Synthetic applications of sulfur-substituted indolizidines and quinolizidines

Article abstract of DOI:10.1021/jo102092b

Starting from the sulfur-substituted indolizidines and quinolizidines, a few useful synthetic transformations have been developed and the synthesis of some natural products including indolizidine 209D, epimyrtine, lasubine II, 8a-epi-dendroprimine, and 5-

Full text of DOI:10.1021/jo102092b

pubs.acs.org/joc
SCHEME 1. Synthesis of Indolizidine 4 and Quinolizidine 5a
Synthetic Applications of Sulfur-Substituted
Indolizidines and Quinolizidines
Shang-Shing P. Chou,* Yi-Ching Chung, Po-An Chen,
Shan-Lun Chiang, and Chien-Jung Wu
Department of Chemistry, Fu Jen Catholic University
Taipei 24205, Taiwan, ROC
chem1004@mails.fju.edu.tw
Received October 22, 2010
aReagents and conditions: (i) (a) Ts;NdCdO (3 equiv), HQ (cat.),
NaHCO3 (1 equiv), Tol, 110 °C, 4.5 h; (b) Et3N; (ii) Bu3SnH (1.2 equiv),
AIBN (0.2 equiv ꢀ 3), Tol, reflux, 4.5 h; (iii) NaH (1.5 equiv), THF,
reflux, 3 h.
SCHEME 2. Synthesis of Indolizidine 209Da
aReagents and conditions: (i) (a) C6H13MgBr (4 equiv), THF, rt, 2 h;
(b) HOAc (4 equiv), 0 °C, 5 min; (c) NaBH4 (10 equiv), MeOH, 0 °C,
30 min, 71%; (ii) Ra-Ni (10 equiv), 95% EtOH, reflux, 2 h, 71%.
Starting from the sulfur-substituted indolizidines and
quinolizidines, a few useful synthetic transformations
have been developed and the synthesis of some natural
products including indolizidine 209D, epimyrtine, lasu-
bine II, 8a-epi-dendroprimine, and 5-epi-cermizine C has
been accomplished.
some indolizidines and quinolizidines.5 For example,
3-sulfolenes 16 reacted with PTSI to generate dihydropyr-
idinones 2, which upon detosylation and intramolecular
cyclization gave the sulfur-substituted indolizidine 4 and
quinolizidine 5 (Scheme 1).5b
We now report some new synthetic applications of com-
pounds 4 and 5. Reaction of compound 4 with hexylmagne-
sium bromide at room temperature, followed by treatment
sequentially with acetic acid and NaBH4/MeOH, gave the
vinyl sulfide 6. The stereochemistry of compound 6 was
established by NOESY spectrum, and was further confirmed
by its subsequent conversion to indolizidine 209D by react-
ing with Ra-Ni in refluxing EtOH (Scheme 2).7
Similar reactions of compound 5 with methylmagnesium
bromide, acetic acid, and NaBH4 yielded the corresponding
vinyl sulfide 7. Hydrolysis of compound 7 with concentrated
hydrobromic acid provided (()-epimyrtine (Scheme 3), the
spectral data of which were in agreement with the literature
report.8
Some alkaloids have the indolizidine or quinolizidine
structures, which often show interesting biological activi-
ties.1 Many methods have been developed for the synthesis of
these novel compounds,2 but those which can be applied
both to the synthesis of indolizidines and quinolizidines are
most useful.3 We have reported a new aza-Diels-Alder
reaction of thio-substituted 3-sulfolenes with p-toluenesul-
fonyl isocyanate (PTSI) to synthesize sulfur-substituted
piperidine derivatives,4 and have used this method to prepare
(1) (a) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed; Wiley: New York, 1986; Vol. 3, Chapter 1,
pp 1-274. (b) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: New
York, 1999; Vol. 13, pp 1-161.
(2) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165. and other reviews in
these series.
(5) (a) Chou, S. S. P.; Chiu, H. C.; Hung, C. C. Tetrahedron Lett. 2003, 44,
4653–4655. (b) Chou, S. S. P.; Ho, C. W. Tetrahedron Lett. 2005, 46, 8551–
8554. (c) Chou, S. S. P.; Liang, C. F.; Lee, T. M.; Liu, C. F. Tetrahedron 2007,
63, 8267–8273. (d) Chou, S. S. P.; Liu, C. F. J. Chin. Chem. Soc. 2010, 57,
811–819.
