Stereoselective total syntheses of three Lycopodium alkaloids, (-)-magellanine, (+)-magellaninone, and (+)-paniculatine, based on two Pauson-Khand reactions

Article abstract of DOI:10.1021/jo702136b

(Chemical Equation Presented) The total syntheses of (-)-magellanine, (+)-magellaninone, and (+)-paniculatine were completed from diethyl L-tartrate via the common intermediate in a stereoselective manner. The crucial steps in these syntheses involved two intramolecular Pauson-Khand reactions of enynes: the first Pauson-Khand reaction constructed the bicyclo[4.3.0] carbon framework, the corresponding A and B rings of these alkaloids in a highly stereoselective manner, whereas the second Pauson-Khand reaction stereoselectively produced the bicyclo[3.3.0]skeleton, which could be converted into the C and D rings of the target natural products.

Full text of DOI:10.1021/jo702136b

Stereoselective Total Syntheses of Three Lycopodium Alkaloids,
-)-Magellanine, (+)-Magellaninone, and (+)-Paniculatine, Based on
Two Pauson-Khand Reactions
(
Takashi Kozaka, Naoki Miyakoshi, and Chisato Mukai*
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and Technology,
Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
ReceiVed October 1, 2007
The total syntheses of (-)-magellanine, (+)-magellaninone, and (+)-paniculatine were completed from
diethyl L-tartrate via the common intermediate in a stereoselective manner. The crucial steps in these
syntheses involved two intramolecular Pauson-Khand reactions of enynes: the first Pauson-Khand
reaction constructed the bicyclo[4.3.0] carbon framework, the corresponding A and B rings of these
alkaloids in a highly stereoselective manner, whereas the second Pauson-Khand reaction stereoselectively
produced the bicyclo[3.3.0]skeleton, which could be converted into the C and D rings of the target natural
products.
Introduction
SCHEME 1. Structure of Magellanine (1), Megellaninone
2), and Paniculatine (3)
(
1
2
Three alkaloids, magellanine (1), magellaninone (2), and
paniculatine (3), which have a 6-5-5-6 tetracyclic framework
3
with five to seven stereogenic centers as a common structural
feature, were isolated from Lycopodium paniculatum and
Lycopodium magellanicum in the mid to late 1970s (Scheme
1
). Because of their unique and challenging structures, several
4
studies on the construction of the core tetracyclic skeleton of
these alkaloids have been reported. In 1994, Overman com-
5
pleted the first total synthesis of (-)-magellanine (1) and (+)-
magellaninone (2) possessing contiguous six and five stereogenic
centers, respectively, via a Prins-pinacol rearrangement, whereas
the total synthesis, based on a tandem Michael-Michael addi-
tion, of both alkaloids in a racemic form was accomplished by
(
1) Castillo, M.; Loyola, L. A.; Morales, G.; Singh, I.; Calvo, C.; Holland,
H. L.; MacLean, D. B. Can. J. Chem. 1976, 54, 2893-2899.
2) Loyola, L. A.; Morales, G.; Castillo, M. Phytochemistry 1979, 18,
721-1723.
3) (a) Castillo, M.; Morales, G.; Loyola, L. A.; Singh, I.; Calvo, C.;
(
6
6a
Paquette in the same year. The masked o-benzoquinone
1
7
Diels-Alder protocol enabled Liao to complete the total
(
8
Holland, H. L.; MacLean, D. B. Can. J. Chem. 1975, 53, 2513-2514. (b)
Castillo, M.; Morales, G.; Loyola, L. A.; Singh, I.; Calvo, C.; Holland, H.
L.; MacLean, D. B. Can. J. Chem. 1976, 54, 2900-2908.
synthesis of (()-1. Recently, Ishizaki completed the formal
(
4) (a) Mehta, G.; Reddy, M. S. Tetrahedron Lett. 1990, 31, 2039-2042.
