Total synthesis of (-)-senepodine G and (-)-cermizine C

Article abstract of DOI:10.1021/jo062067w

(Chemical Equation Presented) An efficient, stereospecific synthesis of the alkaloids senepodine G (2) and cermizine C (1) has been completed using the BF₃·Et₂O-promoted stereospecific addition of Me₂CuLi to α,β-unsaturated lactam 6 to provide lactam 3, the addition of MeMgBr followed by HCl to convert 3 to senepodine G (2) (six steps, 40% overall yield), and the stereospecific NaBH₄ reduction of 2 to give cermizine C (1) (seven steps, 40% overall yield).

Full text of DOI:10.1021/jo062067w

Total Synthesis of (-)-Senepodine G and
-)-Cermizine C
SCHEME 1. Retrosynthesis of Cermizine C (1) and
Senepodine G (2)
(
Barry B. Snider* and James F. Grabowski
Department of Chemistry, MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
ReceiVed October 5, 2006
5, which would cyclize to form lactam 3. Alternatively, it might
be possible to add methylcuprate stereospecifically to unsatur-
ated lactam 6.
Knoevenagel condensations between a ketone and a â-dicar-
bonyl compound are typically carried out using an ammonium
acetate catalyst. Because (()-pelletierine (7) contains a second-
An efficient, stereospecific synthesis of the alkaloids sene-
podine G (2) and cermizine C (1) has been completed using
5
ary amine, we treated it with 1 equiv of AcOH to form the
acetate salt. Heating this salt with 2.4 equiv of Meldrum’s acid
in EtOH required 2 days at 60 °C for the complete consumption
of the pelletierine. To our surprise, we did not isolate 4, but
rather the â,γ-unsaturated lactam 11 in 68% yield. Equilibration
of 11 with K2CO3 in MeOH for 1 day afforded a 3:1 mixture
of R,â-unsaturated lactam 13 and â,γ-unsaturated lactam 11.
Treatment of pure 13 with K2CO3 and MeOH afforded the
identical 3:1 mixture indicating that equilibrium had been
reached. Although R,â-unsaturated carbonyl compounds are
usually much more stable than their â,γ-unsaturated isomers,
there are examples of unsaturated amides in which significant
amounts of both isomers are present at equilibrium.6 Ban
prepared 13 by treatment of N-acetylpelletierine with triethy-
loxonium tetrafluoroborate in CH Cl and then treatment of the
the BF
3
2 2
‚Et O-promoted stereospecific addition of Me CuLi
to R,â-unsaturated lactam 6 to provide lactam 3, the addition
of MeMgBr followed by HCl to convert 3 to senepodine G
(
2) (six steps, 40% overall yield), and the stereospecific
NaBH reduction of 2 to give cermizine C (1) (seven steps,
0% overall yield).
4
4
Kobayashi recently reported the isolation of the lycopodium
alkaloid cermizine C (1) from the club moss Lycopodium
cernuum and the related alkaloid senepodine G (2) from the
1
-3
club moss Lycopodium chinense (see Scheme 1).
The
structures were elucidated by 1D and 2D NMR spectroscopic
methods. Senepodine G (2) is cytotoxic to murine lymphoma
L1210 cells with an IC50 of 7.8 µg/mL. The absolute config-
uration of other co-occurring more complex natural products
was assigned by modified Mosher’s method suggesting that the
absolute configurations of 1 and 2 are as drawn.
2
2
7
resulting intermediate with t-BuOK in t-BuOH. These condi-
tions presumably led to the same 3:1 equilibrium mixture of
13 and 11 that we observed.
Presumably, the Knoevenagel condensation of 7 and Mel-
drum’s acid occurred to give 4, which cyclized readily to give
the conjugated lactam acid 8. Equilibration afforded the un-
conjugated isomer 9, which decarboxylated to give enol 10.
Kinetic protonation of 10 on the R-carbon formed the â,γ-
unsaturated lactam 11. These reaction conditions, with the amine
neutralized as the acetate salt, are mild enough to prevent
equilibration to give R,â-unsaturated lactam 13.
Hydrogenation of either 11 or the 3:1 mixture of 11 and 13
over PtO2 in EtOH at 50 psi of H2 for 6 h as described by Ban
afforded a 16:1 mixture of lactams 12 and 3 in 96% yield.