(6) Chou, S. S. P.; Tsao, H. J.; Lee, C. M.; Sun, C. M. J. Chin. Chem. Soc.
1993, 40, 53–57.
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Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998,
9, 3289–3301.
(3) For some selected syntheses, see: (a) Tehrani, K. A.; D’hooghe, M.;
De Kimpe, N. Tetrahedron 2003, 59, 3099–3108. (b) Katoh, M.; Mizutani,
H.; Honda, T. Heterocycles 2006, 69, 193–216. (c) Turunen, B. J.; Georg,
G. I. J. Am. Chem. Soc. 2006, 128, 8702–8703. (d) Lesma, G.; Colombo, A.;
Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron: Asymmetry 2007, 18,
1948–1954. (e) Amorde, S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron 2009,
65, 3222–3231. (f) Barbe, G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11,
3398–3401. (g) Perreault, S.; Rovis, T. Chem. Soc. Rev. 2009, 38, 3149–3159.
(4) (a) Chou, S. S. P.; Hung, C. C. Tetrahedron Lett. 2000, 41, 8323–8326.
(b) Chou, S. S. P.; Hung, C. C. Synthesis 2001, 2450–2462.
ꢀ
(8) Slosse, P.; Hootele, C. Tetrahedron Lett. 1978, 4, 397–398.
692 J. Org. Chem. 2011, 76, 692–695
Published on Web 12/17/2010
DOI: 10.1021/jo102092b
2010 American Chemical Society
r

Chou et al.
JOCNote
SCHEME 3. Synthesis of Epimyrtinea
TABLE 1. Conversion of Compound 4 to Compound 10a
entry
reagents (equiv)
additive (equiv)
10 (%)
aReagents and conditions: (i) (a) MeMgBr (4 equiv), THF, 70 °C,
2.5 h; (b) HOAc (5 equiv), 0 °C, 10 min; (c) NaBH4 (10 equiv), CH3OH,
0 °C, 30 min, 86%; (ii) concd HBr (excess), 95% EtOH, 75 °C, 2.5 h, 91%.
1
2
3
4
5
6
7
8
MeLi (7), CuI (3.5)
MeLi (6), CuI (3)
MeLi (3.5), CuI (3.5)
MeLi (3.5), CuI (cat.)
MeMgBr (2.2)
none
BF3 Et2O (3)
NRb
NRb
NRb
NRb
NRb
NRb
39c
3
BF3 Et2O (5.5)
BF3 Et2O (5.5)
3
3
SCHEME 4. Formal Synthesis of Lasubine IIa
NiCl2(PPh3)2 (0.03)
BF3 Et2O (5)
MeLi (6), CuCN 2LiCl (3)
MeLi (6), CuCN (3)
MeLi (6), CuI (3)
3
3
BF3 Et2O (5)
BF3 Et2O (5)
3
65d
74
78
3
9
10
MeLi (7), CuI (3.5)
MeMgBr (7), CuI (3.5)
MeLi (7), CuI (3.5)
BF3 Et2O (5.5)
BF3 Et2O (5.5)
3
3
11e
BF3 Et2O (5.5)
96
3
aUnless otherwise indicated, the reaction conditions were as follows: 4
(1 equiv) in THF was added at -78 °C to a mixture of an organometallic
reagent w/o additives. The reaction mixture was slowly warmed to room
temperature, stirred for another 1.5 h, and then quenched with saturated
ammonium chloride. bNo reaction was observed. cCompound 4 was
recovered in 50%. dCompound 4 was recovered in 7%. The reaction
e
mixture was stirred at room temperature for 24 h.
10. However, when BF3 Et2O was used in combination with
3
MeLi/CuCN (2:1, entry 7), compound 10 was obtained in
low yield. Replacement of CuCN with CuI (entry 8) increased
the yield of product 10 significantly, but a small amount of
the starting material 4 remained. Increasing the amount of the
organocuprate (entry 9) completed the reaction. The use of
aReagents and conditions: (i) (a) 3,4-dimethoxyphenylmagnesium
bromide (5 equiv), THF, 70 °C, 2.5 h; (b) HOAc (5 equiv), 0 °C, 10 min;
(c) NaBH4 (10 equiv), MeOH, 0 °C, 30 min, 59%; (ii) concd HBr (’xs),
95 % EtOH, 70 °C, 3 h, 80%.