(6) (a) Paquette, L. A.; Friedrich, D.; Pinard, E.; Williams, J. P.; St.
Laurent, D.; Roden, B. A. J. Am. Chem. Soc. 1993, 115, 4377-4378. (b)
Williams, J. P.; St. Laurent, D. R.; Friedrich, D.; Pinard, E.; Roden, B. A.;
Paquette, L. A. J. Am. Chem. Soc. 1994, 116, 4689-4696.
(7) Yen, C.-F.; Liao, C.-C. Angew. Chem., Int. Ed. 2002, 41, 4090-
4093.
(
2
5
b) Sandham, D. A.; Meyers, A. I. J. Chem. Soc., Chem. Commun. 1995,
511-2512. (c) Mehta, G.; Reddy, M. S.; Thomas, A. Tetrahedron 1998,
4, 7865-7882.
(5) Hirst, G. C.; Johnson, T. O., Jr.; Overman, L. E. J. Am. Chem. Soc.
1
993, 115, 2992-2993.
1
0.1021/jo702136b CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/29/2007
J. Org. Chem. 2007, 72, 10147-10154
10147

Kozaka et al.
SCHEME 2. Retrosynthesis of Magellanine (1),
Magellaninone (2), and Paniculatine (3)
4 would be derived from the angularly fused 6-5-5-5 carbotet-
racycle 5, which might be assembled by the intramolecular PKR
(the second PKR) of the bicyclic compound 6. The enyne 6
might be derived from the bicyclo[4.3.0]nonenone 7 via the
stereoselective introduction of the angular propynyl side chain
as well as a vinyl functionality at the C9-position by taking
advantage of the C2-hydroxyl functionality. The first PKR of
1
0e
the enyne 8, derived from diethyl L-tartrate, could provide
the bicyclo[4.3.0] derivative 7 in a stereoselective manner.
Results and Discussion
Our work began with the improvement of the stereoselectivity
in the PKR of 9, which previously provided the desired bicyclo-
[
4.3.0] compound 10 in 75% yield along with its isomer in 10%
1
0e
yield (88:12) under thermal conditions.
After screening
total synthesis of (()-magellanine (1) based on the intra-
molecular Pauson-Khand reaction (PKR) for the preparation
of the two five-membered rings (B and C rings). In addition,
the first total synthesis of (+)-paniculatine (3) having seven
chiral centers was achieved by the tandem radical cyclization
of R-carbonyl radicals by Sha’s group.9
2 2
various PKR conditions, Sugihara’s procedure (Me S, (CH -
1
2
Cl) , 45 °C) was found to be the best one for the enyne 9
2
giving rise to the highly preferential production of 10 (89%)
1
3
over that of its isomer (3%). The efficient and stereoselective
construction of the quaternary stereogenic center at the C1-
position of 10 was the next subject for our synthesis. We first
examined the direct introduction of alkyl appendages at the C1-
position of 10 by the Michael addition under various conditions,
but no desired products could be obtained. On the other hand,
the simultaneous and stereoselective introduction of the essential
alkyl appendages at not only the C1-position but also the C9-
We have recently been involved in the investigation of not
only the stereoselective Co2(CO)8-mediated intramolecular PKR
of enynes resulting in the efficient formation of the bicyclo-
1
0
[
3.3.0]octenone and bicyclo[4.3.0]nonenone frameworks but
also the Rh(I)-catalyzed intramolecular Pauson-Khand-type
reaction of allenynes,11 which led to the development of a novel
method for the construction of the bicyclo[6.3.0] as well as the
bicyclo[5.3.0] skeletons. As an extension of our work in this
area, we now describe the stereoselective total syntheses of (-)-
magellanine (1), (+)-magellaninone (2), and (+)-paniculatine
14
position was realized by the Ueno-Stork reaction. Selective
deprotection of the C2-siloxy group of 10 with TBAF furnished
11 in 99% yield. The allyl alcohol 11 was treated with ethyl
2-bromovinyl ether under the acidic conditions, and the resulting
bromoacetal derivative was subsequently exposed to the con-
ventional radical condition (AIBN in refluxing benzene) in the
presence of allyltributyltin to give the tricyclic compound with
the quaternary carbon center at the C1-position and an allyl group
at the C9-position, respectively. Chemical transformation of thus
formed five-membered acetal moiety into the γ-lactone func-
(3), which involve a significantly different strategy (the two
PKR as the crucial steps) for the construction of the core
tetracyclic skeleton from those of the previously reported
5
-9
ones.
