Intramolecular α-acylamino radical cyclizations with acylsilanes in the preparation of polyhydroxylated alkaloids: (+)-lentiginosine, (+)-1,8a-di-epi-lentiginosine, and (+)-1,2-di-epi-swainsonine

Article abstract of DOI:10.1016/j.tetlet.2007.07.021

Acylsilanes with latent α-acylamino radical functionality were prepared from different chiral templates. Radical cyclizations of these acylsilanes efficiently constructed polyhydroxylated indolizidine derivatives with excellent stereoselectivity at the br

Full text of DOI:10.1016/j.tetlet.2007.07.021

Tetrahedron Letters 48 (2007) 6271–6274
Intramolecular a-acylamino radical cyclizations with acylsilanes in
the preparation of polyhydroxylated alkaloids: (+)-lentiginosine,
(+)-1,8a-di-epi-lentiginosine, and (+)-1,2-di-epi-swainsonine
Ming-Jen Chen and Yeun-Min Tsai*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC
Received 20 June 2007; accepted 5 July 2007
Available online 30 July 2007
Abstract—Acylsilanes with latent a-acylamino radical functionality were prepared from different chiral templates. Radical cycliza-
tions of these acylsilanes efficiently constructed polyhydroxylated indolizidine derivatives with excellent stereoselectivity at the
bridgehead position. These cyclization products were converted to (+)-lentiginosine, (+)-1,8a-di-epi-lentiginosine, and (+)-1,2-di-
epi-swainsonine.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
molecular cyclizations of a-acylamino radicals4 with
acylsilanes (Scheme 1).5
Acylsilanes belong to an interesting class of compounds
that displays unusual reactivity.1 For example, intramo-
lecular radical cyclizations2 with acylsilanes as the radi-
cal acceptors (Scheme 1) proved to be an useful method
in the construction of five- and six-membered cyclic
alcohols.3 Several years ago we demonstrated that it
was possible to construct silyloxy-substituted pyrrolizid-
inones, indolizidinones, and quinolizidinones via intra-
Polyhydroxylated alkaloids6 (Scheme 2) represented by
lentiginosine (1), 2-epi-lentiginosine (2), swainsonine
(3), and castanospermine (4) can be potent and selective
glycosidase inhibitors and may be useful as anti-cancer,
anti-diabetic, and anti-viral agents, and immune stimu-
lants.7 The biological potential of this class of com-
pounds has triggered the development of many
synthetic methods aiming at the synthesis of these natu-
ral products and their analogs.6 Since our radical cycli-
zation approach provides an easy entry to the basic
skeleton, we decided to advance further to explore the
possibility of using this methodology in the synthesis
of these polyhydroxylated alkaloids and their analogs.
OSiR3
O
R3Si
O
n
R3Si
n = 1 or 2
n
n
OH
OH
1
H
N
H
8
R3SiO
7
R3Si
O
OH
OH
N
4
2
3
6
n
N
m
n
5
N
m
(+)-lentiginosine (1)
(−)-2-epi-lentiginosine (2)
O
O
n, m = 1 or 2
HO
OH
H
HO
OH
H
Scheme 1.
HO
OH
N
N
HO
Keywords: Acylsilane; Radical cyclization; Lentiginosine; 1,8a-Di-epi-
lentiginosine; 1,2-Di-epi-swainsonine.
(−)-swainsonine (3)
(+)-castanospermine (4)
*
Corresponding author. Tel.: +886 2 3366 1651; fax: +886 2 2363
6359; e-mail: ymtsai@ntu.edu.tw
Scheme 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.021