MeMgBr/CuI/BF3 Et2O (entry 10) also achieved the trans-
3
Reaction of compound 5 with 3,4-dimethoxyphenylmag-
nesium bromide, followed by treatment with acetic acid and
NaBH4/MeOH, gave the vinyl sulfide 8, which was hydro-
lyzed by concentrated hydrobromic acid to yield the ketone 9.
It has been reported that ketone 9 can be stereoselectively
reduced to lasubine II by L-Selectride.9 Thus we have
achieved a formal synthesis of (()-lasubine II (Scheme 4).
We have also studied various reaction conditions to con-
vert the phenylthio-substituted compound 4 to the methyl-
substituted product 10 (Table 1). From our previous
studies,4 we expected an organocopper reagent might accom-
plish this transformation. We found that the reaction of
compound 4 with lithium dimethylcuprate (entry 1) gave
formation. Finally, stirring the reaction mixture at room
temperature for 24 h (entry 11) provided the product 10 in
96% yield.
By comparing the results in entries 2 and 8, it can be seen
that the use of the same equivalent of BF3 Et2O as that of
3
Me2CuLi (entry 2) did not give any product 10, whereas the
use of excess equivalent of BF3 Et2O than that of Me2CuLi
3
(entry 8) resulted in 65% yield of the product 10. This seems
to indicate that BF3 Et2O first forms a 1:1 complex with
Me2CuLi, and then the excess BF3 Et2O activates its reac-
3
3
tion with compound 4 by complexing with the amido group
of compound 4. Furthermore, the structure of the copper
reagents used in entries 6, 7, and 8 has a significant impact on
the reaction; CuI is more efficient than CuCN, while
only the recovered starting material. We then used BF3 Et2O
3
to activate the reaction of compound 4 with lithium dimethyl-
cuprate (entry 2),10 lithium dimethylcopper (entry 3), or
methyllithium in the presence of a catalytic amount of CuI
(entry 4),11 still there were no reactions observed. Attempted
reaction of compound 4 with MeMgBr in the presence of
CuCN 2LiCl is totally inactive.
3
Compound 10 was hydrogenated to give the cis-product
11, which has identical spectral data with the literature
values.14 Compound 11 further reacted with methyllithium,
acetic acid, and NaBH4 to give 8a-epi-dendroprimine
(Scheme 5),15 which shows a Bohlmann band at 2793 cm-1
in the IR spectrum indicating that the lone pair electrons of
nitrogen as well as the H5 and H8a are at the axial position.
Compound 5 was also smoothly converted to the methyl-
a nickel catalyst (entry 5),12 or with MeLi/CuCN 2LiCl/
3
BF3 Et2O (entry 6)13 also failed to give any desired product
3
(9) Back, T. G.; Hamilton, M. D.; Lim, V. J. J. Org. Chem. 2005, 70, 967–
972.
(10) (a) Maruyama, K.; Yamamoto, Y. J. Am. Chem. Soc. 1977, 99, 8068–
8070. (b) Kunz, H.; Klegraf, E.; Follmann, M.; Schollmeyer, D. Eur. J. Org.
Chem. 2004, 3346–3360.
substituted compound 12 by Me2CuLi/BF3 Et2O. Since
3
(11) Hambleet, C. L.; Stanton, M. G.; Sloman, D. L.; Kliman, L. T.;
Adams, B.; Ball, R. G. Tetrahedron Lett. 2007, 48, 2079–2082.
(12) Oshima, K.; Yorimitsu, H.; Takami, K.; Kondoh, A. J. Org. Chem.
2005, 70, 6468–6473.
(14) (a) Hua, D, H.; Bharathi, S. N.; Panangadan, J. A. K.; Tsujimoto, A.
J. Org. Chem. 1991, 56, 6998–7007. (b) Diederich, M.; Nubbemeyer, U.
Synthesis 1999, 286–289. (c) Hsu, R.-T.; Cheng, L.-M.; Chang, N.-C.; Tai,
H.-M. J. Org. Chem. 2002, 67, 5044–5047.
(13) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.; Parker, D. J. Org.
Chem. 1984, 49, 3928–3938.
(15) The hydrochloride salt, but not the free base of (-)-8a-epi-dendro-
primine, has been reported in ref 14b.
J. Org. Chem. Vol. 76, No. 2, 2011 693

Chou et al.
