Stereoselective Total Synthesis of (±)-Swainsonine Based on Endo Mode Cyclization

Article abstract of DOI:10.1021/jo980598h

A new stereoselective total synthesis of (±)-swainsonine is described. Successive treatment of cis-3,4-epoxy-7-(p-toluenesulfonamido)-1-heptyne with dicobalt octacarbonyl, Lewis acid, and cerium-(IV) ammonium nitrate effected stereoselective formation of the trans-2-ethynyl-3-hydroxypiperidine skeleton with retention of configuration at the propynyl center. The piperidine derivative thus prepared was converted into the title compound efficiently.

Full text of DOI:10.1021/jo980598h

J . Org. Chem. 1998, 63, 6281-6287
6281
Ster eoselective Tota l Syn th esis of (()-Sw a in son in e Ba sed on En d o
Mod e Cycliza tion
Chisato Mukai,* Yu-ichi Sugimoto, Kana Miyazawa, Sumie Yamaguchi, and Miyoji Hanaoka*
Faculty of Pharmaceutical Sciences, Kanazawa University Takara-machi, Kanazawa 920, J apan
Received April 1, 1998
A new stereoselective total synthesis of (()-swainsonine is described. Successive treatment of cis-
3,4-epoxy-7-(p-toluenesulfonamido)-1-heptyne with dicobalt octacarbonyl, Lewis acid, and cerium-
(IV) ammonium nitrate effected stereoselective formation of the trans-2-ethynyl-3-hydroxypiperidine
skeleton with retention of configuration at the propynyl center. The piperidine derivative thus
prepared was converted into the title compound efficiently.
Sch em e 1
In tr od u ction
In the previous papers,1 we developed a new procedure
for the highly stereoselective construction of tertahydro-
pyran and tetrahydrofuran skeletons 2 possessing the
2-ethynyl-3-hydroxy functionality as a common structural
feature by successive treatment of the epoxy alcohols 1
having an acetylenic functionality adjacent to epoxy
moiety with dicobalt octacarbonyl (Co2(CO)8), Lewis acid,
and cerium(IV) ammonium nitrate (CAN) (Scheme 1).
The most significant point of this method is based on an
endo mode cyclization of dicobalt hexacarbonyl complex
of the epoxy acetylene derivatives 1 under acidic condi-
tions. The other salient feature of this cyclization must
be stereocomplementary formation of 2. Namely trans-1
afforded cis-2, while cis-1 gave trans-2 in either a highly
stereoselective manner or exclusively.
Sch em e 2
In the course of our program directed toward applica-
tion of the newly developed endo mode cyclization reac-
tion to the stereoselective synthesis of natural products,
we chose an indolizidine alkaloid, (()-swainsonine (3) as
our first target natural product. Swainsonine (3), iso-
lated from the fungus Rhizoctonia leguminicola,2 Swain-
sona canescens,3 and Metarhizium anisopliae,4 is a rep-
resentative indolizidine alkaloid having trihydroxy
functionalities. Because of the interesting biological
activities5 of this alkaloid, much effort has so far been
dedicated to synthesis of 3 over the past decade.6
derivative 5 possessing trans-2-ethynyl-3-hydroxy align-
ment by consecutive treatment with Co2(CO)8, Lewis acid,
and CAN. Chemical modification of 5 would effected ring
closure to give the 1,2-dehydroindolizidine framework 4.
By taking advantage of the protecting group on the C-8
hydroxy functionality of 4, stereoselective introduction
of cis-dihydroxy groups would be realized judging from
several literature precedents.6h This simple analysis
Our retrosynthetic analysis is outlined in Scheme 2.
The cis-epoxy amino derivative 6 with a proper protecting
group on the nitrogen atom would produce the piperidine
(6) (a) Ferreira, F.; Greck, C.; Genet, J . P. Bull. Soc. Chim. Fr. 1997,
134, 615. (b) Hembre, E. J .; Pearson, W. H. Tetrahedron 1997, 53,
11021. (c) Hunt, J . A.; Roush, W. R. J . Org. Chem. 1997, 62, 1112. (d)
Pearson, W. H.; Hembre, E. J . J . Org. Chem. 1996, 61, 7217. (e)
Pearson, W. H.; Hembre, E. J . J . Org. Chem. 1996, 61, 5537. (f) Zhou,
W.-S.; Xei, W.-G.; Lu, Z.-H.; Pan, X.-F. J . Chem. Soc., Perkin Trans. 1
1995, 2599. (g) Kang S. H.; Kim, G. T. Tetrahedron Lett. 1995, 36,
5049. (h) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S. Synlett 1995, 404.
(i) Hunt, J . A.; Roush, W. R. Tetrahedron Lett. 1995, 36, 501. (j) Naruse,
M.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1994, 59, 1358. (k) For a
recent review see, Takahata, M.; Momose, T. The Alkaloids 1993, 44,
189. (l) J irousek, M. R.; Cheung, A. W. H.; Babine, R. E.; Sass, P. M.;
Schow, S. R.; Wick, M. M. Tetrahedron Lett. 1993, 34, 3671. (m)
Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L.; Ulgheri, F. J . Org. Chem.
1993, 58, 3397. (n) Gonzalez, F. B.; Barba, A. L.; Espina, M. R. Bull.
Chem. Soc. J pn. 1992, 65, 567. (o) Pearson, W. H.; Lin, K.-C.
Tetrahedron Lett. 1990, 31, 7571. (p) Takahata, H.; Banba, Y.; Momose,
T. Tetrahedron: Asymmetry 1990, 1, 763. (q) Ikota, N.; Hanaki, A.
Chem. Pharm. Bull. 1990, 38, 2712. (r) Miller, S. A.; Chamberlin, A.
R. J . Am. Chem. Soc. 1990, 112, 8100. (s) Carpenter, N. M.; Fleet, G.
W. J .; Cenci di Bello, I.; Winchester, B.; Fellows, L. E.; Nash, R.
Tetrahedron Lett. 1989, 30, 7261. (t) Bennett, R. B., III.; Choi, J .-R.;
Montgomery, W. D.; Cha, J . K. J . Am. Chem. Soc. 1989, 111, 2580. (u)
Dener, J . M.; Hart, D. J .; Ramesh, S. J . Org. Chem. 1988, 53, 602.
(1) (a) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M. Tetrahedron
Lett. 1994, 35, 2179. (b) Mukai, C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka,
M. Tetrahedron Lett. 1994, 35, 2183. (c) Mukai, C.; Sugimoto, Y.; Ikeda,
Y.; Hanaoka, M. J . Chem. Soc., Chem. Commun. 1994, 1161. (d) Mukai,
C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka, M. Tetrahedron 1998, 54, 823.
(2) (a) Guengerich, F. P.; DiMari, S. J .; Broquist, H. P. J . Am. Chem.
Soc. 1973, 95, 2055. (b) Schneider, M. J .; Ungemach, F. S.; Broquist,
H. P.; Harris, T. M. Tetrahedron 1983, 39, 29.
(3) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J . Chem.
1979, 32, 2257.
(4) Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.; Shibata, T.;
Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J . Antibiot. 1985, 38,
926.
(5) (a) Tulsiani, D. R. P.; Harris, T. M.; Touster, O. J . Biol. Chem.
1982, 257, 7936. (b) Kino, T.; Inamura, N.; Nakahara, K.; Kiyoto, S.;
Goto, T.; Terano, H.; Kohsaka, M. J . Antibiot. 1985, 38, 936. (c) Dennis,
J . W. Cancer Res. 1986, 46, 5131. (d) Humphries, M. J .; Matsumoto,
K.; White, S. L.; Olden, K. Cancer Res. 1986, 46, 5215. (e) Humphries,
M. J .; Matsumoto, K.; White, S. L.; Molyneux, R. J .; Olden, K. Cancer
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S0022-3263(98)00598-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/08/1998

6282 J . Org. Chem., Vol. 63, No. 18, 1998
Mukai et al.
Ta ble 1. Rin g Closu r e of Ep oxid es 12, 13
Sch em e 3a
a
Reaction conditions: (a) HN3, DEAD, PPh3, 99%; (b) PPh3,
protecting group on the nitrogen atom in 13 was changed
from Ts group to Boc or acetyl group, decomposition of
the starting material could only be detected leading to
an intractable mixture. The desired cyclized products
were never isolated from the reaction mixture.
H2O, 99%; (c) TsCl, Et3N, 81%; (d) TBAF, 96%; (e) mCPBA, 10 f
12 (57%), 11 f 13 (58%).
prompted us to examine the synthesis of (()-swainsonine
(3) in line with the retrosynthetic format. This paper
deals with the successful application of the newly devel-
oped endo mode cyclization method as a crucial step to
stereoselective total synthesis of indolizidine alkaloid,
(()-swainsonine (3).
