Total synthesis of (-)-stemoamide

Article abstract of DOI:10.1021/jo070498o

(Chemical Equation Presented) A stereocontrolled total synthesis of (-)-stemoamide (1) is presented. The synthesis starts from commercially available (S)-pyroglutaminol (4). A chemoselective iodoboration of 5 was used to access key intermediate 3. The β,γ-unsaturated azepine derivative 2 was obtained via a Pd(0)-catalyzed sp²-sp³ Negishi cross-coupling using a Reformatsky nucleophile followed by a ring-closing metathesis reaction. The required C8-C9 trans-stereochemistry of 1 was accessed through a stereoselective bromolactonization/1,4-reduction sequence.

Full text of DOI:10.1021/jo070498o

Total Synthesis of (-)-Stemoamide
Staffan Torssell, Emil Wanngren, and Peter Somfai*
KTH Chemical Science and Engineering, Department of
Organic Chemistry, Royal Institute of Technology, S-100 44
Stockholm, Sweden
FIGURE 1. Some Stemona alkaloids.
somfai@kth.se
Our initial retrosynthetic analysis of (-)-stemoamide 1
(Scheme 1) set out to install the γ-butyrolactone functionality
with the correct C8-C9 trans-stereochemistry via a stereose-
lective hydroboration of â,γ-unsaturated azepine 2. The late-
stage R-methylation of the γ-butyrolactone is well precedented
in the literature.2e,f,3 The pyrrolo[1,2-a]azepine core was to be
derived from vinyliodide 3 through a Negishi/ring-closing
metathesis (RCM) sequence. In a previous study, the azepine
moiety was constructed by a similar enyne metathesis reaction,2b
which gave some credence to our analysis.
ReceiVed March 9, 2007
Our synthesis began with protection of the primary alcohol
in 4 as the corresponding TBS-ether 6 (Scheme 2). N-Alkylation
of the lactam using NaHMDS at low temperature was followed
by removal of the TBS group to cleanly give alcohol 7 in
excellent yield. Conversion of compound 7 into alkyne 5 was
realized by a high yielding two-step procedure: Swern oxidation
followed by treatment of the crude aldehyde with Ohira-
Bestmann4 diazophosphonate 8 and K2CO3 in MeOH. The
vinyliodide moiety in 3 was installed by a chemoselective
iodoboration of the alkyne functionality in the presence of a
primary alkene using B-I-9-BBN at low temperature,5 which
led to 3 in good yield. The subsequent Pd(0)-catalyzed sp2-
sp3 coupling to install the â,γ-unsaturated ester required some
optimization. Subjecting a mixture of vinyliodide 3 and Pd-
(PPh3)4 in THF/DMPU to Reformatsky reagent 9, derived from
ethyl R-bromoacetate,6 gave compound 10 in high yield. The
use of 15-25 vol % DMPU as cosolvent proved to be crucial
for the successful coupling: When the DMPU was omitted, the
reaction proceeded slowly. With diene 10 in hand, the azepine
ring could be formed by subjecting 10 to Grubbs’ second
generation catalyst7 (G2) in refluxing CH2Cl2 at high dilution
(c ) 0.005 M), which afforded the cyclized product 2 in
excellent yield. When the reaction was run at higher concentra-
tions (c > 0.01 M), the desired product was isolated along with
inseparable dimerization byproducts.
A stereocontrolled total synthesis of (-)-stemoamide (1) is
presented. The synthesis starts from commercially available
(S)-pyroglutaminol (4). A chemoselective iodoboration of 5
was used to access key intermediate 3. The â,γ-unsaturated
azepine derivative 2 was obtained via a Pd(0)-catalyzed sp2-
sp3 Negishi cross-coupling using a Reformatsky nucleophile
followed by a ring-closing metathesis reaction. The required
C8-C9 trans-stereochemistry of 1 was accessed through a
stereoselective bromolactonization/1,4-reduction sequence.