Addition of MeMgBr (4 equiv) in THF to 12 at 60 °C for 2.5
h followed by addition of 3 M HCl in MeOH afforded (()-7-
epi-senepodine G (14) in 100% yield (Scheme 2). A similar
reaction at 25 °C gave 14 in 76% yield. Reduction of 14 with
NaBH4 in MeOH at 25 °C for 10 min occurred stereospecifically
We set out to synthesize these novel alkaloids as a means of
developing chemistry that might be useful for more complex
members of these families. We thought that it should be possible
to prepare cermizine C (1) from senepodine G (2) by reduction
of the iminium cation with NaBH4. Although similar reductions
2
b,4
are known,
the stereoselectivity of this reduction is
uncertain because steric interactions with the methyl group
should direct hydride attack from the bottom face, whereas
steric interactions with the right-hand ring should direct hydride
attack from the top face. Iminium cation 2 can be prepared by
addition of MeMgBr to lactam 3 followed by treatment with
HCl. We conceived of two approaches to lactam 3. We hoped
that it might be possible to carry out a directed conjugate
reduction of unsaturated Meldrum’s acid derivative 4 to give
(
1) Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
004, 60, 7015-7023.
2) For the isolation of other members of these families, see: (a) Morita,
H.; Hirasawa, Y.; Yoshida, N.; Kobayashi, J. Tetrahedron Lett. 2001, 42,
by axial attack from the less-hindered top face to provide (()-
2
8
5
-epi-cermizine C (15) in 82% yield. The stereochemistry of
(
4
5
2
199-4201. (b) Hirasawa, Y.; Morita, H.; Kobayashi, J. Tetrahedron 2003,
9, 3567-3573. (c) Hirasawa, Y.; Morita, H.; Kobayashi, J. Heterocycles
004, 64, 515-521.
(5) Quick, J.; Oterson, R. Synthesis 1976, 745-746.
(6) (a) Meghani, P.; Joule, J. A. J. Chem. Soc., Perkins Trans. 1 1988,
1-8. (b) Janecki, T.; Bodalski, R.; Wieczorek, M.; Bujacz, G. Tetrahedron
(
3) For a review of lycopodium alkaloids, see: Ma, X.; Gang, D. R.
1995, 51, 1721-1740.
Nat. Prod. Rep. 2004, 21, 752-772.
4) Bohlmann, F.; Winterfeldt, E.; Boroschewski, G.; Mayer-Mader, R.;
Gatscheff, B. Chem. Ber. 1963, 96, 1792-1800.
(7) (a) Ban, Y.; Kimura, M.; Oishi, T. Heterocycles 1974, 2, 323-328.
(b) Ban, Y.; Kimura, M.; Oishi, T. Chem. Pharm. Bull. 1976, 24, 1490-
1496.
(
1
0.1021/jo062067w CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/04/2007
J. Org. Chem. 2007, 72, 1039-1042
1039

SCHEME 2. Synthesis of 5-epi-Cermizine C (15) and
-epi-Senepodine G (14)
SCHEME 3. Synthesis of Cermizine C (1) and
Senepodine G (2)
7
1
2 in 77% yield. Addition of MeMgBr (4 equiv) to 3 in
THF at 60 °C for 2.5 h followed by addition of 3 M HCl in
MeOH afforded a 98% yield of (-)-senepodine G (2), with1
spectral data identical to those reported for the natural product.
Lactam 3 was recovered unchanged from treatment with
MeMgBr at 25 °C, although the epimeric lactam 12 was
converted to 14 in 76% yield under these conditions. Presum-
ably, the methyl group blocks the convex face of 3. The methyl
group of 12 is on the concave face making the top, convex face
less hindered so that addition of MeMgBr occurs under milder
conditions.
1
5 was established by NOE studies (see Supporting Information)
permitting the assignment of the stereochemistry of the major
lactam as 12, not 3.