To confirm the stereocomplementarity in this cycliza-
tion, we examined the similar ring closure reaction by
using trans-13. The consecutive treatment of trans-13,
prepared from trans-7 according to the procedure de-
scribed for preparation of cis-13 (see the Experimental
Section), with Co2(CO)8, BF3‚OEt2, and CAN furnished
cis-14 selectively, although the stereoselectivity (trans-
14: cis-14 ) 30:70) was somewhat lower compared with
that of trans-13 as shown in Table 1. Thus, it is obvious
that this endo mode cyclization proceeds stereocomple-
mentarily. Namely, the cis-epoxide provided the trans-
piperidine derivative, while the cis-piperidine derivative
was predominatly produced from the corresponding
trans-epoxide. Control experiment (without formation of
cobalt complex) demonstrated that cobalt complexation
must be mandatory for this type cyclization. Direct
treatment of cis-13 with a catalytic amount of BF3‚OEt2
gave, after acetylation, the exo mode product 16 in a
highly stereoselective manner along with a small amount
of the endo mode product 17.
Resu lts a n d Discu ssion
The required cis-epoxy alkyne derivatives for the endo
mode cyclization were prepared by conventional means.
The alcohol (Z)-71d was exposed to Mitsunobu conditions7
using hydrazoic acid8 and diethyl azodicarboxylate (DEAD)
to give the azido derivative (Z)-8 in 99% yield, which was
further treated with triphenylphosphine (PPh3) in the
presence of water affording the corresponding primary
amino compound (Z)-9 in 99% yield. The amino group
of (Z)-9 was protected with p-toluenesulfonyl (Ts) group
to provide (Z)-10 in 81% yield, oxidation of which with
m-chloroperbenzoic acid (mCPBA) furnished cis-12 in
57% yield. The terminal trimethylsilyl (TMS) group of
(Z)-10 was removed by treatment with tetra-n-butylam-
monium fluoride (TBAF) to give (Z)-11 in 96% yield. The
cis-epoxide 13 was then obtained in 58% yield from (Z)-
11 by similar oxidation with mCPBA (Scheme 3).
The pivotal reaction for this synthesis was undertaken
under the conditions described in the previous papers.1
Exposure of cis-13 to Co2(CO)8 in methylene chloride at
0 °C to give the corresponding cobalt-complexed 13, which
was subsequently treated with a catalytic amount of BF3‚
OEt2 (0.1 mol %) at -78 °C affording the cyclized
products. Decomplexation of cobalt moiety of the result-
ing piperidine derivatives was carried out by CAN
treatment in methanol at 0 °C to afford trans-14 and cis-
14 in 85% overall yield in a highly stereoselective manner
(trans-14:cis-14 ) 90:10) as expected (Table 1, entry 1).
No trace of pyrrolidine compounds resulting from an exo
mode cyclization could be detected in the reaction mix-
ture. Similar successive one-pot treatment of the TMS
congener 12 also provided trans-15 selectively in 83%
yield (trans-15:cis-15 ) 83:17). The cis-epoxides 12 and
13 produced the corresponding trans-ones with retention
of configuration at the propynyl position. This observa-
tion is in good agreement with the results1 obtained in
the reaction of compound 1 (see Scheme 1). When the
The structure of cyclized products 14 and 15 was
determined by careful spectroscopic analysis. 1H NMR
spectrum of trans-14 revealed the H-2 at δ 4.74 as broad
singlet. This observation was in sharp contrast to our
prediction since we anticipated rather large coupling
constant between the H-2 and H-3 due to an axial-axial
1
coupling. In H NMR spectrum of the corresponding cis-
14, the H-2 appeared at δ 4.97 with the small coupling
constant (J ) 4.4 Hz). In the case of 2 (n ) 1, R ) TMS),
the coupling constant between the H-2 and H-3 of trans-2
was 7.3 Hz, a typical axial-axial coupling, while that of
cis-2 showed the smaller one (J ) 3.7 Hz) due to an
axial-equatorial coupling. Similar smaller coupling
constants for both the H-2 of trans-15 (J ) 2.9 Hz) and
cis-15 (5.4 Hz) were recognized. We assumed that the
Ts group on the nitrogen atom might be oriented in a
pseudoequatorial position and govern the preference in
their conformations. Thus, in the most preferred con-
(7) Mitsunobu, O. Synthesis 1981, 1.
(8) Wolff, H. Org. React. 1946, 3, 307.

Total Synthesis of (()-Swainsonine
J . Org. Chem., Vol. 63, No. 18, 1998 6283
Sch em e 4
F igu r e 1.
provide 22 in 97% yield. Half reduction of 22 in the
presence of Lindlar catalyst furnished the (Z)-olefin 23
in 99% yield. Indolizidine skeleton formation was real-
ized by two-step sequences. Treatment of 23 with sodium
naphthalenide,10 generated from sodium and naphtha-
lene in THF, at -65 °C gave the detosylated one, which
was exposed to carbon tetrabromide and PPh3 in the
presence of Et3N6j,11 producing the indolizidine derivative
24 in 57% yield.
The final stage for our synthesis of (()-swainsonine (3)
was now faced to stereoselective dihydroxylation of the
olefine moiety of the indolizidine framework. IR spec-
trum of 24 exhibited Bohlmann bands at 2810 and 2790
cm-1, strongly indicating its preferred conformer to be
the trans-indolizidine skeleton. Therefore, as depicted
in Figure 1 on the basis of the literature precedent,6h we
predicted that dihydroxylation of 24 would predominatly
occur from the face opposite to the C-8a hydrogen in order
to avoid nonbonding interaction between the dihydroxy-
lating reagent and the pseudoaxial C-8a hydrogen result-
ing in preferential formation of the desired dihydroxy-
lated product over its stereoisomer.
Introduction of cis-dihydroxy functionality was carried
out by osmium tetraoxide (OsO4) to give a mixture of the
corresponding diol derivatives.12 Since these cis-dihy-
droxylated products could not be isolated as a pure form
by column chromatography or recrystallization, a mixture
of dihydroxylated compounds was converted into the
corresponding triacetyl derivatives 25 and 26 by succes-
sive treatment with TBAF and acetic anhydride under
conventional conditions. Column chromatography of the
resulting mixture provided 25 and 26 in 67 and 9% yields,
respectively as a pure form (25:26 ) 88:12). Comparison
of 1H NMR spectra of those triacetate derivatives 25 and
26 with that of the authentic triacetate of swainsonine2b
allowed us to confirm these structures as depicted in
Scheme 5. Thus, dihydroxylation of 24 was shown to
occur selectively from the face opposite to the C-8a
hydrogen. Finally, base treatment of 25 with potassium
carbonate in methanol effected deacetylation to provide
(()-swainsonine (3) in 99% yield. Synthetic (()-swain-
sonine was identified with natural one by spectral
comparison.2b
formation of the trans-compounds, the ethynyl moiety at
the C-2 position should take an axial site in order to avoid
nonbonding interaction with the Ts group, thereby both
substituents at the C-2 and C-3 positions on the piperi-
dine skeleton would be in pseudoaxial positions (two
protons at the C-2 and C-3 positions, therefore, are in
pseudoequatorial positions). On the other hand, the cis-
products must have the preferred conformer in which two
substituents possess pseudoaxial and equatorial posi-
tions.
Protection of the secondary hydroxy group of trans- and
cis-14 with tert-butyldimethylsilyl chloride (TBDMSCl)
was followed by hydrogenation in the presence of 10%
Pd-C to afford trans-18 (85%) and cis-18 (95%), respec-
tively, whose 1H NMR spectra disclosed the similar small
coupling constants (2.4 Hz for trans-18 and 4.9 Hz for
cis-18) again (Scheme 4). Treatment of trans- and cis-
18 with sodium naphthalenide effected ease detosylation
to give trans-19 (77%) and cis-19 (72%), respectively.
Coupling constant between the H-2 and the H-3 of trans-
19 was found to be 8.8 Hz, while that of cis-19 has
smaller coupling constant (J ) 2.0 Hz) due to axial-axial
and axial-equatorial couplings, respectively. This ob-
servation strongly supported our conformational analysis
as well as assignment of structures. Final and unam-
biguous confirmation of these structures was made by
X-ray crystallographic analysis. The trans-piperidine
derivative trans-14 was acylated with p-bromobenzoyl
chloride to give the p-bromobenzoate 20, whose X-ray
crystallographic analysis disclosed that 20 has (2R*,3S*)-
3-((4-bromobenzoyl)oxy)-2-ethynyl-1-(p-toluenesulfonyl)-
piperidine structure.9 It should be mentioned that the
H-2 signal appears at δ 5.04 as singlet in its 1H NMR
spectrum. This is in accordance with the small coupling
constants observed in the cases of trans-14 and trans-
15. Thus, we could unambiguously establish the struc-
tures of the cyclized products.