6272
M.-J. Chen, Y.-M. Tsai / Tetrahedron Letters 48 (2007) 6271–6274
2. Results and discussion
by the formation of thiocarbonyl imidazolide 13 (85%)
followed by reduction with TBTH in refluxing toluene
to afford diacetate 14 (60%) that is identical spectroscop-
ically to the enantiomer reported in the literature.14 Fur-
ther reduction of 14 with LAH gave (+)-lentiginosine (1)
in 69% yield.15
As shown in Scheme 3, we started from the chiral tem-
plate imide 6 derived from L-(+)-tartaric acid.8 Mitsun-
obu coupling9 of 6 with alcohol 55 in the presence of
diisopropyl azodicarboxylate (DIAD) and triphenyl-
phosphine gave imide 7 in 77% yield. Reduction of 7
with sodium borohydride in methanol10 afforded carbi-
nol lactam 8. Attempted exchange of the hydroxyl group
with thiophenoxy group under acidic condition met with
failure. This is probably due to the difficulty in the gen-
eration of an a-acyliminium ion intermediate with two
adjacent electron-withdrawing acetoxy groups. We
therefore converted the crude carbinol product 8 to tri-
acetate 9 (93%). With a better leaving group, now triac-
etate 9 can be exchanged successfully with thiophenol in
the presence of a catalytic amount of p-toluenesulfonic
acid monohydrate.10 Due to the observation of some
acetate hydrolysis, the crude product was reacetylated
to give sulfide 10 in 87% yield. Hydrolysis of the dithiane
moiety with iodobenzene bistrifluoroacetate in wet ace-
tonitrile11 gave acylsilane 11 in 84% yield.
The stereochemistry of exo-12 can be identified by com-
paring with the literature report of its enantiomer.10 The
fact that the Barton deoxygenation process12 gave a sin-
gle isomer 14 proved that the other isomer present in 12
was the endo-isomer and the stereoselectivity of the
cyclization at the bridgehead was excellent.10 The radi-
cal generated from sulfide 11 prefers to attack the acyl-
silane from the face opposite to the C(4)-acetoxy group
as reported by Dener et al.10
In systems such as 2-epi-lentiginosine (2) and swainso-
nine (3), the C(1)- and C(2)-hydroxy groups adopt cis-
relationship. Retrosynthetically the imide approach
can be traced back to the non-optically active meso-tar-
taric acid. We therefore switched to a different chiral
template as shown in Scheme 4. Alkylation of 2-trimeth-
ylsilyl-1,3-dithiane (15) with bromide 1616 followed by
For the key radical cyclization, acylsilane 11 was treated
with tributyltin hydride (TBTH) in refluxing toluene in
the presence of a catalytic amount of 2,20-azobisisobuty-
ronitrile (AIBN). The crude product was stirred directly
with tetrabutylammonium fluoride (TBAF) in THF to
yield 65% of alcohol 12 as an inseparable mixture of
exo- and endo-isomers (exo/endo = 4/1). Deoxygen-
ation12,13 of the C(8)-hydroxy group was accomplished
OH
1)
O
O
1) BuLi
2)
Br
N
O
O
CHPh
3
(18)
(16)
S
S
S
S
NH2
3) PhNHNH2
EtOH, rt
MeOH, rt
Σ
3
Σ
2) Pb(OAc)4, K2CO3
CH3CN, 0 oC
17 (76%)
15
Σ = SiMe3
3) AcOH (cat.), CH2Cl2
OAc
OAc
S
OAc
OAc
O
O
Ph3P
S
S
S
O
O
O
PhO
S
O
N
+
HO
S
OH
3
HN
Σ
N
3
DIAD
THF
PhI(OCOCF3)2
O
PhOCSCl
S
O
Σ
N
O
Σ = SiMePh2
DIPEA
4-DMAP
CH2Cl2
NaHCO3, rt
S
S
0 o
C
3
3
7 (77%)
5
6
Σ
Σ
O
O
CH3CN/H2O
19 (84%)
20 (80%)
1) NaBH4
MeOH
OAc
OAc
0 o
C
1) TsOH
(cat.)
PhSH
OAc
OAc
RO
PhS
S
S
−10 o
C
1) NaH, CS2
MeI, THF
0 o
C
S
1) TBTH
AIBN
(cat.)
Y
N
N
O
O
PhO
O
N
X
H
N
2) Ac2O
DMAP
Et3N
2) Ac2O
DMAP
Et3N
S
S
3
3
Σ
Σ
O
O
O
O
O
8 R = H
9 R = Ac (93%)
toluene
2) TBTH
AIBN
10 (87%)
CH2Cl2
CH2Cl2
Σ
3
110 oC
2) TBAF
THF, rt
O
O
1) TBTH
AIBN
(cat.)
HO
(cat.)
22a X = H, Y = OH
22b X = OH, Y = H
OAc
OAc
OAc
21 (91%)
H
N
PhS
O
PhI(OCOCF3)2
benzene
80 o
OAc
C
22a/22b = 1/0.7 (91%)
toluene
NaHCO3, rt
CH3CN/H2O
N
Σ
3
110 oC
2) TBAF
THF, rt
O
O
OH
H
O
H
N
12 (65%)
exo/endo = 4/1
11 (84%)
ref 20
O
OH
N
RO
OAc
OAc
O
OAc
H
H
N
O
(Im)2C=S
TBTH
AIBN
23 (68%)
LAH
THF
24
1
OAc
N
O
HO
(69%)
OH
O
H
H
N
1) BH3
THF
(cat.)
O
NaBH4
DMP
O
toluene
110 oC
S
22
22a
(70%)
OH
14 (60%)
N
CH2Cl2
rt
2) HCl
(1 N)
MeOH
−40 oC
R =
N
N
O
25 (87%)
13 (85%)
26 (73%)
Scheme 3.
Scheme 4.

