); 13C NMR (CDCl
, 90 MHz) δ 14.65, 19.69, 21.80, 28.83,
3
9.45, 34.17, 39.73, 43.30, 55.05, 60.28, 65.07 (overlap), 103.69,
67.85, 173.43]. After cooling the tube to 0 °C and unsealing,
being stirred vigorously for 1 h, the mixture was filtered and
the filter cake was washed with ether (20 mL). The filtrate
was concentrated to give 0.154 g (97% crude) of the lactol as
colorless oil. Potassium bis(trimethysilyl)amide (3.64 mL, 1.82
mmol, 0.5 M solution in toluene) was added to a suspension
the contents were washed from the tube with dichloromethane
10 mL) and the solvent was removed under reduced pressure
(
to give 27 as a colorless oil. A solution of 27 in dry THF (1.5
mL) was added to a suspension of LiAlH4 (32.6 mg, 0.860
mmol) in dry THF (1.5 mL) at -78 °C, followed by the addition
of trimethylaluminum (0.43 mL, 0.860 mmol, 2.0 M solution
in hexane).16 After 30 min, the solution was warmed to -40
1
4
of [Ph
3
P(CH
2 3 2
) CO Et]Br (26, 824 mg, 1.82 mmol) in dry THF
(
°
4.4 mL) at 0 °C. After 30 min, the mixture was cooled to -78
C and the lactol in dry THF (9.0 mL) was added. After 30
min at -78 °C, the mixture was warmed to 0 °C, stirred for 2
h, then quenched with saturated aqueous NH Cl (20 mL), and
extracted with ether (20 mL × 3). The organic extracts were
dried (Na SO ) and concentrated. The residue was purified
chromatographed (3:1 hexane/ethyl acetate) to give 0.124 g
52%) of the title compound as colorless oil, which was found
°
C for 1 h, then -20 °C for 1 h, and finally 0 °C for 1 h. The
4
mixture was diluted with ether (2 mL) and treated with
sodium fluoride (68 mg, 1.63 mmol) followed by the cautious
dropwise addition of water (0.05 mL). After 15 min, the
resulting slurry was filtered through Celite, washing the filter
pad with ether (20 mL). The combined filtrates were dried
2
4
(
1
to be a 1:1.2 mixture of diastereomers (both Z-alkenes) by H
NMR spectroscopy. R
(
(Na
2 4
SO ) and concentrated. The residue was chromatographed
f
) 0.38 (1:1 hexane/ethyl acetate); IR
1 1
-
(90:9:1, CHCl /MeOH/NH OH) to give 14.2 mg (68%) of 28 as
neat) 3504 (br), 1732 (s) cm ; H NMR (C
6
D
6
, 300 MHz) δ
3
4
a colorless oil, which was found to be a single diastereomer
0
1
3
.90 (d, J ) 6.6 Hz, 3H × 1.2/2.2), 0.91 (d, J ) 6.5 Hz, 3H ×
/2.2), 0.947 (t, J ) 7.2 Hz, 3H × 1.2/2.2), 0.954 (t, J ) 7.1 Hz,
H × 1/2.2), 1.15-1.60 (m, 4H), 1.80-1.84 (m, 2H), 2.15-2.50
1
13
by H and C NMR spectroscopy. R
f
) 0.12 (90:9:1, CHCl
3
/
,
-
1
1
MeOH/NH OH); IR (neat) 3332 (br) cm ; H NMR (CDCl
4
3
3
00 MHz) δ 1.24-1.74 (m, 13H), 1.95 (ddd, J ) 5.5, 8.7, 14.2
Hz, 1H), 2.64 (br s, 2H), 2.80-2.95 (m, 1H), 3.10-3.25 (m, 1H),
.64 (t, J ) 6.5 Hz, 2H), 3.80-4.01 (m, 4H), 4.93 (t, J ) 5.0
(
m, 5H), 2.75 (d, J ) 2.5 Hz, 1H × 1/2.2), 2.83 (d, J ) 2.7 Hz,
1
7
4
H × 1.2/2.2), 3.18-3.44 (m, 4H), 3.93 (m, 1H), 3.94 (q, J )
.2 Hz, 2H × 1/2.2), 3.95 (q, J ) 7.1 Hz, 2H × 1.2/2.2), 4.86-
.90 (m, 1H), 5.12-5.18 (m, 1H), 5.23-5.32 (m, 1H); 13C NMR
3
1
3
Hz, 1H); C NMR (CDCl , 90 MHz) δ 20.09, 22.56, 31.22,
3
3
1
2
2.03, 32.99, 34.19, 37.80, 47.42, 50.71, 62.84, 64.87, 65.10,
04.00; MS (CI, NH
42 (20), 224 (8), 171 (12), 170 (75); HRMS (CI, NH
(
3
3
CDCl , 100 MHz) δ 14.45, 21.48, 21.59, 23.27, 31.86, 31.94,
+
) m/z (rel intense) 244 [(M + H) , 39],
3.18, 33.41, 34.76, 35.33, 35.45, 40.36, 60.50, 64.93, 65.13,
8.05, 68.25, 103.81, 126.46, 126.49, 137.61, 137.69, 179,71;
3
) calcd for
6
3
+
+
C H O H [(M + H) ] 244.1913, found 244.1917.
MS (CI, NH
2
3
) m/z (rel intense) 301 [(M + H) ,23], 230 (33),
13 25
3
14 (14), 213 (38), 200 (18), 199 (100), 196 (14), 195 (20), 186
Assign m en t of th e Rela tive Con figu r a tion of 28. Ac-
cording to literature precedent, the CHN methine protons in
simple cis-2,6-dialkylpiperidines typically appear at δ 2.4-2.7
ppm, whereas these protons appear at approximately δ 2.8-
+
(
3
12), 185 (76); HRMS (CI, NH
01.2015, found 301.2018. Anal. Calcd for C16
H, 9.40. Found: C, 63.60; H, 9.49.