Our retrosynthetic analysis is depicted in Scheme 2.
The 6-5-5-6 tetracyclic enone 4 was envisioned as the common
synthetic intermediate for the transformation into the three target
alkaloids. The piperidine ring containing tetracyclic framework
1
5
tionality was achieved by exposure to mCPBA and BF3‚OEt21
to yield the corresponding cis-fused γ-lactone derivative 12 6
in 65% overall yield. Thus, we succeeded in the stereoselective
introduction of carbon appendages at both C1- and C9-positions
from a convex face by taking advantage of the C2-hydroxyl
functionality. Stereoselective reduction of 12 with NaBH4 was
followed by protection with the MOM group to exclusively
afford 13 in 90% yield. The allyl group at the C9-position of
13 was transformed into a vinyl group by successive ozonolysis,
(
8) (a) Ishizaki, M.; Niimi, Y.; Hoshino, O. Terahedron Lett. 2003, 44,
029-6031. (b) Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi,
Y. Tetrahedron 2005, 61, 4053-4065.
9) Sha, C.-K.; Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121,
875-9876.
10) (a) Mukai, C.; Uchiyama, M.; Hanaoka, M. J. Chem. Soc., Chem.
6
(
1
7
9
(
Commun. 1992, 1014-1015. (b) Mukai, C.; Uchiyama, M.; Sakamoto, S.;
Hanaoka, M. Tetrahedron Lett. 1995, 36, 5761-5764. (c) Mukai, C.; Kim,
J. S.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M. J. Chem. Soc., Perkin
Trans. 1 1998, 2903-2915. (d) Mukai, C.; Kim, J. S.; Uchiyama, M.;
Hanaoka, M. Tetrahedron Lett. 1998, 39, 7909-7912. (e) Mukai, C.; Kim,
J. S.; Sonobe, H.; Hanaoka, M. J. Org. Chem. 1999, 64, 6822-6832. (f)
Mukai, C.; Sonobe, H.; Kim, J. S.; Hanaoka, M. J. Org. Chem. 2000, 65,
(12) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett
1999, 771-773.
(13) The product ratio of 10 to its epimer was markedly improved to
97:3.
6
654-6659. (g) Mukai, C.; Kobayashi, M.; Kim, I. J.; Hanaoka, M.
(14) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J. Am. Chem. Soc. 1982, 104, 5564-5566. (b) Wakamatsu, T.; Hara, H.;
Ban, Y. J. Org. Chem. 1985, 50, 108-112. (c) Ueno, Y.; Moriya, O.; Chino,
K.; Watanabe, M.; Okawara, M. J. Chem. Soc., Perkin Trans. 1 1986, 1351-
1356. (d) Stork, G.; Mook, Jr., R.; Biller, S. A.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1983, 105, 3741-3742. (e) Stork, G.; Sher, P. M. J. Am. Chem.
Soc. 1986, 108, 303-304. (f) Stork, G.; Sher, P. M.; Chen, H.-L. J. Am.
Chem. Soc. 1986, 108, 6384-6385. (g) Stork, G. Bull. Chem. Soc. Jpn.
1988, 61, 149-154. (h) Stork, G. Bull. Soc. Chim. Fr. 1990, 127, 675-
680. (i) For review; Salom-Roig, X. J.; D e´ n e` s, F.; Renaud, P. Synthesis
2004, 1903-1928.