Because we could not isolate 4 and explore the directed
conjugate reduction to give 5, we turned our attention to the
alternate route to senepodine G starting with unsaturated lactam
6
. Batey prepared amide alcohol 17 by protection of 2-pip-
eridineethanol (16) with TBDMSCl, acylation, and deprotec-
9
10
Reduction of 2 with NaBH4 in MeOH at 25 °C for 10 min
provided (-)-cermizine C (1), which was isolated as its
tion. We found that reaction of (S)-16 with 3 equiv of
diethoxyphosphoryl)acetyl chloride11 and 3.1 equiv of Et(i-
(
8
hydrochloride salt in 82% yield. The spectral data for cermizine
Pr)2N in THF afforded the crude ester amide. The ester was
selectively hydrolyzed with K2CO3 in EtOH at 60 °C for 4.5 h
to provide amide alcohol 17 in 81% yield (see Scheme 3).
Dess-Martin oxidation (79% yield) and intramolecular Horner-
Wadsworth-Emmons Wittig reaction (80% yield) as described
hydrochloride (1) are identical to those reported for the
1
natural product, which was isolated in minute amounts (2.2
mg) and not indicated to be the protonated form. Hydride
addition to 2 took place stereospecifically by axial attack
from the bottom face. Apparently the directing effect of the
methyl group is greater than that of the right-hand ring (see
Figure 1).
9
by Batey provided a practical route to optically pure R,â-
unsaturated lactam (S)-6.
Conjugate addition of Me2CuLi promoted by BF3‚Et2O12
occurred selectively by axial attack from the less-hindered top
face to give a > 99:1 mixture of the desired lactam 3 and the
epimeric lactam 12 in 80% yield. A similar addition of
Me2CuLi promoted by TMSCl13 gave a 14:1 mixture of 3 and
(
8) In 1935, Ochiai reported the addition of MeMgI to 12 or its
FIGURE 1. Stable conformations of 5-epi-cermizine C (15), cermizine
C (1), and senepodine G (2).
diastereomer, followed by high-pressure hydrogenation to give 14 or a
diastereomer: Ochiai, E.; Tsuda, K.; Yokoyama, J. Chem. Ber. 1935, 68,
2
291-2298. For a related conversion of a lactam to a methyl quinolizidine
Neutralization of the hydrochloride salt of 1 gave the free
amine, which is not stable in air. On the other hand, the free
base of 5-epi-cermizine C (15) is stable in air. The stable
conformation of 5-epi-cermizine C (15) is a trans-quinolizidine,
with MeMgBr and NaBH3CN, see: Comins, D. L.; Zheng, Z.; Goehring,
R. R. Org. Lett. 2002, 4, 1611-1613.
(9) (a) Grzyb, J. A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7485-
7
488. (b) Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.;
Batey, R. A. Tetrahedron 2005, 61, 7153-7175.
10) (a) Toy, M. S.; Price, C. C. J. Am. Chem. Soc. 1960, 82, 2613-
616. (b) Beyerman, H. C.; Van Den Bosch, S.; Breuker, J. H.; Maat, L.
-
1
as indicated by a Bohlmann band at 2783 cm , while the most
(
2
stable conformation of cermizine C (1) was shown to be a cis-
Recl. TraV. Chim. Pays-Bas 1971, 90, 755-764. (c) Craig, J. C.; Lee, S.-
Y. C.; Pereira, W. E., Jr.; Beyerman, H. C.; Maat, L. Tetrahedron 1978,
3
1
quinolizidine by Kobayashi (see Figure 1). cis-Quinolizidines
have been reported to react with air to give N-oxides more
4, 501-504.
11) Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6,
477-3480.
12) (a) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.;
(
3
(13) (a) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I.
Tetrahedron 1989, 45, 349-362. (b) Nakamura, E.; Yamanaka, M.; Mori,
S. J. Am. Chem. Soc. 2000, 122, 1826-1827. (c) Alexakis, A.; Berlan, J.;
Besace, Y. Tetrahedron Lett. 1986, 27, 1047-1050.
(
Maruyama, K. J. Org. Chem. 1982, 47, 119-126. (b) Smith, A. B., III;
Jerris, P. J. J. Am. Chem. Soc. 1981, 103, 194-195.