The Stemona class of natural products, comprising 42 isolated
structures, represents a family of polycyclic alkaloids structurally
characterized by the presence of a pyrrolo[1,2-a]azepine core,
and several members also contain an R-methyl-γ-butyrolactone
subunit (Figure 1).1 This class of natural products has received
considerable attention in recent years due to their interesting
biological properties as well as their structural diversity, which
makes them suitable targets for total synthesis.2 Traditionally,
the root extracts of Stemona tuberosa have been employed in
Chinese and Japanese folk medicine for respiratory disorders
and also as an antihelminthic.1 Of the plethora of alkaloids
present in Stemona tuberosa, (-)-stemoamide (1), isolated in
1992 by Xu and co-workers,1a is structurally the simplest
member of the Stemona class containing a tricyclic core and
four contiguous stereogenic centers. The first total synthesis of
1 was reported by Williams and co-workers in 1994.2a
Unfortunately, all attempts to install the C8-hydroxy group
along with the correct C8-C9 trans-stereochemistry by treating
â,γ-unsaturated ester 2 with a variety of hydroborating agents
failed (Scheme 3). When using 9-BBN in THF at reflux,8 no
(3) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063-
2070.
(4) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
(5) (a) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.
1983, 24, 731-734. (b) Hodgson, D. M.; Foley, A. M.; Lovell, P. J. Synlett
1999, 744-746.
(1) (a) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571-576.
(b) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17, 117-
127 and references cited therein.
(2) Total and formal syntheses of (-)-stemoamide: (a) Williams, D. R.;
Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417-6420. (b)
Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356-8357. (c) Jacobi,
P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295-4303. (d) Gurjar, M.
K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295-298. (e) Sibi, M. P.;
Subramanian, T. Synlett 2004, 1211-1214. (f) Olivo, H. F.; Tovar-Miranda,
R.; Barraga´n, E. J. Org. Chem. 2006, 71, 3287-3290.
(6) Roberts, C. D.; Schu¨tz, R.; Leumann, C. J. Synlett 1999, 819-821.
(7) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204-2207.
(8) For hydroboration of trisubstituted â,γ-unsaturated amides using
9-BBN, see: Vedejs, E.; Kruger, A. W. J. Org. Chem. 1999, 64, 4790-
4794.
10.1021/jo070498o CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/24/2007
4246
J. Org. Chem. 2007, 72, 4246-4249

SCHEME 1. Retrosynthetic Analysis of (-)-Stemoamide
SCHEME 4. Bromolactonization and Endgame
In these cases, either no reaction occurred or the amide was
reduced along with hydroboration of the olefin. It has been
reported by others that hydroboration of hindered trisubstituted
olefins in the presence of amides can be troublesome.11
To modify our synthetic strategy, we decided to install the
butyrolactone moiety using a bromolactonization reaction, a
strategy that was successfully used by Mori and co-workers in
their efforts toward 1.2b
SCHEME 2. Construction of Pyrrolo[1,2-a]azepine Core
Thus hydrolysis of ethyl ester 2 using LiOH gave the crude
acid (Scheme 4), which upon exposure to CuBr2 on alumina at
65 °C in CHCl3 successfully gave the desired 5-endo cyclization
product, which, followed by treatment with triethylamine at
room temperature, effected elimination to butenolide 12 as a
single diastereomer (65% yield from ester 2).2b,12 The formation
of the C8 â-epimer in the bromolactonization was gratifying,
although it was not easily predicted from molecular models.
The same observations were made by Mori and co-workers.
The C8-C9 trans-stereochemistry required for 1 was then
introduced via a stereoselective 1,4-reduction of butenolide 12
from the sterically most accessible â-face using NiCl2‚6H2O
and NaBH4,2b,c,e,13 which gave the known lactone 13 in high
yield.2e,f,3 Finally, R-methylation of lactone 13 under the reported
conditions finished the synthesis of (-)-stemoamide.2e,f,3 Ana-
lytical data for 1 were in all aspects identical with those reported
in the literature.2
SCHEME 3. Failed Hydroboration Attempts
In conclusion, we have developed a 12-step, stereoselective
total synthesis of (-)-stemoamide (1) in 20% overall yield
starting from commercially available (S)-pyroglutaminol (4). The
key features of the synthesis are (i) an iodoboration/Negishi/
RCM sequence for the construction of â,γ-unsaturated azepine
derivative 2 and (ii) a stereoselective bromolactonization/1,4-
reduction strategy for the installation of the requisite C8-C9
trans-stereochemistry.
