Stereoselective construction of the pyrrolizidine bridgehead stereochemistry by the adjacent hydroxyl group in the synthesis of (+)-heliotridine and (-)-retronecine

Article abstract of DOI:10.1016/j.tetlet.2004.02.097

Formal total synthesis of (+)-heliotridine (4) and total synthesis of (-)-retronecine (5) were accomplished by using (S)-3-acetoxysuccinimide (6) as the common starting material. The stereogenic center of 6 ended up as C-1 in both alkaloids. The chiral centers at C-7a of the alkaloids were stereoselectively constructed through the help of the adjacent functionality at C-1. The B-rings of the alkaloids were formed through α-sulfonyl radical cyclizations.

Full text of DOI:10.1016/j.tetlet.2004.02.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3047–3050
Stereoselective construction of the pyrrolizidine bridgehead
stereochemistry by the adjacent hydroxyl group in the synthesis
of (+)-heliotridine and ())-retronecine
Jie-Ming Huang, Sea-Chuan Hong, Kun-Liang Wu and Yeun-Min Tsai*
Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan, ROC
Received 30 January 2004; revised 17 February 2004; accepted 19 February 2004
Abstract—Formal total synthesis of (+)-heliotridine (4) and total synthesis of ())-retronecine (5) were accomplished by using (S)-3-
acetoxysuccinimide (6) as the common starting material. The stereogenic center of 6 ended up as C-1 in both alkaloids. The chiral
centers at C-7a of the alkaloids were stereoselectively constructed through the help of the adjacent functionality at C-1. The B-rings
of the alkaloids were formed through a-sulfonyl radical cyclizations.
Ó 2004Elsevier Ltd. All rights reserved.
Pyrrolizidine alkaloids are an important class of com-
pounds that continue to attract the attention of syn-
thetic chemists.1;2 Several years ago (Scheme 1), we
developed an a-sulfonyl free radical cyclization
approach for the synthesis of supinidine (3), the most
simple unsaturated necine base of the pyrrolizidine
alkaloids.3;4 In this letter, we wish to report the suc-
cessful stereoselective synthesis of (+)-heliotridine (4)
and ())-retronecine (5) using similar methodology.
Our synthetic approach started from enantiopure imide
6 (Scheme 2), which can be synthesized easily from ())-
malic acid.5;6 The pre-existing stereogenic center in imide
6 can be transformed into C-1 of (+)-heliotridine (4) and
())-retronecine (5). Relying on the oxygen functionality
of this stereogenic center, we planned to construct the
adjacent chiral center in a controlled fashion.
As shown in Scheme 3, imide 6 was coupled with
2-phenylthioethanol using triphenylphosphine and
diisopropyl azodicarboxylate (DIAD).7 The resulting
imide acetate product was then stirred in methanol with
the presence of catalytic amount of camphor sulfonic
acid (CSA) to afford imide alcohol 9 in 78% yield.
Treatment of imide alcohol 9 with excess lithium tri-
methylsilylacetylide (3 equiv) gave a mixture of diaste-
reomeric lactam diol 10a. This diol mixture was directly
reduced with triethylsilane and borontrifluoride etherate
SiMe3
Bu3Sn
N
OH
Bu3SnH
(2 equiv)
SiMe3
Cl
N
N
SO2Ph
O
O
3
2
1
supinidine
8
5
OH
OH
HO
1
2
HO
H
H
7
7a
N
4
6
N
3
SiMe3
Cl
SiMe3
Cl
AcO
AcO
O
5
AcO
O
H
N
H
N
O
4
(− )-retronecine
(+)-heliotridine
NH
SO2Ph
SO2Ph
O
Scheme 1.
8
5
6
7
4
Keywords: Pyrrolizidines; (+)-Heliotridine; ())-Retronecine; Total
synthesis; Radical cyclization.
* Corresponding author. Tel.: +886-2-23690152x117; fax: +886-2-23-
636359; e-mail: ymtsai@ntu.edu.tw
Scheme 2.
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.097

3048
J.-M. Huang et al. / Tetrahedron Letters 45 (2004) 3047–3050
HO
O
C-4oxygen substituent that directs the triethylsilane to
attack the acylimminium ion intermediate from the
same side.8a;9 The stereoselectivity was converted into
slight preference of the cis-isomer (entries 5–7) when
using sodium cyanoborohydride in acetic acid. How-
ever, the reduction of carbinol 10d (entry 8) under this
condition still gave 11d as the major product.