With the required trans-piperidine compound, trans-
14, for target natural product in hand, we tried to
transform it into the desired indolizidine derivative. The
secondary hydroxy group of trans-14 was silylated with
TBDMSCl to afford 21 in 99% which was successively
treated with n-butyllithium and paraformaldehyde to
In conclusion, a new synthetic route to (()-swainsonine
was developed that is based on endo mode cyclization as
a crucial step where stereoselective construction of trans-
2-ethynyl-3-hydroxypiperidine skeleton from cobalt-com-
(9) Crystal data: C21H20BrNO4S, M ) 462.36, orthorhombic, a )
7.615(2) Å, b ) 20.427(3) Å, c ) 7.355(1) Å, V ) 1016.2(4) Å3, Z ) 2,
Dc ) 1.511 g/cm3, space group P1 (No. 1), µ(Mo KR) ) 21.25 cm-1. A
colorless prisms crystal, ca. 0.4 × 0.4 × 0.1 mm, was mounted on a
(10) (a) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.;
Closson, W. D. J . Am. Chem. Soc. 1967, 89, 5311. (b) McIntosh, M. J .;
Matassa, L. J . Org. Chem. 1988, 53, 4452.
(11) (a) Rassu, G.; Casiraghi, G.; Pinna, L.; Spanu, P.; Ulgheri, F.
Tetrahedron 1993, 49, 6627. (b) Casiraghi, G.; Rassu, G.; Spanu, P.;
Pinna, L.; Ulgheri, F. J . Org. Chem. 1993, 58, 3397.
(12) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
glass fiber. All measurements were made on
a Rigaku AFC5R
diffractometer. The cell dimensions and intensities were refined by
the least-squares method, using 25 reflections on the diffractometer
with Mo KR radiation with ω-scan mode for 2θ less than 55.0°. The
structure was solved by direct method (MITHRIL method). The final
cycle of full-matrix least-squares refinement was based on 2525
observed reflections. The final R value was 0.052.

6284 J . Org. Chem., Vol. 63, No. 18, 1998
Mukai et al.
Sch em e 5a
and PPh3 (1.49 g, 5.68 mmol) in THF (50 mL) was stirred at
room temperature for 4 h, and then H2O (3.0 mL) was added
to the reaction mixture which was heated under reflux for 4
h. The reaction mixture was concentrated and passed through
a short pad of silica gel with AcOEt-MeOH to give (Z)-9 (1.03
g, 99%). To a solution of (Z)-9 (1.03 g, 5.68 mmol) and Et3N
(1.00 mL) in CH2Cl2 (47 mL) was added a solution of TsCl (1.31
g, 6.82 mmol) and N,N-(dimethylamino)pyridine (DMAP) (71.0
mg, 0.57 mmol) in CH2Cl2 (9.5 mL) at 0 °C. The reaction
mixture was stirred for 1 h, washed with water and brine,
dried, and concentrated to dryness. Chromatography of the
residue with hexane-AcOEt (5:1) afforded (Z)-10 (1.12 g, 81%)
as colorless solids, mp 64.5-65.0 °C (hexane-CH2Cl2): MS
m/z 335 (M+, 20), 320 (23), 180 (100), 155 (37), 91 (66); IR 3400,
1
2140, 1330, 1160 cm-1; H NMR δ 7.74 (d, 2H, J ) 8.2 Hz),
7.30 (d, 2H, J ) 8.2 Hz), 5.81 (dt, 1H, J ) 10.6, 7.6 Hz), 5.50
(d, 1H, J ) 10.6 Hz), 4.59 (t, 1H, J ) 6.9 Hz), 2.94 (q, 2H, J )
6.9 Hz), 2.42 (s, 3H), 2.34 (q, 2H, J ) 6.9 Hz), 1.60 (quint, 2H,
J ) 6.9 Hz), 0.21 (s, 9H); 13C NMR δ 143.26, 143.06, 137.11,
129.65, 127.05, 110.68, 101.53, 99.72, 42.20, 28.29, 26.94,
21.47, -0.09. Anal. Calcd for C17H25NO2SSi: C, 60.85; H,
7.51; N, 4.17. Found: C, 60.94; H, 7.42; N, 4.28.
(E)-1-(Tr im eth ylsilyl)-7-(p-tolu en esu lfon a m id o)-3-h ep -
ten -1-yn e [(E)-10]. According to the procedure described for
preparation of (Z)-10, (E)-10 (1.72 g, 81% overall yield) was
obtained from (E)-8 (1.30 g, 6.28 mmol) as colorless solids, mp
96.0-97.0 °C (hexane-CH2Cl2): MS m/z 335 (M+, 30), 320 (41),
a
Reaction conditions: (a) TBDMSCl, imidazole, 99%; (b) n-BuLi,
(HCHO)n, 97%; (c) H2, Lindlar cat., 99%; (d) (1) Na, naphthalene,
(2) CBr4, PPh3, Et3N, 57%; (e) (1) OsO4, NMO, (2) TBAF, (3) Ac2O,
pyridine, DMAP, 76% (25:26 ) 88:12); (f) K2CO3, MeOH, 99%.
180 (100), 155 (48), 91 (70); IR 3400, 2130, 1330, 1160 cm-1
;
plexed cis-3,4-epoxy-7-(p-toluenesulfonamido)-1-heptyne
was achieved. Studies on further application of the endo
mode cyclization to stereoselective total synthesis of
natural products are now in progress.
1H NMR δ 7.73 (d, 2H, J ) 8.2 Hz), 7.31 (d, 2H, J ) 8.2 Hz),
6.06 (dt, 1H, J ) 15.8, 7.3 Hz), 5.43 (dt, 1H, J ) 15.8, 1.3 Hz),
4.41 (t, 1H, J ) 7.3 Hz), 2.94 (q, 2H, J ) 7.3 Hz), 2.42 (s, 3H),
2.09 (qd, 2H, J 7.3, 1.3 Hz), 1.55 (quint, 2H, J ) 7.3 Hz), 0.17
(s, 9H); 13C NMR δ 143.93, 143.44, 136.88, 129.73, 127.05,
110.80, 103.56, 93.29, 42.42, 29.84, 28.53, 21.49, -0.09. Anal.
Calcd for C17H25NO2SSi: C, 60.85; H, 7.51; N, 4.17. Found:
C, 60.86; H, 7.53; N, 4.13.
Exp er im en ta l Section
Melting points are uncorrected. IR spectra were measured
in CHCl3 unless otherwise mentioned. 1H NMR spectra were
taken in CDCl3 unless otherwise indicated. CHCl3 (7.26 ppm)
was used as an internal standard for silyl compounds. TMS
was employed as an internal standard for other compounds.
13C NMR spectra were recorded in CDCl3 with CHCl3 (77.00
ppm) as an internal standard. CH2Cl2 was freshly distilled
from phosphorus pentoxide, and THF was from sodium diphe-
nyl ketyl, prior to use. All reactions were carried out under
nitrogen atmosphere otherwise stated. Silica gel (silica gel
60, 230-400 mesh, Merck) was used for chromatography.
Organic extracts were dried over anhydrous Na2SO4.
(Z)-7-(p-Tolu en esu lfon a m id o)-3-h ep ten -1-yn e [(Z)-11].