M.-J. Chen, Y.-M. Tsai / Tetrahedron Letters 48 (2007) 6271–6274
6273
C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19,
147–195; (c) Cirillo, P. F.; Panek, J. S. Org. Prep. Proced.
Int. 1992, 24, 553–582; (d) Page, P. C. B.; McKenzie, M.
J.; Klair, S. S.; Rosenthal, S. In The Chemistry of Organic
Silicon Compounds; Rappoport, Z., Apeloig, Y., Eds.;
John Wiley & Sons: New York, 1998; Vol. 2, pp 1599–
1665, Chapter 27; (e) Bonini, B. F.; Comes-Franchini, M.;
Fochi, M.; Mazzanti, G.; Ricci, A. J. Organomet. Chem.
1998, 567, 181–189.
phenylhydrazine treatment gave us amine 17 in 76%
yield.17 This amine reacted with the commercially avail-
able 2,3-isopropylidene-D-ribono-1,4-lactone (18), and
the resulting crude amide diol was treated with lead tet-
raacetate followed by acid treatment to afford a single
isomer of lactam carbinol 19 in 84% yield over three
steps.18 Exchanging the hydroxyl group in 19 with
thiophenol under acidic condition was not successful
possibly due to the presence of an acid sensitive isopro-
pylidene protecting group. We therefore took a different
approach by converting lactam carbinol 19 to thiocar-
bonate 20 (80%).19 Hydrolysis11 of the dithiane moiety
as above gave acylsilane 21 in 91% yield. Radical cycli-
zation reaction of 21 followed by desilylation gave an
isomeric mixture of alcohols 22 (22a/22b = 1/0.7; 91%
yield). Barton deoxygenation12 removed the C(8)-hydr-
oxy group to afford indolizidinone 23 in 68% yield. This
material had been converted to (+)-1,8a-di-epi-lentigi-
nosine (24) by Heitz and Overman.20
2. (a) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in
Organic Chemistry; John Wiley & Sons: New York, 1995;
(b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.;
Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48,
301–856; (c) Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001.
3. Huang, C.-H.; Chang, S.-Y.; Wang, N.-S.; Tsai, Y.-M. J.
Org. Chem. 2001, 66, 8983–8991, and references cited
therein.
4. Hart, D. J. in Ref. 1c, Vol. 2, pp 279–302.
5. Tsai, Y.-M.; Nieh, H.-C.; Pan, J.-S.; Hsiao, D.-D. Chem.
Commun. 1996, 2469–2470.
6. For reviews about the synthesis of polyhydroxylated
alkaloids, see: (a) Revuelta, J.; Cicchi, S.; Goti, A.;
Brandi, A. Synthesis 2007, 485–504; (b) Michael, J. P.
Nat. Prod. Rep. 2005, 22, 603–626; (c) Pyne, S. G. Curr.
Org. Synth. 2005, 2, 39–57; (d) Yoda, H. Curr. Org. Chem.
2002, 6, 223–243; (e) Nemr, A. E. Tetrahedron 2000, 56,
8579–8629.
7. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R.
J.; Nash, R. J. Phytochemistry 2001, 56, 265–295.
8. Hwang, D. J.; Kim, S. N.; Choi, J. H.; Lee, Y. S. Bioorg.
Med. Chem. 2001, 9, 1429–1437.
9. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L.
Org. React. 1992, 42, 335–656.
10. Dener, J. M.; Hart, D. J.; Ramesh, S. J. Org. Chem. 1988,
53, 6022–6030.
11. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–
290.
12. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
Alternatively, alcohols 22 were oxidized with Dess–Mar-
tin periodinane (DMP) to yield ketone 25 (87%) as a sin-
gle isomer. This indicated that the two isomers of 22
were epimeric at C(8). Sodium borohydride reduction
of ketone 25 in methanol gave selectively the exo-isomer
22a in 70% yield. Borane reduction of 22a followed by
acid hydrolysis furnished (+)-1,2-di-epi-swainsonine21,22
(26) in 73% yield. This alkaloid is a potent inhibitor of a-
D-mannosidase (jack bean) with Ki of 6 lM.22 Again,
