Synthesis of (-)-stemoamide using a stereoselective anti-aldol step

Article abstract of DOI:10.1021/jo052364l

The synthesis of (-)-stemoamide was achieved in 11 steps from 5-acetoxy-N-crotyl pyrrolidinone. A chiral N-acyl thiazolidinethione was employed in a stereoselective addition to a cyclic N-acyl iminium ion to install the required stereochemistry of carbon

Full text of DOI:10.1021/jo052364l

tricyclic core.5 With the exception of Jacobi’s seven-step
synthesis of stemoamide,3d,4b syntheses of stemoamide either
are too long or lack a complete stereochemical control during
the installation of the contiguous stereocenters and consequently
require extra steps to correct their stereochemistry. As part of
our program in the synthesis and pharmacology of Stemona
alkaloids with unique biological properties,6 we sought to
develop enantioselective strategies which will allow us to
prepare large amounts of these alkaloids. As a first step toward
this goal, we embarked on a practical synthesis of (-)-
stemoamide.
Synthesis of (-)-Stemoamide Using a
Stereoselective anti-Aldol Step
Horacio F. Olivo,* Ricardo Tovar-Miranda, and
Efra´ın Barraga´n
DiVision of Medicinal and Natural Products Chemistry, College
of Pharmacy, The UniVersity of Iowa, Iowa City, Iowa 52242
horacio-oliVo@uiowa.edu
ReceiVed NoVember 15, 2005
We envisioned a synthetic strategy of (-)-stemoamide that
relied on installing the correct stereochemistry of the three
contiguous stereocenters C8, C9, and C9a employing a chiral
thiazolidinethione as illustrated in Scheme 1. Conversion of the
SCHEME 1. Retrosynthetic Analysis of (-)-Stemoamide
The synthesis of (-)-stemoamide was achieved in 11 steps
from 5-acetoxy-N-crotyl pyrrolidinone. A chiral N-acyl
thiazolidinethione was employed in a stereoselective addition
to a cyclic N-acyl iminium ion to install the required
stereochemistry of carbon C9a. This iminium ion addition
product was employed in a stereoselective MgBr2-catalyzed
anti-aldol reaction to install the required stereochemistry of
carbons C8 and C9. The X-ray crystal analysis of (-)-
stemoamide confirmed the structure and the stereochemical
outcome of these selective reactions.
hydrogenated product of 2 to stemoamide is well precedented.3f,4a
The lactone ring would be prepared from Wittig olefination
product 3, and the azepine ring would be formed by a ring-
closing olefin metathesis (RCM). Installing the correct stereo-
chemistry of C8 and C9 would require an anti-aldol reaction
of N-acyl thiazolidinethione 4, and introducing the stereochem-
istry of C9a would require the addition of a chiral N-acetylimide
to a cyclic iminium ion.
We recently reported the stereoselective addition of the
titanium(IV) enolate of N-acetyl-4S-isopropylthiazolidinethiones
to cyclic N-acyl iminium ions.7 Addition of a metal enolate
derived from N-acetyl thiazolidinethione to a cyclic N-acyl imine
creates a stereocenter with stereochemistry opposite of the one
The Stemonaceae plant family is a rich source of bioactive
alkaloids with more than 70 alkaloids isolated to date.1 The
rhizomes and root extracts of these plants have been used in
traditional Chinese and Japanese folk medicine as insecticides,
as vermifuges, and also for the treatment of respiratory diseases
such as bronchitis, pertussis, and tuberculosis. (-)-Stemoamide
(1) was isolated from the roots and rhizomes of Stemona
tuberosa by Xu et al., in 1992.2 Stemoamide is one of the
structurally simplest members of the Stemona family possessing
a γ-lactone fused to a pyrrolo[1,2a]azepine nucleus. Several
syntheses of racemic and natural stemoamide have been
achieved to date3,4 as well as have several approaches to the
(1) (a) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Res. 2000, 17,
117. (b) Seger, C.; Mereiter, K.; Kaltenegger, E.; Pacher, T.; Greger, H.;
Hofer, T. Chem. BiodiVersity 2004, 1, 265. (c) Wiboonpun, N.; Phuwaprai-
sirisan, P.; Tip-pyang, S. Phytother. Res. 2004, 18, 771. (d) Pilli, R. A.;
Rosso, G. B.; de Oliveira, M. C. F. In The Alkaloids; Cordell, G. A., Ed.;
Elsevier: New York, 2005; Vol. 62, Chapter 2, pp 77-173.
