Short Enantioselective Total Syntheses of the Piperidine Alkaloids (S)-Coniine and (2R,6R)-trans-Solenopsin A via Catalytic Asymmetric Imine Hydrosilylation

Article abstract of DOI:10.1021/jo980808q

The enantioselective syntheses of (S)-coniine and (2R,6R)-trans-solenopsin A are reported. The key step in both syntheses is the catalytic asymmetric hydrosilylation of a cyclic imine.

Full text of DOI:10.1021/jo980808q

6
344
J . Org. Chem. 1998, 63, 6344-6347
Sh or t En a n tioselective Tota l Syn th eses of th e P ip er id in e Alk a loid s
(
S)-Con iin e a n d (2R,6R)-tr a n s-Solen op sin A via Ca ta lytic
Asym m etr ic Im in e Hyd r osilyla tion
Matthew T. Reding and Stephen L. Buchwald*
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received April 29, 1998
The enantioselective syntheses of (S)-coniine and (2R,6R)-trans-solenopsin A are reported. The
key step in both syntheses is the catalytic asymmetric hydrosilylation of a cyclic imine.
In tr od u ction
We have recently described an efficient and highly
enantioselective catalytic method for the hydrosilylation
of imines.1 To demonstrate the utility of our method, we
undertook the preparation of (S)-coniine (1), the poison-
ous hemlock alkaloid, and (2R,6R)-trans-solenopsin A (2),
a constituent of fire-ant venom.
Recent asymmetric syntheses of coniine have generally
involved the use of auxiliaries derived from the chiral
pool.2 An asymmetric aza-Diels-Alder reaction requir-
ing a stoichiometric amount of a chiral Lewis acid
,5
6
promoter has also been described, as well as the use of
a chiral borohydride reducing agent that was employed
in greater than stoichiometric amounts.7 A recent ap-
proach utilized the Sharpless asymmetric dihydroxyla-
tion reaction to catalytically introduce chirality for the
synthesis of 1.8
The solenopsin alkaloids were the subject of a recent
exhaustive review.9 In addition to numerous routes to
racemic trans-solenopsin A, there have also been reports
of several asymmetric syntheses, all of which began with
optically active amino acids or employed chiral auxilia-
ries. Our synthesis of trans-solenopsin A (vide infra) is
the first to take advantage of a catalytic asymmetric
transformation.
Due to their often potent biological activities, optically
active piperidine alkaloids containing a stereogenic car-
bon atom in the 2-position are an important group of
natural products, and they have been the target of
numerous synthetic strategies.2 Prior syntheses of this
type of alkaloid (vide infra) have generally involved the
use of asymmetry derived from naturally occurring
compounds; most often, this requirement directly pro-
hibits the availability of both antipodes of a given
product. The key step in our synthesis is the asymmetric
reduction of a cyclic imine using a chiral titanocene
Resu lts a n d Discu ssion
Endocyclic imines of the type required by our synthetic
strategy have themselves been the subject of much
synthetic effort.1
0-13
Our attempt at direct synthesis of
these compounds from 5-chlorovaleronitrile and organo-
metallic reagents1
0,13,14
did not afford the expected cyclic
5
catalyst. Since both enantiomers of the ethylenebis(η -
1
,2,3,4-tetrahydroindenyl)titanium difluoride precatalyst
(
5) (a) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7084.
employed here ((EBTHI)TiF , 3) can be obtained from a
2
,4
(
b) Fr e´ ville, S.; C e´ l e´ rier, J . P.; Thuy, V. M.; Lhommet, G. Tetrahe-
single synthetic procedure,3 products of either absolute
configuration can be prepared from the same substrate.