1
040 J. Org. Chem., Vol. 72, No. 3, 2007

readily than trans-quinolizidines.14 Quinolizidines are also
The spectral data for 12 were determined from the mixture: 1
H
known to readily scavenge carbon dioxide from the air to form
NMR 4.76 (br d, 1, J ) 13.8), 3.17 (dddd, 1, J ) 11.0, 11.0, 6.7,
bicarbonate salts.15
2.5), 2.45 (ddd, 1, J ) 16.4, 3.4, 3.4), 2.39 (br dd, 1, J ) 13.8,
1
(
2
2.8), 1.98-1.66 (m, 6), 1.46-1.30 (m, 2), 1.26-1.10 (m, 2), 0.97
The optical rotation of synthetic senepodine G (2), [R]D -77,
d, 3, J ) 6.1); 13C NMR 169.4, 56.6, 41.8, 41.1, 39.5, 34.5, 26.4,
5.3, 24.2, 21.2; IR (neat) 1643. The spectral data match those
1
has the same sign as that of natural senepodine G, [R]D -35,
suggesting that the natural product has the absolute configuration
shown. The difference in magnitude may result from errors
resulting from the small amount (1 mg) of the natural product
available. The optical rotation of synthetic cermizine C (1),
7
previously reported for 12.
,6,7,8,9,9a-Hexahydro-2-methyl-(4H)-quinolizin-4-one (13).
CO (293 mg, 2.12 mmol) was added to a solution of 11 (35
1
K
2
3
mg, 0.21 mmol) in MeOH (2 mL), and the resulting suspension
was stirred at 25 °C for 22 h. The suspension was filtered through
Celite and MgSO , and the resulting solution was concentrated
4
[
[
R]D -2, has the opposite sign as that of natural cermizine C,
1
R]D +4. However, Kobayashi indicated that the [R]D value
of cermizine C is not reliable due to the small amount of sample
and the small value of the optical rotation. It is most likely that
cermizine C has the same absolute configuration as senepodine
G, although this need not be the case because they were isolated
from different Lycopodium species. Because of the low value,
the [R]D of cermizine C is not very useful. We have therefore
provided the CD spectra of synthetic senepodine G (2) and
cermizine C (1) from 200 to 400 nm in the Supporting
Information. These data may be more useful for comparison
purposes.
under reduced pressure to give 35 mg of a 3:1 mixture of 13
and 11. Flash chromatography on silica gel (EtOAc) yielded
3 mg of 13, followed by 29 mg of a 3:1 mixture of 13 and 11, and
1 mg of 11.
1
Data for 13: H NMR 5.69 (s, 1), 4.48 (br d, 1, J ) 13.0), 3.42-
3.35 (m, 1), 2.50 (br dd, 1, J ) 13.0, 12.6), 2.37 (dd, 1, J ) 17.4,
6.1), 2.15 (br dd, 1, J ) 17.4, 9.8), 1.90-1.65 (m, 3), 1.86 (s, 3),
1.55-1.35 (m, 3); 13C NMR 166.3, 149.0, 120.0, 54.6, 42.7, 36.3,
33.4, 24.8, 23.9, 22.7; IR (neat) 1674, 1612. The spectral data match
those previously reported.7
K
2
CO
1 mg, 0.006 mmol) in MeOH (1 mL), and the resulting suspension
was stirred at 25 °C for 22 h. The suspension was filtered through
Celite and MgSO , and the resulting solution was concentrated
3
(8 mg, 0.06 mmol) was added to a solution of 13
In conclusion, we have developed an efficient, stereospecific
synthesis of the alkaloids senepodine G (2) and cermizine C
(
(
1) using the BF3‚Et2O-promoted stereospecific addition of Me2-
4
CuLi to R,â-unsaturated lactam 6 to give lactam 3, the addition
of MeMgBr followed by HCl to convert 3 to senepodine G (2)
under reduced pressure to give 1 mg of a 3:1 mixture of 13
and 11.
(six steps, 40% overall yield), and the stereospecific NaBH4
7-epi-Senepodine G Chloride (14). A 1.4 M solution of
reduction of 2 to give cermizine C (1) (seven steps, 40% overall
yield).
MeMgBr in 3:1 toluene/THF (0.84 mL, 1.2 mmol) was added
dropwise to a solution of 12 (49 mg, 0.29 mmol) in dry THF (4
mL), and the resulting solution was stirred at 60 °C for 2.5 h. The
solution was allowed to cool. MeOH (5 mL) was added, and the
resulting solution was concentrated under reduced pressure. HCl
(3 M) in MeOH (2 mL) was added, and the resulting solution was
concentrated under reduced pressure. Flash chromatography on
Experimental Section
3,6,7,8,9,9a-Hexahydro-2-methyl-(4H)-quinolizin-4-one (11).