3
) calcd for C16
H
28
O
5
H [(M + H) ]
28 5
H O : C, 63.97;
3
.3 ppm in the trans diastereomers.17 In 28, the appearance
Eth yl (Z)-9-Azid o-10-(1,3-d ioxola n -2-yl)-6-m eth yl-4-d e-
cen oa te (25). Methanesulfonyl chloride (0.278 g, 0.19 mL, 2.43
mmol) was added to a cold (-40 °C) solution of 24 (0.146 g,
of the two CHN methine protons at ca. δ 2.9 and 3.2 ppm is
most consistent with the trans-2,6 diastereomer. In the other
possible diastereomer (29, see below), these protons appear
at ca. δ 2.5 and 2.7 ppm, consistent with the cis-2,6 diastere-
omer.
0
.486 mmol) and triethylamine (0.270 g, 0.37 mL, 2.67 mmol)
in dry CH Cl (6.7 mL). After 1 h at room temperature, ether
20 mL) was added and the mixture was washed with ice-cold
2
2
(
2
% HCl (20 mL) and then saturated NaHCO
3
(20 mL). The
cis-2-[(1,3-Dioxola n -2-yl)m eth yl]-6-(4-h yd r oxybu tyl)p i-
organic phase was dried (MgSO
4
) and concentrated to give pale
6 6
p er id in e (29). A solution of 23 (25.3 mg, 0.0813 mmol) in C D
yellow oil that was dissolved in dry THF (2.4 mL) and treated
with tetra-n-butylammonium azide (1.94 mL, 1 M solution in
THF, 1.94 mmol). After being stirred for 17 h at room
temperature, the mixture was diluted with dichloromethane
and washed with water (20 mL) and then the organic phase
(1.0 mL) in a sealable NMR tube was degassed and heated as
above. After cooling the tube to 0 °C and unsealing, the
contents were washed from the tube with benzene (10 mL)
and the solvent was removed under reduced pressure to give
2 2
27 as a colorless oil. A solution of 27 in dry CH Cl (0.5 mL)
was dried (Na
2
SO
4
) and concentrated. The residue was chro-
was treated with DIBALH (0.27 mL, 0.41 mmol, 1.5 M solution
in toluene) at -78 °C.16 After 30 min, the solution was warmed
to -40 °C for 1 h, then -20 °C for 1 h, and finally 0 °C for 1
h. The mixture was diluted with ether (2 mL) and treated with
sodium fluoride (68 mg, 1.63 mmol) followed by the cautious
dropwise addition of water (0.05 mL). After 15 min, the
resulting slurry was filtered through Celite, washing the filter
pad with ether (20 mL). The combined filtrates were dried
matographed (10:1 hexane/ethyl acetate) to give 0.137 g (87%)
of the title compound as colorless oil, which was found to be
an inseparable 1:1.2 mixture of diastereomers (both with the
1
Z-alkene geometry) by H NMR spectroscopy. R
f
) 0.48 (3:1
-
1
1
hexane/ethyl acetate); IR (neat) 2102 (s), 1732 (s) cm ; H
NMR (C
6
D
6
, 400 MHz) δ 0.82 (d, J ) 6.6 Hz, 3H × 1/2.2), 0.83
(
1
(
7
d, J ) 6.2 Hz, 3H × 1.2/2.2), 0.96 (t, J ) 7.1 Hz, 3H), 1.00-
.46 (m, 4H), 1.69-1.75 (m, 1H), 1.86-1.94 (m, 1H), 2.14 -2.35
(Na
(90:9:1, CHCl
2
SO
4
) and concentrated. The residue was chromatographed
/MeOH/NH OH) to give 5.5 mg (28%) of 27 as a
m, 5H), 3.31-3.37 (m, 2H), 3.43-3.53 (m, 3H), 3.96 (q, J )
3
4
.1 Hz, 2H), 4.91-4.94 (m, 1H), 5.01-5.07 (m, 1H), 5.21-5.29
colorless oil, which was found to be a single diastereomer by
1
3
1
13
(
m, 1H); C NMR (C
6
D
6
, 100 MHz) δ 14.66, 21.76, 21.88, 23.76,
2.09, 32.19, 33.51, 33.60, 34.04, 34.12, 34.91, 39.53, 39.60,
9.87, 60.08, 60.48, 65.11, 65.25, 102.62, 127.51, 127.58,
37.41, 137.52, 172.72; MS (CI, NH ) m/z (rel intense) 298 [(M
) , 100], 282 (2), 254 (2), 227 (8), 226 (38); HRMS
H and C NMR spectroscopy. R
f
-
) 0.21 (90:9:1, CHCl
3
/MeOH/
, 300 MHz)
1 1
3
5
1
+
(
NH
4
OH); IR (neat) 3334 (br) cm ; H NMR (CDCl
3
δ 0.98-1.85 (m, 14H), 2.13 (br, 2H), 2.43-2.55 (m, 1H), 2.69-
3
2.80 (m, 1H), 3.64 (t, J ) 6.5 Hz, 2H), 3.80-4.02 (m, 4H), 4.97
+
13
H - N
2
(dd, J ) 4.1, 5.5 Hz, 1H); C NMR (CDCl , 90 MHz) δ 22.21,
3
+
CI, NH
3
) calcd for C16
98.2018, found 298.2023. Anal. Calcd for C16
9.06; H, 8.36; N, 12.91. Found: C, 59.25; H, 8.16; N, 12.88.