This is demonstrated in principle here by the opposing
sense of asymmetry required for the syntheses of natural
coniine (S) and solenopsin A (R).
dron: Asymmetry 1995, 6, 2651. (c) Oppolzer, W.; Bochet, C. G.;
Merifield, E. Tetrahedron Lett. 1994, 35, 7015. (d) Amat, M.; Llor, N.;
Bosch, J . Tetrahedron Lett. 1994, 35, 2223. (e) Al-awar, R. S.; J oseph,
S. P.; Comins, D. L. J . Org. Chem. 1993, 58, 7732. (f) Suzuki, H.;
Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1994, 35, 6119. (g) Enders,
D.; Tiebes, J . Liebigs Ann. Chem. 1993, 173. (h) Higashiyama, K.;
Nakahata, K.; Takahashi, H. Heterocycles 1992, 33, 17. (i) Ito, M.;
Maeda, M.; Kibayashi, C. Tetrahedron Lett. 1992, 33, 3765. (j) Comins,
D. L.; Hong, H.; Salvador, J . M. J . Org. Chem. 1991, 56, 7197. (k)
Kiguchi, T.; Nakazono, Y.; Kotera, S.; Ninomiya, I.; Naito, T. Hetero-
cycles 1990, 31, 1525. (l) Moody, C. J .; Lightfoot, A. P.; Gallagher, P.
T. J . Org. Chem. 1997, 62, 746. (m) Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 1997, 38, 4623. (n) Kim, Y. H.; Choi, J . Y. Tetrahe-
dron Lett. 1996, 37, 5543. (o) Weymann, M.; Pfrengle, W.; Schollmeyer,
D.; Kunz, H. Synthesis-Stuttgart 1997, 1151.
(
6) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749.
(7) Archer, J . F.; Boyd, D. R.; J ackson, W. R.; Grundon, M. F.; Khan,
W. A. J . Chem. Soc. C 1971, 2560.
8) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahe-
(
dron Asymmetry 1996, 7, 3047.
(9) Leclercq, S.; Daloze, D.; Braekman, J .-C. Org. Prep. Proced. Int.
1996, 28, 499.
(10) Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, 836.
(11) Fukuda, Y.; Matsubara, S.; Utimoto, K. J . Org. Chem. 1991,
56, 5812.
(
1) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L.
J . Am. Chem. Soc. 1996, 118, 6784.
2) (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. J . Chem. Soc.,
(
Chem.Commun. 1998, 633. (b) Hammann, P. In Organic Synthesis
Highlights II; Waldmann, H., Ed.; VCH: New York, 1995; p 323.
(
(
3) Chin, B.; Buchwald, S. L. J . Org. Chem. 1996, 61, 5650.
4) The difluoride precatalyst is available in one step from
(12) Vaultier, M.; Lambert, P. H.; Carri e´ , R. Bull. Soc. Chim. Fr.
1986, 83.
3
enantiomerically pure (EBTHI)Ti-2,2′-binaphth-1,1′-diol or (EBTHI)-
TiCl . See the Experimental Section and ref 1.
(13) Gallulo, V.; Dimas, L.; Zezza, C. A.; Smith, M. B. Org. Prep.
Proced. Int. 1989, 21, 297.
2
S0022-3263(98)00808-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/19/1998

Total Syntheses of (S)-Coniine and (2R,6R)-trans-Solenopsin A
J . Org. Chem., Vol. 63, No. 18, 1998 6345
Sch em e 1
Sch em e 4
Sch em e 2
afford (2R,6R)-trans-solenopsin A (2) in 88% yield (Scheme
4
). This alkylation procedure was previously applied to
2
0
the synthesis of racemic 2 by Beak and co-workers.
Con clu sion
Sch em e 3
Asymmetric syntheses of the piperidine alkaloids (S)-
coniine and (2R,6R)-trans-solenopsin A have been carried
out. Our recently published method for highly enantio-
selective imine hydrosilylation allows for a direct and
efficient route to these interesting chiral amines.
Exp er im en ta l Section
imines; however, ω-chloro ketones 4a and 4b which were
instead obtained (Scheme 1) served as useful synthetic
intermediates.15 Transient preparation of ω-azido ke-
Gen er a l Meth od s. All manipulations, unless otherwise
specified, were carried out under an argon atmosphere using
standard air-free techniques; glassware was oven-dried and
cooled under vacuum. All reagents were either commercially
available and used as obtained or were prepared according to
published methods. Ether and THF were distilled from
sodium/benzophenone ketyl under argon. TMEDA (Aldrich)
was distilled from calcium hydride prior to use. Yields, unless
otherwise stated, refer to isolated yields of compounds greater
1
6
tones via solid/liquid phase-transfer catalysis followed
by aza-Wittig cyclization1
2,17,18
afforded the desired imines.