Meldrum’s acid (778 mg, 5.40 mmol) and AcOH (0.26 mL, 4.5
mmol) were added in succession to a solution of pelletierine (7)5
(
636 mg, 4.50 mmol) in EtOH (5 mL), and the resulting clear
silica gel (70:29:1 CH
mg (100%) of 14 as a clear wax: H NMR (CD OD) 4.51 (br d,
2 2
Cl /MeOH/3 M HCl in MeOH) yielded 59
1
solution was heated to 60 °C and stirred for 1 day. The yellow
3
solution was allowed to cool; an aliquot was concentrated under
reduced pressure, and the H NMR spectrum indicated that there
1, J ) 12.5), 3.95-3.80 (m, 1), 3.43 (br dd, 1, J ) 12.5, 12.2),
2.94 (br d, 1, J ) 20.8), 2.58-2.40 (m, 1), 2.47 (s, 3), 2.20-2.10
(m, 2), 2.06-1.68 (m, 5), 1.57 (dddd, 1, J ) 12.2, 12.2, 12.2, 4.3),
1
was a 3:1 mixture of 11 and 7 and that no Meldrum’s acid remained.
Meldrum’s acid (778 mg, 5.40 mmol) was added to the yellow
solution, and the resulting solution was heated to 60 °C and stirred
for 1 day. The EtOH was removed under reduced pressure, and
the resulting yellowish liquid was diluted with EtOAc (30 mL).
1
3
1.36 (ddd, 1, J ) 12.4, 12.4, 12.4), 1.04 (d, 3, J ) 6.7); C NMR
(CD OD) 188.8, 64.3, 54.6, 44.1, 38.5, 34.9, 26.1, 24.6, 24.1, 23.6,
3
+
20.4; HRMS (EI) calcd for C11
H20N (M ) 166.1596, found
166.1599.
The resulting solution was washed with a saturated Na
2
CO
3
solution
5-epi-Cermizine C (15). NaBH (4 mg, 0.104 mmol) was added
to a solution of 14 (19 mg, 0.094 mmol) in MeOH (4 mL), and the
4
(
6 mL), dried over MgSO , and concentrated under reduced pressure
4
to give 638 mg of a yellowish liquid. Flash chromatography on
resulting suspension was stirred at 25 °C for 10 min. AcOH
(∼2 drops) was then added, and the resulting solution was
concentrated under reduced pressure. The residue was diluted with
a 3:1 H O/saturated Na CO solution (4 mL), and the resulting
1
silica gel (EtOAc) yielded 503 mg (68%) of 11: H NMR 5.30 (br
s, 1), 4.85 (ddd, 1, J ) 12.5, 2.4, 2.4), 3.75 (br d, 1, J ) 11.0),
2
1
1
1
1
1
.86 (br d, 1, J ) 20.8), 2.83 (br d, 1, J ) 20.8), 2.46 (ddd, 1, J )
2.8, 12.5, 2.5), 1.92-1.78 (m, 3), 1.70 (s, 3), 1.58-1.35 (m, 2),
.23 (dddd, 1, J ) 12.2, 12.2, 11.0, 3.7); 13C NMR 166.0, 128.9,
2
2
3
aqueous solution was extracted with EtOAc (3 × 10 mL). The
combined extracts were dried over MgSO and concentrated under
4
1
20.1, 58.2, 42.1, 36.3, 34.3, 25.3, 24.7, 21.8; IR (neat)
reduced pressure to give 13 mg (82%) of 15 as a clear oil: H
+
644; HRMS (ES) calcd for C10
66.1228.
H
16NO (MH ) 166.1232, found
NMR (CD OD) 3.35-3.27 (m, 1), 2.20-2.10 (m, 1), 2.02-1.92
3
(m, 1), 1.84 (br dd, 1, J ) 11.9, 11.9), 1.76-1.50 (m, 6), 1.40-
(
2S*,5R)-2-Octahydro-2-methyl-(4H)-quinolizin-4-one (12).