(4) For racemic synthesis of (()-stemoamide: (a) Kohno, Y.; Narasaka,
K. Bull. Chem. Soc. Jpn. 1996, 69, 2063. (b) Jacobi, P. A.; Lee, K. J. Am.
Chem. Soc. 1997, 119, 3409.
(5) Approaches to pyrroloazepine core: (a) Alibe´s, R.; Blanco, P.; Casas,
E.; Closa, M.; de March, P.; Figueredo, M.; Font, J.; Sanfeliu, E.; Alvarez-
Larena, A. J. Org. Chem. 2005, 70, 3157. (b) Bogliotty, N.; Dalko, P. I.;
Cossy, J. Synlett 2005, 349. (c) Khim, S. K.; Schultz, A. G. J. Org. Chem.
2004, 69, 7734. (d) Cid, P.; Closa, M.; de March, P.; Figueredo, M.; Font,
J.; Sanfeliu, E.; Soria, A. Eur. J. Org. Chem. 2004, 4215.
(6) Vela´zquez, F.; Olivo, H. F. Org. Lett. 2002, 4, 3175.
(7) Barraga´n, E.; Olivo, H. F.; Romero-Ortega, M.; Sarduy, S. J. Org.
Chem. 2005, 70, 4214.
(2) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
(3) Syntheses of (-)-stemoamide: (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) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122,
4295. (e) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295. (f)
Sibi, M. P.; Subramanian, T. Synlett 2004, 1211.
10.1021/jo052364l CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/14/2006
J. Org. Chem. 2006, 71, 3287-3290
3287

to the corresponding aldehyde,12 we were unable to partially
reduce thiazolidinethione 9 to aldehyde 11 in good yields.
However, reduction of thiazolidinethione with sodium borohy-
dride occurred in 96% yield, and oxidation of the alcohol 10 to
aldehyde 11 occurred in 90% yield.
SCHEME 2. Chiral Thiazolidinethione-Directed Addition to
Iminium Ion and anti-Aldol
Aldehyde 11 was reacted with the phosphonium salt
Ph3P+CH2OCH3Cl- in the presence of NaHMDS to give an
inseparable E,Z-mixture of methylvinyl ethers; under acidic
conditions, the silyl ether was removed and the methylvinyl ether
was hydrolyzed to deliver a diastereomeric mixture of lactols
in 88% yield. Oxidation of the lactols with PCC gave the desired
lactone 12 in very good yield. Although many combinations of
dienes have been reported in ring-closing olefin metathesis
(RCM), we found no RCM literature precedent with vinylic
methyl and phenyl groups.13 We found that RCM using the
second generation of Grubbs’ catalyst (Grubbs II) in refluxing
1,2-dichloroethane furnished azepine 2 in 60% yield.
obtained when added to an N-acyl iminium ion using the same
chiral auxiliary.8,9 Because N-acetyl-4R-isopropylthiazolidineth-
ione would be too costly to prepare, we selected the 4R-phenyl
thiazolidinethione 5 for the construction of the required stere-
ochemistry of C9a as found in natural stemoamide (Scheme
2). Addition of the titanium enolate of 5 to the iminium ion
formed from 5-acetoxy pyrrolidinone 610 gave the desired
diastereomeric product 7 in 92% isolated yield after column
chromatography.