the radical cyclization of acylsilane 21 gave very good
stereoselectivity at the bridgehead position as in the case
of acylsilane 11. Although the stereochemistry at C(8) is
plagued with the lack of stereoselectivity at the hydro-
gen atom abstraction step of the cyclization reaction,
we demonstrated that the orientation of the C(8)-hydr-
oxy group could be manipulated through simple oxida-
tion and reduction processes.
13. For a review about radical chemistry associated with the
thiocarbonyl group, see Crich, D.; Quintero, L. Chem.
Rev. 1989, 89, 1413–1432.
14. Gurjar, M. K.; Ghosh, L.; Syamala, M.; Jayasree, V.
Tetrahedron Lett. 1994, 35, 8871–8872.
In summary, we have demonstrated that the a-acyl-
amino radical chemistry pioneered by Hart4 can be cou-
pled with the acylsilane functionality to produce
polyhydroxylated alkaloids in a versatile way. This
methodology can well-adopt readily available chiral
templates as starting materials. The cyclizations gave
excellent stereoselectivity at the bridgehead of the bicy-
clic structures. Although the stereochemistry of the new-
ly formed silyloxy group cannot be controlled in a
highly selective fashion, the stereochemistry can be con-
veniently manipulated through simple processes. This
work also demonstrated that the acylsilane functionality
embedded in a complex molecular system can be synthe-
sized and utilized in an useful way.
15. (a) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K.
Tetrahedron: Asymmetry 1993, 4, 1455–1456; (b) Cor-
dero, F. M.; Cicchi, S.; Goti, A.; Brandi, A. Tetrahedron
Lett. 1994, 35, 949–952; (c) Brandi, A.; Cicchi, S.;
Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.;
Vogel, P. J. Org. Chem. 1995, 60, 6806–6812; (d) Ha, D.-
C.; Yun, C.-S.; Lee, Y. J. Org. Chem. 2000, 65, 621–623;
(e) Ichikawa, Y.; Ito, T.; Isobe, M. Chem. Eur. J. 2005,
11, 1949–1957; (f) Yoda, H.; Kawauchi, M.; Takabe, K.
Synlett 1998, 137–138; (g) Cardona, F.; Moreno, G.;
Guarna, F.; Vogel, P.; Schuetz, C.; Merino, P.; Goti, A.
J. Org. Chem. 2005, 70, 6552–6555; (h) Rasmussen, M.
O.; Delair, P.; Greene, A. E. J. Org. Chem. 2001, 66,
5438–5443; (i) Klitzke, C. F.; Pilli, R. A. Tetrahedron
Acknowledgment
´
Lett. 2001, 42, 5605–5608; (j) Rabiczko, J.; Urbanczyk-
Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58,
1433–1441; (k) El-Nezhawy, A. O. H.; El-Diwani, H. I.;
Schmidt, R. R. Eur. J. Org. Chem. 2002, 4137–4142; (l)
Raghavan, S.; Sreekanth, T. Tetrahedron: Asymmetry
2004, 15, 565–570.
Financial support by the National Science Council of
the Republic of China is gratefully acknowledged.
References and notes
16. Lai, G. Synth. Commun. 2001, 31, 565–568.
17. Metcalf, B. W.; Bey, P.; Danzin, C.; Jung, M. J.; Casara,
P.; Vevert, J. P. J. Am. Chem. Soc. 1978, 100, 2551–
2553.
1. For recent reviews about acylsilanes, see: (a) Ricci, A.;
Degl’Innocenti, A. Synthesis 1989, 647–660; (b) Page, P.

6274
M.-J. Chen, Y.-M. Tsai / Tetrahedron Letters 48 (2007) 6271–6274
18. Miller, S. A.; Chamberlin, A. R. J. Am. Chem. Soc. 1990,
112, 8100–8112.
19. Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem.
Soc. 1983, 105, 4059–4065.
21. (a) Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693–
5706; (b) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002,
67, 7774–7780.
´
22. de Vicente, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C.
˜
20. Heitz, M.-P.; Overman, L. E. J. Org. Chem. 1989, 54,
2591–2596.
Synlett 2000, 53–56.