To a solution of (Z)-10 (319 mg, 0.95 mmol) in THF (10 mL)
was added a solution of TBAF (1.0 M THF solution, 1.14 mL,
1.14 mmol) at room temperature. The reaction mixture was
stirred at the same temperature for 30 min and diluted with
Et2O. The ether solution was washed with water and brine,
dried, and concentrated to dryness. Chromatography of the
residue with hexane-AcOEt (5:1) afforded (Z)-11 (241 mg,
96%) as a colorless oil: MS m/z 263 (M+, 6.4), 184 (52), 155
(90), 91 (100); IR 3400, 3325, 1330, 1160 cm-1; 1H NMR δ 7.74
(d, 2H, J ) 8.2 Hz), 7.30 (d, 2H, J ) 8.2 Hz), 5.90 (dt, 1H, J )
10.9, 7.6 Hz), 5.46 (ddt, 1H, J ) 10.9, 2.3, 1.0 Hz), 4.66 (t, 1H,
J ) 6.6 Hz), 3.12 (d, 1H, J ) 2.3 Hz), 2.95 (q, 2H, J ) 6.6 Hz),
2.42 (s, 3H), 2.34 (qd, 2H, J ) 7.6, 1.0 Hz), 1.60 (m, 2H); 13C
NMR δ 143.95, 143.17, 136.80, 129.54, 126.92, 109.14, 82.04,
(Z)-7-Azido-1-(tr im eth ylsilyl)-3-h epten -1-yn e [(Z)-8]. To
a solution of (Z)-7 (5.50 g, 30.1 mmol) and PPh3 (8.71 g, 33.2
mmol) in THF (150 mL) was successively added a 4-6%
solution of hydrazoic acid in benzene (60 mL), generated from
NaN3 and H2SO4, and DEAD (5.20 mL, 33.2 mmol) at 0 °C.
After 10 min of stirring at room temperature, the reaction
mixture was concentrated to leave the residual oil, which was
chromatographed with hexane-AcOEt (40:1) to afford (Z)-8
(6.19 g, 99%) as a colorless oil: FABMS m/z 208 (M++1, 1.8),
165 (3.2), 154 (16), 136 (26), 107 (12), 91 (21), 73 (100); IR 2150,
2100 cm-1; 1H NMR δ 5.92 (dt, 1H, J ) 10.9, 7.3 Hz), 5.55 (dt,
1H, J ) 10.9, 1.3 Hz), 3.30 (t, 2H, J ) 7.3 Hz), 2.42 (qd, 2H,
80.01, 42.29, 28.25, 26.94, 21.34. Anal. Calcd for C14H17
-
NO2S: C, 63.85; H, 6.51; N, 5.32. Found: C, 63.51; H, 6.50;
N, 5.13.
(E)-7-(p-Tolu en esu lfon a m id o)-3-h ep ten -1-yn e [(E)-11].
According to the procedure described for preparation of (Z)-
11, (E)-11 (677 mg, 99%) was obtained from (E)-10 (874 mg,
2.60 mmol) as colorless solids, mp 88.0-89.0 °C (hexane-CH2-
Cl2): MS m/z 263 (M+, 6.8), 184 (53), 155 (83), 108 (30), 91
(100); IR 3400, 3320, 1330, 1160 cm-1; 1H NMR δ 7.73 (d, 2H,
J ) 8.2 Hz), 7.31 (d, 2H, J ) 8.2 Hz), 6.11 (dt, 1H, J ) 15.8,
7.3 Hz), 5.40 (dd, 1H, J ) 15.8, 2.0 Hz), 4.37 (t, 1H, J ) 5.9
Hz), 2.98-2.91 (m, 2H), 2.79 (d, 1H, J ) 2.0 Hz), 2.43 (s, 3H),
J ) 7.3, 1.3 Hz), 1.73 (quint, 2H, J ) 7.3 Hz), 0.20 (s, 9H); 13
NMR δ 143.02, 110.66, 101.42, 99.46, 50.82, 27.91, 27.37,
-0.09; HRFABMS calcd for
208.1261.
C
C10H17N3Si 208.1270, found
(E)-7-Azido-1-(tr im eth ylsilyl)-3-h epten -1-yn e [(E)-8]. Ac-
cording to the procedure described for preparation of (Z)-8,
(E)-8 (6.53 g, 99%) was obtained from (E)-7 (6.60 g, 31.8 mmol)
as a colorless oil: FABMS m/z 208 (M+ + 1, 16), 165 (6.1), 154
2.11 (q, 2H, J ) 7.3, 1.0 Hz), 1.57 (quint, 2H, J ) 7.3 Hz); 13
NMR δ 144.65, 143.45, 136.80, 129.72, 127.03, 109.67, 82.03,
76.19, 42.34, 29.74, 28.41, 21.48. Anal. Calcd for C14H17
C
-
NO2S: C, 63.85; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.62;
N, 5.32.
(17), 136 (27), 107 (13), 91 (23), 73 (100); IR 2090 cm-1 1H
;
NMR δ 6.16 (dt, 1H, J ) 15.8, 6.9 Hz), 5.54 (dt, 1H, J ) 15.8,
1.3 Hz), 3.28 (t, 2H, J ) 6.9 Hz), 2.19 (qd, 2H, J ) 6.9, 1.3
Hz), 1.67 (quint, 2H, J ) 6.9 Hz), 0.18 (s, 9H); 13C NMR δ
143.83, 111.02, 103.52, 93.39, 50.57, 29.98, 27.84, -0.09;
HRFABMS calcd for C10H17N3Si 208.1270, found 208.1251.
(Z)-1-(Tr im eth ylsilyl)-7-(p-tolu en esu lfon a m id o)-3-h ep -
ten -1-yn e [(Z)-10]. A solution of (Z)-8 (1.17 g, 5.68 mmol)
(3R *,4S *)-3,4-E p oxy-1-t r im e t h ylsilyl-7-(p -t olu e n e -
su lfon a m id o)-1-h ep t yn e (cis-12). To a solution of (Z)-10
(500 mg, 1.49 mmol) in CH2Cl2 (25 mL) were added Na2HPO4
(2.13 g, 15.0 mmol) and mCPBA (80% purity, 971 mg, 4.59
mmol) at room temperature. The suspension was stirred at
room temperature for 24 h and filtered. The filtrate was
washed with saturated Na2SO3 solution, water, and brine,

Total Synthesis of (()-Swainsonine
J . Org. Chem., Vol. 63, No. 18, 1998 6285
dried, and concentrated to dryness. Chromatography of the
residue with hexane-AcOEt (5:1) afforded cis-12 (298 mg,
57%) as a colorless oil: MS m/z 351 (M+, 1.2), 224 (100), 196
(2R*,3S*)- a n d (2R*,3R*)-3-Hyd r oxy-2-[(2′-tr im eth ylsi-
lyl)eth yn yl]-1-(p-tolu en esu lfon yl)piper idin e (tr a n s-15 an d
cis-15). According to the procedure described for preparation
of 14, trans-15 (24.8 mg, 69%) and cis-15 (5.1 mg, 14%) were
obtained from cis-12 (36.0 mg, 0.10 mmol). trans-15 was
obtained as colorless solids, mp 154-155 °C (hexane-CH2-
Cl2): MS m/z 351 (M+, 0.2), 336 (2.3), 196 (100), 139 (6.2), 126
(14), 91 (29); IR 3600, 2160, 1345, 1160 cm-1; 1H NMR δ 7.70
(d, 2H, J ) 8.3 Hz), 7.28 (d, 2H, J ) 8.3 Hz), 4.69 (d, J ) 2.9
Hz, 1H), 3.93 (qd, 1H, J ) 9.8, 2.9 Hz), 3.71 (m, 1H), 2.85 (dt,
1H, J ) 11.7, 2.9 Hz), 2.42 (s, 3H), 2.40 (d, 1H, J ) 9.8 Hz),
1.94-1.83 (m, 2H), 1.71 (m, 1H), 1.56 (m, 1H), -0.04 (s, 9H);
13C NMR δ 143.42, 134.98, 129.36, 128.02, 97.94, 93.77, 67.92,
52.83, 41.65, 25.64, 21.49, 19.31, -0.53. Anal. Calcd for
(45), 180 (48), 155 (61), 91 (96); IR 3400, 2160, 1330, 1160 cm-1
;
1H NMR δ 7.75 (d, 2H, J ) 8.3 Hz), 7.31 (d, 2H, J ) 8.3 Hz),
4.53 (t, 1H, J ) 6.3 Hz), 3.40 (d, 1H, J ) 3.9 Hz), 3.03 (q, 2H,
J ) 6.8 Hz), 2.97 (td, 1H, J ) 6.8, 3.9 Hz), 2.43 (s, 3H), 1.77-
1.66 (m, 4H), 0.18 (s, 9H); 13C NMR δ 143.40, 137.02, 129.72,
127.06, 99.86, 77.22, 57.40, 45.32, 42.64, 26.26, 21.49, -0.34.
Anal. Calcd for C17H25NO3SSi: C, 58.08; H, 7.17; N, 3.98.
Found: C, 57.84; H, 7.19; N, 3.95.