Tetrahedron 2002, 58, 5225-5230. (h) Mukai, C.; Kozaka, T.; Suzuki, Y.;
Kim, I. J. Tetrahedron Lett. 2002, 43, 8575-8578. (i) Nomura, I.; Mukai,
C. Org. Lett. 2002, 4, 4301-4304. (j) Mukai, C.; Kozaka, T.; Suzuki, Y.;
Kim, I. J. Tetrahedron 2004, 60, 2497-2507. (k) Nomura, I.; Mukai, C. J.
Org. Chem. 2004, 69, 1803-1812.
(11) (a) Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett.
2
2
002, 4, 1755-1758. (b) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem.
003, 68, 1376-1385. (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Kitagaki, S.
Tetrahedron Lett. 2004, 45, 4117-4121. (d) Mukai, C.; Inagaki, F.; Yoshida,
T.; Yoshitani, K.; Hara, Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159-
7
171. (e) Mukai, C.; Hirose, T.; Teramoto, S.; Kitagaki, S. Tetrahedron
(15) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
19, 419-420.
2
005, 61, 10983-10994. (f) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani,
A. Org. Lett. 2006, 8, 83-86. (g) Inagaki, F.; Mukai, C. Org. Lett. 2006,
(16) The newly generated stereogenic centers (C1 and C9) of compound
12 were confirmed by an NOE experiment. Thus, irradiation of the C2-H
of 12 produced a 3.3% enhancement of the C9-H.
8
6
, 1217-1220. (h) Inagaki, F.; Kawamura, T.; Mukai, C. Tetrahedron 2007,
3, 5154-5160.
10148 J. Org. Chem., Vol. 72, No. 26, 2007

StereoselectiVe Total Syntheses of Lycopodium Alkaloids
SCHEME 3. Synthesis of Enyne Precursor 15 to the Second
PKR
SCHEME 4. Synthesis of Piperidine Derivative 19
regioselective introduction of a double bond during a subsequent
stage. The resulting TMS derivative 16 again underwent
1
2
Sugihara’s conditions to stereoselectively produce the tetra-
21
cyclic compound 17 with the proper stereochemistry in 79%
22
yield from 15 along with its epimer (16%). Other conventional
Pauson-Khand conditions afforded 17 with a rather low
selectivity. The hydrogenation of 17 was followed by reduction
of the carbonyl group to provide the secondary hydroxyl
2
0
compound, the Peterson olefination of which with KH easily
proceeded to provide 18 in 94% yield as anticipated. The next
phase of this synthesis was confronting the construction of the
piperidine ring (D ring). According to the precedents,5 the
dihydroxylation of 18 with OsO4, followed by treatment with
NaIO4 and NaBH4, gave the tricyclic diol derivative, which was
then exposed to mesyl chloride and methylamine to produce
the piperidine derivative 19 in 92% overall yield (Scheme 4).
Finally, elaboration of the required functionalities on both
the A and B rings remained before completing the total
synthesis. First, introduction of the double bond was achieved
by (i) selective removal of the TBS group of 19 by TBAF, (ii)
activation of the resulting hydroxyl group as a mesylate, and
,7
reduction, and Grieco olefination,18 followed by LiAlH4 reduc-
tion, to produce the diol derivative 14 in 54% yield. The
propargyl functionality at the C1-position, which is essential for
the second PKR, was prepared by manipulation involving
protection of the secondary hydroxyl group of 14, oxidation of
the primary alcohol into the aldehyde, and treatment with
Ohira-Bestmann reagent19 to give the desired enyne 15 in 87%
overall yield (Scheme 3).