RO
O
SiMe3
SPh
OH
N
O
a,b
c
6
N
SPh
9
10a R = H
SiMe3
h,i
RO
SiMe3
H
N
AcO
O
H
d
f,g
With lactam 11a in hand, the hydoxyl group was then
protected as acetate by the reaction with acetic anhy-
dride to afford 11b (92%). Treatment of 11b with NCS in
carbon tetrachloride gave a-chloro sulfide10 12 that was
directly oxidized with MCPBA without purification to
obtain a-chloro sulfone 7 (86%). The reaction of 7 with
excess tributyltin hydride (3 equiv) afforded bicyclic
lactam 13 (81%) as a mixture of two isomers epimeric at
the exo-cyclic chiral center.3;11–14
R1
N
SPh
R2
O
11a R = H
R = Ac
12 R1 = Cl, R2 = SPh
R1 = Cl, R2 = SO2Ph
e
11b
7
X
SiMe3
OAc
SiMe3
AcO
AcO
AcO
O
H
N
H
N
H
N
j
X
O
O
15
16 X = SePh
X = Br
13 X = SnBu3
14
The final stage of the synthesis requires the conversion
of the allyl moiety to an allylic alcohol. This was
accomplished by the reaction of bicyclic lactam 13 with
2 equiv of phenylslenenyl bromide in acetonitrile to
obtain bromide 14 in 90% yield.3 This process involved
the formation of selenide 16 that further reacted with
phenylslenenyl bromide to give bromide 14. Note that a
large excess of lithium bromide (8 equiv) was added to
facilitate the reaction. Without the addition of lithium
bromide the initial formation of selenide 16 was always
contaminated with allyl bromide 17. Bromide 14 was
displaced with potassium acetate in the presence of
18-crown-6. The silyl group was also removed in the
same step when a small amount of water was present.
This led to the formation of diacetate 1515;16 in 58%
yield. The conversion of diacetate 15 to (+)-heliotridine
(4) has been reported by Dener and Hart.16a
17
X = Br
Scheme 3. Reagents and conditions: (a) Ph3P, DIAD, PhS(CH2)2OH;
(b) MeOH, CSA (cat.), 78%; (c) LiCCSiMe3 (3 equiv), )78 °C; (d)
Et3SiH, BF3ÆOEt2, CH2Cl2, )78 to 0 °C, 96% from 9; (e) Ac2O,
4-DMAP (cat.), Et3N, CH2Cl2, 92%; (f) NCS, CCl4; (g) MCPBA,
CH2Cl2, 86%; (h) Bu3SnH (3 equiv), AIBN (0.1 equiv), C6H6, 80 °C,
81%; (i) PhSeBr (2 equiv), LiBr (8 equiv), CH3CN, )40 °C to rt, 90%;
(j) KOAc (2.5 equiv), 18-crown-6 (0.1 equiv), H2O (1.2 equiv), CH3CN,
58%.
to give lactam 11a as a single isomer (96% yield from 9).8
The stereocontrol of the reduction step was excellent.
In fact we surveyed several blocking groups on the C-4
hydroxyl group of lactam diol 10a to examine the ste-
reoselectivity of the reduction (Table 1). In the case with
triethylsilane and borontrifluoride etherate (entries 1–4),
the reduction of the unprotected lactam diol 10a (entry
1) gave the highest yield with excellent trans-stereo-
selectivity. Even when we used a bulky t-butyldiphe-
nylsilyl group to protect the C-4hydroxyl group (entry
4), the reduction yielded lactam 11d as the major
product (trans/cis ¼ 75/25). These stereochemical out-
comes can be rationalized by the chelation effect of the
As mentioned above, sodium cyanoborohydride reduc-
tion of lactam diol 10a in acetic acid (Table 1, entry 5)
afforded the cis-isomer of lactam 11a as the major
product. However, the stereoselectivity of this reduction
is not satisfactory for the synthesis of ())-retronecine
(5). We decided to employ the methodology reported by
17
€
Vasella and Burli to intramolecularly deliver the
trimethylsilylacetylene group with the help of the adja-
cent hydroxyl group. In this direction (Scheme 4), we
started from imide 9 and regioselectively reduced the
carbonyl group adjacent to the hydroxyl group using
sodium borohydride under the condition reported by
Speckamp.18 The resulting crude a-acylamino alcohol
was converted directly to the methyl ether 18 (95%) in
methanol with catalytic amount of p-toluenesulfonic
acid.
