Synthesis of (-)-9,10-epi-stemoamide

Article abstract of DOI:10.1021/jo049083i

An efficient synthesis of (-)-9,10-epi-stemoamide has been accomplished in nine steps and 13% overall yield. The synthesis features a lithium hydroxide-promoted fragmentation and an intramolecular 7-exo-trig radical cyclization.

Full text of DOI:10.1021/jo049083i

SCHEME 1 a
Syn th esis of (-)-9,10-epi-Stem oa m id e
Seock-Kyu Khim* and Arthur G. Schultz†
Department of Chemistry, Rensselaer Polytechnic Institute,
Troy, New York 12180
seock-kyu_khim@berlex.com
Received J une 1, 2004
Abstr a ct: An efficient synthesis of (-)-9,10-epi-stemoamide
has been accomplished in nine steps and 13% overall yield.
The synthesis features a lithium hydroxide-promoted frag-
mentation and an intramolecular 7-exo-trig radical cycliza-
tion.
a
Reagents and conditions: (a) K, NH3, THF, t-BuOH (1 equiv),
-78 °C, piperylene, MeI; (b) 6 N HCl, MeOH, rt; (c) I2, THF/H2O
(1:1), rt, 81% for three steps; (d) LiOH‚H2O, THF/H2O (10:1), rt,
41% for 7 and 40% for 8.
Extracts from the roots of Stemona tuberosa Lour. and
related Stemona species have been used in traditional
Chinese medicine as anticough agents and insecticides.
In 1992, Xu and his colleagues isolated and elucidated
the structures of several Stemona alkaloids.1 (-)-Ste-
moamide (1), one of these Stemona alkaloids, is composed
of a perhydropyrroloazepine ring fused to a γ-butyrolac-
tone moiety, and it contains four contiguous stereogenic
centers. Due to its interesting biological activity and
structural complexity, it has been a challenging target
for synthetic organic chemists. To date, there have been
five total syntheses of stemoamides reported in the
literature. In 1994, Williams et al. reported the first total
synthesis of (-)-stemoamide by a linear approach start-
ing from (R)-methyl 3-hydroxy-2-methylpropionate.2a The
syntheses of both (()- and (-)-stemoamides by Mori et
al. featured a ruthenium-catalyzed enyne metathesis as
a key step.2b,c Narasaka et al. utilized an oxidative
coupling reaction of R-stannyl pyrrolidinone with silyl
enol ether.2d The total syntheses by J acobi et al. of both
(()- and (-)-stemoamides used alkyne oxazole Diels-
Alder and retro-Diels-Alder reaction sequences to es-
tablish the tricyclic skeleton of stemoamide.2e,f Recently,
Gurjar et al. reported a formal synthesis utilizing a ring-
closing metathesis.2g Herein, we report an efficient
synthesis of (-)-9,10-epi-stemoamide (2) via a sequential
asymmetric Birch reduction-alkylation, lithium hydrox-
ide-promoted fragmentation, and a 7-exo-trig radical
reaction.
procedure developed in our laboratory, Birch reduction
of 3 under the standard reaction conditions (K, NH3,
THF, t-BuOH, -78 °C) provided the chiral enolate, which
was then alkylated in situ with methyl iodide to yield
the corresponding 1,4-cyclohexadiene 4 as a single dias-
tereomer.3 Enol ether hydrolysis of 4 with 6 N aqueous
HCl solution in MeOH at room temperature gave the â,γ-
enone 5. Subsequent iodolactonization of 5 with I2 in
THF/H2O (1:1) at room temperature afforded the enan-
tiomerically pure carbolactone 6 in 81% isolated yield for
three steps. Treatment of 6 with lithium hydroxide
monohydrate in THF/H2O (10:1) at room temperature
provided the requisite intermediate, butenolide carboxylic
acid 7 in 41% yield, along with the side product, 2-methyl-
4-hydroxy-2-cyclohexen-1-one (8) in 40% yield.4-6
Next, the butenolide carboxylic acid 7 was converted
into the phenylthiolactam 12 for radical cyclization, as
depicted in Scheme 2. First, 7 was reduced uneventfully
to provide the corresponding alcohol 9 in 92% yield by
using a borane-tetrahydrofuran complex (BH3‚THF) in
THF at -30 °C.7 Mitsunobu reaction8(Ph3P, DEAD, THF,
25 °C) of 9 with succinimide afforded the cyclic imide 10
(2) (a) Williams, D. R.; Reddy, J . P.; Amato, G. S. Tetrahedron Lett.