PtO (8 mg, 0.03 mmol) was added to a solution of 11 (440 mg,
.66 mmol) in EtOH (4 mL), and the resulting suspension was
shaken under 50 psi of H for 6 h. The catalyst was removed by
1.25 (m, 2), 1.14-0.88 (m, 3), 1.12 (d, 3, J ) 6.1), 0.90 (d, 3, J )
6.1); 13C NMR (CD
OD) 64.4, 62.1, 52.5, 43.9, 42.6, 33.8, 31.4,
2
3
2
26.4, 24.9, 22.1, 19.8; IR (neat) 2926, 2783; HRMS (ES) calcd for
+
11
C H
22N (MH ) 168.1752, found 168.1752. TFA (excess) was
added to a solution of 5 in CD OD) 3.79 (br
OD: 1H NMR (CD
d, 1, J ) 12.5, H1eq), 3.21-3.10 (m, 1, H ), 3.06 (br dd, 1, J )
11.3, 11.3, H ), 2.74 (ddd, 1, J ) 12.8, 12.5, 2.5, H1ax), 2.15-1.65
m, 7, contains H ), 1.62-1.48 (m, 2), 1.40-1.24 (m, 2), 1.37 (d,
, J ) 6.7), 0.98 (d, 3, J ) 6.1).
Diethoxyphosphoryl)acetyl Chloride. (Diethoxyphosphoryl)-
2
filtration through Celite, and the resulting solution was concentrated
under reduced pressure to give 425 mg (96%) of a 16:1 mixture of
3
3
9
12 and 3 as a clear liquid.
5
(
3
7
(
14) Nizamkhodzhaeva, A. N.; Ishbaev, A. I.; Aslanov, Kh. A.;
Mukhamedzhanov, S. Z. Chem. Abstr. 1978, 88, 121499v.
15) Moynehan, T. M.; Schofield, K.; Jones, R. A. Y.; Katritzky, A. R.
J. Chem. Soc. 1962, 2637-2658.
(
(
acetic acid (3.001 g, 15.3 mmol) was added dropwise to thionyl
chloride (3 mL), and the resulting solution was stirred at 25 °C
J. Org. Chem, Vol. 72, No. 3, 2007 1041

for 1.75 h and concentrated under reduced pressure (<20 °C) to
give (diethoxyphosphoryl)acetyl chloride which was used without
further purification. The spectral data matched those previously
reported.11
were dried over MgSO
under reduced pressure to give 456 mg of a yellow amorphous solid.
Flash chromatography on silica gel (49:1 to 23:1 CH Cl /MeOH)
-21 (c 1.0, CHCl
4
. The resulting solution was concentrated
2
2
23
1
gave 215 mg (80%) of 3 as an oil: [R]
D
3
); H
NMR 4.76 (dddd, 1, J ) 13.1, 4.0, 2.0, 2.0), 3.37-3.29 (m, 1),
Diethyl{2-[(2S)-2-(2-hydroxyethyl)piperidin-1-yl]-2-oxoethyl}-
phosphonate (17). A solution of (diethoxyphosphoryl)acetyl
chloride (3.283 g, 15.3 mmol) in dry THF (6 mL) was added
2
2
.46 (br d, 1, J ) 16.5), 2.41 (ddd, 1, J ) 13.1, 12.8, 3.0), 2.11-
.00 (m, 1), 1.97 (dd, 1, J ) 16.5, 9.2), 1.92-1.84 (m, 1), 1.72-
13
dropwise to a solution of (S)-2-piperdineethanol10b (659 mg, 5.10
1.32 (m, 7), 0.98 (d, 3, J ) 6.1); C NMR 168.5, 55.5, 43.0, 40.6,
36.8, 33.6, 25.4, 25.0, 24.4, 20.4; IR (neat) 1639; HRMS (EI) calcd
mmol) in dry THF at 0 °C. (The detailed procedure for the
resolution of 2-piperidineethanol is provided in the Supporting
+
for C10H17NO (M ) 167.1310, found 167.1313.