(iii) E2-type elimination by treatment with DBU to give 20 in
With the enyne 15 in hand, our endeavor focused on the
second PKR, which should provide a 6-5-5-5 carbotetracycle,
a precursor for the core 6-5-5-6 tetracyclic ring system of the
target natural products. Prior to carrying out the second PKR,
a TMS group was introduced at the triple bond terminus of 15
by taking into account the Peterson olefination2 for the
8
0% yield. Cesium fluoride at 170 °C in DMF effected the
removal of the 2-(trimethylsilyl)ethoxymethyl group of 20 to
furnish the allyl alcohol, which was oxidized with Dess-Martin
periodinane (DMP) affording 21 in 65% yield. Thus, the
plausible common synthetic intermediate 21 in our protocol was
stereoselectively prepared. The R,â-unsaturated compound 21
0
(
17) The stereochemical assignment of the secondary hydroxyl moiety
(20) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784. (b) Subburaj,
K.; Okamoto, S.; Sato, F. J. Org. Chem. 2002, 67, 1024-1026.
(21) An NOE experiment of 17 revealed a 9.4% enhancement between
Ha and Hb, strongly indicating that the newly generated stereogenic center
must be (R). The stereoselective formation of 17 might be tentatively
rationalized on the basis of the mechanistic hypothesis for the intramolecular
PKR proposed by Magnus, the same as the interpretation for the stereose-
lective construction of compound 10;1 see: (a) Magnus, P.; Principe, L.
M. Tetrahedron Lett. 1985, 26, 4851-4854. (b) Magnus, P.; Exon, C.;
Albaugh-Robertson, P. Tetrahedron 1985, 41, 5861-5869.
was established by an NOE experiment of compound 13′, which is an
intermediate during the conversion of 13 to 14. Thus, irradiation of the
C8-H produced a 4.5% enhancement of the Ha on a vinyl moiety.
(
18) (a) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947-
9
1
49. (b) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
485-1486. (c) Reich, H.J.; Wollowitz, S.; Trend, J. E.; Chow, F.;
0e
Wendelborn, D. F. J. Org. Chem. 1978, 43, 1697-1705.
(
19) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) M u¨ ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522. (c) Roth,
G. J.; Liepold, B.; M u¨ ller, S. G.; Bestmann, H. J. Synthesis 2004, 59-62.
(22) The ratio between compound 17 and its epimer is 83 to 17.
J. Org. Chem, Vol. 72, No. 26, 2007 10149

Kozaka et al.
SCHEME 5. Completion of Total Synthesis of
the B ring was then removed by acid treatment, and the resulting
hydroxyl derivative was successively oxidized with DMP to
afford, after removal of the benzoyl group, (+)-3 in 55%
overall yield (Scheme 5).
(-)-Magellanine (1), (+)-Magellaninone (2), and
(+)-Paniculatine (3)
30
In conclusion, we have completed the total syntheses of three
Lycopodium alkaloids, (-)-magellanine (1), (+)-magellaninone
(2), and (+)-paniculatine (3), from diethyl L-tartrate in a
stereoselective manner (1, 43 steps, 1.7% overall yield; 2, 43
steps, 1.9% overall yield; 3, 45 steps, 2.8% overall yield). The
noteworthy tactical feature of our synthesis involves the two
PKR of enynes, which enabled us to accomplish the new total
synthesis of these three alkaloids.
Experimental Section
(
2S,3S,6S)-2,3-Bis(tert-butyldimethylsilyloxy)bicyclo[4.3.0]-
non-1(9)-en-8-one ((-)-10). To a solution of (-)-9 (937 mg, 2.54
mmol) in 1,2-dichloroethane (51 mL) was added Co (CO) (1.04
2
8
g, 3.05 mmol) at room temperature. After being stirred for 30 min
at the same temperature, dimethyl sulfide (1.9 mL, 25 mmol) was
added to the reaction mixture and stirred for additional 12 h at 45
°
C. The reaction mixture was passed through a short pad of silica
gel with hexane-AcOEt (2:1), and the filtrate was concentrated to
dryness. The residue was chromatographed on silica gel with
10e
hexane-AcOEt (10:1) to give (-)-10 (896 mg, 89%) as a
10e
colorless oil and the (+)-epimer of (-)-10 (32.8 mg, 3%) as
colorless solids.