1994, 35, 6417. (b) Kinoshita, A.; Mori, M. J . Org. Chem. 1996, 61,
8356. (c) Kinoshita, A.; Mori, M. Heterocycles 1997, 46, 287. (d) Kohno,
Y.; Narasaka, K. Bull. Chem. Soc. J pn. 1996, 69, 2063. (e) J acobi, P.
A.; Lee, K. J . Am. Chem. Soc. 1997, 119, 3409. (f) J acobi, P. A.; Lee,
K. J . Am. Chem. Soc. 2000, 122, 4295. (g) Gurjar, M. K.; Reddy, D. S.
Tetrahedron Lett. 2002, 43, 295.
(3) For reviews of Birch reduction-alkylation methodologies and
their synthetic applications, see: (a) Schultz, A. G. Acc. Chem. Res.
1990, 23, 207. (b) Schultz, A. G. J . Chin. Chem. Soc. (Taipei) 1994,
41, 487. (c) Schultz, A. G. Chem. Commun. 1999, 14, 1263.
(4) (a) Schultz, A. G.; Dai, M.; Khim, S.-K.; Pettus, L.; Thakkar, K.
Tetrahedron Lett. 1998, 39, 4203. (b) Khim, S.-K.; Dai, M.; Zhang, X.;
Lei, C.; Pettus, L.; Thakkar, K.; Schultz, A. G. J . Org. Chem. 2004,
69, 7728.
(5) The enantiomeric excesses (ee %) of 7 and 8 were determined
by chiral HPLC to be >99 and >96%, respectively.
(6) Compound 7 could be obtained in a slightly better yield by taking
a different route (two-step sequence): Schultz, A. G.; Zhang, X. Chem.
Commun. 2000, 399.
The synthesis commenced with the preparation of the
intermediate 7, as shown in Scheme 1. Following the
(7) Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky,
T. P. J . Org. Chem. 1973, 38, 2786.
(8) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React.
1992, 42, 335.
* To whom correspondence should be addressed.
† Deceased J anuary 20, 2000.
(1) Lin, W.-H.; Ye, Y.; Xu, R.-S. J . Nat. Prod. 1992, 55, 571.
10.1021/jo049083i CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/05/2004
7734
J . Org. Chem. 2004, 69, 7734-7736

SCHEME 2 a
2 is thermodynamically more stable than â-Me isomer
13 by 2.8 kcal/mol (MM2 calculations).14
In summary, we have demonstrated an efficient syn-
thesis of (-)-9,10-epi-stemoamide 2. Lithium hydroxide-
promoted fragmentation of carbolactone to butenolide
carboxylic acid (6 f 7) and the intramolecular 7-exo-trig
radical cyclization reaction of phenylthiolactam to (-)-
9,10-epi-stemoamide (12 f 2) are noteworthy.
Exp er im en ta l Section 15
(5R)-5-(3′-Hyd r oxyp r op yl)-3-m eth yl-2(5H)-fu r a n on e (9).
To a solution of butenolide acid 7 (250 mg, 1.5 mmol) in THF
(20 mL) was added dropwise BH3‚THF (1.0 M in THF, 1.6 mL,
1.6 mmol) at 0 °C. The resulting solution was stirred overnight
at room temperature. The reaction mixture was treated with
H2O and extracted with CH2Cl2. The organic layers were
isolated, dried over anhydrous Na2SO4, and concentrated in
vacuo. Flash column chromatography (hexanes/EtOAc, 1:1) of
a
Reagents and conditions: (a) BH3‚THF, THF, -30 °C, 92%;
(b) succinimide, Ph3P, DEAD, THF, rt, 92%; (c) NaBH4, MeOH,
-10 °C, 88%; (d) PhSH, TsOH‚H2O, benzene, 0 °C, 70%; (e)
n-Bu3SnH, AIBN, benzene, reflux, 24 h, [c] ) 3.5 mM; (f) K2CO3,
MeOH, rt, 74% for two steps.