SCHEME 9. Suzuki Coupling Reactions of Compounds 13
JOCNote
SCHEME 5. Synthesis of 8a-epi-Dendropriminea
aReagents and conditions: (i) H2 (1 atm), PtO2 (10 mol %), EtOAc, rt,
28 h, 96%; (ii) (a) CH3Li (3 equiv), THF, rt, 5 h; (b) HOAc (excess), 0 °C,
10 min; (c) NaBH4 (10 equiv), CH3OH, 0 °C, 3 h, 68%.
SCHEME 10. Bromination and Suzuki Coupling of 14a
SCHEME 6. Formal Synthesis of 5-epi-Cermizine Ca
the phenylated products 15a and 15b, respectively, in good
yield (Scheme 9).
Compound 14a also reacted with NBS to give the vinyl
bromide 16, which underwent Suzuki coupling reaction with
phenylboronic acid to afford the phenylated product 17 in
good yield (Scheme 10).
In summary, we have developed a few useful synthetic
transformations of sulfur-substituted indolizidine 4 and
quinolizidine 5 to the vinyl bromides 13a, 13b, and 16,
aromatic compounds 14a and 14b, and Suzuki coupling
products 15a, 15b, and 17. We have also accomplished the
synthesis of some natural products including indolizidine
209D, epimyrtine, lasubine II, 8a-epi-dendroprimine, and
5-epi-cermizine C.
aReagents and conditions: (i) MeLi (7 equiv), CuI (3.5 equiv), THF,
BF3 Et2O (5.5 equiv), -78 °C to rt, 1.5 h, 84%.
3
SCHEME 7. Preparation of Vinyl Bromides 13
SCHEME 8. Preparation of Elimination Products 14
Experimental Section
Indolizidine 209D. A mixture of compound 6 (34 mg, 0.107
mmol) and a W-2 Ra-Ni (91 mg) in 95% EtOH (5 mL) was
heated at reflux under nitrogen for 2 h. The solid was filtered off,
and the residue was evaporated under vacuum in an ice bath.
The crude product was purified by flash chromatography using
Et3N/ethyl acetate/hexanes (1:1:20) as eluent to give indoliz-
idine 209D (15 mg, 71%) as a colorless liquid, the spectral data
of which were identical with the literature values.7
Epimyrtine. To a solution of compound 7 (50 mg, 0.19 mmol)
in 95% EtOH (4 mL) was added dropwise a 50% HBr (3 mL).
The mixture was heated at 70 °C under nitrogen for 2.5 h. The
solvent and excess HBr solution were removed under vacuum,
and saturated sodium bicarbonate was slowly added. The solu-
tion was extracted with CH2Cl2, dried (MgSO4), and evaporated
under vacuum. The crude product was purified by flash chroma-
tography using ethyl acetate/hexanes (1:8) containing 5% Et3N
as eluent to give epimyrtine as a colorless oil (29 mg, 91%), the
spectral data of which are identical with the literature values.8
cis-4-(3,4-Dimethoxyphenyl)hexahydro-1H-quinolizin-2(6H)-
one (9). The procedure was the same as that for the preparation
of epimyrtine from compound 7. Starting from compound 8 (20
mg, 0.07 mmol), product 9 (12 mg, 80%) was obtained as a
colorless oil, the spectral data of which are identical with the
literature values.9
compound 12 has been selectively transformed into 5-epi-
cermizine C,16 our method constitutes a formal synthesis of
racemic 5-epi-cermizine C (Scheme 6).
Compounds 4 and 5 also reacted with N-bromosuccini-
mide (NBS) in refluxing acetonitrile to give the vinyl
bromides 13a and 13b, together with the corresponding
elimination products 14a and 14b (Scheme 7). Varying the
reaction solvent or temperature still led to a mixture of
compounds 13 and 14, which were effectively separated by
column chromatography. We also found that reaction of
compounds 4 and 5 with NBS at reflux followed by treat-
ment with NaOH/MeOH afforded the elimination products
14a and 14b in good yield (Scheme 8). This indicates that
compounds 14a and 14b derived from further elimination
of compounds 13a and 13b, which involves the isomeriza-
tion of the double bond of compounds 13 followed by 1,4-
elimination of HBr.