The two remaining steps to complete the total synthesis are
illustrated in Scheme 4. Palladium-catalyzed hydrogenation of
SCHEME 4. Completion of the Synthesis
A highly diastereoselective anti-aldol reaction employing
chiral thiazolidinethione auxiliaries was recently disclosed by
Evans.11 The reaction is catalytic in magnesium salts and is
facilitated by silylation with chlorotrimethylsilane at room
temperature. We reported this anti-aldol reaction when the
aldehyde employed was cinnamaldehyde and the N-acyl thia-
zolidinethione was the addition product of the titanium(IV)
enolate of N-acetyl-4S-isopropylthiazolidinethione with N-crotyl-
5-acetoxy pyrrolidinone.7 An X-ray crystallographic analysis
confirmed the stereochemical output of the reaction. When
thiazolidinethione 7 was employed in the anti-aldol reaction with
acrolein, no reaction was observed. However, when the aldehyde
employed was cinnamaldehyde, aldol product 8 was obtained
in 74% yield after column chromatography (Scheme 2). Because
the reactions were carried out with the 4S-substituted thiazo-
lidinethione instead of with the 4R-isomer, as previously
described,7 we presumed aldol product 8 had a stereochemistry
opposite of the product obtained when using the 4R-isomer.
Thus, aldol product 8 possesses the required stereochemistry
of carbons C8, C9, and C9a for the synthesis of (-)-stemoamide.
Aldol product 8 was protected as the triethylsilyl ether 9 in
quantitative yield.
the unsaturated azepine 2 gave compound 13 in almost
quantitative yield. Stereoselective methylation of C10 on the
less-hindered face of lactone 13 at low temperature gave
stemoamide 1 in 70% yield, as previously reported by Narasaka4a
and Sibi.3f All spectroscopic data and physical data of stemoa-
mide were in agreement with the published data.2,3 The X-ray
crystallographic analysis of (-)-stemoamide confirmed the
stereochemistry of the product as envisioned in the synthetic
plan.
In summary, we have achieved a synthesis of (-)-stemoamide
in 11 steps starting from easily prepared starting materials (14%
overall yield). We have demonstrated the utility of the stereo-
selective addition of a titanium(IV) enolate of N-acetyl thiazo-
lidinethione to a cyclic iminium ion and the use of the same
chiral auxiliary to control the stereochemistry in a MgBr2-
catalyzed anti-aldol reaction for the synthesis of (-)-stemoa-
mide. The structure of (-)-stemoamide was confirmed by X-ray
crystallographic analysis.
Homologation of the acyl group of 9 to form the γ-lactone
and RCM to form the azepine ring are illustrated in Scheme 3.
Although many chiral thiazolidinethiones can be reduced directly
SCHEME 3. Homologation and Azepine Construction
3288 J. Org. Chem., Vol. 71, No. 8, 2006

7.43-7.24 (10H, m), 6.64 (1H, dd, J ) 16.0, 1.7 Hz), 6.23 (1H,
dd, J ) 16.0, 4.0 Hz), 5.95 (1H, d, J ) 7.8 Hz), 5.33 (1H, m), 5.32
(1H, dd, J ) 6.8, 3.6 Hz), 5.21 (1H, m), 4.63 (1H, bs), 4.29 (1H,
m), 4.17 (1H, dd, J ) 15.2, 5.6 Hz), 3.38 (1H, dd, J ) 11.2, 8.1
Hz), 3.23 (1H, dd, J ) 15.2, 6.6 Hz), 2.94 (1H, dd, J ) 11.2 Hz),
2.60 (1H, dt, J ) 17.0, 9.2 Hz), 2.30 (1H, dd, J ) 9.7, 3.5 Hz),
2.01 (1H, m), 1.66 (1H, m), 1.58 (3H, d, J ) 6.2 Hz); 13C NMR
(CDCl3) δ 203.1 (CS), 175.6 (CO), 174.3 (CO), 138.8 (C), 136.2
(C), 130.0 (CH), 129.8 (CH), 129.6 (CH), 129.3 (2CH), 129.0 (CH),
128.9 (CH), 128.3 (CH), 126.5 (2CH), 125.6 (2CH), 124.9 (CH),
70.5 (CH), 70.2 (CH), 56.9 (CH), 50.4 (CH), 43.1 (CH2), 36.7
(CH2), 30.1 (CH2), 21.8 (CH2), 17.9 (CH3).