Our stereochemical model for the hydrosilylation of
1
imines (which follows from the related imine hydrogena-
tion)19 predicts that the precatalyst required for the
production of the natural S enantiomer of coniine is
(
5
%
R,R)-3. Accordingly, room-temperature reaction of imine
a with 2 equiv of phenylsilane in the presence of 1 mol
(R,R)-3 (which had been activated by treatment with
1
than 95% pure as assessed by capillary GC and H NMR. All
compounds were further characterized by IR, and previously
unreported compounds gave satisfactory elemental analyses.
5
pyrrolidine and methanol; see Experimental Section),
followed by acidic hydrolysis of the initially formed
aminosilane, afforded (S)-coniine (1) with an ee of 99%
(R,R)-Eth ylen ebis(η -tetr a h yd r oin d en yl)tita n iu m Di-
2
flu or id e ((R,R)-(EBTHI)TiF ), (R,R)-3. (R,R,R)-(EBTHI)-
3
Ti-2,2′-binaphth-1,1′-diol (1.0 g, 1.68 mmol) was suspended
in ether (50 mL). Methyllithium (1.4 M in hexanes, 6.0 mL,
.40 mmol) was added with stirring over 10 min at room
temperature. The deep red mixture turned bright yellow over
the next 1.25 h. The ether was removed in vacuo, and hexane
20 mL) was added. The supernatant was removed by cannula
(
8
(
Scheme 2). This product was immediately converted in
0% overall yield from 5a to the tert-butoxycarbamate
BOC) derivative 6 to facilitate product isolation, due to
8
the volatility of 1.
(
The synthesis of trans-solenopsin A required the
construction of a new stereogenic center with R absolute
configuration (in contrast to the case of coniine). There-
fore, in a similar sequence, imine 5b was hydrosilylated
using (S,S)-3 to give (R)-amine 7 with an ee greater than
filtration, and the solids were rinsed with additional hexane
(10 mL). The combined orange filtrates were cooled on an ice
bath, and pyridine‚HF adduct (0.15 mL, approximately 5
mmol) was added via syringe (Ca u tion : this complex will etch
glass syringes; use of a plastic syringe is advised). The yellow
mixture was stirred for an additional 30 min, and the reaction
mixture was quenched with saturated sodium bicarbonate. The
layers were separated, and the aqueous portion was extracted
(3 × 20 mL CH Cl ). The combined organic layers were
9
9%. Amine 7 was directly converted to the BOC
derivative 8 (Scheme 3). Optically active carbamate 8
was methylated in the 6-position in a stereocontrolled
manner. The resulting carbamate 9 was deprotected to
2
2
4
washed (brine), dried (MgSO ), filtered, and concentrated in
vacuo to afford a bright yellow solid. This was recrystallized
in two crops from hot toluene/hexane as air-stable yellow
plates, 481 mg, 82%.21 The ee of this complex was determined
to be g99%, as demonstrated by using it as a precatalyst for
the hydrosilylation of N-(1-phenylethylidene)methylamine,
which afforded (R)-N-methyl-1-phenylethylamine with 99%
(
14) Treatment of 5-bromovaleronitrile with n-propylmagnesium
chloride provided a mixture that was 52% 5a by GC analysis (uncor-
rected for response factors). Reaction of n-undecylmagnesium bromide
with the same bromonitrile gave a mixture that contained only 5% 5b
by GC analysis.
(15) By employing benzene as a cosolvent during the Grignard
1
1
ee: mp 235 °C; H NMR (300 MHz, CDCl
Hz, 2 H), 5.68 (d, J ) 3.0 Hz, 2 H), 3.16 (m, 2 H), 3.13 (m, 2
H), 2.41-2.75 (m, 8 H), 1.88 (m, 4 H), 1.58 (m, 4 H); C NMR
3
) δ 6.00 (d, J ) 2.9
reaction and performing the imine hydrolysis at 60 °C instead of room
temperature, we have been able to prepare the related 2-ethyl-3,4,5,6-
tetrahydropyridine without isolation of the intermediate chloroketone
in 67% overall yield after distillation: Yang, B. H.; Buchwald, S. L.