Experimental Section
reaction occurred. Treatment of 2 with BH3‚THF at low
temperature (T < -25 °C) gave no reaction, while increasing
the reaction temperature gave a complex mixture of products.
It is known that hydroboration of â,γ-unsaturated esters using
BH3‚THF can lead to reduction of the ester moiety, furnishing
the corresponding primary alcohol.9 Therefore, in order to test
the hydroboration reaction without the interfering ester reduc-
tion, 2 was reduced to alcohol 11 using LiBH4 in excellent yield.
Alcohol 11 was then subjected to the same hydroboration
conditions, as well as Evans’ catecholborane/SmI3 procedure.10
For general experimental procedures, see Supporting Information.
(S)-5-(tert-Butyldimethylsilanyloxymethyl)pyrrolidin-2-one (6).
To a solution of 1° alcohol 4 (1.000 g, 8.69 mmol) in CH2Cl2 (15
mL) and DMF (2 mL) was added TBSCl (1.570 g, 10.42 mmol)
followed by imidazole (1.480 g, 21.71 mmol), and the resultant
(10) Evans, D. A.; Muci, A. R.; Stu¨rmer, R. J. Org. Chem. 1993, 58,
5307-5309.
(11) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou,
M.-I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538-10551.
(12) Rood, G. A.; DeHaan, J. M.; Zibuck, R. Tetrahedron Lett. 1996,
37, 157-158.
(9) Simila, S. T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006,
47, 2933-2936.
(13) Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19, 817.
J. Org. Chem, Vol. 72, No. 11, 2007 4247

mixture was stirred for 3.5 h at rt and then quenched with H2O.
The phases were separated, and the aqueous layer was extracted
three times with CH2Cl2. The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Flash chroma-
tography (heptane/EtOAc 1:2) of the residue gave 6 (1.944 g, 98%)
extracts were dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography (pentane/EtOAc 3:1 f 1:1) of the
residue gave 5 (588 mg, 92% from 7) as a clear oil: [R]20D -24.6
1
(c 1.0, CHCl3); IR (film) 3295, 2928, 1688, 1416 cm-1; H NMR
(500 MHz, CDCl3) δ 5.81 (tdd, J ) 16.9, 10.2, 6.6 Hz, 1H), 5.00
(m, 2H), 4.32 (m, 1H), 3.63 (ddd, J ) 13.8, 8.9, 7.0 Hz, 1H), 3.12
(ddd, J ) 13.8, 8.3, 5.4 Hz, 1H), 2.50 (m, 1H), 2.40 (d, J ) 2.1
Hz, 1H), 2.34 (m, 2H), 2.09 (m, 3H), 1.66 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 174.1, 137.6, 115.1, 81.5, 73.3, 48.9, 40.6, 31.1,
29.9, 26.3, 26.3; HRMS (FAB+) calcd for C11H16NO [M + H]+
178.1226, found 178.1232.
as a clear oil: [R]20 44.7 (c 1.8, CHCl3); IR (film) 1692, 1463,
D
1
1255, 1114 cm-1; H NMR (500 MHz, CDCl3) δ 5.96 (br s, 1H),
3.74 (ddd, J ) 12.6, 7.8, 4.8 Hz, 1H), 3.61 (dd, J ) 10.1, 4.0 Hz,
1H), 3.44 (dd, J ) 10.1, 7.6 Hz, 1H), 2.33 (m, 2H), 2.16 (m, 1H),
1.73 (m, 1H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 177.9, 66.9, 55.8, 29.8, 25.8, 22.7, 18.2, -5.46, -5.47;
HRMS (ESI+) calcd for C11H24NO2Si [M + H]+ 230.1571, found
230.1570.