(3R*,4S*)-3,4-E p oxy-7-(p -t olu en esu lfon a m id o)-1-h ep -
tyn e (cis-13). According to the procedure described for
preparation of cis-12, cis-13 (182 mg, 58%) was obtained from
(Z)-11 (297 mg, 1.13 mmol) as a colorless oil: MS m/z 279 (M+,
0.4), 224 (67), 155 (76), 91 (100); IR 3400, 3320, 1330, 1160
cm-1; 1H NMR δ 7.75 (d, 2H, J ) 8.3 Hz), 7.31 (d, 2H, J ) 8.3
Hz), 4.54 (t, 1H, J ) 6.3 Hz), 3.41 (dd, 1H, J ) 3.9, 1.9 Hz),
3.03 (q, 2H, J ) 6.3 Hz), 3.00 (td, 1H, J ) 6.8, 3.9 Hz), 2.43 (s,
3H), 2.36 (d, 1H, J ) 1.9 Hz), 1.80-1.65 (m, 4H); 13C NMR δ
143.25, 136.76, 129.58, 126.90, 78.43, 73.95, 56.95, 44.61,
42.55, 26.19, 25.89, 21.34. Anal. Calcd for C14H17NO3S: C,
60.19; H, 6.13; N, 5.01. Found: C, 60.06; H, 6.16; N, 4.96.
(3R*,4R*)-3,4-E p oxy-7-(p -t olu en esu lfon a m id o)-1-h ep -
tyn e (tr a n s-13). According to the procedure described for
preparation of cis-12, trans-13 (336 mg, 51%) was obtained
from (E)-11 (615 mg, 2.34 mmol) as a colorless oil: MS m/z
279 (M+, 10), 224 (53), 184 (40), 155 (100), 124 (50), 91 (95);
C
17H25NO3SSi: C, 58.08; H, 7.17; N, 3.98. Found: C, 58.00;
H, 7.14; N, 3.98. cis-15 was obtained as colorless solids, mp
127-128 °C (hexane-CH2Cl2): MS m/z 351 (M+, 3.4), 196
(100), 126 (32), 91 (73); IR 3600, 2150, 1345, 1160 cm-1 1H
;
NMR δ 7.71 (d, 2H, J ) 8.3 Hz), 7.28 (d, 2H, J ) 8.3 Hz), 4.93
(d, 1H, J ) 5.4 Hz), 3.75 (dt, 1H, J ) 10.7, 5.4 Hz), 3.69 (m,
1H), 2.67 (dt, 1H, J ) 12.2, 2.9 Hz), 2.42 (s, 3H), 1.99 (m, 1H),
1.71-1.62 (m, 2H), 1.67 (d, 1H, J ) 10.7 Hz), 1.47 (dq, 1H, J
) 12.2, 4.4 Hz), -0.04 (s, 9H); 13C NMR δ 143.36, 135.17,
129.36, 127.92, 96.87, 94.83, 68.41, 52.63, 40.81, 28.86, 23.65,
21.48, -0.43. Anal. Calcd for C17H25NO3SSi: C, 58.08; H,
7.17; N, 3.98. Found: C, 57.99; H, 7.18; N, 3.93.
(2R*,3R*)-2-(1′-Acet oxy-2′-p r op yn -1′-yl)-1-(p -t olu en e-
su lfon yl)am ido]pyr r olidin e (16) an d (2R*,3R*)-3-Acetoxy-
2-eth yn yl-1-(p-tolu en esu lfon yl)p ip er id in e (17). A solution
of BF3‚OEt2 in CH2Cl2 (0.1 M solution, 0.10 mL, 0.01 mmol)
was added to a solution of cis-13 (28.0 mg, 0.10 mmol) in CH2-
Cl2 (3.0 mL) at -78 °C. The reaction mixture was stirred at
the same temperature for 10 min, gradually warmed to 0 °C,
and then quenched by addition of water. The CH2Cl2 layer
was separated, washed with brine, dried, and concentrated to
dryness. The residue was dissolved in CH2Cl2 (1.0 mL) to
which acetic anhydride (0.01 mL, 0.11 mmol), Et3N (0.02 mL,
0.14 mmol), and DMAP (92.0 mg, 0.02 mmol) were added. The
reaction mixture was allowed to stand for 1 h, diluted with
CH2Cl2, which was washed with water and brine, dried, and
concentrated to dryness. Chromatography of the residue with
hexane-AcOEt (3:1) afforded 16 (25.4 mg, 79%) and 17 (2.4
mg, 7%). Compound 16 was obtained as colorless solids, mp
110-111 °C (hexane-AcOEt): MS m/z 321 (M+, 1.4), 278 (6.4),
261 (11), 166 (100), 139 (14), 124 (36), 91 (53), 43 (63); IR 3330,
1
IR 3400, 3320, 1325, 1155 cm-1; H NMR δ 7.74 (d, 2H, J )
8.8 Hz), 7.31 (d, 2H, J ) 8.8 Hz), 4.55 (t, 1H, J ) 6.3 Hz),
3.08-2.96 (m, 4H), 2.43 (s, 3H), 2.31 (d, 1H, J ) 1.7 Hz), 1.81-
1.60 (m, 3H), 1.41 (m, 1H); 13C NMR δ 143.45, 136.84, 129.72,
127.01, 80.00, 72.04, 59.53, 44.78, 42.50, 28.48, 25.81, 21.48.
Anal. Calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01.
Found: C, 59.85; H, 6.19; N, 4.90.
(2R*,3S*)- a n d (2R*,3R*)-2-E t h yn yl-3-h yd r oxy-1-(p -
tolu en esu lfon yl)p ip er id in e (tr a n s-14 a n d cis-14). To a
solution of cis-13 (28.0 mg, 0.10 mmol) in CH2Cl2 (3.0 mL) was
added Co2(CO)8 (40 mg, 0.11 mmol) at room temperature. After
15 min of stirring, the reaction mixture was cooled to -78 °C
and held at the same temperature for 30 min. A solution of
BF3‚OEt2 in CH2Cl2 (0.1 M solution, 0.10 mL, 0.01 mmol) was
added to the reaction mixture, which was further stirred for
10 min, quenched by addition of water, and gradually warmed
to 0 °C. The CH2Cl2 layer was separated, washed with brine,
dried, and concentrated to dryness. To a solution of the
residual oil in MeOH (3.0 mL) was added CAN (219 mg, 0.40
mmol) at 0 °C. After 30 min of stirring, the reaction mixture
was concentrated, diluted with water, and extracted with
AcOEt. The extract was washed with water and brine, dried,
and conentrated to dryness. Chromatography of the residue
with hexane-AcOEt (5:1) afforded trans-14 (21.4 mg, 76%) and
cis-14 (2.4 mg, 9%). trans-14 was obtained as colorless solids,
mp 132-133 °C (hexane-CH2Cl2): MS m/z 279 (M+, 0.2), 155
(3.7), 139 (3.8), 124 (100), 91 (36); IR 3600, 3320, 1345, 1160
cm-1; 1H NMR δ 7.72 (d, 2H, J ) 8.3 Hz), 7.28 (d, 2H, J ) 8.3
Hz), 4.74 (bs, 1H), 3.96 (qd, 1H, J ) 9.3, 2.4 Hz), 3.69 (m, 1H),
2.86 (dt, 1H, J ) 11.7, 3.4 Hz), 2.44 (d, 1H, J ) 9.3 Hz), 2.42
(s, 3H), 2.10 (d, 1H, J ) 2.0 Hz), 1.97-1.84 (m, 2H), 1.72 (m,
1H), 1.56 (m, 1H); 13C NMR δ 143.64, 134.90, 129.27, 128.03,
76.83, 76.41, 67.76, 51.85, 41.64, 25.63, 21.49, 19.14. Anal.
Calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01. Found: C,
60.30; H, 6.08; N, 4.97. cis-14 was obtained as colorless solids,
mp 128-129 °C (hexane-CH2Cl2): MS m/z 279 (M+, 0.4), 155
(8.4), 139 (11), 124 (100), 91 (67); IR 3600, 3320, 1345, 1160
cm-1; 1H NMR δ 7.71 (d, 2H, J ) 8.3 Hz), 7.28 (d, 2H, J ) 8.3
Hz), 4.97 (dd, 1H, J ) 4.4, 2.0 Hz), 3.77 (m, 1H), 3.63 (m, 1H),
2.70 (dt, 1H, J ) 12.2, 2.9 Hz), 2.42 (s, 3H), 2.08 (d, 1H, J )
2.0 Hz), 1.94-1.48 (m, 5H), 1.72 (m, 1H); 13C NMR δ 143.56,
134.97, 129.24, 127.87, 76.96, 75.90, 68.41, 51.72, 40.77, 28.45,
23.51, 21.42. Anal. Calcd for C14H17NO3S: C, 60.19; H, 6.13;
N, 5.01. Found: C, 60.14; H, 6.21; N, 4.95. trans-13 (29.1
mg, 0.10 mmol) provided trans-14 (7.8 mg, 27%) and cis-14
(18.1 mg, 62%) under the same conditions described for ring
closure of cis-13.