Unpublished results. See also ref 10.
1
3
(75 MHz, CDCl
3
): δ 136.3, 133.9, 125.5, 123.8, 108.8, 27.9,
-1
2
2
0
3.9, 23.6, 22.0 (2 carbons); IR (KBr pellet, cm ) 3083, 2930,
(
16) Koziara, A.; Osowska-Pacewicka, K.; Zawadzki, S.; Zwierzak,
A. Synthesis 1985, 202.
17) Khoukhi, M.; Vaultier, M.; Carri e´ , R. Tetrahedron Lett. 1986,
7, 1031.
18) Lambert, P. H.; Vaultier, M.; Carri e´ , R. J . Chem. Soc., Chem.
Commun. 1982, 1224.
19) (a) Willoughby, C. A.; Buchwald, S. L. J . Am. Chem. Soc. 1994,
20
852, 1444, 1290, 832, 810, 566, 551, 499; [R]
D
) +85.2° (c
1
20
1
.81, CH
2
Cl
2
(lit. for (S,S)-3 [R]
D
) -76.0° (c 0.96, CHCl
3
)).
(
2
Anal. Calcd for C20
68.73; H, 7.15.
H F Ti: C, 68.57; H, 6.91. Found: C,
24 2
(
(
1
1
1
16, 11703. (b) Willoughby, C. A.; Buchwald, S. L. J . Am. Chem. Soc.
994, 116, 8952. (c) Willoughby, C. A.; Buchwald, S. L. J . Org. Chem.
993, 58, 7627. (d) Willoughby, C. A.; Buchwald, S. L. J . Am. Chem.
(20) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(21) This compound may also be obtained by treating the binaphthol
complex with KHF
results.
2
: Hansen, M. C.; Buchwald, S. L. Unpublished
Soc. 1992, 114, 7562.

6
346 J . Org. Chem., Vol. 63, No. 18, 1998
-Ch lor o-5-octa n on e, 4a .12 To a solution of n-propylmag-
Reding and Buchwald
1
(br, s, 2 H), 2.02 (t, 2 H, J ) 3.9 Hz), 1.69 (m, 2 H), 1.61 (m, 2
-
1
nesium bromide (1.0 M in ether, 27.0 mL, 27.0 mmol) in a 100
mL Schlenk flask was added 5-chlorovaleronitrile (3.04 mL,
2
H), 1.29 (m, 4 H), 0.81 (t, 3 H, J ) 7.2 Hz); IR (neat, cm )
1662.
7.0 mmol), dropwise, via syringe. The reaction mixture was
2-Un decyl-3,4,5,6-tetr ah ydr opyr idin e, 5b.23 Sodium azide
stirred for 2 h, at which time analysis by GC showed no
remaining nitrile. The reaction vessel was cooled on an ice
bath, and ice was added in portions to the reaction mixture.
Vigorous bubbling took place. The reaction mixture was
acidified (1 M HCl) and extracted (5 × 30 mL ether). The
(1.07 g, 16.5 mmol) and tetrabutylammonium bromide (8.2
mmol, 0.26 g) were suspended in benzene (5 mL) in a 100 mL
Schlenk flask. To the resulting solution was added a benzene
solution of 4b (8.2 mmol, 2.25 g), and then the flask was
equipped with a condenser equipped with an argon balloon.
