Tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes. 12. Synthesis of (-)-platynecine

Full text of DOI:10.1021/jo961919x

J . Org. Chem. 1997, 62, 435-436
435
Ta n d em [4 + 2]/[3 + 2] Cycloa d d ition s of
Nitr oa lk en es. 12. Syn th esis of
(-)-P la tyn ecin e
Scott E. Denmark,* Dann L. Parker, J r., and
J ulie A. Dixon
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
Received October 10, 1996
F igu r e 1. Structure of necine bases of pyrrolizidine alkaloids.
Pyrrolizidine alkaloids are attractive targets for syn-
thesis due to their structural diversity and interesting
biological properties.1 We have developed a highly
versatile method for the construction of pyrrolizidine
frameworks through the use of the tandem [4 + 2]/[3 +
2] cycloaddition of nitroalkenes.2 This reaction has
served admirably as the key step in the synthesis of
several pyrrolizidines including (-)-hastanecine (1),3 (-)-
rosmarinecine (2),4 and (+)-crotanecine (3),5 Figure 1. A
remarkable feature of these syntheses is the use of an
enantiomerically pure vinyl ether to control the absolute
configuration of the target molecules. Additionally, the
intramolecular nature of the [3 + 2] cycloaddition and
the length and configuration of the tether are used to
control the relative configuration of the critical centers.
Thus, in (-)-rosmarinecine (2), the all-cis relationship
between C(1), C(7a), and C(7) is established in the [3 +
2] cycloaddition. This same relationship (also in an
absolute sense) exists in (-)-platynecine (4), which
implied that deoxygenation (instead of inversion4) at C(6)
would provide access to this simpler pyrrolizidine con-
gener from a common synthetic intermediate. This paper
describes the synthesis of (-)-platynecine in four steps
from an advanced intermediate in the (-)-rosmarinecine
synthesis.
1. The tricyclic lactam (+)-7 was prepared in four steps
from the known nitroalkene 5 in 40% yield.4 The key
transformation is the tandem cycloaddition of nitroalkene
5 with vinyl ether (-)-6, which ultimately provides the
lactam (+)-7.
To accomplish the synthesis of (-)-platynecine (4), the
intermediate (+)-7 needed to be deoxygenated at C(3),
deprotected, and fully reduced, Scheme 2. Treatment of
lactam (+)-7 with phenyl chlorothionocarbonate in the
presence of 4-(N,N-dimethylamino)pyridine (DMAP) af-
forded the thionocarbonate (+)-8 in 80% yield.14 The
enantiomeric purity of intermediate (+)-8 was deter-
mined to be 97% ee by chiral HPLC analysis (Regis,
(R,R)-Whelko-01 column). Subsequent radical deoxygen-
ation15 was accomplished by heating the thionocarbonate
(+)-8 in benzene during a slow addition of a solution of
2,2′-azobis(isobutyronitrile) (AIBN) and tributyltin hy-
dride in benzene to provide the lactam (+)-9 in 84% yield.
Deprotection of the methyl acetal using 90% trifluroacetic
acid afforded a 10/1 mixture of anomeric lactols 10. The
final step of the synthesis mandated the reduction of the
lactam and lactol moieties present in 10. Accordingly,
Red-Al reduction in refluxing THF provided (-)-platyne-
cine (4) in 74% yield after purification. An analytically
pure sample was obtained after recrystallization. The
1H and 13C NMR spectral data of the synthetic product
were found to be identical with spectral data obtained
from a natural sample. Furthermore, the observed
melting point (145-146 °C) and the optical rotation
(-)-Platynecine (4) was first isolated in 1935 from
Senecio Platyphyllusis6 and is the necine base portion of
several pyrrolizidine alkaloids including platyphyllin,6
neoplatyphilline,7 bulgarsenine,8 nemorensine,9 retro-
isosenine,8 mulgediifoline,10 and ligularinine.11 The syn-
thesis of platynecine (4) has been reported in racemic
form12 as well as three times in enantiomerically enriched
form.13
([R]22 -61.5° (CHCl3, c ) 1)) are in full agreement with
D
literature values.16
The total synthesis of (-)-platynecine was accom-
plished in eight steps and 19% overall yield from the
nitroalkene 5. The three contiguous stereogenic centers
of the natural product were created with high selectivity
in the tandem [4 + 2]/[3 + 2] cycloaddition sequence. This
work further demonstrates the flexibility of nitroalkene
tandem cycloaddition chemistry for the asymmetric
synthesis of polyhydroxylated pyrrolizidine alkaloids.