H
27
O
4
N
3
H-N
2
[(M + H - N
2
) ]
24.97, 32.39, 32.96, 33.19, 36.98, 40.92, 53.68, 57.02, 62.83,
64.87, 65.12, 103.82; MS (CI, NH ) m/z (rel intense) 244 [(M
+ H) , 100], 242 (16), 171 (11), 170 (56); HRMS (CI, NH ) calcd
2
5
H
27
O
4
N
3: C,
3
+
3

9
916 J . Org. Chem., Vol. 63, No. 26, 1998
Pearson and Suga
+
for C13
H
25
O
3
H [(M + H) ] 244.1913, found 244.1901. See above
5.16. Found: C, 61.75; H, 9.23; N, 5.14. Data for 34: R
(2:1 CHCl /MeOH); colorless prisms (MeOH-ether); mp 204-
207 °C (dec); IR (KBr) 3434 (br), 1638 (w), 1546 (s) cm ; H
NMR [CDCl /methanol-d (1:1), 200 MHz] δ 1.01(d, J ) 7.3
f
) 0.18
for the assignment of the relative configuration of 27.
-(3-Ca r boeth oxyp r op yl)-6-[(1,3-d ioxola n -2-yl)m eth yl]-
-m eth ylp ip er id in e (32), (2R*,3S*,6R*)-2-(3-Ca r boxyp r o-
pyl)-6-[(1,3-dioxolan -2-yl)m eth yl]-3-m eth ylpiper idin e (33),
a n d (2R*,3R*,6R*)-2-(3-Ca r boxyp r op yl)-6-[(1,3-d ioxola n -
3
-
1
1
2
3
3
6
Hz, 3H), 1.45-2.40 (m, 13H), 3.07-3.30 (m, 2H), 3.85-4.06
(m, 4H), 5.02 (t, J ) 4.9 Hz, 1H); MS (CI, NH
3
) m/z (rel intense)
271 [(M + H - N ) , 87], 271 (16), 270 (70), 254 (26), 185 (15),
+
2
[
(
-yl)m eth yl]-3-m eth ylp ip er id in e (34). Three solutions of 25
46.6 mg (0.143 mmol), 44.9 mg (0.138 mmol), and 42.1 mg
0.129 mmol)] in C
2
184 (100), 182 (24), 166 (30); HRMS (CI, NH ) calcd for
3
D
6
(3 × 1.0 mL) in sealable NMR tubes
+
6
C
H
O
NH [(M + H) ] 272.1862, found 272.1852. Anal. Calcd
14
25
4
were degassed using three freeze/thaw cycles and then sealed
under vacuum. The tubes were heated in an oil bath to 130
for C14
25 4
H O N: C, 61.97; H, 9.29; N, 5.16. Found: C, 61.67;
H, 8.97; N, 5.13.
°
C for 66 h. After ca. 15 h, an intermediate was observed by
1
(2R*,3S*,6R*)-6-[(1,3-Dioxolan -2-yl)m eth yl]-2-(4-h ydr oxy-
bu tyl)-3-m eth ylp ip er id in e (35). Lithium aluminum hydride
H NMR spectroscopy, assigned as the triazolines 30 [partial:
δ 4.9 (dd), 4.7 (brq), 0.5 (d)]. After the full 66 h, the imine 31
was observed as the major product (dioxolanyl methine proton
appears as a multiplet at ca. δ 5.5 ppm), accompanied by
(17.3 mg, 0.456 mmol) was added to a solution of 33 (42.8 mg,
0
.158 mmol) in dry THF (4.5 mL) at 0 °C, and the mixture
was allowed to warm to room temperature. After 17.5 h, the
mixture was cooled to 0 °C and more lithium aluminum
hydride (10.2 mg, 0.269 mmol) was added. After 7 h at room
temperature, the mixture was cooled to 0 °C, diluted with ether
(15 mL), and treated with sodium fluoride (0.133 g, 3.16 mmol)
and water (0.1 mL). After 10 min, the resulting slurry was
filtered through a pad of Celite and sodium sulfate, washing
the filter cake with ether (50 mL). Concentration of the filtrate
and chromatography of the residue (90:9:1 CHCl /MeOH/NH -
another compound, believed to be the aziridine (dioxolanyl
methine proton appears as a multiplet at ca. δ 5.2 ppm).25 The
tubes were cooled to 0 °C and unsealed, and the contents were
rinsed out with CH
were concentrated and immediately dissolved in dry ethanol
6.6 mL) and mixed with PdCl (94.7 mg, 0.534 mmol) followed
by NaBH (46.4 mg, 1.233 mmol) at 0 °C. The mixture was
2 2
Cl (5 mL each). The combined solutions
(
2
1
8
4
allowed to warm to room temperature and, after 1 h, was
filtered through Celite, washing the filter cake with ethyl
acetate (20 mL × 3). The filtrate was washed with 15% NaOH
3
4
OH) provided 34.1 mg (84%) of 35 as colorless oil. R
f
) 0.31
(50 mL), dried (Na
2
SO
4
), concentrated, and passed through a
-1
1
(
90:9:1 CHCl
NMR (CDCl
J ) 4.0, 13.2 Hz, 1H), 1.15-1.39 (m, 4H), 1.47-1.80 (m, 8H),
3 4
/MeOH/NH OH); IR (neat) 3334 (br) cm ; H
short plug of silica gel (160:8:1, CHCl
7.4 mg of the ester 32 as colorless oil, which was found to be
3 4
/MeOH/NH OH) to give
3
, 500 MHz) δ 0.84 (d, J ) 6.2 Hz, 3H), 1.08 (dq,
8
1
a 1:1.3 mixture of diastereomers by H NMR spectroscopy. This