1
2120, 1745, 1350, 1160 cm-1; H NMR δ 7.74 (d, 2H, J ) 8.8
Hz), 7.31 (d, 2H, J ) 8.8 Hz), 5.72 (dd, 1H, J ) 5.9, 2.4 Hz),
3.84 (ddd, 1H, J ) 8.3, 5.4, 4.4 Hz), 3.43 (dt, 1H, J ) 10.7, 7.3
Hz), 3.29 (dt, 1H, J ) 10.7, 7.3 Hz), 2.43 (s, 3H), 2.42 (d, 1H,
J ) 2.4 Hz), 2.08 (m, 1H), 2.11 (s, 3H), 1.98 (m, 1H), 1.72 (m,
1H), 1.49 (m, 1H); 13C NMR δ 169.32, 143.68, 134.43, 129.74,
127.57, 78.83, 74.97, 65.79, 60.65, 49.51, 27.62, 24.25, 21.49,
20.84. Anal. Calcd for C16H19NO4S: C, 59.79; H, 5.96; N, 4.36.
Found: C, 60.00; H, 6.04; N, 4.33. Compound 17 was obtained
as colorless solids, mp 108-110 °C (hexane-AcOEt): MS m/z
321 (M+, 0.2), 279 (0.3), 262 (1.3), 224 (100), 155 (83), 91 (100),
43 (31); IR 3330, 2110, 1745, 1350, 1160 cm-1; 1H NMR δ 7.70
(d, 2H, J ) 8.3 Hz), 7.28 (d, 2H, J ) 8.3 Hz), 5.10 (dd, 1H, J
) 4.9, 2.0 Hz), 4.79 (td, 1H, J ) 11.2, 4.9 Hz), 3.65 (m, 1H),
2.80 (dt, 1H, J ) 12.2, 2.4 Hz), 2.42 (s, 3H), 2.07 (s, 3H), 2.04
(d, 1H, J ) 2.0 Hz), 1.77-1.64 (m, 3H), 1.87 (m, 1H); 13C NMR
δ 169.79, 143.63, 135.29, 129.31, 127.98, 76.04, 75.74, 69.99,
48.70, 40.92, 25.00, 23.36, 21.51, 20.97. Anal. Calcd for
C
16H19NO4S: C, 59.79; H, 5.96; N, 4.36. Found: C, 59.89; H,
6.03; N, 4.37.
(2R*,3S*)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-eth yn yl-1-
(p-tolu en esu lfon yl)p ip er id in e (21). To a solution of trans-
14 (121 mg, 0.43 mmol) in N,N-dimethylformamide (0.5 mL)
was added imidazole (64.0 mg, 0.95 mmol) and tert-butyldim-
ethylsilyl chloride (TBDMSCl) (72.0 mg, 0.47 mmol). The
reaction mixture was heated at 70 °C for 1 h, cooled to room
temperature, and diluted with Et2O. The Et2O layer was
washed with water several times, brine, dried, and concen-
trated to dryness. Chromatography of the residue with
hexane-AcOEt (20:1) afforded 21 (166 mg, 97%) as colorless

6286 J . Org. Chem., Vol. 63, No. 18, 1998
Mukai et al.
solids, mp 112-113 °C (hexane-AcOEt): MS m/z 378 (M+
-
61.42, 44.48, 30.44, 25.72, 22.48, 18.03, 17.29, 9.76, -4.45,
-5.05; HRMS calcd for C13H29NOSi 243.2018, found 243.2041.
(2R*,3S*)-3-[(4′-Br om oben zoyl)oxy]-2-eth yn yl-1-(p-tol-
u en esu lfon yl)p ip er id in e (20). To a solution of trans-14
(30.0 mg, 0.11 mmol) and Et3N (0.02 mL, 0.17 mmol) in CH2-
Cl2 (1.1 mL) were added p-bromobenzoyl chloride (26.0 mg,
0.12 mmol) and DMAP (3.0 mg, 0.02 mmol) at 0 °C. The
reaction mixture was stirred at the same temperature for 30
min, quenched by addition of saturated NH4Cl solution, and
extracted with CH2Cl2. The extract was washed with water
and brine, dried, and concentrated to dryness. Chromatog-
raphy of the residue with hexane-AcOEt (7:1) afforded 20
(47.0 mg, 94%) as colorless crystals, mp 170.5-171.5 °C
(Et2O): MS m/z 308 (M+ - Ts, 38), 306 (M+ - Ts, 39), 278
(31), 261 (100), 185 (83), 183 (85), 155 (54), 91 (77); IR 3300,
Me, 3.8), 336 (100), 238 (85), 185 (16), 73 (31); IR 3330, 1345,
1160 cm-1; 1H NMR δ 7.74 (d, 2H, J ) 8.3 Hz), 7.24 (d, 2H, J
) 8.3 Hz), 4.69 (bs, 1H), 3.97 (q, 1H, J ) 2.9 Hz), 3.56 (m,
1H), 2.90 (dt, 1H, J ) 12.2, 2.9 Hz), 2.40 (s, 3H), 2.18 (d, 1H,
J ) 2.4 Hz), 1.99 (m, 1H), 1.86 (m, 1H), 1.59 (m, 1H), 1.39 (m,
1H), 0.93 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR δ 143.00,
136.42, 129.15, 127.84, 78.26, 75.53, 68.39, 51.47, 41.49, 26.99,
25.72, 21.48, 19.14, 18.08, -4.96, -5.00. Anal. Calcd for
C
20H31NO3SSi: C, 61.03; H, 7.94; N, 3.56. Found: C, 61.12;
H, 8.02; N, 3.70.
(2R*,3S*)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-eth yl-1-(p-
tolu en esu lfon yl)p ip er id in e (tr a n s-18). A solution of 21
(166 mg, 0.42 mmol) in AcOEt (3.0 mL) was hydrogenated for
4 h at room temperature under hydrogen atmosphere in the
presence of 10% Pd-C (12.0 mg). The catalyst was filtered
off, and the filtrate was concentrated to leave the residue,
which was chromatographed with hexane-AcOEt (20:1) to give
trans-18 (103 mg, 88%, 85% overall yield from trans-14) as
colorless solids, mp 75.5-76.0 °C (hexane): MS m/z 396 (M+
- H, 0.5), 340 (100), 242 (18), 73 (31); IR 1345, 1160 cm-1; 1H
NMR δ 7.89 (d, 2H, J ) 8.3 Hz), 7.23 (d, 2H, J ) 8.3 Hz), 3.95
(td, 1H, J ) 7.3, 2.4 Hz), 3.84 (q, 1H, J ) 2.4 Hz), 3.32 (m,
1H), 2.93 (dt, 1H, J ) 13.2, 2.5 Hz), 2.40 (s, 3H), 1.75 (m, 1H),
1.69-1.53 (m, 4H), 1.23 (m, 1H), 1.00 (t, 3H, J ) 7.3 Hz), 0.92
(s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR δ 142.44, 138.72,
129.16, 127.64, 67.21, 61.12, 40.02, 26.63, 25.88, 22.79, 21.42,
18.40, 18.31, 11.11, -4.89. Anal. Calcd for C20H35NO3SSi: C,
60.41; H, 8.87; N, 3.52. Found: C, 60.45; H, 8.87; N, 3.46.
(2R*,3R*)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-eth yl-1-(p-
tolu en esu lfon yl)p ip er id in e (cis-18). According to the pro-
cedure described for preparation of trans-18, cis-14 (85.0 mg,
0.30 mmol) was successively treated with TBDMSCl and
hydrogenated to give cis-18 (114 mg, 95% overall yield) as
colorless solids, mp 66.0-67.5 °C (hexane): MS m/z 396 (M+
- H, 0.2), 340 (100), 242 (69), 73 (36); IR 1345, 1150 cm-1; 1H
NMR δ 7.72 (d, 2H, J ) 8.3 Hz), 7.27 (d, 2H, J ) 8.3 Hz), 3.81
(td, 1H J ) 10.4, 4.9 Hz), 3.72 (dd, 1H, J ) 13.2, 4.4 Hz), 3.48
(td, 1H, J ) 10.2, 4.9 Hz), 2.83 (dt, 1H, J ) 13.2, 2.4 Hz), 2.42
(s, 3H), 1.69 (m, 1H), 1.52-1.41 (m, 4H), 1.33 (m, 1H), 0.86 (t,
3H, J ) 7.3 Hz), 0.85 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 13C
NMR δ 142.80, 139.12, 129.54, 126.90, 68.95, 59.75, 39.14,
28.23, 25.70, 23.99, 21.40, 17.92, 15.80, 10.78, -4.80. Anal.