Experimental Section
(-)-5(S)-[2-(4(R)-Phenyl-2-thioxo-thiazolidine-3-yl)-2-oxo-eth-
yl]-1-(but-2-enyl)-pyrrolidine-2-one 7. A solution of TiCl4 (1 M
in CH2Cl2, 1.5 mL, 1.5 mmol) was added to a solution of N-acetyl-
4(R)-phenyl thiazolidinethione (356 mg, 1.5 mmol) in CH2Cl2 (5
mL) cooled to 0 °C. The solution was stirred for 5 min and then
cooled to -30 °C. The reaction mixture was treated with a solution
of diisopropylethylamine (220 mg, 1.7 mmol) in CH2Cl2 (5 mL).
The reaction mixture was stirred for 40 min and cooled to -78
°C. A solution of 5-acetoxy N-crotyl pyrrolidine-2-one (395 mg,
2.0 mmol) in CH2Cl2 (5 mL) was added to the reaction mixture
via cannula. The reaction mixture was stirred and warmed to 0 °C
for 6 h. The reaction was quenched by addition of saturated NH4-
Cl solution and stirred for 5 min. The aqueous layer was extracted
with CH2Cl2 (2 × 25 mL). The combined organic layer was then
washed with saturated NaHCO3 and brine. The organic layer was
dried over Na2SO4, filtered, concentrated in vacuo, and purified
by silica gel column chromatography (CHCl3-EtOAc-petroleum
ether, 4:2:1) to afford 516 mg of 7 as a yellow oil (92% yield): Rf
TES-Protected Aldol Product 9. To a dichloromethane solution
cooled to -50 °C was added TESOTf (0.2 mL, 0.89 mmol) and
2,6-lutidine (0.1 mL, 0.89 mmol). After the solution was stirred
for 15 min, the alcohol 8 dissolved in dichloromethane was added
via cannula. The reaction mixture was warmed to room temperature
overnight. The solution was washed with saturated Na2CO3. The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 7:3) to give 366 mg (99%).
Rf 0.34 (7:3, petroleum ether-ethyl acetate); [R]D25 ) -286 (c 1.0,
25
0.35 (CHCl3-EtOAc-Petroleum Ether, 4:2:1); [R]D ) -359 (c
1.0, CHCl3); IR 3002, 1683, 1377, 1332, 1259, 1159 cm-1; 1H NMR
(CDCl3) δ 7.44-7.33 (5H, m), 6.22 (1H, d, J ) 8.2 Hz), 5.57 (1H,
dq, J ) 15.2, 6.4 Hz), 5.32 (1H, m), 4.07 (2H, bs), 3.96 (1H, dd,
J ) 11.3, 8.3 Hz), 3.90 (1H, dd, J ) 17.6, 3.3 Hz), 3.52 (1H, dd,
J ) 15.2, 7.0 Hz), 3.16 (1H, dd, J ) 17.5, 9.8 Hz), 3.09 (1H, dd,
J ) 10.4, 1.5 Hz), 2.48-2.17 (3H, m), 1.66 (3H, d, J ) 6.4 Hz),
1.63 (1H, m); 13C NMR (CDCl3) δ 202.4 (C), 174.7 (C), 170.9
(C), 139.1 (C), 129.5 (CH), 129.3 (2CH), 128.9 (CH), 125.6 (2CH),
125.4 (CH), 69.7 (CH), 54.3 (CH), 42.7 (2CH2), 36.6 (CH2), 29.7
(CH2), 24.6 (CH2), 17.7 (CH3).
1
CHCl3); IR 2955, 2911, 1690, 1161 cm-1; H NMR (CDCl3) δ
7.41-7.22 (10H, m), 6.55 (1H, d, J ) 15.9 Hz), 6.16 (1H, dd, J )
15.8, 7.2 Hz), 6.08 (1H, d, J ) 7.9 Hz), 5.52 (1H, m), 5.48 (1H,
dq, J ) 6.9, 4.9 Hz), 5.24 (1H, m), 4.68 (1H, t, J ) 7.1 Hz), 4.14
(2H, m), 3.74 (1H, dd, J ) 11.3, 8.0 Hz), 3.22 (1H, dd, J ) 15.3,
7.2 Hz), 3.01 (1H, d, J ) 11.3 Hz), 2.28 (3H, m), 1.98 (1H, m),
1.62 (3H, d, J ) 6.3 Hz), 0.96 (9H, t, J ) 8 Hz), 0.62 (6H, q, J )
7.8 Hz); 13C NMR (CDCl3) δ 203.1 (C), 175.3 (C), 172.7 (C), 139.1
(C), 136.2 (C), 131.6 (CH), 129.9 (CH), 129.2 (CH), 129.1 (2CH),
128.9 (2CH), 128.6 (CH), 128.2 (CH), 126.7 (2CH), 125.4 (2CH),
125.3 (CH), 73.3 (CH), 70. 4 (CH), 56.0 (CH), 52.1 (CH), 43.0
(CH2), 37.1 (CH2), 30.4 (CH2), 21.1 (CH2), 17.9 (CH3), 7.0 (3CH3),
5.3 (3CH2).