material was saponified without further purification (see
below). In a previous run, a sample of the pure ester 32 was
obtained by careful chromatography (160:8:1, CHCl
NH OH), again as an inseparable 1:1.3 mixture of diastereo-
mers (1:1.3): R ) 0.27 (90:9:1, CHCl /MeOH/NH OH); IR
neat) 3340 (w), 1731 (s) cm ; H NMR (CDCl , 400 MHz) δ
1
3
.91 (br, 2H), 2.14 (dt, J ) 2.1, 9.2 Hz, 1H), 2.71 (m, 1H), 3.62-
.70 (m, 2H), 3.82-3.88 (m, 2H), 3.94-4.00 (m, 2H), 4.98 (dd,
1
3
J ) 3.7, 5.5 Hz, 1H); C NMR (CDCl
2
6
3
, 100 MHz) δ 18.62,
3
/MeOH/
1.85, 32.96, 33.23, 33.52, 34.52, 36.26, 40.75, 53.53, 62.69,
4
2.79, 64.87, 65.11, 103.91; MS (CI, NH
3
) m/z (rel intense) 258
f
3
4
+
-
1
1
[(M + H) , 100], 257 (1), 241 (1), 240 (5), 238 (3), 184 (10), 170
(
3
+
(6); HRMS (CI, NH
3
) calcd for C14
H
27
O
3
NH [(M + H) ]
0
1
1
2
(
7
.84 (d, J ) 6.3, 3H × 1.3/2.3), 0.90 (d, J ) 6.6 Hz, 3H × 1/2.3),
.06-1.41 (m, 4H), 1.26 (t, J ) 7.1 Hz, 3H), 1.41-1.80 (m, 7H),
.90 (br, 1H), 2.13 (dt, J ) 2.6, 9.2 Hz, 1H × 1.3/2.3), 2.24-
.42 (m, 2H), 2.65 (dt, J ) 2.7, 6.9 Hz, 1H × 1/2.3), 2.68-2.78
2
58.2069, found 258.2064. See below for a discussion of the
relative configuration of 35.
(2R*,3R*,6R*)-6-[(1,3-Dioxolan-2-yl)methyl]-2-(4-hydroxy-
bu tyl)-3-m eth ylp ip er id in e (36). Lithium aluminum hydride
(79.6 mg, 2.10 mmol) was added to a solution of 34 (0.114 g,
m, 1H), 3.81-3.89 (m, 2H), 3.93-4.01 (m, 2H), 4.126 (q, J )
.1 Hz, 2H), 4.129 (q, J ) 7.1 Hz, 2H), 4.96 (t, J ) 6.2 Hz, 1H
1
3
×
1/2.3), 4.97 (t, J ) 6.0 Hz, 1H × 1.3/2.3); C NMR (CDCl
3
,
0
.419 mmol) in dry THF (21 mL) at 0 °C, and the mixture was
1
3
5
00 MHz) δ 11.63, 14.47, 18.58, 21.44, 21.85, 30.41, 32.45,
allowed to warm to room temperature. After 26 h, the mixture
was cooled to 0 °C, diluted with ether (30 mL), and treated
with sodium fluoride (0.352 g, 8.38 mmol) and water (0.2 mL).
After 10 min, the resulting slurry was filtered through a pad
of Celite and sodium sulfate, washing the filter cake with ether
3.58, 33.90, 34.54, 34.66, 36.14, 40.80, 41.15, 53.55, 54.44,
9.36, 60.42, 62.68, 64.83, 64.87, 65.14, 103.83, 103.88, 173.83;
) m/z (rel intense) 300 [(M + H) , 62], 212 (42),
29 4
84 (100), 166 (25); HRMS (CI, NH3) calcd for C16H O NH [(M
H) ] 300.2175, found 300.2170.
Sodium hydroxide (29.2 mg, 0.731 mmol) was added to a
solution of the ester 32 from above (87.4 mg) in ethanol (26
mL), and the mixture was heated at reflux for 1 h. After cooling
to room temperature, the mixture was concentrated and
+
MS (CI, NH
3
1
+
+
(
100 mL). Concentration of the filtrate and chromatography
of the residue (90:9:1 CHCl /MeOH/NH OH) provided 86.1 mg
80%) of 36 as colorless oil. R ) 0.16 (90:9:1 CHCl /MeOH/
, 500 MHz)
3
4
(
f
3
-1
1
4 3
NH OH); IR (neat) 3360 (br) cm ; H NMR (CDCl
δ 0.90 (d, J ) 7.3 Hz, 3H), 1.24-1.48 (m, 5H), 1.55-1.83 (m,
chromatographed (2:1, CHCl
to give 37.5 mg (34% from 25) of 33 as a colorless solid and
9.2 mg (26% from 25) of 34 as a colorless solid. See below
reductions of 33 and 34 to 35 and 36) for assignment of the
relative configurations. Data for 33: R ) 0.28 (2:1 CHCl
MeOH); colorless prisms (CHCl -hexane); mp ) 160-162 °C;
IR (KBr) 3422 (br), 1638 (w), 1560 (s) cm ; H NMR [CDCl
methanol-d (1:1), 360 MHz] δ 1.00 (d, J ) 6.5 Hz, 3H), 1.45-
.22 (m, 12H), 2.41 (m, 1H), 2.61 (br t, J ) 7.8 Hz, 1H), 3.17
m, 1H), 3.87-4.04 (m, 4H), 5.04 (t, J ) 4.0 Hz, 1H); MS (CI,
3
/MeOH) without further workup
1
6
)
2
6
0H), 2.65 (dt, J ) 2.9, 7.0 Hz, 1H), 2.73 (m, 1H), 3.65 (t, J )
.6 Hz, 2H), 3.81-3.90 (m, 2H), 3.91-4.03 (m, 2H), 4.96 (dd J
2
(
4.4, 5.9 Hz, 1H); 13C NMR (CDCl
, 75 MHz) δ 11.84, 22.59,
3
8.21, 30.64, 32.54, 33.08, 34.09, 41.17, 54.47, 59.60, 62.98,
f
3
/
4.86, 65.16, 103.79; MS (CI, NH
3
) m/z (rel intense) 258 [(M
3
+
-
1
1
+ H) , 100], 256 (14), 238 (16), 185 (12), 184 (61), 170 (29);
HRMS calcd for C14
258.2062.