Calcd for C20H35NO3SSi: C, 60.41; H, 8.87; N, 3.52. Found:
C, 60.45; H, 8.81; N, 3.64.
1
1720, 1345, 1165 cm-1; H NMR δ 7.93 (dd, 2H, J ) 8.8, 2.0
Hz), 7.68 (d, 2H, J ) 8.3 Hz), 7.60 (dd, 2H, J ) 8.8, 2.0 Hz),
7.22 (d, 2H, J ) 8.3 Hz), 5.17 (dd, 1H, J ) 2.9, 2.4 Hz), 5.04
(bs, 1H), 3.79 (m, 1H), 3.02 (dt, 1H, J ) 12.2, 2.4 Hz), 2.39 (s,
3H), 2.22 (d, 1H, J ) 2.4 Hz), 2.08-1.95 (m, 3H), 1.63 (m, 1H);
13C NMR δ 164.87, 143.38, 135.96, 131.78, 131.36, 129.33,
128.73, 128.42, 127.59, 76.44, 76.36, 69.78, 48.71, 41.28, 23.78,
21.51, 20.17. Anal. Calcd for C21H20BrNO4S: C, 54.55; H,
4.36; N, 3.03. Found: C, 54.93; H, 4.52; N, 2.89.
(2R*,3S*)-3-[(ter t-Bu tyldim eth ylsilyl)oxy]-2-(3′-h ydr oxy-
1′-p r op yn yl)-1-(p-tolu en esu lfon yl)p ip er id in e (22). To a
solution of 21 (535 mg, 1.34 mmol) in THF (15 mL) was added
a solution of n-BuLi (1.59 M hexane solution, 0.94 mL, 1.49
mmol) at -78 °C, and the reaction mixture was stirred for 1
h. Paraformaldehyde (85.0 mg, 2.83 mmol) was added to the
reaction mixture, which was then stirred at room temperature
for 1 h. The reaction was quenched by addition of saturated
NH4Cl solution and extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to
dryness. Chromatography of the residue with hexane-AcOEt
(3:1) afforded 22 (557 mg, 97%) as a colorless oil: MS m/z 423
(M+, 0.2), 408 (9.9), 366 (100), 292 (3.1), 268 (99), 185 (28),
1
120 (11), 91 (57); IR 3600, 3500, 1340, 1210 cm-1; H NMR δ
7.74 (d, 2H, J ) 8.3 Hz), 7.27 (d, 2H, J ) 8.3 Hz), 4.67 (m,
1H), 3.98 (dd, 2H, J ) 6.3, 2.0 Hz), 3.94 (q, 1H, J ) 2.4 Hz),
3.57 (m, 1H), 2.85 (dt, 1H, J ) 12.2, 2.4 Hz), 2.41 (s, 3H), 1.99
(m, 1H), 1.80 (m, 1H), 1.56 (m, 1H), 1.41 (m, 1H), 1.32 (t, 1H,
J ) 6.3 Hz), 0.92 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR
δ 143.10, 136.34, 129.07, 128.03, 85.56, 80.01, 68.28, 51.80,
50.78, 41.70, 27.10, 25.71, 21.46, 19.14, 18.06, -4.95, -4.99.
Anal. Calcd for C21H33NO4SSi: C, 59.54; H, 7.85; N, 3.31.
Found: C, 59.37; H, 8.07; N, 3.20.
(2R*,3S*)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-eth ylp ip -
er id in e (tr a n s-19). To a solution of trans-18 (100 mg, 0.25
mmol) in THF (2.5 mL) was added a solution of sodium
naphthalenide in THF (0.2 M solution, 3.7 mL, 0.75 mmol) at
-60 °C. The reaction mixture was stirred for 20 min at the
same temperature, quenched by addition of saturated NH4Cl
solution, diluted with water, and extracted with AcOEt. The
extract was washed with water and brine, dried, and concen-
trated to dryness. Chromatography of the residue with
CHCl3-MeOH (10:1) afforded trans-19 (47 mg, 77%) as color-
less crystals, mp 172-173 °C (hexane-CHCl3): MS m/z 243
(2R*,3S*)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-[(Z)-3′-h y-
dr oxy-1′-pr open -1′-yl]-1-(p-tolu en esu lfon yl)piper idin e (23).
A solution of 22 (557 mg, 1.31 mmol) in AcOEt (7.0 mL) was
hydrogenated for 30 min under hydrogen atmosphere in the
presence of Lindlar catalyst (280 mg). The catalyst was
filtered off, and the filtrate was concentrated to dryness.
Chromatography of the residue with hexane-AcOEt (3:1)
afforded 23 (554 mg, 99%) as colorless solids, mp 92.0-93.0
(CHCl3-MeOH): MS m/z 425 (M+, 0.1), 410 (11), 368 (98), 352
(3.9), 270 (86), 213 (28), 185 (17), 155 (29), 138 (100), 120 (24),
(M+, 13), 214 (72), 186 (65), 112 (27), 72 (100); IR 3150 cm-1
;
1
91 (99); IR 3500, 3420, 1340, 1160 cm-1; H NMR δ 7.75 (d,
1H NMR δ 3.79 (dt, 1H J ) 8.8, 3.9 Hz), 3.39 (m, 1H), 2.82 (dt,
1H, J ) 12.2, 3.4 Hz), 2.75 (dt, 1H, J ) 8.8, 3.9 Hz), 2.08-
1.95 (m, 3H), 1.90 (m, 1H), 1.83 (m, 1H), 1.45 (m, 1H), 1.15 (t,
3H, J ) 7.3 Hz), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C
NMR δ 71.70, 64.13, 45.52, 33.95, 25.75, 24.17, 24.14, 17.94,
9.99, -4.08, -4.80; HRMS calcd for C13H29NOSi 243.2018,
found 243.2040.
2H, J ) 8.3 Hz), 7.24 (d, 2H, J ) 8.3 Hz), 5.76 (dddd, 1H, J )
11.2, 8.3, 5.9, 1.0 Hz), 5.66 (dd, 1H, J ) 11.2, 9.8 Hz), 4.69
(dd, 1H, J ) 9.8, 2.9 Hz), 4.41 (m, 1H), 4.07 (m, 1H), 3.70 (m,
1H), 3.35 (dt, 1H, J ) 12.7, 3.9 Hz), 3.06 (dt, 1H, J ) 12.7, 2.9
Hz), 2.40 (s, 3H), 2.23 (dd, 1H, J ) 7.8, 4.4 Hz), 1.94 (m, 1H),
1.68-1.56 (m, 2H), 1.42 (m, 1H), 0.90 (s, 9H), 0.09 (s, 3H), 0.05
(s, 3H); 13C NMR δ 143.01, 137.30, 131.64, 129.30, 127.55,
126.32, 68.99, 58.14, 56.88, 41.22, 27.24, 25.76, 21.46, 18.86,
18.06, -4.75, -5.01. Anal. Calcd for C21H35NO4SSi: C, 59.26;
H, 8.29; N, 3.29. Found: C, 59.29; H, 8.44; N, 3.21.