The preparation of the branch point intermediate for
the synthesis of the two alkaloids is outlined in Scheme
(1) (a) Leonard, N. J . In The Alkaloids; Manske, R. H. F., Holmes,
H. L., Eds.; Academic Press: New York, 1950; Vol. 1, Chapter 4. (b)
Leonard, N. J . In The Alkaloids; Manske, R. H. F., Eds.; Academinc
Press: New York, 1960; Vol. 6, Chapter 3. (c) Robbins, D. J . Nat. Prod.
Rep. 1995, 12, 413 and references cited therein.
(2) Denmark, S. E.; Thorarensen, A. Chem Rev. 1996, 96, 137.
(3) Denmark, S. E.; Thorarensen, A. J . Org. Chem.. 1995, 60, 3221.
(4) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J . Am. Chem.
Soc. 1996, 118, 8266.
Exp er im en ta l Section
(5) Denmark, S. E.; Thorarensen, A. J . Am. Chem. Soc. 1997, 119,
125.
(6) (a) Orechoff, A. Ber. Dtsch. Chem. Ges. 1935, 68, 650. (b) Orechoff,
A.; Konowalowa, R. Ber. Dtsch. Chem. Ges. 1935, 68, 1886.
(7) Danilova, A . V.; Utkin, L. M. Kozyreva, G. V.; Syreneva, Y. I. J .
Gen. Chem. [USSR] 1958, 29, 2396.
(8) Nghia, N. T.; Semera, P.; Kla´sek, A.; Boeva, A.; Drjanovska, L.
Dolejs, L.; Santavy, F. Collect. Czech. Chem. Commun. 1976, 41, 2952.
(9) Kla´sek, A.; Semera, P.; Vokoun, J .; Boeva, A.; Dvora´ckova´, S.;
Santavy, F. Collect. Czech. Chem. Commun. 1980, 45, 548.
(10) Romo de Vivar, A.; Pe´rezm A.-L.; Arciniegas, A.; Vidales, P.;
Gavino, R.; Villasenor, J . L. Tetrahedron 1995, 46, 12521.
(11) Asada, Y; Furuya, T. Chem. Pharm. Bull. 1984, 32, 475.
(12) (a) Ro¨derm E.; Bourauel, T.; Wiedenfeld, H. Liebigs Ann. Chem.
1990, 607. (b) Viscontini, M.; Buzek, H. Helv. Chim. Acta 1972, 55,
670.
Gen er a l Exp er im en ta l P r oced u r es. See r ef 3. (2S,-
2a R,3R,7a R,7bR)-Hexa h yd r o-2-m eth oxy-3-[[p h en oxy(th io-
ca r b on yl)]oxy]fu r o[2,3,4-gh ]p yr r olizin -4[2H]-on e ((+)-8).
(13) (a) Ru¨eger, H.; Benn, M. Heterocycles 1983, 20, 1331. (b) Fleet,
G. W. J .; Seijas, J . A.; Vazquez-Tato, M. P. Tetrahedron 1991, 47, 525.
(c) Hashimura, K.; Tomita, S.; Hiroya, K.; Ogasawara, K. J . Chem.
Soc., Chem. Commun. 1995, 2291.
(14) A protocol for the deoxygenation of a similar R-hydroxy lactam
has been reported in the synthesis of hastanecine (1).
(15) (a) Barton, D. H. R.; Dorchak, J .; J aszberenyi, J . Cs. Tetrahe-
dron 1992, 48, 7435. (b) Robins, M. J .; Wilson, J . S.; Hansske, F. J .
Am. Chem. Soc. 1983, 105, 4059.
(16) Lit.6b mp 148.0-148.5 °C; [R]D -56.8° (CHCl3, c ) 1.3). Lit.13b
mp 147.5-149 °C; [R]22 -65.5 °C (CHCl3, c ) 0.75).
D
S0022-3263(96)01919-6 CCC: $14.00 © 1997 American Chemical Society

436 J . Org. Chem., Vol. 62, No. 2, 1997
Notes
(dd, J ) 4.7, 3.4 Hz, 1 H), 3.99-3.92 (m, 1 H), 3.28 (s, 3H), 3.04-
2.97 (m, 1 H), 2.92 (dd, J ) 9.3, 7.8 Hz, 1 H) 2.82 (dd, J ) 9.5,
Sch em e 1
6.2 Hz, 1 H), 2.36 (d, J ) 16.1 Hz, 1 H), 2.24-2.12 (m, 2 H); 13
C
NMR (100.6 MHz, CDCl3) δ 177.28, 112.71, 80.20, 70.19, 54.36,
44.14, 43.13, 37.57, 31.33; IR (CHCl3) 1691 (s), 1061 (s), 1000
(s) cm-1; MS (FAB) m/ z 184 (M+ + 1, 100); TLC Rf ) 0.16
(EtOAc); [R]22 +146 (c ) 0.93, CHCl3). Anal. Calcd for C9H13
-
D
NO3 (183.21): C, 59.00; H, 7.15; N, 7.65. Found: C, 58.86; H,
7.13; N, 7.66.