3
/
+
H
27
O
3
NH [(M + H) ] 258.2069, found
6
2
(
Assign m en t of Rela tive Con figu r a tion s of 35 a n d 36.
+
NH
3
) m/z (rel intense) 272 [(M + H) , 70], 271 (28), 270 (100),
54 (64), 252 (26), 185 (15), 184 (100), 182 (24), 166 (30); HRMS
(
1) Cis r ela tion sh ip a t C(2) a n d C(6). For both 35 and 36,
2
1
the H NMR chemical shifts of the CHN methine protons
appear in the appropriate range for cis-2,6-disubstituted
piperidines (see the discussion above for 28 and 29). A
+
(CI, NH
3
) calcd for C14
H
25
O
4
NH [(M + H) ] 272.1862, found
N: C, 61.97; H, 9.29; N,
2
72.1873. Anal. Calcd for C14
25 4
H O
comparison to 29 is informative (Figure 3). H
consistently at ca. 2.7-2.8 ppm in 29, 35, and 36. H
at ca. 2.5 ppm in 29, but 35 and 36 (H ) 2.14 and 2.65 ppm,
b
appears
appears
(
25) In a separate experiment, chromatography of the imine 28 was
a
attempted (2:1 ethyl acetate/hexane followed by methanol/chloroform).
Although a pure sample of 28 could not be obtained due to its
decomposition, an impure byproduct was isolated in 15% yield that
had spectral data consistent with an aziridine. This material exhibited
the same multiplet at δ 5.2 ppm as that observed in the sealed tube
experiments.
a
respectively) show considerable variation from this value,
although still within the expected range for cis-2,6-disubsti-
tuted piperidines.17 However, correcting the H
shifts in 35
and 36 for the effect of a neighboring equatorial or axial methyl
a

Total Synthesis of (()-Quinolizidine 217A
J . Org. Chem., Vol. 63, No. 26, 1998 9917
(
2
t, J ) 6.6 Hz, 2H × 1/2.4), 3.80-3.90 (m, 2H), 3.93-4.02 (m,
H), 4.93 (t, J ) 4.6 Hz, 1H × 1.4/2.4), 4.96 (t, J ) 4.9 Hz, 1H
+
×
1/2.4); MS (CI, NH
3
) m/z (rel intense) 258 [(M + H) , 100],
2
56 (14), 240 (13), 238 (10), 184 (23), 170 (41); HRMS calcd
+
for C14
27 3
H O NH [(M + H) ] 258.2069, found 258.2057. See
above for a discussion of the methods used to determine the
relative configuration at C(2) and C(3).
(
1S*,4R*,10R*)-4-[(1,3-Dioxola n -2-yl)m et h yl]-1-m et h -
ylqu in olizid in e (37). Carbon tetrachloride (40.8 mg, 0.026
mL, 0.265 mmol) was added to a solution of 35 (34.1 mg, 0.132
mmol), triphenylphosphine (69.5 mg, 0.265 mmol), and Et
26.8 mg, 0.037 mL, 0.265 mmol) in dry MeCN (2 mL) at 0 °C.
After being stirred at room temperature for 20 h, the mixture
was concentrated and chromatographed (160:8:1 CHCl /MeOH/
NH OH) to give 23.7 mg (75%) of the title compound as
colorless oil. R ) 0.43 (90:9:1 CHCl /MeOH/NH OH); IR (neat)
876 (m), 2854 (m), 2787 (m), 2756 (w) cm ; H NMR (CDCl
00 MHz) δ 0.86 (d, J ) 6.2 Hz, 3H), 1.00-2.14 (m, 16H), 3.26
3
N
(
3
4
f
3
4
-
1 1
2
4
3
,
(
br d, J ) 11.1 Hz, 1H), 3.79-3.88 (m, 2H), 3.92-4.01 (m, 2H),
4
2
6
.93 (t, J ) 4.8 Hz, 1H); 13C NMR (CDCl
4.76, 26.35, 30.31, 32.76, 33.92, 36.13, 39.01, 51.99, 60.14,
4.87, 64.96, 69.92, 103.65; MS (CI, NH ) m/z (rel intense) 240
3
, 100 MHz) δ 19.47,
3
+
[
(M + H) , 73], 238 (6), 167 (19), 153 (17), 152 (100); HRMS
+
(
CI, NH
40.1928.
1R*,4R*,10R*)-4-[(1,3-Dioxola n -2-yl)m et h yl]-1-m et h -
ylqu in olizid in e (38). Carbon tetrachloride (0.208 g, 0.13 mL,
.35 mmol) was added to a solution of 36 (34.7 mg, 0.135
mmol), triphenylphosphine (0.354 g, 1.35 mmol), and Et
3 2
) calcd for C14H25NO H [(M + H) ] 240.1963, found
2
(
1
F igu r e 3. Assignment of relative configurations of 35 and 36.
group (see 42 and 43)26 allows an excellent correlation with
3
N
(0.137 g, 0.19 mL, 1.35 mmol) in dry MeCN (2 mL) at 0 °C.