The mixture was heated in an 80 °C oil bath overnight (ca. 12
h). GC analysis showed no remaining chloroketone, and the
reaction mixture was cooled to room temperature. The
mixture was filtered, and the solids were rinsed with ether;
the filtrate was washed (1 × 20 mL water), and the aqueous
layer was extracted (3 × 20 mL ether). The combined ether
4
combined ether layers were washed (brine), dried (MgSO ),
filtered, and concentrated in vacuo to afford a yellow oil. This
was passed through a plug of silica gel (10:1 hexane/ethyl
acetate), concentrated, and vacuum distilled to afford a clear
1
oil: 2.44 g, 55%; H NMR (300 MHz, CDCl
3
) δ 3.53 (t, 2 H, J
)
6.4 Hz), 2.44 (t, 2 H, J ) 6.8 Hz) 2.38 (t, 2 H, J ) 7.7 Hz),
.77 (m, 4 H), 1.59 (m, 2 H), 0.94 (t, 3 H, J ) 7.3 Hz); IR (neat,
1
layers were washed (brine), dried (MgSO ), and filtered. The
4
-
1
cm ) 1714.
volume of solvent was reduced to 20 mL (see warning above),
and the resulting solution was placed in a dry 100 mL Schlenk
flask and purged with argon. Triphenylphosphine (3.93 g, 15.0
mmol) was added, and the reaction mixture was stirred
overnight. The mixture was diluted with pentane and filtered,
and the solids were rinsed with additional pentane. The
solution was then passed through neutral Activity I alumina.
1
-Ch lor o-5-h exa d eca n on e, 4b. A three-necked 100 mL
round-bottomed flask was equipped with a stirbar, condenser,
and an addition funnel and purged with argon. Magnesium
turnings (729 mg, 30 mmol) and a small crystal of iodine were
placed in the flask, and 10 mL of ether was added. A solution
of undecyl bromide (6.70 mL, 30 mmol) in 10 mL of ether was
prepared in the addition funnel, and a few drops of this was
added to the magnesium with stirring; the brown suspension
immediately became colorless. Additional ether (10 mL) was
placed in the addition funnel, and the solution was added
dropwise, with stirring, to the magnesium at such a rate to
maintain a gentle reflux. The mixture was stirred for an
additional 3 h and then transferred via cannula into a 100
mL Schlenk flask. 5-Chlorovaleronitrile (3.38 mL, 30.0 mmol)
was added dropwise, via syringe, and the reaction mixture was
stirred overnight. The reaction vessel was then cooled on an
ice bath, and ice was added in portions to the reaction mixture.
Vigorous bubbling took place. The reaction mixture was
acidified (1 M HCl) and extracted (5 × 30 mL ether). GC
analysis showed approximately 45% desired product, along
with undecane and docosane as impurities. The undecane was
removed by vacuum distillation, and the remaining material
was purified by column chromatography (20:1 hexane/ethyl
The solution was concentrated in vacuo, and the resulting oil
was distilled (Kugelrohr, 10-2 Torr, 90-95 °C) to give a clear,
faintly yellow, air-sensitive oil, 1.16 g, 60%. The imine was
1
stored at -20 °C in a nitrogen-filled glovebox:
H NMR (300
MHz, C D ): δ 3.55 (m, 2 H), 2.10 (m, 4 H), 1.64 (m, 2 H), 1.54
(m, 4 H), 1.29 (br s, 16 H), 0.88 (t, J ) 6.3 Hz, 3 H); IR (neat,
6
6
cm-1) 1664.
(
S)-(+)-N-(ter t-Bu toxycar bon yl)-2-pr opylpiper idin e ((S)-
5g
(
+)-N-BOC-con iin e), 6.