1-(4R-Phenyl-2-thioxo-1,3-thiazolidin-3-yl)-(2S,3R)-3-hydroxy-
2-(1-but-2-enyl-5-oxo-pyrrolidin-2(S)-yl)-5-phenyl-pent-4-en-1-
one 8. To a solution of compound 7 (748 mg, 2 mmol) in ethyl
acetate (6 mL) was added MgBr2‚OEt2 (78 mg, 0.3 mmol),
cinnamaldehyde (0.278 mL, 2.2 mmol), triethylamine (0.558 mL,
4 mmol), and TMSCl (0.381 mL, 3 mmol). The mixture was stirred
at room temperature for 36 h. The reaction was filtered through a
plug of silica and eluted with ethyl acetate. The eluent was
concentrated in vacuo, and the residue was dissolved in 20 mL of
THF and 5 mL of 1 N HCl. After stirring for 1h at room
temperature, the mixture was diluted with 100 mL of AcOEt and
100 mL of water. The phases were separated, and the organic layer
was washed with a saturated solution of NaHCO3 (2 × 30 mL)
and brine (2 × 30 mL), dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel eluting with petroleum ether-acetone (7:3, 6:4,
5:5, and 4:6): 772 mg (74% yield); Rf 0.32 (4:2:1, chloroform-
ethyl acetate-petroleum ether); [R]D25 ) -331 (c 1.0, CHCl3); IR
Alcohol 10. To a solution of thiazolidinethione 9 (257 mg, 0.414
mmol) in dry ethanol (4 mL) cooled to -15 °C was added NaBH4
(32 mg, 0.86 mmol). The reaction was stirred at 4 °C overnight.
Excess borohydride was quenched at 0 °C with diluted HCl and
concentrated. The residue was partitioned between water and ether,
and the organic layer was separated and washed with saturated Na2-
CO3 and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate, 7:3) to give 177 mg of 10
(96%) as a colorless oil: Rf 0.22 (1:1, petroleum ether-ethyl
acetate); [R]D25 ) -17 (c 1.0, CHCl3); IR 3405, 2955, 1668, 1449,
1
1422 cm-1; H NMR (CDCl3) δ 7.39-7.24 (5H, m), 6.50 (1H, d,
J ) 15.9 Hz), 6.28 (1H, dd, J ) 15.9, 6.5 Hz), 5.61 (1H, dq, J )
15.3, 6.5 Hz), 5.35 (1H, m), 4.54 (1H, dd, J ) 7.6, 3.2 Hz), 4.40
(1H, ddt, J ) 15.0, 4.9, 1.5 Hz), 3.99-3.89 (2H, m), 3.78 (1H, m),
3.44 (1H, dd, J ) 15.0, 7.8 Hz), 3.11 (1H, bs), 2.45 (1H, m), 2.35
(1H, m), 2.24-2.08 (2H, m), 1.86 (1H, m), 1.66 (3H, d, J ) 6.5
Hz), 0.96 (9H, t, J ) 8.0 Hz), 0.62 (6H, q, J ) 8.0 Hz); 13C NMR
(CDCl3) δ 175.7 (C), 136.3 (C), 131.2 (CH), 131.0 (CH), 129.6
(CH), 128.9 (2CH), 128.2 (CH), 126.7 (2CH), 125.5 (CH), 74.6
(CH), 61.5 (CH2), 57.1 (CH), 48.1 (CH), 43.4 (CH2), 30.4 (CH2),
22.5 (CH2), 17.9 (CH3), 6.9 (3CH3), 5.2 (3CH2).