After stirring at room temperature for 47 h, the mixture was
the value for H in 29 (i.e., 2.14 + 0.31 ) 2.45 for 35; 2.65-
a
0
.25 ) 2.40 for 36; compared with ca. 2.5 for 29). Finally, the
concentrated and chromatographed (160:8:1 CHCl
NH OH) to give 19.7 mg (61%) of the title compound as pale
yellow oil. R ) 0.42 (90:9:1 CHCl /MeOH/NH OH); IR (neat)
2880 (m), 2856 (m), 2790 (w), 2758 (w) cm ; H NMR (CDCl
3
/MeOH/
corresponding trans-2,6-disubstituted piperidines 44 (see be-
low) were also synthesized, each showing CHN methine
4
f
3
4
-
1 1
chemical shifts (H
a
+ H
b
) 2.8-2.95 ppm for the minor trans
3
,
diastereomer and 2.46 + 3.28 ppm for the major trans
diastereomer) downfield in value from 35/36, again consistent
with literature data and the assignments for 28 and 29
400 MHz) δ 0.99 (d, J ) 6.9 Hz, 3H), 1.18-2.08 (m, 16H), 3.29
(br d, J ) 11.1 Hz, 1H), 3.82-3.88 (m, 2H), 3.92-4.00 (m, 2H),
4.94 (dd, J ) 4.3, 5.5 Hz, 1H); 13C NMR (CDCl
, 100 MHz) δ
3
1
7
above.
2) Con figu r a tion of C(3) m eth yl gr ou p . Beyond the
consistency of the effect of the C(3) methyl configuration on
the chemical shifts of H discussed above, typical axial-axial
and axial-equatorial coupling constants are observed for 35
ac ) 9.2 Hz) and 36 (J ac ) 2.9 Hz), respectively.
2R*,3R*/S*,6S*)-6-[(1,3-Dioxola n -2-yl)m eth yl]-2-(4-h y-
d r oxybu tyl)-3-m eth ylp ip er id in e (44). A solution of 25 (40.5
mg, 0.124 mmol) in C (1.0 mL) in a sealable NMR tube
13.57, 25.22, 26.56, 27.81, 3.86, 32.12, 33.48, 38.66, 53.30,
61.34, 64.83, 64.95, 66.38, 103.64; MS (CI, NH ) m/z (rel
intense) 240 [(M + H) , 24], 167 (12), 166 (7), 153 (17), 152
(
3
+
+
(100); HRMS (CI, NH
240.1964, found 240.1957.
3 2
) calcd for C14H25NO H [(M + H) ]
a
(J
(1S*,4R*,10R*)-1-Meth yl-4-(Z)-(5-(tr im eth ylsilyl)p en t-
2-en -4-yn yl)qu in olizid in e (39). A solution of 37 (32.9 mg,
0.137 mmol) in THF and 1 M HCl (4:1, 8.4 mL) was heated at
50 °C for 25 h. After the solution was cooled to room
(
6
D
6
was degassed using three freeze/thaw cycles and then sealed
under vacuum. The tube was then heated in an oil bath at
temperature, saturated NaHCO
mixture, which was then extracted with ethyl acetate (30 mL
SO ) and concentrated
3
(20 mL) was added to the
1
20 °C for 67 h and then cooled to 0 °C and opened, and the
× 3). The organic phase was dried (Na
2
4
contents were rinsed out with CH Cl (10 mL). After concen-
2
2
to give pale yellow oil. In a separate flask, tert-butyllithium
(0.16 mL, 0.274 mmol, 1.7 M solution in pentane) was added
to a solution of 3-(tert-butyldimethylsilyl)-1-(trimethylsilyl)-
1-propyne (77.7 mg, 0.343 mmol)19 in dry THF (2.9 mL) at -78
°C. After 1 h, titanium tetraisopropoxide (96.3 mg, 0.10 mL,
0.339 mmol) was added to the mixture. After 10 min, a solution
of the crude aldehyde in dry THF (2.9 mL) was added to the
organotitanium reagent and the resulting mixture was held
at -78 °C for 1 h, -20 °C for 2 h, and at room temperature
tration, the residue was dissolved in THF (1.5 mL) and added
to a suspension of lithium aluminum hydride (47.1 mg, 1.24
mmol) in dry THF (1.5 mL) at -78 °C. Trimethylaluminum
(
0.62 mL, 1.24 mol, 2.0 M solution in hexane) was then added.16
After 30 min, the mixture was held at -40 °C for 1 h, -20 °C
for 1 h, and 0 °C for 1 h. The mixture was diluted with ether
(2 mL) and treated with sodium fluoride (68 mg, 1.63 mmol)
followed by the cautious dropwise addition of water (0.05 mL).
After 15 min, the resulting slurry was filtered through a short
pad of Celite, washing with ether (20 mL). The combined
for 2 h, after which saturated NH
the mixture was extracted with ethyl acetate (30 mL × 3). The
combined organic phases were dried (Na SO ) and concen-
trated. Chromatography (20:1 CHCl /MeOH) provided 16.6 mg
(42%) of the title compound as colorless oil. R ) 0.47 (90:9:1
CHCl /MeOH/NH OH); IR (neat) 2852 (m), 2784 (w), 2747 (w),
2149 (m) cm ; H NMR (CDCl , 400 MHz) δ 0.19 (s, 9H), 0.85
4
Cl (20 mL) was added and
filtrates were dried (Na
was chromatographed (90:4:1, CHCl
0.3 mg (32%) of the title compound as colorless oil, which was
2
SO
4
), and concentrated. The residue
2
4
3
/MeOH/NH OH) to give
4
3
1
f
found to be an inseparable 1:1.4 mixture of diastereomers as
3
4
1
-1 1
determined by H NMR analysis, both with the trans relative
3
configuration at C(2) and C(6). IR (neat) 3333 (br) cm-1; H
1
(d, J ) 6.6 Hz, 3H), 0.94-1.76 (m, 12H), 1.88-1.94 (m, 1H),
2.01-2.08 (m, 1H), 2.44-2.51 (m, 1H), 2.59-2.66 (m, 1H), 3.30
(br d, J ) 11.3 Hz, 1H), 5.54 (dt, J ) 10.7, 1.3 Hz, 1H), 6.04
NMR (CDCl
.93 (d, J ) 6.6 Hz, 3H × 1.4/2.4), 0.87-2.30 (m, 15H), 2.46
dt, J ) 3.4, 8.3 Hz, 1H × 1.4/2.4), 2.80-2.95 (m, 2H × 1/2.4),
.28 (m, 1H × 1.4/2.4), 3.64 (t, J ) 6.3 Hz, 2H × 1.4/2.4), 3.66
3
, 500 MHz) δ 0.84 (d, J ) 6.8 Hz, 3H × 1/2.4),
0
(dt, J ) 10.7, 7.4 Hz, 1H); 13C NMR (CDCl
, 100 MHz) δ 0.24,
19.42, 24.77, 26.29, 30.22, 32.00, 33.99, 35.08, 36.40, 52.02,
3.69, 69.87, 99.14, 102.36, 110.65, 142.83; MS (CI, NH ) m/z
rel intense) 290 [(M + H) , 39], 289 (3), 288 (9), 275 (3), 274
(10), 153 (15), 152 (100); HRMS (CI, NH ) calcd for C18
NSiH [(M + H) ] 290.2304, found 290.2308.