A resealable Schlenk flask was
charged with (R,R)-3 (3.5 mg, 10 µmol). THF (0.8 mL) was
then added via syringe, followed by phenylsilane (0.25 mL,
2
0
.0 mmol), pyrrolidine (8 µL, 0.1 mmol), and methanol (4 µL,
.1 mmol). The mixture was stirred in a 50 °C oil bath for 10
min. During this time, a color change from yellow to emerald
green occurred. The flask was then sealed and transferred to
a nitrogen-filled glovebox. Imine 5a was added (125 mg, 1.0
mmol), and the flask was resealed, removed from the glovebox,
and stirred at room temperature. When GC analysis showed
consumption of the starting material was complete (about 6
h), the reaction mixture was diluted with THF (20 mL) and
stirred with 1 M HCl (10 mL) for 0.5 h (Ca u tion : vigorous
bubbling). The mixture was washed (3 × 20 mL of 1 M HCl),
and the combined aqueous layers were made basic with 4 M
NaOH and extracted (3 × 20 mL of ether). The combined ether
1
acetate) to afford a clear oil, 2.41 g, 29%: H NMR (300 MHz,
CDCl
3
) δ 3.54 (t, 2 H, J ) 7.0 Hz), 2.41 (m, 4 H), 1.77 (m, 4
H), 1.57 (m, 2 H), 1.29 (br, s, 16 H), 0.88 (t, 3 H, J ) 7.2 Hz);
1
3
C NMR (75 MHz, CDCl
9.9, 29.8, 29.7, 29.6, 24.2, 23.0, 21.4, 14.4; IR (neat, cm
715. Anal. Calcd for 31ClO: C, 69.91; H, 11.37.
3
) δ 210.8, 44.9, 43.2, 42.0, 32.4, 32.3,
-
1
2
1
)
16
C H
Found: C, 69.75; H, 11.23.
-P r op yl-3,4,5,6-tetr a h yd r op yr id in e, 5a . Sodium azide
1.95 g, 30.0 mmol) and tetrabutylammonium bromide (0.48
1
2
2
4
layers were washed (brine), dried (MgSO ), and filtered. To
(
this solution of the free amine was immediately added di-tert-
butyl dicarbonate (0.218 g, 1.0 mmol) and triethylamine (0.28
mL, 2.0 mmol), and the mixture was stirred for 2-3 h at room
temperature. The mixture was concentrated in vacuo, and the
residue was dissolved in THF (10 mL). Unreacted di-tert-butyl
dicarbonate was destroyed by adding 4 M NaOH (5 mL). After
g, 1.5 mmol) were suspended in benzene (10 mL) in a 100 mL
Schlenk flask. 4a (2.44 g, 15.0 mmol) was added as a solution
in benzene, and the flask was equipped with a condenser
equipped with an argon balloon. The mixture was heated in
an 80 °C oil bath overnight (ca. 12 h). At this point, GC
analysis showed no remaining chloroketone, and the reaction
mixture was cooled to room temperature. The mixture was
filtered, and the solids were rinsed with ether; the filtrate was
washed (1 × 20 mL water) and the aqueous layer was
extracted (3 × 20 mL ether). The combined ether layers were
1
h, the reaction mixture was acidified and extracted (5 × 15
mL ether). The combined ether layers were washed (brine),
dried (MgSO ), filtered, and concentrated in vacuo to afford a
4
slightly yellow oil. This was purified by column chromatog-
raphy (15:1 hexane/ethyl acetate, 0.5% triethylamine) to give
4
washed (brine), dried (MgSO ), and filtered. The volume of
a clear oil, 183 mg, 80% from 5a : 1H NMR (300 MHz, CDCl
3
)
solvent was reduced to 20 mL (Ca u tion : azides are potential
δ 4.21 (br s, 1 H), 3.95 (br, d, 1 H, J ) 11.0 Hz), 2.74 (t, 1 H,
J ) 12.5 Hz), 1.45 (s, 9H), 1.20-1.65 (m, 10 H), 0.92 (t, 3 H,
2
2
shock and contact explosives), and the resulting solution was
placed in a dry 100 mL Schlenk flask and purged with argon.
Triphenylphosphine (3.93 g, 15.0 mmol) was added, and the
reaction mixture was stirred overnight. The mixture was
diluted with pentane and filtered, and the solids were rinsed
with additional pentane. The solution was then passed
through neutral Activity I alumina. The solution was con-
centrated in vacuo, and the resulting oil was distilled (short-
path, 1 atm Ar, 168 °C) to give a clear, faintly yellow, air-
-1
J ) 7.2 Hz); IR (neat, cm ) 1694. Chiral GC analysis of the
trifluoroacetamide derivative (prepared after removing the
20
BOC group with TFA in CH
2
Cl
2
) showed an ee of 99%: [R]
D
24
5g
20
)
+29.8° (c 1.3, CHCl
3
)
(lit. [R]
D
) +33.5° (c 0.43, CHCl
3
)).