Sch em e 2
(2a S,7a R,7b R)-Hexa h yd r o-2-h yd r oxyfu r o[2,3,4-gh ]p yr -
r olizin -4[2H]-on e (10). Acetal 9 (114 mg, 0.62 mmol) was
dissolved in 50 mL of a 90% solution of trifluoroacetic anhydride
in water and was allowed to stir at rt for 4 h. The reaction
mixture was then concentrated in vacuo to provide an orange
oil. The crude product was purified by silica gel column
chromatography (EtOAc) to afford 99 mg (94%) of an amorphous
white solid that was determined by 1H NMR to be a 10:1 mixture
of anomers: 1HNMR (500 MHz, CD3OD) δ 5.37 (s, 1 H), 4.69
(dd, J ) 4.9, 3.5, 1 H), 4.43 (dd, J ) 6.1, 3.4 Hz, 1 H), 3.84 (ddd,
J ) 11.6, 9.2, 5.5 Hz, 1 H), 3.06-2.98 (m, 2 H), 2.82 (dd, J )
8.8, 6.2 Hz, 1 H), 2.36 (d, J ) 17.1 Hz, 1 H), 2.29-2.22 (m, 1 H)
2.11 (ddd, J ) 14.4, 9.2, 5.1 Hz, 1 H); 13C NMR (125.7 MHz,
CD3OD) δ 180.12, 107.59, 82.16, 72.10, 46.39, 43.85, 38.77, 32.18;
IR (CHCl3) 1690 (s), 1227 (s) cm-1; MS (FAB) m/ z 170 (M+ + 1,
78); HRMS calcd for C8H12NO3 (170.08172), found 170.08180;
TLC Rf ) 0.34 (CHCl3/MeOH, 10/1).
(-)-P la tyn ecin e (4). Sodium bis(2-methoxyethoxy)alumi-
num hydride (Red-Al) (65 wt % solution in toluene, 1.29 mL,
6.64 mmol, 12 equiv) was added dropwise to a stirring solution
of lactol 10 (93.6 mg, 0.55 mmol) in THF (37 mL). The resulting
clear colorless solution was allowed to stir at rt for 40 min and
was then heated to reflux for 3 h. After being cooled to rt, the
reaction mixture was quenched with water (0.6 mL), 15% NaOH
(0.6 mL), and water (1.0 mL) and was stirred for 0.5 h. The
resulting solution, which contained aluminum salts, was con-
centrated to provide a white solid. The crude product was
purified by silica gel column chromatography (CHCl3/MeOH/
NH4OH, 10/5/1) to afford 64 mg (74%) of platynecine as a white
solid. An analytical sample was obtained after recrystallization
(acetone) to provide a white crystalline solid (45 mg): mp 145-
4-(N,N-Dimethylamino)pyridine (DMAP) (97 mg, 0.79 mmol,
0.67 equiv) and phenyl chlorothionoformate (0.11 mL, 0.79 mmol,
0.67 equiv) were added to a solution of lactam 7 (236 mg, 1.2
mmol) in CH3CN (40 mL) . The resulting yellow solution was
stirred at room temperature in a foil-covered round-bottomed
flask for 2.5 h, after which time an additional portion of DMAP
(97 mg, 0.79 mmol, 0.67 equiv) and phenyl chlorothionoformate
(0.11 mL, 0.79 mmol, 0.67 equiv) were added. The solution was
allowed to stir for an additional 2.5 h and then was concentrated
to afford a yellow oil. The crude product was purified by silica
gel column chromatography (hexane/EtOAc, 1/1, 1/2, 0/1) to
provide 358 mg of a white solid. The solid was recrystallized
(hexane/EtOAc) to afford 320 mg (80%) of analytically pure (+)-8
146 °C; 1H NMR (500 MHz, CD3OD) δ 4.25 (ABMXY (q), J mx
)
2.3, J my ) 2.3 Hz, 1H), 4.00 (ABX, J ab ) 11.2, J ax ) 2.7 Hz, 1
H), 3.96 (ABX, J bx ) 5.3 Hz, 1H), 3.26 (dd, J ) 7.6, 2.5 Hz, 1 H),
3.22 (ABMXY, J ab ) -9.0, J ax ) 12.0, J ay ) 5.0 Hz, 1 H), 3.14