(
3
3
6
(
3
+
(26) Pretsh, E.; Clerc, T.; Seibl, J .; Simon, W. Tables of Spectral Data
for Structure Determination of Organic Compounds; Springer-Verlag:
Berlin, 1989.
3
31
H -
+

9
918 J . Org. Chem., Vol. 63, No. 26, 1998
1R*,4R*,10R*)-1-Meth yl-4-(Z)-(5-(tr im eth ylsilyl)p en t-
Pearson and Suga
(
salt: 1H NMR (acetone-d
6
, 500 MHz) δ 0.95 (d, J ) 6.6 Hz,
2
0
5
-en -4-yn yl)qu in olizid in e (40). A solution of 38 (17.0 mg,
.0710 mmol) in THF and 1 M HCl (4:1, 5 mL) was heated at
0 °C for 22 h. After the solution was cooled to room
1H, H-11), 1.33 (qd, J ) 12.4, 3.7 Hz, 1H, Hax-2), 1.49 (tq, J
) 4.0, 13.2 Hz, 1H, Hax-8), 1.74-1.88 (m, 4H, Heq-2, Heq-3,
Heq-7, Heq-8), 1.88-2.00 (m, 1H, Heq-9), 2.00-2.14 (m, 1H,
Hax-9), 2.14-2.31 (m, 3H, H-1, Hax-3, Hax-7), 2.67-2.78 (m,
2H, Hax-6, H-10), 2.89 (dddd, J ) 15.0, 7.7, 7.3, 1.5 Hz, H-12b),
2.95-3.14 (m, 2H, H-4, H-12a), 3.73 (d, J ) 1.8, 1H, H-16),
3.82 (dtt, J ) 12.1, 4.0, 1.8 Hz, 1H, Heq-6), 5.65 (dddd, J )
11.0, 2.2, 1.8, 1.5 Hz, 1H, H-14), 6.31 (dddd, J ) 11.0, 7.3, 7.0,
temperature, saturated NaHCO
mixture, which was then extracted with ethyl acetate (30 mL
3). The organic phase was dried (Na SO ) and concentrated
to give pale yellow oil. In a separate flask, tert-butyllithium
0.07 mL, 0.119 mmol, 1.7 M solution in pentane) was added
to a solution of 3-(tert-butyldimethylsilyl)-1-(trimethylsilyl)-
3
(20 mL) was added to the
×
2
4
(
1
7.0 Hz, 1H, H-13). The H NMR spectroscopic and mass
1
9
1
°
0
-propyne (32.4 mg, 0.143 mmol) in dry THF (1.5 mL) at -78
C. After 1 h, titanium tetraisopropoxide (38.5 mg, 0.04 mL,
.136 mmol) was added to the mixture. After 10 min, a solution
spectrometric data matched the literature values (see Sup-
7
6
porting Information), as did the IR spectal data.
(1R*,4R*,10R*)-1-Meth yl-4-(Z)-(p en t-2-en -4-yn yl)qu in o-
lizid in e (41). Tetra-n-butylammonium fluoride (0.23 mL, 0.23
mmol, 1.0 M solution in THF) was added to a solution of 40
(6.7 mg, 0.0231 mmol) in dry DMF (2 mL) at room tempera-
ture. After 2 h, the solution was diluted with ethyl acetate
of the crude aldehyde in dry THF (2.9 mL) was added to the
organotitanium reagent and the resulting mixture was held
at -78 °C for 1 h, -40 °C for 2 h, -20 °C for 1 h, and room
temperature for 2.5 h, after which saturated NH
was added and the mixture was extracted with ethyl acetate
10 mL × 3). The combined organic phases were dried (Na
SO ) and concentrated. Chromatography (30:1 CHCl /MeOH)
provided 8.1 mg (39%) of the title compound as colorless oil.