3345, 2937, 1669, 1449, 1256, 1161 cm-1; H NMR (CDCl3) δ
1
(8) (a)Nagao, Y.; Dai, W.-M.; Ochiai, M.; Shiro, M. Tetrahedron 1990,
46, 6361. (b) Nagao, Y.; Dai, W.-M.; Ochiai, W. Tetrahedron Lett. 1988,
29, 6133.
(9) For other stereoselective additions of titanium(IV) enolates of chiral
N-acyl oxazolidinones and thiazolidinethiones to cyclic iminium ions: (a)
Pereira, E.; Alves, C. F.; Bo¨ckelmann, M. A.; Pilli, R. A. Tetrahedron Lett.
2005, 46, 2691. (b) Pilli, R. A.; Bo¨ckelmann, M. A.; Alves, C. F. J. Braz.
Chem. Soc. 2001, 12, 634. (c) Pilli, R. A.; Bo¨ckelmann, M. A.; Mascarenhas,
Y. P.; Nery, J. G.; Vencato, I. Tetrahedron Lett. 1999, 40, 2891.
(10) A number of N-substituted 5-hydroxypyrrolidinones were prepared
by partial reduction of N-substituted succinimides with NaBH4, but we were
unable to prepare the corresponding N-allyl derivative by this method; see
ref 7.
(11) (a) Evans, D. A.; Downey, C. W.; Shaw, T. J.; Tedrow, J. S. Org.
Lett. 2002, 4, 1127. (b) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey,
C. W. J. Am. Chem. Soc. 2002, 124, 392.
(12) Vela´zquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 303.
(13) (a) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 10103. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders,
D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
Aldehyde 11. To a solution of alcohol 10 (95 mg, 0.22 mmol)
in 9.5 mL of DCM was added molecular sieves (170 mg),
4-methylmorpholine N-oxide (47 mg, 0.4 mmol), and TPAP (7 mg,
0.02 mmol). The mixture was stirred at room temperature and
followed by TLC. After 1 h, the reaction was completed and it
was filtered through a short column of silica gel and eluted with
acetone to give 85 mg (90%) of aldehyde 11: Rf 0.5 (1:1, petroleum
25
ether-ethyl acetate); [R]D ) - 90.8 (c 1.0, CHCl3); IR 2954,
1
2361, 1690, 1454, 1418, 1244 cm-1; H NMR (CDCl3) δ 10.00
(1H, d, J ) 1.6 Hz), 7.40-7.25 (5H, m), 6.56 (1H, d, J ) 15.8
Hz), 6.34 (1H, dd, J ) 15.8, 8.1 Hz), 5.59 (1H, dq, J ) 15.3, 6.4
J. Org. Chem, Vol. 71, No. 8, 2006 3289

Hz), 5.33 (1H, m), 4.67 (1H, dd, J ) 8.2, 3.3 Hz), 4.31 (1H, ddt,
J ) 15.2, 5.3, 1.5 Hz), 4.20 (1H, dd, J ) 11.6, 6.6 Hz), 3.30 (1H,
dd, J ) 15.2, 7.6 Hz), 2.75 (1H, m), 2.56-2.31 (2H, m), 2.24-
2.16 (2H, m), 1.66 (3H, dd, J ) 6.5, 0.9 Hz), 0.93 (9H, t, J ) 8.0
Hz), 0.60 (6H, q, J ) 7.8 Hz); 13C NMR (CDCl3) δ 201.8 (CH),
175.5 (C), 135.8 (C), 132.0 (CH), 130.0 (CH), 129.8 (CH), 128.9
(2CH), 128.4 (CH), 126.7 (2CH), 125.1 (CH), 71.6 (CH), 59.4 (CH),
55.8 (CH), 43.2 (CH2), 30.2 (CH2), 21.4 (CH2), 17.8 (CH3), 6.9
(3CH3), 5.3 (3CH2).