Information.) EtN(i-Pr)
2
(2.8 mL, 16 mmol) was added dropwise
Alternatively, TMSCl was used to promote the conjugate addition
to the yellow suspension, and the resulting dark orange suspension
according to the following procedure: 1.6 M MeLi in Et O (0.35
2
was stirred at 0 °C for 1 h. The suspension was allowed to warm
mL, 0.56 mmol) was added dropwise to a suspension of CuI (56
to 25 °C and was stirred for an additional 1 h. H
added to the suspension, and the aqueous solution was extracted
2
O (50 mL) was
mg, 0.29 mmol) in dry THF (3 mL) at 0 °C, and the resulting
solution was stirred at 0 °C for 30 min. The solution was cooled to
-78 °C, and a solution of 6 (21 mg, 0.14 mmol) and TMSCl (0.035
mL, 0.28 mmol) in dry THF (2 mL) was added dropwise. The
resulting solution was allowed to warm to 25 °C over 1 h. Saturated
with EtOAc (4 × 120 mL). The combined extracts were dried over
4
MgSO and concentrated under reduced pressure to yield 3 g of
the crude ester amide as a yellowish liquid, which was used without
purification.
NH Cl solution (5 mL) was added, and the layers were separated.
4
K
2
CO
3
(3.524 g, 25.5 mmol) was added to a solution of crude
The aqueous layer was extracted with EtOAc (3 × 10 mL), and
ester amide (3 g) in dry EtOH (40 mL), and the resulting suspension
was heated to 60 °C and stirred for 4.5 h. The suspension was
allowed to cool, and excess EtOH was removed under reduced
pressure. The residue was diluted in EtOAc (100 mL), and the
suspension was filtered through Celite. The resulting solution was
concentrated under reduced pressure to give 3 g of a dark yellow
oil. Flash chromatography on silica gel (39:1 to 23:2 CH
MeOH) yielded 1.264 g (81% from (S)-2-piperdineethanol) of 17
as a light yellow oil: [R]
941, 1624, 1450, 1248; HRMS (ES) calcd for C13H27NO P (MH )
08.1627, found 308.1638; the H NMR and C NMR
spectra indicated a complex mixture of amide rotamers that match
those previously reported and are available in the Supporting
Information.
Diethyl {2-Oxo-2-[(2S)-2-(2-oxoethyl)piperidin-1-yl]ethyl} Phos-
phonate. Dess-Martin reagent (840 mg, 1.98 mmol) was added
to a solution of 17 (484 mg, 1.58 mmol) in dry CH Cl (15 mL),
2 2
2 4
the combined extracts were dried over Na SO . The resulting
solution was concentrated under reduced pressure to give 30 mg
of a yellow amorphous solid. Flash chromatography on silica gel
(49:1 to 24:1 CH
2 2
Cl /MeOH) gave 18 mg (77%) of a 14:1 mixture
of 3 and 12 as an oil.
Senepodine G Chloride (2). MeMgBr (1.4 M) in 3:1 toluene/
THF (0.36 mL, 0.50 mmol) was added dropwise to 3 (21 mg, 0.13
mmol) in dry THF (4 mL), and the resulting solution was heated
to 60 °C for 2.5 h. The solution was allowed to cool. MeOH
(5 mL) was added, and the resulting solution was concentrated
under reduced pressure. HCl (3 M) in MeOH (2 mL) was added,
and the resulting solution was concentrated under reduced
pressure. Flash chromatography on silica gel (70:29:1 CH Cl /
2 2
Cl /
23
D
-29 (c 1.0, CHCl
3
); IR (neat) 3424,
+
2
3
5
13
1
9
2
2
MeOH/3 M HCl in MeOH) yielded 25 mg (98%) of 2 as a clear
2
3
1
26
wax: [R]
D
-77 (c 1.0, MeOH), lit. [R]
H NMR (CD OD) 4.51 (br d, 1, J ) 12.8), 4.25-3.93 (m, 1),
3.55 (br dd, 1, J ) 12.8, 12.8), 3.01 (dd, 1, J ) 20.7, 4.3), 2.55-
D
-35 (c 0.3, MeOH);
1
3
1
3
and the resulting suspension was stirred for 15 h at 25 °C. The
suspension was filtered through Celite and K CO , and the
resulting solution was concentrated under reduced pressure to give
.314 g of a white solid. Flash chromatography on silica gel (49:1
EtOAc/Et N) yielded 383 mg (79%) of the aldehyde as a clear oil:
-22 (c 1.0, CHCl ); the spectral data match those previously
2.42 (m, 1), 2.46 (s, 3), 2.10-1.72 (m, 9), 1.05 (d, 3, J ) 6.7);
NMR (CD OD) 186.9, 64.8, 56.1, 43.9, 35.5, 34.7, 27.6, 24.7, 23.9,
21.9, 20.5; HRMS (EI) calcd for C11
C
2
3
3
+
H
20N (M ) 166.1596, found
1
166.1599. The spectral data match those reported for the natural
product.1
3
23
[
R]
reported.