(td, J ) 9.6, 7.8 Hz, 1 H), 2.89 (ABMXY, J ab ) 9.0, J bx ) 9.1, J by
) 9.1 Hz, 1 H), 2.80 (ddd, J ) 10.4, 9.0, 2.9 Hz, 1 H), 2.49 (ABX,
J ) 11.0, 8.0 Hz, J bx ) 5.3, J ax ) 2.7 Hz, 1 H), 2.08 (tt, J ) 11.7,
8.7 Hz, 1 H), 1.90 (ABMXY, J xy ) -9.0, J xm ) 2.3, J ym ) 2.3 Hz,
2 H), 1.71 (dtd, J ) 11.9, 7.4, 3.0 Hz, 1H); 13C NMR (125 MHz,
CD3OD) δ 73.15, 72.62, 61.73, 56.58, 54.81, 45.08, 37.33, 28.87;
IR (CHCl3) 3329 (br), 3026 (s), 3005 (s), 2972 (s), 2943 (s), 2882
(s) cm-1; MS (FAB) m/ z 158 (M+ + 1, 100); TLC Rf ) 0.03
1
as white needles: mp 140-141 °C; H NMR (400 MHz, CDCl3)
δ 7.45-7.40 (m, 2 H), 7.32-7.29 (m, 1 H), 7.17-7.14 (m, 2 H),
6.28 (d, J ) 8.3 Hz, 1 H), 5.12 (s, 1 H), 4.68 (dd, J ) 3.7, 3.7 Hz,
1 H), 4.22 (dd, J ) 5.6, 3.2 Hz, 1 H), 4.04 (ddd, J ) 13.8, 9.0, 6.8
Hz, 1 H), 3.44 (dd, J ) 8.3, 5.6 Hz, 1 H), 3.34 (s, 3 H), 3.12 (ddd,
J ) 15.4, 10.9, 4.5 Hz, 1 H), 2.29-2.13 (m, 2 H); 13C NMR (100.6
MHz, CDCl3) δ 194.10, 170.52, 153.43, 129.56, 126.73, 121.67,
105.77, 81.67, 79.73, 66.30, 54.90, 49.62, 42.99, 29.59; IR (CCl4)
1737 (s), 1282 (s), 1218 (s), 1199 (s) cm-1; MS (FAB) m/ z 336
(CHCl3/MeOH/NH4OH, 10/5/1); [R]22 -61.5 (c ) 1.0, CHCl3).
(M+ + 1, 93); TLC Rf ) 0.33 (EtOAc/hexane, 2/1); [R]22 +47.3
D
D
Anal. Calcd for C8H15NO2 (157.2): C, 61.12; H, 9.62; N, 8.91.
Found: C, 61.12; H, 9.63; N, 8.71.
(c ) 0.90, CHCl3); chiral HPLC (column: Regis, (R,R)-Whelko-
01 (hexane/EtOAc, 70/30), 0.5 mL/min) tR (+)-8 19.0 min (98.6%);
tR (-)-8 23.1 min (1.4%); 97% ee. Anal. Calcd for C16H17NO5S
(335.38): C, 57.30; H, 5.11; N, 4.18; S, 9.56. Found: C, 57.23;
H, 5.04; N, 4.25; S, 9.31.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-30938) for financial support.
We also thank Neil Anderton for the gift of a sample of
natural platynecine. D.L.P. thanks the Snyder Scholar-
ship Fund for a summer fellowship.
(2S,2a S,7a R,7b R)-H exa h yd r o-2-m et h oxyfu r o[2,3,4-gh ]-
p yr r olizin -4[2H]-on e (+)-(9). A solution of tributyltin hydride
(0.29 mL, 1.06 mmol, 1.3 equiv) and 2,2′-azobisisobutyronitrile
(AIBN) (0.24 mg, 0.16 mmol, 0.2 equiv) in benzene (10 mL) was
added dropwise over a 50 min period to a refluxing solution of
thionocarbonate 8 (273 mg, 0.81 mmol) in benzene (75 mL). The
resulting solution was heated to reflux for an additional 2.5 h
and then was concentrated in vacuo. The crude product was
purified by silica gel column chromatography with a plug of
potassium fluoride at the top of the column (EtOAc/hexane, 1/1,
2/1, 1/0) to give 125 mg of a white solid. The solid was
recrystallized (hexane/EtOAc) to afford 118 mg (80%) of (+)-9
as a highly crystalline white solid: mp 94-95 °C; 1H NMR (400
MHz, CDCl3) δ 4.74 (s, 1 H), 4.53 (dd, J ) 4.6, 3.4 Hz, 1 H), 4.29
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
1
10, complete H and 13C NMR assignments, IR and MS data
for all characterized compounds, along with comparison 1H
NMR and 13C NMR spectra of natural and synthetic (-)-
platynecine (8 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O961919X