dichloromethane, 5:95); IR 3456, 2920, 1783, 1683, 1418, 1276,
1183, 1023 cm-1; 1H NMR (CDCl3) δ 5.93 (1H, d, J ) 11.3 Hz),
5.76 (1H, dddd, J ) 11.3, 6.0, 2.3, 1.8 Hz), 5.03 (1H, dq, J )
10.5, 1.7 Hz), 4.74 (1H, dd, J ) 18.4, 6.0 Hz), 4.10 (1H, dt, J )
9.8, 6.6 Hz), 3.45 (1H, bd, J ) 18.4 Hz), 3.13 (1H, m), 2.70-2.46
(4H, m), 2.12 (1H, m), 2.12 (1H, m), 1.77 (1H, m); 13C NMR
(CDCl3) δ 175.5 (C), 173.9 (C), 129.4 (CH), 128.6 (CH), 78.1 (CH),
57.0 (CH), 44.9 (CH), 40.7 (CH2), 31.1 (CH2), 30.9 (CH2), 21.2
(CH2); m/e calcd for C11H14NO3 208.0974, found 208.0969.
Desmethylstemoamide 13. To a solution of olefin 2 (52 mg,
80 µmol) in methanol (4 mL) was added 10% Pd-C (6 mg). The
suspension was stirred overnight under H2 atmosphere. The reaction
was filtered through a small bed of Celite, and the solvent was
evaporated to give desmethylstemoamide 13 (50 mg, 99%): Rf 0.26
(methanol-dichloromethane, 5:95); [R]D25 ) -144 (c 1.0, CHCl3);
Lactone 12. To a suspension of MeOCH2PPh3Cl (1.100 g, 3.2
mmol) in dry THF (10 mL) at -78 °C was added NaHMDS (1 M
in THF, 2.68 mL, 2.68 mmol) dropwise, and the mixture was stirred
for 20 min. Aldehyde 11 (458 mg, 1.071 mmol) in dry THF (1
mL) was added dropwise to the reaction mixture. The reaction was
stirred for 3 h at -78 °C and then allowed to warm to room
temperature. The reaction was quenched with NH4Cl (saturated, 5
mL), and the mixture was extracted with ethyl acetate. The organic
layer was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (petroleum
ether/ethyl acetate, 3:2) to yield the Wittig product as a mixture of
geometric isomers (371 mg, 76%). The Wittig product (334 mg,
0.733 mmol) was dissolved in THF-H2O (16 mL, 3:1), and
p-TsOH (140 mg, 0.733 mmol) was added. The mixture was
refluxed for 4 h. The reaction was allowed to cool to room
temperature and treated with NaHCO3. The reaction mixture was
extracted with dichloromethane. The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (petroleum ether/acetone, 6:4)
to give 210 mg of a mixture of lactols (88%) as colorless oil. To
a solution of lactols (200 mg, 0.61 mmol) in dichloromethane (60
mL) was added PCC (263 mg, 1.22 mmol) and sodium acetate (132
mg, 1.6 mmol). The mixture was stirred for 6 h at room temperature.
The reaction was diluted with AcOEt (20 mL), filtered on a small
column of silica gel (5 cm), and washed with dichloromethane.
The solvent was evaporated to give lactone 12 (173 mg, 87%): Rf
1
IR 2931, 1776, 1671, 1420, 1185 cm-1; H NMR (CDCl3) δ 4.29
(1H, dt, J ) 10.4, 3.0 Hz), 4.15 (1H, dt, J ) 14.0, 2.1 Hz), 4.00
(1H, dt, J ) 10.7, 6.6 Hz), 2.92-2.80 (1H, m), 2.77-2.63 (1H,
m), 2.65 (1H, dd, J ) 17.4, 8.5 Hz), 2.46-2.36 (4H, m), 2.13-
2.03 (1H, m), 1.90-1.84 (1H, m), 1.72 (1H, quin, J ) 10.7 Hz),
1.62-1.52 (2H, m); 13C NMR (CDCl3) δ 174.9 (C), 174.2 (C),
80.0 (CH), 56.2 (CH), 45.1 (CH), 40.4 (CH2), 34.8 (CH2), 31.2
(CH2), 30.7 (CH2), 25.7 (CH2), 22.8 (CH2); m/e calcd for C11H16-
NO3 210.1130, found 210.1130.