the crude residue gave 9 (210 mg, 92%) as a colorless oil: [R]23
D
1
-37.0 (c 1.27, CHCl3); H NMR (500 MHz, CDCl3) δ 7.04-7.03
(m, 1H), 4.91-4.88 (m, 1H), 3.62-3.58 (m, 2H), 2.76 (br s, 1H),
1.84 (d, J ) 1.9 Hz, 3H), 1.98-1.79 (m, 1H), 1.67-1.57 (m, 3H);
13C NMR (126 MHz, CDCl3) δ 174.5 (s), 149.0 (d), 129.6 (s), 80.9
in 92% yield. Reduction of cyclic imide was effected with
NaBH4 in MeOH at -10 °C to provide the carbinol lactam
11 in 88% yield.9 Direct treatment of 11 with ben-
zenethiol and p-toluenesulfonic acid monohydrate in
benzene at 0 °C afforded the required radical reaction
substrate, phenylthiolactam 12 in 70% yield.10
(d), 61.6 (t), 29.7 (t), 27.8 (t), 10.4 (q); IR ν 3422, 2930, 1743 cm-1
;
CIMS 157 (M+ + 1, 100); HRMS calcd for C8H13O3 (M+ + 1)
157.0870, found 157.0865.
Cyclic Im id e (10). To a solution of alcohol 9 (270 mg, 1.7
mmol), triphenylphosphine (500 mg, 1.9 mmol), and succinimide
(171 mg, 1.7 mmol) in THF (5 mL) was added diethyl azodicar-
boxylate (DEAD, 300 µL, 1.9 mmol). The resulting solution was
stirred overnight and then concentrated in vacuo. Diethyl ether
was added to the residue, and after removal of a white
precipitate, the solution was concentrated in vacuo. The crude
residue was purified by flash column chromatography (hexanes/
EtOAc, 1:2) to give the cyclic imide 10 (377 mg contaminated
With phenylthiolactam 12 in hand, we executed the
key step, a radical-promoted cyclization.11 Thus, employ-
ing the standard radical reaction protocol, a solution of
tributyltin hydride and 2,2′-azobisisobutyronitrile (AIBN)
in benzene was added in a period of 24 h to the gently
refluxing solution of phenylthiolactam 12 in benzene
(final concentration ∼ 3.5 mM). To our delight, the
desired intramolecular 7-exo-trig radical reaction12 took
place in a remarkably efficient manner, resulting in the
formation of a mixture of two diastereomers of constitu-
tional stemoamide (2 and 13) as an inseparable mixture
(∼10:1).13 As expected, compounds 2 and 13 are epimers
at C-10 with a cis ring fusion stereorelationship at C-8
and C-9 and resulted from the complete facial selective
addition (â-face addition) of an amido radical to a
conjugated C-C double bond of the γ-lactone moiety.
Subjection of these two diastereomers to K2CO3 in MeOH
at room temperature furnished only a single stereoisomer
2 in 74% isolated yield. The facile epimerization at C-10
of 13 to 2 is in good accord with the fact that R-Me isomer
with a small amount of triphenylphosphine oxide, 92%) as a
1
colorless oil: [R]27 -29.7 (c 0.74, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 6.96 (quint, J ) 1.5 Hz, 1H), 4.84 (m, 1H), 3.50-3.44
(m, 2H), 2.65 (s, 4H), 1.83 (d, J ) 1.5 Hz, 3H), 1.74-1.59 (m,
3H), 1.54-1.48 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 177.2,
173.9, 148.1, 130.3, 80.2, 38.1, 30.6, 28.1, 23.4, 10.5; IR (neat) ν
2944, 1752, 1700 cm-1; CIMS 238 (M+ + 1, 100); HRMS calcd
for C12H16NO4 (M+ + 1) 238.1079, found 238.1080.
Ca r bin ol La cta m (11). To a solution of cyclic imide 10 (408
mg, 1.7 mmol) in MeOH (5 mL) was added portionwise NaBH4
(650 mg, 17 mmol) at -10 °C. The resulting solution was stirred
for 0.5 h at the same temperature and quenched with water (10
mL). The reaction mixture was extracted with CH2Cl2 (5 × 10
mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated in vacuo to give the residue (388 mg,
94%). Flash column chromatography (EtOAc) of the residue gave
the carbinol lactam 11 (362 mg, 88%) as a colorless oil: [R]25
D
-29.4 (c 0.34, CHCl3); 1H NMR (diastereomeric mixture, 500
MHz, CDCl3) δ 7.04 (q, J ) 1.5 Hz) and 7.03 (q, J ) 1.5 Hz, 1H),
5.23-5.02 (m, 1H), 4.96-4.91 (m, 1H), 3.67-3.04 (m, 2H), 2.58-
2.50 (m, 1H), 2.37-2.22 (m, 3H), 1.85 (d, J ) 1.7 Hz) and 1.85
(d, J ) 1.9 Hz, 3H), 2.02-1.45 (m, 5H); 13C NMR (diastereomeric
mixture, 126 MHz, CDCl3) δ 175.1, 175.0, 174.5 (overlapped),
149.0, 148.9, 129.9, 129.8, 83.4, 83.1, 80.9, 80.7, 39.7, 39.3, 30.6,
30.5, 28.9, 23.4, 23.3, 10.5; IR (neat) ν 3403, 2930, 1752, 1670
cm-1; CIMS 222 (M+ - 18, 100); HRMS calcd for C12H18NO4 (M+
+ 1) 240.1235, found 240.1226.