7-Methyl-1,2,3,5,8,8a-hexahydro-5-indolizinone (10). To a
mixture of CuI (271 mg, 1.43 mmol) in THF (6 mL) at 0 °C
was added dropwise a solution of MeLi (2.2 M in diethyl ether,
1.30 mL, 2.86 mmol). After stirring at 0 °C for 30 min, the mix-
Vinyl bromides 13a and 13b were successfully converted
by Suzuki coupling reactions with phenylboronic acid to give
ture was cooled to -78 °C, and BF3 OEt2 (0.28 mL, 2.24 mmol)
3
was added and stirred for 5 min. Then a solution of compound 4
(100 mg, 0.41 mmol) in THF (6 mL) precooled at -78 °C was
(16) Snider, B. B.; Grabowski, J. F. J. Org. Chem. 2007, 72, 1039–1042.
694 J. Org. Chem. Vol. 76, No. 2, 2011

Chou et al.
JOCNote
added dropwise. The reaction mixture was slowly warmed to
room temperature, stirred for another 24 h, and quenched with
saturated ammonium chloride. The aqueous solution was ex-
tracted with CH2Cl2, combined with the organic layer, dried
(MgSO4), and concentrated under vacuum. The crude product
was purified by flash chromatography using ethyl acetate/
hexanes (2:1) and then ethyl acetate as eluent to give product
(0.06 mL, 1.1 mmol) was then added dropwise. The mixture
was stirred for 10 min, and NaBH4 (82.3 mg, 2.2 mmol) and
methanol (2 mL) were added sequentially. After stirring for 3 h,
the solvent was removed under vacuum, and saturated sodium
bicarbonate was added. The mixture was extracted with ethyl
acetate, dried (MgSO4), and evaporated. The crude product was
purified by flash chromatography on silica gel using ethyl
acetate/hexanes (1:4) as eluent to give 8a-epi-dendroprimine
10 (59 mg, 96%) as a colorless oil: IR (neat) 1658 cm-1
;
1H NMR (CDCl3) δ 7.74 (1H, q, J= 1.2 Hz), 3.74-3.59 (2H, m),
3.50-3.40 (1H, m), 3.31 (1H, dd, J = 16.8, 5.4 Hz), 2.24-2.11
(2H, m), 2.06-1.98 (1H, m), 1.91 (3H, s), 1.88-1.71 (1H, m),
1.66-1.53 (1H, m); 13C NMR (CDCl3) δ 164.0, 149.6, 121.0,
56.3, 43.7, 35.9, 33.4, 22.9, 22.7; EI-MS (rel intensity) m/z 151
(Mþ, 100), 150 (43), 96 (44), 82 (94), 70 (77); HRMS m/z calcd
for C9H13NO 151.0997, found 151.0996.
(22.6 mg, 68%) as a colorless oil: IR (neat) 2793 cm-1
;
1H NMR (CDCl3) δ 3.25 (1H, td, J = 8.4, 2.1 Hz), 2.10-1.40
(11H, m), 1.10(3H, d, J=6.3Hz), 1.05-0.85 (m, 1H), 0.90 (3H, d,
J = 6.6 Hz); 13C NMR (CDCl3) δ 64.8, 58.2, 51.4, 43.1, 39.4,
31.4, 30.4, 22.0, 21.0, 20.8; EI-MS (rel intensity) m/z 153 (Mþ,
44), 152 (47), 138 (100), 136 (17), 133 (18), 132 (16), 119 (31), 105
(31), 91 (34), 70 (34), 55 (35), 43 (37), 41 (40); HRMS m/z calcd
for C10H19N 153.1517, found 153.1513.
cis-7-Methyl-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone (11).
A mixture of compound 10 (54.2 mg, 0.36 mmol) and PtO2
(12 mg) in ethyl acetate (2 mL) was stirred vigorously under
a balloon of hydrogen at room temperature for 24 h. The
mixture was diluted with ethyl acetate, filtered through Celite,
dried (MgSO4), and evaporated under vacuum to give product
11 (52.5 mg, 96%) as a colorless liquid. Its spectral data are
identical with the literature values.14
Acknowledgment. Financial support of this work by the
National Science Council of the Republic of China (NSC 97-
2113-M-030-001-MY3) and Fu Jen Catholic University
(9991A15/10973104995-4) is gratefully acknowledged.
8a-epi-Dendroprimine. To a solution of compound 11 (33.3mg,
0.22 mmol) in THF (3 mL) at room temperature was added
slowly another solution of MeLi (2.2 M in hexane, 0.30 mL,
0.66 mmol). The reaction mixture was stirred at room tem-
perature for 5 h, and then cooled in an ice bath. Acetic acid
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 2-8 and
12-17 and 1H and 13C NMR spectra for compounds 2-17
and 8a-epi-dendroprimine. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 695