(-)-Stemoamide 1. To a solution of desmethylstemoamide 13
(35 mg, 0.167 mmol) in anhydrous THF (1 mL) at - 78 °C was
added 1 M LiHMDS solution in THF (0.3 mL). After 1 h, MeI
(0.02 mL, 0.32 mmol) was added and stirring was continued for
an additional 1 h. The reaction mixture was quenched with saturated
ammonium chloride, extracted with ethyl acetate, dried over Na2-
SO4, and concentrated in vacuo. The crude residue was purified
by silica gel chromatography by eluting with dichloromethane/
25
methanol (9.5:0.5) to give stemoamide (25 mg, 70%): [R]D
)
1
-187 (c 0.5, CH3OH); mp ) 185-186 °C; H NMR (CDCl3) δ
4.21 (1H, dt, J ) 10.6, 3.0 Hz), 4.16 (1H, m), 4.00 (1H, dt, J )
10.8, 6.4 Hz), 2.66 (1H, dd, J ) 14.3, 12.3 Hz), 2.60 (1H, dq, J )
12.5, 6.8 Hz), 2.45-2.38 (4H, m), 2.09-1.84 (1H, m), 1.90-1.84
(1H, m), 1.72 (1H, quint, J ) 10.8 Hz), 1.58-1.49 (2H, m), 1.31
(3H, d, J ) 6.9 Hz); 13C NMR (CDCl3) δ 177.55 (C), 174.22 (C),
77.81 (CH), 56.01 (CH), 52.87 (CH), 40.41 (CH2), 37.51 (CH),
34.99 (CH2), 30.81 (CH2), 25.80 (CH2), 22.77 (CH2), 14.30 (CH3).
25
0.43 (petroleum ether-ethyl acetate, 1:4); [R]D ) +70.1 (c 1.0,
1
CHCl3); IR 3025, 2928, 1777, 1684, 1424, 1171, 971 cm-1; H
NMR (CDCl3) δ 7.40-7.28 (5H, m), 6.64 (1H, d, J ) 15.8 Hz),
6.11 (1H, dd, J ) 15.8, 7.0 Hz), 5.64 (1H, dq, J ) 15.3, 6.4 Hz),
5.33 (1H, m), 4.89 (1H, dd, J ) 7.1, 3.3 Hz), 4.34 (1H, d, J )
15.3 Hz), 3.84 (1H, m), 3.34 (1H, dd, J ) 15.2, 7.6 Hz), 2.89-
2.77 (2H, m), 2.57-2.32 (3H, m), 2.24-2.11 (1H, m), 1.89-1.77
(1H, m), 1.67 (3H, d, J ) 6.3 Hz); 13C NMR (CDCl3) δ 175.4 (C),
175.2 (C), 135.4 (C), 133.9 (CH), 130.3 (CH), 128.9 (2CH), 128.3
(CH), 127.0 (2CH), 125.6 (CH), 125.1 (CH), 80.5 (CH), 58.2 (CH),
43.2 (CH2), 42.1 (CH), 31.0 (CH2), 30.1 (CH2), 20.1 (CH2), 17.9
(CH3).
RCM Product 2. To a solution of diene 12 (26 mg, 80 µmol)
in ethylene dichloride (10 mL) was added Grubb’s catalyst second
generation (6.8 mg, 8 µmol) dissolved in ethylene dichloride (6
mL) over 5 h. The reaction mixture was stirred at 110 °C for 20 h.
The reaction was filtered on a plug of silica gel using acetone as
solvent. The solvent was evaporated, and the residue was purified
by column chromatography (methanol-dichloromethane, 5:95) to
give metathesis product 2 (10 mg, 60%): Rf 0.29 (methanol-
Acknowledgment. This research was supported by the
National Science Foundation (CHE-0111292). We are indebted
to Dr. Blake Watkins (University of Mississippi) for obtaining
all the HRMS and to Dr. Dale Swenson for the X-ray
crystallographic analysis of stemoamide.
Supporting Information Available: Copies of 1H- and 13C-spec-
tra for selected compounds (7, 9-11, and 1) and ortep drawing
and CIF file for the X-ray structure of (-)-stemoamide (1). This
material is available free of charge via the Internet at http://pubs.acs.
org.
JO052364L
3290 J. Org. Chem., Vol. 71, No. 8, 2006