P h en ylth iola cta m (12). To a solution of carbinol lactam 11
(117 mg, 0.50 mmol) in benzene (3 mL) was added p-TsOH (1
mg) and thiophenol (75 µL, 0.73 mmol) at 0 °C. The resulting
solution was stirred at room temperature overnight, diluted with
diethyl ether, and washed with water. The organic layers were
(9) (a) Chamberlin, A. R.; Nguyen, D. H.; Chung, J . Y. L. J . Org.
Chem. 1984, 49, 1682. (b) Hiemstra, H.; Speckamp, W. In Compre-
hensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press:
Oxford, 1991; Vol. 2, p 1047.
(10) For the preparation of phenylthiolactam and its use in radical
cyclization reactions, see: Choi, J .-K.; Hart, D. J . Tetrahedron 1985,
41, 3959 and references therein.
(11) For recent reviews of the radical cyclization reactions, see: (a)
Curran, D. P. In Comprehensive Organic Synthesis; Semmelhack, M.
F., Ed.; Pergamon Press: Oxford, 1991; Vol. 4, p 779. (b) Renaud, P.;
Giraud, L. Synthesis 1996, 913.
(12) For a few examples of seven-membered ring formations by
intramolecular radical cyclizations, see: (a) Beckwith, A. L. J .; Moad,
G. J . Chem. Soc., Chem. Commun. 1974, 472. (b) Beckwith, A. L. J .;
Roberts, D. H. J . Am. Chem. Soc. 1986, 108, 5893. (c) Bachi, M. D.;
Hoornaert, C. Tetrahedron Lett. 1981, 22, 2693. (d) Ghosh, A. K.;
Ghosh, K.; Pal, S.; Ghatak, U. R. J . Chem. Soc., Chem. Commun. 1993,
809. (e) Rigby, J . M.; Qabar, M. N. J . Org. Chem. 1993, 58, 4473. (f)
Rigby, J . M.; Laurent, S.; Cavezza, A.; Heeg, M. J . J . Org. Chem. 1998,
63, 5587.
(14) 1H and 13C NMR spectra of 2 were identical to those prepared
by J acobi and Lee (see ref 2e).
(15) For general experimental procedures and full characterization
data of 3-8, see ref 4b.
(13) The ratio was determined by 1H NMR analysis of the crude
reaction mixture.
J . Org. Chem, Vol. 69, No. 22, 2004 7735

isolated, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by flash column chromatography
(hexanes/EtOAc, 1:3) to give the phenylthiolactam 12 (112 mg,
CH2Cl2. The organic layers were isolated, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by flash column chromatography (hexanes/EtOAc, 1:10) to give
2 (37 mg, 74%) as the only detectable product, a colorless
70%) as a colorless oil: [R]25 -10.2 (c 0.59, CHCl3); 1H NMR
D
(diastereomeric mixture, 500 MHz, CDCl3) δ 7.41-7.39 (m, 2H),
7.35-7.30 (m, 3H), 7.00 (br t, J ) 1.5 Hz, 1H), 6.98 (br t, J )
1.5 Hz, 1H), 4.92-4.87 (m, 2H), 3.80-3.69 (m, 1H), 3.35-3.27
(m, 1H), 2.49-2.40 (m, 1H), 2.22-2.17 (m, 1H), 2.12-2.05 (m,
1H), 1.90 (br t, J ) 1.5 Hz, 3H), 1.89 (br t, J ) 1.5 Hz, 3H),
1.81-1.62 (m, 3H), 1.60-1.46 (m, 2H); 13C NMR (diastereomeric
mixture, 126 MHz, CDCl3) δ 174.7, 174.6, 174.1, 174.0, 148.5,
148.3, 135.0, 134.9, 132.1, 130.6, 130.5, 130.2, 130.1, 129.3, 129.0,