/MeOH); IR (neat) 2856 (m), 2788 (w),
755 (w), 2149 (m) cm-1; 1H NMR (CDCl
, 400 MHz) δ 0.19 (s,
H), 0.97 (d, J ) 6.9 Hz, 3H), 1.18-1.97 (m, 14H), 2.47 (ddd,
4
Cl (10 mL)
(
2
-
4
3
R
2
9
f
) 0.23 (20:1 CHCl
3
3
J ) 7.4, 7.4, 14.6 Hz, 1H), 2.60 (dd, J ) 7.4, 14.6 Hz, 1H),
.32 (br d, J ) 11.5 Hz, 1H), 5.54 (d, J ) 11.0 Hz, 1H), 6.07
3
1
3
(30 mL) and washed with water (30 mL × 5). The organic
(
1
6
dt, J ) 11.0, 7.4 Hz, 1H); C NMR (CDCl
3
, 100 MHz) δ 0.25,
3.61, 25.25, 26.61, 26.96, 31.73, 32.23, 33.59, 34.74, 53.09,
4.47, 66.13, 98.88, 102.56, 110.44, 143.06; MS (CI, NH ) m/z
2 4
phase was dried (Na SO ) and concentrated. Chromatography
(
15:1 CHCl
as pale yellow oil. R
(w), 2933 (s), 2854 (m), 2753 (w), 1442 (w), 1378 (w), 1342 (w),
321 (w), 1125 (w), 1102 (w), 1054 (w), 742 (w), 632 (w), 604
3
/MeOH) gave 3.7 mg (74%) of the title compound
3
+
f
) 0.24 (15:1 CHCl /MeOH); IR (neat) 3311
3
(
rel intense) 290 [(M + H) , 100], 289 (2), 288 (6), 182 (2), 164
+
(
2); HRMS (CI, NH
90.2304, found 290.2312.
1S*,4R*,10R*)-1-Meth yl-4-(Z)-(p en t-2-en -4-yn yl)qu in o-
3
) calcd for C18H31NSiH [(M + H) ]
1
(
2
-
1
1
3
w) cm ; H NMR (CDCl , 400 MHz) δ 0.97 (d, J ) 6.9 Hz,
(
3
2
5
H), 1.18-1.80 (m, 12H), 1.88-2.00 (m, 2H), 2.50-2.60 (m,
lizid in e (2). Qu in olizid in e 217A. Tetra-n-butylammonium
fluoride (0.53 mL, 0.53 mmol, 1.0 M solution in THF) was
added to a solution of 39 (15.4 mg, 0.0532 mmol) in dry DMF
H), 3.07 (d, J ) 1.6 Hz, 1H), 3.28 (br d, J ) 11.5 Hz, 1H),
.51 (dq, J ) 10.1, 1.9 Hz, 1H), 6.14 (dt, J ) 10.1, 7.4 Hz, 1H);
1
3
C NMR (CDCl , 100 MHz) δ 13.63, 25.22, 26.60, 26.83, 31.71,
3
(2 mL) at room temperature. After 1.5 h, the solution was
3
1
1
2.22, 33.57, 34.68, 52.98, 64.10, 66.06, 81.60, 109.28, 128.55,
43.69; MS (EI) m/z (rel intense) 217 (0.4), 216 (0.9), 202 (0.6),
53 (12), 152 (100), 150 (2.5), 136 (2.4), 110 (8.6), 91 (2.8), 84
(
2.9), 82 (2.5), 77 (2.3), 67 (2.6), 65 (2.6), 56 (2.7), 55 (6.3), 54
+
(2.5), 41 (6.5), 39 (3.9); HRMS (EI) calcd for C15
17.1830, found 217.1830.
H23N [M ]
2
Ack n ow led gm en t is made to the National Institutes
of Health for support of this research. We thank Drs.
J ohn W. Daly and Tom Spande (NIH-NIDDK) for
helpful discussions and for providing us with the results
of comparisons of our synthetic quinolizidine 217A with
the natural alkaloid by GC-FTIR and chiral GC.
diluted with ethyl acetate (50 mL) and washed with water (50
mL × 5). The organic phase was dried (Na SO ) and concen-
trated. Chromatography (15:1 CHCl /MeOH) gave 10.4 mg
90%) of the title compound as pale yellow oil. R ) 0.24 (15:1
/MeOH); IR (neat) 3311 (m), 2972 (w), 2927 (s), 2870
2
4
3
(
f
CHCl
3
(
(
7
0
2
w), 2851 (m), 2784 (w), 2747 (w), 1451 (w), 1441 (w), 1336
w), 1263 (w), 1127 (w), 1108 (w), 1085 (w), 1056 (w), 963 (w),
Su p p or tin g In for m a tion Ava ila ble: Text describing
experimental procedures for the preparation of 9, 10, and 14-
54 (m), 634 (m), 500 (m) cm-1; 1H NMR (CDCl
, 400 MHz) δ
3
1
1
9, a table comparing H NMR spectroscopic data for synthetic
.85 (d, J ) 6.6 Hz, 3H), 0.94-1.80 (m, 12H), 1.91 (m, 1H),
vs natural quinolizidine 217A (2), and photocopy figures
.07 (m, 1H), 2.50-2.65 (m, 2H), 3.07 (d, J ) 1.6 Hz, 1H), 3.27
1
showing of H NMR spectra of new compounds without
(
br d, J ) 11.0 Hz, 1H), 5.52 (ddt, J ) 1.9, 10.7, 1.6 Hz, 1H),
1
13
elemental analysis, including H and C NMR spectra of
synthetic quinolizidine 217A (2), its DCl salt, and its C(1)
epimer 41 (33 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.
6
1
6
.10 (dt, J ) 10.7, 8.0 Hz, 1H); 13C NMR (CDCl
, 100 MHz) δ
3
9.44, 24.76, 26.34, 30.28, 31.85, 33.99, 35.07, 36.39, 51.88,
3.24, 69.75, 80.83, 81.79, 109.51, 143.54. MS (EI) m/z (rel
intense) 217 (0.3), 216 (0.8), 202 (0.5), 153 (11.5), 152 (100),
1
5
50 (2), 136 (2.2), 110 (8.8), 91 (2.4), 84 (2.4), 67 (2.0), 65 (2.3),
6 (2.7), 55 (5.3), 54 (2.1), 41 (5.8), 39 (3.2); HRMS (EI) calcd
+
for C15
H
23N [M ] 217.1830, found 217.1837. Data for DCl
J O981695D