The spectral data for this compound matched that reported
5g
in the literature.
(
23) Bacos, D.; C e´ l e´ rier, J . P.; Marx, E.; Rosset, S.; Lhommet, G. J .
Heterocycl. Chem. 1990, 27, 1387.
24) The specific optical rotation for this compound was determined
sensitive oil, 1.16 g, 62%. The imine was stored at -20 °C in
1
a nitrogen-filled glovebox: H NMR (300 MHz, C
6
D
6
) δ 3.55
(
on a sample obtained according to the method described herein that
was spectroscopically ( H NMR) identical to previously prepared
1
(22) Grashey, R. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: New York, 1991; Vol. 6, p 245.
samples.

Total Syntheses of (S)-Coniine and (2R,6R)-trans-Solenopsin A
J . Org. Chem., Vol. 63, No. 18, 1998 6347
(
R )-(-)-N -(t er t -B u t o x y c a r b o n y l)-2-u n d e c y lp ip e r i-
mmol) was added dropwise, and the solution was allowed to
warm slowly over 1 h to -20 °C and stirred at that temper-
ature for an addition 30 min. The solution was then recooled
to -65 °C, and dimethyl sulfate (1.0 mmol, 0.1 mL) was added.
The mixture was allowed to warm to room temperature
overnight. The reaction mixture was then quenched with
d in e, 8. A resealable Schlenk flask was charged with (S,S)-
1
3
(3.5 mg, 10 µmol). THF (0.8 mL) was then added via
syringe, followed by phenylsilane (0.25 mL, 2.0 mmol), pyr-
rolidine (8 µL, 0.1 mmol), and methanol (4 µL, 0.1 mmol). The
mixture was stirred in a 50 °C oil bath for 10 min. During
this time, a color change from yellow to emerald green
occurred. The flask was then sealed and transferred to a
nitrogen-filled glovebox. Imine 5b was added (237 mg, 1.0
mmol), and the flask was resealed, removed from the glovebox,
and stirred at room temperature. When GC analysis showed
consumption of the starting material was complete (about 6
h), the reaction mixture was diluted with THF (20 mL) and
stirred with 1 M HCl (10 mL) for 0.5 h (Ca u tion : vigorous
bubbling). The mixture was washed (3 × 20 mL of 1 M HCl),
and the combined aqueous layers were made basic with 4 M
NaOH and extracted (3 × 20 mL ether). The combined ether
water (10 mL), extracted (6 × 10 mL ether), dried (MgSO
4
),
filtered, and concentrated in vacuo to afford a clear oil.
Purification by column chromatography (15:1 hexane/ethyl
1
acetate, 0.5% triethylamine) gave a clear oil, 154 mg, 87%. H
NMR indicated the presence of a single diastereomer. The de
of this compound was determined to be g99% by chiral GC
analysis of the trifluoroacetamide derivative (prepared after
1
removing the BOC group with TFA in CH
MHz, CDCl
1.90 (m, 29 H). 0.88 (t, 3 H, J ) 6.2 Hz); C NMR (75 MHz,
CDCl ) δ 155.3, 78.6, 51.7, 47.0, 34.4, 31.9, 29.6, 29.5, 29.3,
28.5, 27.1, 23.5, 22.6, 20.8, 14.0; IR (neat, cm ) 2923, 2854,
2
Cl
2
): H NMR (300
3
) δ 3.93 (m, 1 H), 3.80 (m, 1 H); 1.46 (s, 9 H), 1.20-
13
3
-
1
4
layers were washed (brine), dried (MgSO ), and filtered. To
this solution of the free amine were immediately added di-
tert-butyl dicarbonate (0.218 g, 1.0 mmol) and triethylamine
0.28 mL, 2.0 mmol), and the mixture was stirred for 2-3 h
2
0
1690, 1392, 1364, 1324, 1178; [R]
D
) -26.3° (c 4.7, CH
2 2
Cl ).