(S)-5-(1-Iodovinyl)-1-(pent-4-enyl)pyrrolidin-2-one (3). To a
solution of alkyne 5 (30.0 mg, 0.169 mmol) in CH2Cl2/hexane (1:
1, 2 mL) was added B-I-9-BBN14 (508 µL, 0.508 mmol, 1.0 M in
hexanes) dropwise at -20 °C. The resultant mixture was stirred at
-20 °C for 17 h, then AcOH (540 µL) was added and the
temperature was increased to 0 °C. After 70 min, NaOH (3.8 mL,
3M) and H2O2 (700 µL, 35 wt %) were added and the mixture was
warmed to rt. After 1.5 h, the reaction mixture was diluted with
H2O (1 mL) and the phases were separated. The aqueous layer was
extracted twice with CH2Cl2, and the combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure. Flash
chromatography (pentane/EtOAc 2:1) of the residue gave 3 (37.2
(S)-5-(Hydroxymethyl)-1-(pent-4-enyl)pyrrolidin-2-one (7). To
a solution of amide 6 (887 mg, 3.87 mmol), 5-bromopent-1-ene
(920 µL, 7.73 mmol), and tetrabutylammonium iodide (143 mg,
0.387 mmol) in DMF (50 mL) was added dropwise NaHMDS (4.64
mL, 4.64 mmol, 1.0 M in THF) at -15 °C. The resultant mixture
was stirred at -15 °C for 10 min, at rt for 3 h, and then quenched
with saturated NH4Cl (10 mL). The mixture was diluted with H2O
and extracted three times with CH2Cl2. The combined organic
extracts were washed twice with H2O and brine, dried (MgSO4),
and concentrated under reduced pressure to give the amide as a
yellow oil (1.317 g). The residue was carried on to the next step
directly. An analytically pure sample was obtained with flash
mg, 72%) as a pale yellow oil: [R]20 20.8 (c 0.4, CHCl3); IR
D
1
(film) 2932, 1680, 1419, 915 cm-1; H NMR (500 MHz, CDCl3)
chromatography (pentane/EtOAc 1:1): [R]20 9.0 (c 1.5, CHCl3);
δ 6.36 (d, J ) 1.8 Hz, 1H), 5.92 (d, J ) 1.9 Hz, 1H), 5.79 (tdd, J
) 16.9, 10.2, 6.6 Hz, 1H), 5.01 (m, 2H), 3.89 (dd, J ) 8.7, 3.8 Hz,
1H), 3.69 (ddd, J ) 13.9, 8.9, 7.1 Hz, 1H), 2.74 (ddd, J ) 14.0,
8.4, 5.4 Hz, 1H), 2.58 (ddd, J ) 17.3, 10.4, 7.1 Hz, 1H), 2.36 (ddd,
J ) 17.1, 10.6, 5.2 Hz, 1H), 2.17 (m, 1H), 2.05 (m, 2H), 1.86 (m,
1H), 1.59 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 174.9, 137.6,
127.7, 116.0, 115.1, 66.9, 40.2, 31.1, 29.4, 26.1, 24.7; HRMS
(ESI+) calcd for C11H17INO [M + H]+ 306.0349, found 306.0344.
Ethyl 3-((S)-5-Oxo-1-(pent-4-enyl)pyrrolidin-2-yl)but-3-enoate
(10). To a solution of vinyliodide 3 (102.0 mg, 0.334 mmol) and
Pd(PPh3)4 (38.6 mg, 0.0334 mmol) in THF/DMPU (3:1, 5.5 mL)
was added Reformatsky reagent 9 (1.240 mL, 0.668 mmol, c <
0.54 M)6 at 50 °C. The resultant mixture was stirred at 50 °C for
50 min and then quenched with saturated NH4Cl (2 mL) and poured
into Et2O/H2O. The phases were separated, and the aqueous layer
was extracted twice with Et2O. The combined organic extracts were
washed with H2O, dried (MgSO4), and concentrated under reduced
pressure. Flash chromatography (pentane/EtOAc 1:1) of the residue
gave 10 (69.7 mg, 78%) as a clear oil: [R]20D 22.3 (c 0.4, CHCl3);
D
IR (film) 2955, 1671, 1422, 1112 cm-1
;
1H NMR (500 MHz,
CDCl3) δ 5.80 (tdd, J ) 16.9, 10.2, 6.6 Hz, 1H), 4.98 (m, 2H),
3.62 (m, 4H), 3.00 (ddd, J ) 13.9, 8.9, 5.2 Hz, 1H), 2.43 (ddd, J
) 17.3, 9.5, 8.0 Hz, 1H), 2.28 (ddd, J ) 16.8, 10.2, 4.9 Hz, 1H),
2.05 (m, 3H), 1.81 (m, 1H), 1.68 (m, 1H), 1.57 (m, 1H), 0.87 (s,
9H), 0.04 (d, J ) 2.9 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
175.4, 137.8, 115.0, 64.1, 59.1, 40.5, 31.1, 30.4, 26.6, 25.8, 21.5,
18.1, -5.6; HRMS (ESI+) calcd for C16H32NO2Si [M + H]+
298.2197, found 298.2208.