2S)-1,6,7,8,9,9a-Hexahydro-(4H)-quinolizin-4-one (6). NaH
60% dispersion in oil, 43 mg, 1.1 mmol) was added to a solution
D
3
Cermizine C Hydrochloride (1). NaBH (5 mg, 0.1 mmol) was
4
9
added to a solution of 2 (25 mg, 0.12 mmol) in MeOH (4 mL),
(
and the resulting suspension was stirred at 25 °C for 10 min. HCl
(3 M) in MeOH (1 mL) was added, and the resulting solution was
concentrated under reduced pressure. The residue was diluted with
(
of the above aldehyde (312 mg, 1.02 mmol) in dry THF (20 mL)
at 0 °C, and the resulting suspension was allowed to warm to
3:1 CH
filtered to remove inorganic solids, dried over Na
concentrated under reduced pressure to give 25 mg (99%) of 1 as
2
Cl
2
/MeOH (10 mL), and the resulting suspension was
2
5 °C over 30 min. The orange solution was diluted with H
mL) and CH Cl , and the organic and aqueous layers were
separated. The aqueous layer was extracted with EtOAc (3 × 80
mL), and the combined organic extracts were dried over MgSO
The resulting solution was concentrated under reduced pressure to
give 180 mg of a clear oil. Flash chromatography on silica gel (49:1
2
O (20
2
SO , and
4
2
2
2
3
1
25
a clear wax: [R]
D
-2 (c 0.4, MeOH), lit. [R]
3
D
+4 (c 0.8,
1
4
.
MeOH); H NMR (CD OD) 3.90-3.80 (m, 1), 3.68-3.55 (m, 2),
3.08 (ddd, 1, J ) 13.4, 13.4, 3.0), 2.17 (dddd, 1, J ) 13.4, 13.4,
13.4, 4.3), 2.06-1.54 (m, 9), 1.38-1.20 (m, 1), 1.33 (d, 3, J )
/MeOH) afforded 124 mg (80%) of 6 as a clear oil: [R]23
13
2
CH Cl
2
D
6.1), 0.95 (d, 3, J ) 6.7); C NMR (CD
3
OD) 61.3, 51.2, 49.9,
+
47 (c 1.0, CHCl
3
); the spectral data match those previously
41.7, 38.3, 25.4, 24.6, 23.8, 21.6, 18.4, 17.7; HRMS (EI) calcd for
9
+
reported.
2S,5S)-2-Octahydro-2-methyl-(4H)-quinolizin-4-one (3). MeLi
1.6 M) in Et O (4.0 mL, 6.4 mmol) was added dropwise to a
suspension of CuI (625 mg, 3.28 mmol) in dry THF (20 mL) at
°C, and the resulting solution was stirred at 0 °C for 30 min. The
solution was cooled to -78 °C, and BF ‚OEt (0.41 mL, 3.2 mmol)
11
C H21N (M ) 167.1673, found 167.1674. The spectral data match
those reported for the natural product.
1
(
(
2
Acknowledgment. We thank the NIH (GM50151) for
generous financial support.
0
3
2
was added dropwise. The resulting solution was stirred at -78 °C
for 5 min. A solution of 6 (242 mg, 1.60 mmol) in dry THF (10
mL) was added dropwise, and the resulting solution was allowed
to warm to 25 °C over 20 min. Saturated NH Cl solution (40 mL)
4
was added, and the layers were separated. The aqueous layer was
Supporting Information Available: General procedures, details
1
13
of NOE experiments on 15, and copies of H and C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
extracted with EtOAc (3 × 100 mL), and the combined extracts
JO062067W
1
042 J. Org. Chem., Vol. 72, No. 3, 2007