Table 1. The stereochemical outcome of the reduction of lactam car-
binols 10a–d
Entry Substrate
Methoda Products (trans/cis)b
Yields
(%)
1
2
3
4
5
6
7
8
10a
10b R ¼ Ac
A
A
A
A
B
B
B
B
11ac
11bc
11cc
96
17
51
10c R ¼ Bn
10d R ¼ TBDPS
11d+cis-isomer (75/25) 68d
11a+cis-isomer (40/60) 70d
11b+cis-isomer (43/57) 72d
11c+cis-isomer (40/60) 73d
11d+cis-isomer (60/40) 40d
The methyl ether 18 was first silylated with diethyl
trimethylsilylethynyl chloro silane17 in the presence of
triethylamine and catalytic amount of 4-DMAP in
dichloromethane. The reaction mixture was then cooled
to )78 °C followed by the addition of excess titanium
tetrachloride (3.7 equiv). This one pot process success-
fully gave the lactam alcohol 19 with a cis-relationship
of the hydroxyl and acetylenic groups. This reaction
involved the formation of silyl ether 23 (Scheme 5) first.
The addition of titanium tetrachloride to the solution of
10a
10b
10c
10d
a Method A: Et3SiH, BF3ÆOEt2, CH2Cl2, )72 to 0 °C; Method B:
NaBH3CN, HOAc, rt.
b The stereochemistry was determined by NOE experiments.
c Only observed the trans-isomer.
d The two isomers can be separated easily by silica gel column chro-
matography. The yields are combined isolation yields.

J.-M. Huang et al. / Tetrahedron Letters 45 (2004) 3047–3050
3049
HO
O
Acknowledgements
HO
O
SiMe3
SPh
H
N
OMe
a,b
c
9
N
Financial support by the National Science Council of
the Republic of China is gratefully acknowledged.
SPh
18
19
X
SiMe3
Y
AcO
O
References and notes
AcO
H
N
H
j
g–i
d–f
5
Cl
1. Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine
Alkaloids; Academic: New York, 1986.
2. Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773–781.
3. Tsai, Y.-M.; Ke, B.-W.; Yang, C.-T.; Lin, C.-H. Tetrahe-
dron Lett. 1992, 33, 7895–7898.
N
SO2Ph
O
20 X = SnBu3, Y = SiMe3
21 X = Br, Y = SiMe3
22 X = OAc, Y = H
8
4. For recent reviews about radical cyclizations in alkaloid
synthesis: (a) Hart, D. J. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: New York,
2001; vol. 2, pp 279–302; (b) Bowman, W. R.; Fletcher, A.
J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans. 1 2002,
2747–2762.
5. (a) Chamberlin, A. R.; Chung, J. Y. J. Am. Chem. Soc.
1983, 105, 3653–3656; (b) Choi, J.-K.; Hart, D. J.
Tetrahedron 1985, 41, 3959–3971.
Scheme 4. Reagents and conditions: (a) NaBH4, 0 °C, THF/EtOH; (b)
p-TsOH, MeOH, 95%; (c) ClEt2Si(CCSiMe3) (1.5 equiv), Et3N
(1.5 equiv), 4-DMAP (cat.), CH2Cl2, rt, TiCl4 (3.7 equiv), )78 °C, 80%;
(d) Ac2O, 4-DMAP (cat.), Et3N, CH2Cl2; (e) NCS, CCl4; (f) MCPBA,
CH2Cl2, 85%; (g) Bu3SnH (2.5 equiv), AIBN (0.1 equiv), C6H6, 80 °C,
58% of 20; (h) PhSeBr (2 equiv), LiBr (8 equiv), CH3CN, )40 °C to rt,
97% of 21; (i) KOAc, 18-crown-6, H2O, CH3CN, rt, 84% of 22; (j)
LAH, THF, D, 63%.
6. For the utilization of malic acid in the asymmetric
synthesis of pyrrolizidines, see: Dai, W.-M.; Nagao, Y.;
Fujita, E. Heterocycles 1990, 30, 1231–1261, and refer-
ences cited therein.
7. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L.
Org. React. 1992, 42, 335–656.
Si
O
SiMe3
TiCl4
Si
O
SiMe3
SPh
Si
N
O
8. (a) Huang, P. Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.;
Huang, Y. Q.; Zheng, H.; Gao, J. X. Tetrahedron 1998, 54,
12547–12560; (b) Yoda, H.; Kitayama, H.; Yamada, W.;
Katagiri, T.; Takabe, K. Tetrahedron: Asymmetry 1993, 4,
1451–1454.
SiMe3
SPh
OMe
19
N
N
SPh
O
O
O
23
24
25
9. For alternative explanations, see: (a) Cieplak, A. S. Chem.
Rev. 1999, 99, 1265–1336; (b) Ohwada, T. Chem. Rev.
1999, 99, 1337–1375.
Scheme 5.
10. Dilworth, B. M.; McKervey, M. A. Tetrahedron 1986, 42,
3731–3752.
11. Ke, B.-W.; Liu, C.-H.; Tsai, Y.-M. Tetrahedron 1997, 53,
7805–7826.