To a solution of the crude lactam (1.317 g) in THF (20 mL)
was added TBAF (1.340 g, 4.25 mmol) in one portion at 0 °C.
The resultant mixture was stirred at 0 °C for 1 h and then
concentrated under reduced pressure. Flash chromatography (EtOAc
f EtOAc + 4% MeOH) of the residue gave 7 (650 mg, 92% from
6) as a clear oil: [R]20 15.0 (c 0.3, CHCl3); IR (film) 3344 (br),
D
2931, 1664, 1422, 1150 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.81
(tdd, J ) 16.9, 10.2, 6.6 Hz, 1H), 5.01 (m, 2H), 3.79 (m, 1H), 3.70
(td, J ) 13.0, 4.3 Hz, 1H), 3.64 (m, 2H), 3.00 (ddd, J ) 14.1, 9.1,
5.1 Hz, 1H), 2.47 (ddd, J ) 17.3, 10.0, 7.3 Hz, 1H), 2.33 (ddd, J
) 17.0, 10.2, 5.4 Hz, 1H), 2.10 (m, 3H), 1.95 (m, 1H), 1.83 (br s,
1H), 1.69 (m, 1H), 1.59 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
175.7, 137.6, 115.2, 63.0, 58.9, 40.4, 31.1, 30.4, 26.6, 21.2; HRMS
(ESI+) calcd for C10H18NO2 [M + H]+ 184.1332, found 184.1335.
IR (film) 1729, 1675, 1522, 1422 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 5.78 (tdd, J ) 16.9, 10.2, 6.6 Hz, 1H), 5.14 (s, 1H), 5.07
(s, 1H), 4.98 (m, 2H), 4.18 (dd, J ) 8.7, 3.7 Hz, 1H), 4.15 (q, J )
7.2 Hz, 2H), 3.66 (ddd, J ) 13.7, 8.8, 7.2 Hz, 1H), 3.00 (dd, JABX
) 15.5, 0.6 Hz, 1H), 2.95 (dd, JABX ) 15.5, 0.9 Hz, 1H), 2.72
(ddd, J ) 13.8, 8.5, 5.5 Hz, 1H), 2.44 (m, 1H), 2.33 (ddd, J )
16.9, 9.8, 4.6 Hz, 1H), 2.20 (m, 1H), 2.03 (m, 2H), 1.79 (m, 1H),
1.57 (m, 2H), 1.26 (t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 175.2, 170.8, 140.5, 137.7, 116.0, 114.99, 114.96, 62.2, 61.0,
40.2, 37.5, 31.1, 29.6, 26.2, 23.8, 14.1; HRMS (ESI+) calcd for
C15H24NO3 [M + H]+ 266.1751, found 266.1750.
(S)-5-Ethynyl-1-(pent-4-enyl)pyrrolidin-2-one (5). To a solu-
tion of DMSO (770 µL, 10.85 mmol) in CH2Cl2 (20 mL) was added
oxalyl chloride (480 µL, 5.43 mmol) at -78 °C, and the mixture
was stirred for 20 min. To this mixture was added alcohol 7 (663
mg, 3.62 mmol) in CH2Cl2 (10 mL) at -78 °C, and the resultant
mixture was stirred for 2 h. Freshly distilled Et3N (2.52 mL, 18.09
mmol) was then added. After 1 h, the mixture was allowed to warm
to rt. The reaction was quenched with H2O (6 mL) and brine (6
mL), and the phases were separated. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts were
dried (MgSO4) and concentrated under reduced pressure. The
resultant crude aldehyde was used directly in the next step.