128.9, 80.3, 80.2, 67.1, 67.0, 39.7, 39.4, 30.7, 30.6, 29.1, 29.0,
semisolid: [R]21 -63.3 (c 1.69, MeOH); 1H NMR (500 MHz,
D
CDCl3) δ 4.60 (ddd, J ) 10.6, 7.8, 2.7 Hz, 1H), 4.17 (dt, J ) 13.8,
4.7 Hz, 1H), 3.61 (dd, J ) 9.8, 7.8 Hz, 1H), 2.76 (ddd, J ) 13.9,
10.6, 3.4 Hz, 1H), 2.58-2.53 (m, 1H), 2.48 (m, 1H), 2.41 (m, 1H),
2.35-2.24 (m, 2H), 2.11-2.06 (m, 1H), 1.95-1.80 (m, 3H), 1.65-
1.57 (m, 1H), 1.37 (d, J ) 7.1 Hz, 3H); 1H NMR (500 MHz, C6D6)
δ 3.98 (dtd, J ) 13.6, 4.6, 0.8 Hz, 1H, H-5a), 3.80 (ddd, J ) 11.0,
8.1, 3.0 Hz, 1H, H-8), 2.42 (ddd, J ) 9.9, 8.1, 1.6 Hz, 1H, H-9a),
2.07 (ddd, J ) 13.7, 10.5, 3.4 Hz, 1H, H-5b), 1.95 (ddd, J ) 16.6,
8.5, 10.9 Hz, 1H, H-2), 1.82 (ddd, J ) 16.6, 9.5, 1.1 Hz, 1H, H-2),
1.65 (dq, J ) 8.6, 7.4 Hz, 1H, H-10), 1.48-1.44 (m, 1H, H-7),
1.37 (dt, J ) 10.1, 8.3 Hz, 1H, H-9), 1.28-1.20 (m, 1H, H-1b),
1.19-1.08 (m, 2H, H-6a and H-7), 1.00-0.92 (m, 1H, H-6a), 0.84
(d, J ) 7.4 Hz, 3H, H-12), 0.85-0.80 (m, 1H, H-1a); 13C NMR
(126 MHz, CDCl3) δ 177.9, 174.6, 80.7, 60.5, 50.7, 44.0, 39.0,
30.0, 28.9, 25.4, 23.9, 15.8; 13C NMR (126 MHz, C6D6) δ 177.4
(s), 173.6 (s), 80.4 (d), 60.0 (d), 50.6 (d), 43.9 (t), 38.9 (d), 30.3
(t), 29.1 (t), 25.5 (t), 24.6 (t), 15.9 (q); IR (neat) ν 2938, 1769,
26.6, 26.5, 22.7, 22.5, 10.6, 10.5; IR (neat) ν 1752, 1686 cm-1
;
CIMS 332 (M+ + 1, 3), 222 (100); HRMS calcd for C18H22NO3S
(M+ + 1) 332.1320, found 332.1315.
(-)-9,10-ep i-St em oa m id e (2). To a solution of phenyl-
thiolactam 12 (74 mg, 22 µmol, 5.5 mM) in benzene (40 mL) was
added a solution of n-Bu3SnH (93 µL, 33 mmol) and AIBN (11
mg, 6.7 µmol) in benzene (25 mL) via a syringe pump over a
period of 24 h at 85 °C (oil bath temperature). The resulting
solution was stirred at reflux for an additional 24 h. The reaction
mixture was cooled to room temperature and concentrated in
vacuo. The residue was dissolved in diethyl ether, and DBU16
was added until the white precipitate remained. Then, iodine
was added until the yellow color remained. The resulting
suspension was passed through a short column to remove tin
material. The solution was concentrated in vacuo, dissolved in
MeOH (2 mL), and treated with K2CO3 (30 mg, 22 µmol). The
resulting reaction mixture was stirred at room temperature for
48 h and concentrated. The residue was then treated with water,
neutralized with 10% aqueous HCl solution, and extracted with
1686 cm-1; CIMS 224 (M+ + 1, 100); HRMS calcd for C12H18
NO3 (M+ + 1) 224.1286, found 224.1289.
-
Ack n ow led gm en t. Financial support for this work
was provided by the National Institutes of Health (GM
26568).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of new compounds 2 and 9-12. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989, 54, 3140.
J O049083I
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