12. Clive, D. L. J.; Boivin, T. L. B.; Angoh, A. G. J. Org.
Chem. 1987, 52, 4943–4953.
13. Paquette, L. A. Synlett 2001, 1–12.
23 generated the acyliminium ion 24 that cyclized to
form the vinyl cation intermediate 25. Desilylation of 25
regenerated the acetylenic group at the same side of the
transporting oxygen atom.
The rest of the synthesis was carried out in a similar
fashion as in the case of (+)-heliotridine (4). Thus, as
shown in Scheme 4, acetylation of lactam 19 followed by
chlorination and oxidation afforded a-chloro sulfone 8
in an 85% overall yield. Radical cyclization of 8 pro-
vided bicyclic lactam 20 (58%). The bicyclic lactam 20
was then converted to allyl bromide 21 (97%). Substi-
tution of bromide 21 with potassium acetate gave the
desilylated diacetate 2219 (84%). Finally, lithium alumi-
num hydride reduction of 22 produced ())-retronecine
(5)20–22 in 63% yield.
14. Ueno, Y.; Aoki, S.; Okawara, M. J. Am. Chem. Soc. 1979,
101, 5414–5415.
15. The spectroscopic data of this material is identical to that
22:8
reported in the literature (Ref. 5,16). ½aꢀ
+34.7 (c, 0.92
D
25
D
in CHCl3) [lit.16b ½aꢀ +34.4 (c, 2.2 in CHCl3)].
16. (a) Dener, J. M.; Hart, D. J. Tetrahedron 1988, 44, 7037–
7046; (b) Kametani, T.; Yukawa, H.; Honda, T. J. Chem.
Soc., Perkin Trans. 1 1990, 571–577.
€
17. Burli, R.; Vasella, A. Helv. Chim. Acta. Acta 1996, 79,
1159–1168.
18. Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437–1441.
26
D
19. Characterization of 22: ½aꢀ +67.2 (c, 1.11 in CHCl3); IR
In summary, starting from ())-malic acid derived imide
6 we were able to synthesize either (+)-heliotridine (4) or
())-retronecine (5) with high stereoselectivity. Relying
on the pre-existing stereogenic center in imide 6, we
could control the stereochemistry of the newly formed
adjacent chiral center at will. The B-ring of the target
alkaloids was formed through a key radical cyclization
step involving a-sulfonyl radical. The synthetic
approach developed here has the potential to be ex-
tended to the synthesis of the more functionalized
alkaloids of the same family.
(CH2Cl2) 1746 (C@O), 1709 (C@O) cmꢁ1
;
1H NMR
(CDCl3, 400 MHz) d 2.01 (s, 3H, COCH3), 2.06 (s, 3H,
COCH3), 2.38 (d, J ¼ 17:2 Hz, 1H, COCH2), 2.98 (dd,
J ¼ 17:2, 4.8 Hz, 1H, COCH2), 3.77 (br d, J ¼ 17:0 Hz,
1H, NCH2), 4.43 (br d, J ¼ 17:0 Hz, 1H, NCH2), 4.60 (d
of AB, J ¼ 12:8 Hz, 1H, OCH2), 4.69 (d of AB,
J ¼ 12:8 Hz, 1H, OCH2), 4.84 (br s, 1H, NCH), 5.52 (t,
J ¼ 4:0 Hz, 1H, OCH), 5.88 (br s, 1H, @CH); 13C NMR
(CDCl3, 100 MHz) d 20.7 (q), 21.0 (q), 41.9 (t), 49.7 (t),
60.2 (t), 71.0 (d), 72.5 (d), 127.4(d), 134.3 (s), 170.0 (s),
170.5 (s), 175.1 (s); HRMS calcd for C12H15NO5 m=z
253.0945, found m=z 253.0948.

3050
J.-M. Huang et al. / Tetrahedron Letters 45 (2004) 3047–3050
20. The spectroscopic data of this material is identical to that
)53.2 (c, 1.15 in
D
21. (a) Niwa, H.; Miyachi, Y.; Okamoto, O.; Uosaki, Y.;
Kuroda, A.; Ishiwata, H.; Yamada, K. Tetrahedron 1992,
48, 393–412; (b) Drewes, S. E.; Antonowitz, I.; Kaye, P.
T.; Coleman, P. C. J. Chem. Soc., Perkin Trans. 1 1981,
287–289.
23:1
D
reported in the literature (Ref. 21). ½aꢀ
20
EtOH) [lit.22 ½aꢀ )52.9 (EtOH)].
22. Nishimura, Y.; Kondo, S.; Umezawa, H. J. Org. Chem.
1985, 50, 5210–5214.