Anal. Calcd for C22
74.46; H, 12.20.
H43NO : C, 74.73; H, 12.26. Found: C,
2
(
at room temperature. The mixture was concentrated in vacuo,
and the residue was dissolved in THF (10 mL). Unreacted
di-tert-butyl dicarbonate was destroyed by adding 4 M NaOH
(2R,6R)-(-)-tra ns-2-Undecyl-6-methylpiperidine ((2R,6R)--
(-)-tr a n s-Solen op sin A), 2.25 The title compound was
prepared by stirring carbamate 9 (28.1 mg, 0.08 mmol) with
(
5 mL). After 1 h, the reaction mixture was acidified and
extracted (5 × 15 mL ether). The combined ether layers were
washed (brine), dried (MgSO ), filtered, and concentrated in
excess TFA (ca. 10 equiv) in CH
reaction mixture was quenched with saturated NaHCO
the aqueous layers were extracted (5 × 10 mL ether). The
combined organic layers were dried (MgSO ) and concentrated
in vacuo to afford a clear oil, 18.4 mg, 91%: H NMR (300
MHz, CDCl ) δ 3.16 (m, 2 H), 2.85 (m, 2 H), 1.35-1.65 (m, 9
2
Cl
2
(1 mL) overnight. The
3
, and
4
vacuo to afford a faintly yellow oil. This was purified by
column chromatography (15:1 hexane/ethyl acetate, 0.5%
4
1
1
triethylamine) to give a clear oil, 279 mg, 82% from 5b:
NMR (300 MHz, CDCl
4.7 Hz), 2.74 (t, 1 H, J ) 16.4 Hz), 1.55 (s, 9 H), 1.20-1.65
H
3
3
) δ 4.18 (br s, 1 H), 3.96 (br d, 1 H, J )
H), 1.25 (br s, 18 H), 1.09 (d, J ) 6.3 Hz, 3 H), 0.88 (t, J ) 7.2
-
1
1
Hz, 3 H); IR (neat, cm ) 2935, 2851, 1467, 1382, 1140, 1064.
Chiral GC of the trifluoroacetamide derivative showed a de of
1
3
(
m, 26 H), 0.88 (t, 3 H, J ) 6.4 Hz); C NMR (75 MHz, CDCl
δ 155.1, 78.8, 50.4, 38.7, 31.9, 29.7, 29.6, 29.5, 29.3, 28.5, 26.3,
5.7, 22.6, 19.0, 14.0; IR (neat, cm-1) 1693. Chiral GC analysis
of the trifluoroacetamide derivative (prepared after removing
the BOC group with TFA in CH Cl ) showed an ee of 99%:
). Anal. Calcd for C21
C, 74.28; H, 12.17. Found: C, 74.15; H, 11.99.
2R,6R)-(-)-tr a n s-N-(ter t-Bu toxyca r bon yl)-2-u n d ecyl-
-m eth ylp ip er id in e ((2R,6R)-(-)-tr a n s-N-BOC-solen op -
sin A), 9. The title compound was prepared according to the
3
)
2
4
25
99%: [R]
1.3 in CHCl
matched that reported in the literature.
D
) -1.2° (c ) 1.2 in CHCl
3
) (lit. [R]
D
) -1.3° (c )
25
2
3
)). The spectral data for those compound
2
5
2
2
2
0
[
R]
D
) -21.2° (c 4.4, CH
2
Cl
2
H
41NO
2
:
Ack n ow led gm en t. We thank the National Insti-
tutes of Health for support of this work and Boulder
Scientific for a gift of chiral metallocene. We thank
Marcus Hansen for assistance in preparing this manu-
script.
(
6
2
0
method of Beak. Carbamate 8 (170 mg, 0.5 mmol) was placed
in a dry Schlenk tube under argon. Ether (1.7 mL) and
TMEDA (0.1 mL) were added, and the solution was cooled to
J O980808Q
-65 °C. sec-Butyllithium (1.4 M in cyclohexane, 0.46 mL, 0.65
(25) J efford, C. W.; Wang, J . B. Tetrahedron Lett. 1993, 34, 2911.