(2R*,3R*)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-eth ylp ip -
er id in e (cis-19). According to the procedure described for
preparation of trans-19, cis-19 (20 mg, 72%) was obtained from
cis-18 (45 mg, 0.11 mmol) as colorless solids, mp 181-182 °C
(hexane-CHCl3): MS m/z 243 (M+, 12), 214 (61), 186 (67), 112
(8R*,8a R*)-8-[(ter t-Bu t yld im et h ylsilyl)oxy]-1,2-d eh y-
d r oin d olizid in e (24). To a solution of 23 (530 mg, 1.25 mmol)
in THF (12 mL) was added sodium naphthalenide (0.20 M THF
solution, 18.8 mL, 3.76 mmol) at -78 °C. After 20 min of
stirring at the same temperature, the reaction was quenched
by addition of water and extracted with AcOEt. The extract
was washed with water and brine, dried, and concentrated to
1
(26), 72 (100); IR 3350 cm-1; H NMR δ 4.06 (t, 1H J ) 2.0
Hz), 3.47 (dt, 1H, J ) 12.7, 2.0 Hz), 2.89 (dt, 1H, J ) 12.7, 3.4
Hz), 2.86 (m, 1H), 2.15(m, 1H), 1.97 (m, 1H), 1.91 (m, 1H),
1.74 (m, 1H), 1.64 (m, 1H), 1.55 (m, 1H), 1.00 (t, 3H, J ) 7.3
Hz), 0.95 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR δ 64.34,

Total Synthesis of (()-Swainsonine
J . Org. Chem., Vol. 63, No. 18, 1998 6287
dryness. The residue was passed through a short pad of silica
gel with CHCl3-MeOH (10:1) to give the secondary amine
derivative (304 mg, 1.12 mmol), which was dissolved in CH2-
Cl2 (11 mL). Carbon tetrabromide (482 mg, 1.46 mmol) and
PPh3 (440 mg, 1.68 mmol) was added to the CH2Cl2 solution
at 0 °C. The reaction mixture was stirred at the same
temperature for 10 min and then Et3N (3.1 mL, 22.4 mmol)
was added. After 30 min of stirring at room temperature, the
reaction was quenched by addition of water and extracted with
CH2Cl2. The extract was washed with water and brine, dried,
and concentrated to dryness. Chromatography of the residue
with hexane-AcOEt (1:1) afford 24 (179 mg, 57% overall yield)
as a colorless oil: MS m/z 253 (M+, 6.0), 238 (2.2), 196 (100),
154 (36), 120 (86), 75 (20); IR 2860, 2790, 2715 cm-1; 1H NMR
δ 6.05 (m, 1H), 5.89 (m, 1H), 3.64 (dddd, 1H, J ) 12.7, 3.9,
2.4, 1.5 Hz), 3.46 (ddd, 1H, J ) 10.3, 9.3, 4.4 Hz), 3.23 (dddd,
1H, J ) 12.7, 6.4, 2.4, 1.5 Hz), 2.92 (m, 1H), 2.86 (m, 1H), 2.39
(m, 1H), 1.93 (m, 1H), 1.68-1.63 (m, 2H), 1.26 (m, 1H), 0.89
(s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR δ 131.51, 128.46,
73.95, 71.93, 57.89, 48.84, 34.29, 25.79, 24.35, 18.03, -4.28,
-4.70; HRMS calcd for C14H27NOSi 253.1861, found 253.1868.
(1R*,2S*,8S*,8a S*)- a n d (1R*,2S*,8R*,8a R*)-1,2-Dia c-
etoxy-8-[(ter t-bu tyldim eth ylsily)oxy]in dolizidin es (25 an d
26). To a solution of 24 (130 mg, 0.51 mmol) and NMO (120
mg, 1.03 mmol) in a combined solution of acetone (2.1 mL)
and H2O (0.7 mL) was added 4% aqueous solution of OsO4 (0.26
mL, 0.05 mmol) at room temperature. The reaction was
stirred at room temperature for 3 h, quenched by addition of
saturated NaHSO3, and stirred for an additional 30 min. The
reaction mixture was extracted with AcOEt, which was washed
with brine, dried, and concentrated to dryness. The residue
was passed through a short pad of silica gel with CHCl3-
MeOH (10:1) to give a mixture of crude dihydroxylated
products. To a solution of the crude dihydroxylated compounds
in THF (2.0 mL) was added a solution of TBAF (1.0 M THF
solution, 0.52 mL, 0.52 mmol) at room temperature. The
reaction mixture was stirred at room temperature for 2 h and
concentrated to leave the residue which was taken up in CH2-
Cl2 (2.0 mL). Pyridine (0.2 mL, 2.47 mmol), DMAP (10 mg,
0.08 mmol), and acetic anhydride (0.14 mL, 1.48 mmol) were
added to the CH2Cl2 solution. After 1 h of stirring at room
temperature, the reaction mixture was diluted with MeOH and
concentrated to dryness. Chromatography of the residue with
hexane-AcOEt (2:1) afforded 25 (102 mg, 67%) and 26 (14.0
mg, 9%). Compound 25 was a colorless oil: MS m/z 299 (M+,
0.1), 256 (3.1), 239 (70), 180 (82), 154 (30), 137 (51), 120 (100),
13C NMR δ 170.18, 169.94, 169.90, 70.15, 69.74, 69.18, 68.00,
59.21, 51.72, 29.73, 23.22, 20.99, 20.58, 20.45. Anal. Calcd
for C14H21NO6: C, 56.18; H, 7.07; N, 4.68. Found: C, 56.14;
H, 7.12; N, 4.58. Compound 26 had mp 117-118 °C (colorless
solids from CHCl3-MeOH): MS m/z 299 (M+, 0.1), 256 (3.0),
239 (69), 180 (80), 154 (29), 137 (51), 120 (100), 96 (15); IR
1
2810, 2760, 1750 cm-1; H NMR δ 5.20 (td, 1H, J ) 7.3, 5.4
Hz), 5.01 (t, 1H, J ) 7.3 Hz), 4.69 (ddd, 1H, J ) 11.2, 7.3, 4.9
Hz), 3.57 (dd, 1H, J ) 9.8, 7.3 Hz), 2.93 (m, 1H), 2.33 (dd, 1H,
J ) 9.8, 5.4 Hz), 2.29 (t, 1H, J ) 7.3 Hz), 2.13-2.06 (m, 2H),
2.04 (s, 6H), 2.00 (s, 3H), 1.72 (m, 1H), 1.63 (m, 1H), 1.24 (m,
1H); 13C NMR δ 170.01, 169.86, 169.14, 73.88, 72.91, 68.36,
67.41, 58.53, 51.19, 30.05, 23.58, 20.99, 20.64, 20.38. Anal.
Calcd for C14H21NO6: C, 56.18; H, 7.07; N, 4.68. Found: C,
56.14; H, 7.13; N, 4.56.
(1R*,2S*,8S*,8a S*)-1,2,8-tr ih yd r oxyin d olizid in e [(()-
Sw a in son in e (3)]. To a solution of 25 (87.0 mg, 0.29 mmol)
in MeOH (3.0 mL) was added K2CO3 (20.0 mg, 0.15 mmol).
The reaction mixture was stirred at room temperature for 1.5
h and concentrated to dryness. Chromatography of the residue
with CHCl3-MeOH (5:1) afforded (()-swainsonine (3)(50.0 mg,
99%) as colorless solids, mp 143-144 °C (CHCl3-Et2O): MS
m/z 173 (M+, 28), 155 (30), 138 (13), 129 (6.6), 113 (100), 96
(75), 84 (15), 72 (35); IR(KBr) 3430, 3370, 2810, 2730 cm-1
;
1H NMR δ (in D2O; sodium 3-(trimethylsilyl)propanesulfonate
was used as an internal standard) 4.35 (ddd, 1H, J ) 7.8, 5.9,
2.5 Hz), 4.26 (dd, 1H, J ) 5.9, 3.9 Hz), 3.81 (ddd, 1H, J ) 10.8,
9.8, 4.4 Hz), 2.91 (m, 1H), 2.89 (dd, 1H, J ) 11.2, 2.5 Hz), 2.55
(dd, 1H, J ) 11.2, 7.8 Hz), 2.07 (m, 1H), 1.96 (dt, 1H, J ) 12.2,
2.9 Hz), 1.92 (dd, 1H, J ) 9.8, 3.9 Hz), 1.72(m, 1H), 1.52 (m,
1H), 1.24 (m, 1H); 13C NMR δ (in D2O; CH3OH was used as
an internal reference) 73.40, 70.24, 69.60, 66.95, 61.22, 52.24,
33.08, 23.78. Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73;
N, 8.09. Found: C, 55.13; H, 8.66; N, 8.01.
Ack n ow led gm en t. The authors thank Dr. Shinzo
Hosoi, Faculty of Pharmaceutical Sciences, Kanazawa
University for X-ray crystallographic analysis. This
work was supported in part by Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science
and Culture of J apan, to which the authors’ thanks are
due.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds (E)-8, (Z)-8, and 24 and X-ray analysis
data and ORTEP drawing of compound 20 (17 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microform version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
96 (15); IR 2810, 2740, 1740 cm-1; H NMR δ 5.52 (dd, 1H, J
) 6.4, 3.9 Hz), 5.22 (ddd, 1H, J ) 7.8, 6.4, 2.0 Hz), 4.96 (ddd,
1H, J ) 11.2, 9.8, 4.9 Hz), 3.17 (dd, 1H, J ) 11.2, 2.0 Hz),
3.06 (dt, 1H, J ) 11.2, 2.9 Hz), 2.58 (dd, 1H, J ) 11.2, 7.8 Hz),
2.16-2.12 (m, 2H), 2.09 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.93
(dt, 1H, J ) 11.2, 3.9 Hz), 1.81-1.72 (m, 2H), 1.24 (m, 1H);
J O980598H