To a solution of crude aldehyde and K2CO3 (1.500 g, 10.85
mmol) in dry MeOH (20 mL) was added phosphonate 8 (1.040 g,
5.43 mmol) in dry MeOH (10 mL) at 0 °C. After the addition was
complete, the mixture was allowed to reach rt. After 1 h at rt, the
reaction mixture was diluted with Et2O (30 mL), H2O (10 mL),
and brine (10 mL), and the phases were separated. The aqueous
layer was extracted twice with Et2O, and the combined organic
â,γ-Unsaturated Ester 2. To a solution of diene 10 (50.0 mg,
0.188 mmol) in CH2Cl2 (37 mL) was added Grubbs’ second
generation catalyst (8.0 mg, 0.0094 mmol) in CH2Cl2 (1 mL) at
reflux. The resultant mixture was refluxed for 3.5 h and then
concentrated under reduced pressure. Flash chromatography (pen-
tane/EtOAc 1:3 f 1:5) of the residue gave 2 (41.3 mg, 92%) as a
clear oil: [R]20D -78.7 (c 1.2, CHCl3); IR (film) 1730, 1681, 1420,
1
1266, 1165 cm-1; H NMR (500 MHz, CDCl3) δ 5.66 (dd, J )
8.4, 5.4 Hz, 1H), 4.21 (dt, J ) 7.5, 1.3 Hz, 1H), 4.13 (dq, J ) 7.1,
1.2 Hz, 2H), 4.04 (ddd, J ) 13.7, 8.0, 3.7 Hz, 1H), 2.96 (m, 3H),
2.40 (m, 2H), 2.27 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1H), 1.71 (m,
(14) Commercial grade, freshly opened bottle.
4248 J. Org. Chem., Vol. 72, No. 11, 2007

1H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
174.5, 171.4, 134.4, 129.0, 63.5, 60.8, 40.8, 39.4, 30.4, 25.6, 24.8,
22.7, 14.2; HRMS (ESI+) calcd for C13H20NO3 [M + H]+
238.1438, found 238.1442.
Butenolide 12. To a solution of ester 2 (110 mg, 0.463 mmol)
in THF/MeOH/H2O (18 mL, 2:1:1) was added LiOH‚H2O (39 mg,
0.927 mmol). The resultant mixture was stirred for 2 h at rt and
then acidified with HCl (5.5 mL, 1 M) and extracted five times
with EtOAc. The combined organic extracts were dried (MgSO4)
and concentrated under reduced pressure to give the crude acid
(106 mg) as a white solid, which was used directly in the next
step.
concentrated under reduced pressure. Flash chromatography (2 f
4% MeOH in CH2Cl2) of the residue gave 13 (21.7 mg, 90%) as a
clear oil: [R]20 -94.0 (c 0.4, CHCl3) [lit. [R]25 -144 (c 1.0,
D
D
CHCl3)2e]; H NMR (500 MHz, CDCl3) δ 4.29 (dt, J ) 10.2, 3.0
Hz, 1H), 4.16 (m, 1H), 3.99 (td, J ) 10.6, 6.4 Hz, 1H), 2.85 (m,
1H), 2.68 (m, 1H), 2.65 (dd, J ) 17.4, 8.8 Hz, 1H), 2.51 (dd, J )
17.3, 12.7 Hz, 1H), 2.45-2.35 (m, 3H), 2.07 (m, 1H), 1.91-1.85
(m, 1H), 1.71 (quint, J ) 10.7 Hz, 1H), 1.59-1.53 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 174.6, 174.0, 79.8, 56.0, 44.9, 40.2,
34.6, 31.0, 30.6, 25.5, 22.7.
1
(-)-Stemoamide (1). To a solution of lactone 13 (8.2 mg, 39.2
µmol) in THF (0.5 mL) was added LiHMDS (43 µL, 43.1 µmol,
1.0 M in toluene) at -78 °C. After 10 min, the reaction flask was
placed in a 0 °C ice bath for 5 min and then recooled to -78 °C.
MeI (12.2 µL, 196 µmol) was added, and stirring was continued
for 3 h at -78 °C after which the mixture was allowed to reach rt.
The reaction was quenched with saturated NH4Cl (0.5 mL),
extracted four times with EtOAc, dried (MgSO4), and concentrated
under reduced pressure. Flash chromatography (3% MeOH in CH2-
Cl2) of the residue gave 1 (6.8 mg, 78%) as a white solid: mp
182-183 °C; [R]20D -141 (c 0.3, MeOH) [lit. [R]26D -141 (c 0.19,
MeOH),2a [R]26 -181 (c 0.89, MeOH),2a [R]30 -219.3 (c 0.5,
To a solution of the crude acid (106 mg) in CHCl3 (46 mL) was
added CuBr2 on Al2O3 (1.570 g, 2.315 mmol).15 The resultant
heterogeneous solution was heated to 65 °C in a preheated oil bath
for 4 h. The reaction mixture was then cooled to rt, Et3N (320 µL,
2.315 mmol) was added, and the stirring was continued for 3 h.
The reaction mixture was filtered, and the solid was washed with
MeOH followed by concentration of the filtrate under reduced
pressure. The residue was dissolved in water and extracted five
times with EtOAc, dried (MgSO4), and concentrated. Flash chro-
matography (4% MeOH in CH2Cl2) of the residue gave 12 (62 mg,
65% from 2) as a white solid: mp 157-158 °C; [R]20D -224.0 (c
D
D
MeOH),2b [R]25 -183.5 (c 1.36, MeOH),2c [R]25 -187 (c 0.5,
D
D
0.4, CHCl3); IR (film) 2930, 1756, 1689, 1522, 1429 cm-1; H
MeOH)2f]; H NMR (500 MHz, CDCl3) δ 4.18 (m, 2H), 3.99 (dt,
J ) 10.8, 6.4 Hz, 1H), 2.69-2.56 (m, 2H), 2.45-2.38 (m, 4H),
2.08-2.02 (m, 1H), 1.89-1.84 (m, 1H), 1.71 (dq, J ) 12.2, 10.7
Hz, 1H), 1.59-1.50 (m, 2H), 1.31 (d, J ) 6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 177.3, 174.0, 77.6, 55.8, 52.7, 40.2, 37.3,
34.8, 30.6, 25.6, 22.6, 14.1.
1
1
NMR (500 MHz, CDCl3) δ 5.95 (t, J ) 1.4 Hz, 1H), 4.99 (m,
1H), 4.77 (tt, J ) 8.1, 1.2 Hz, 1H), 4.27 (m, 1H), 2.48 (m, 5H),
1.85 (m, 2H), 1.69 (m, 1H), 1.41 (ddt, J ) 13.4, 11.8, 3.5, Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 174.5, 174.0, 171.6, 115.8,
82.8, 58.1, 43.3, 34.4, 30.1, 27.6, 25.6; HRMS (FAB+) calcd for
C11H14NO3 [M + H]+ 208.0968, found 208.0972.
Lactone 13. To a solution of butenolide 12 (24.0 mg, 116 µmol)
in MeOH (2.0 mL) was added NiCl2‚6H2O (6.9 mg, 29 µmol)
followed by NaBH4 (17.5 mg, 463 µmol) at -30 °C. After 3 h, the
solution was quenched with HCl (1.0 mL, 1 M) and diluted with
CH2Cl2 (3 mL). The phases were separated, and the aqueous layer
was extracted three times with CH2Cl2, dried (MgSO4), and
Acknowledgment. This work was financially supported by
AstraZeneca So¨derta¨lje, the Swedish Research Council, and the
Knut and Alice Wallenberg Foundation.
Supporting Information Available: General experimental
procedures and 1H and 13C NMR spectra for compounds 1-3, 5-7,
10, 12, and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) For the preparation of CuBr2 on Al2O3, see: Kodomari, M.; Satoh,
H.; Yoshitomi, S. Bull. Chem. Soc. Jpn. 1988, 61, 4149-4150.
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