(2S,3S,6S)-3-tert-Butyldimethylsilyloxy-2-hydroxybicyclo[4.3.0]-
non-1(9)-en-8-one ((-)-11). To a solution of (-)-10 (656 mg, 1.65
mmol) in THF (1.7 mL) was added dropwise TBAF (1.0M in THF;
2
.0 mL, 2.0 mmol) at -20 °C. The reaction mixture was stirred
for 12 h at the same temperature, quenched by addition of saturated
aqueous NH Cl, extracted with AcOEt, washed with water and
4
was susceptible to the highly stereoselective 1,4-conjugate
brine, dried, and concentrated to dryness. The residue was chro-
matographed on silica gel with hexane-AcOEt (4:1) to give (-)-
11 (461 mg, 99%) as colorless needles: mp 95.5-96.0 °C (hexane);
addition with Me2Cu(CN)Li2 to furnish 22,23 which was then
2
4
oxidized with N-tert-butylbenzenesulfinimidoyl chloride to
[R]26
-188.5 (c 1.74, CHCl
5.94 (d, 1H, J ) 1.2 Hz), 4.44 (d, 1H, J ) 3.1 Hz), 4.08-4.05 (m,
-1
1
produce, after removal of the MOM group, 5-epimagellanine
D
3
); IR 1705, 1632 cm ; H NMR δ
25
26
(
23) in 44% yield from 21. The standard Mitsunobu reaction
1
H), 3.11 (s, 1H), 3.06-2.99 (m, 1H), 2.51 (dd, 1H, J ) 18.9, 6.1
of 23, followed by basic hydrolysis, provided (-)-magellanine
Hz), 2.08-2.00 (m, 1H), 1.97 (dd, 1H, J ) 18.9, 1.8 Hz), 1.89-
(
1) in 75% yield, whereas the oxidation of 23 with DMP pro-
27,28
1.84 (m, 1H), 1.62-1.57 (m, 1H), 1.56-1.46 (m, 1H), 0.81 (s,
duced (+)-magellaninone (2) in 85% yield.
On the other
9
7
H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR δ 209.9, 182.2, 129.9,
hand, compound 22 was transformed into (+)-paniculatine (3)
as follows. The stereoselective reduction of 2223 with L-Selec-
tride gave the corresponding alcohol with the desired stereo-
chemistry, which was subsequently protected with a benzoyl
1.7, 70.1, 42.2, 37.2, 28.8, 27.3, 25.6, 17.9, -4.9, -5.0; FAB
+
MS m/z 283 (M + 1, 25.5). FAB HRMS calcd for C15
27 3
H O Si
2
83.1730, found 283.1726. Anal. Calcd for C15
H, 9.28. Found: C, 63.65; H, 9.34.
(1S,5S,6S,9S,12R)-6-tert-Butyldimethylsilyloxy-12-(2-prope-
26 3
H O Si: C, 63.78;
2
9
group. The MOM group on the secondary hydroxyl group of
1,5
nyl)-4-oxatricyclo[7.3.0.0 ]dodecane-3,11-dione ((-)-12). To a
suspension of (-)-11 (5.93 g, 21.0 mmol) and ethyl 2-bromovinyl
ether (6.34 g, 42.0 mmol) were added PPTS (527 mg, 2.10 mmol)
and camphorsulfonic acid (487 mg, 2.10 mmol) at room temper-
ature. The reaction mixture was stirred for 6 h at the same
(
23) Compound 22 was obtained as an inseparable mixture with its epimer
1
in the ratio of 93:7 (by H NMR analysis). This mixture was used for further
reactions.
(
24) Mukaiyama, T.; Matsuo, J.; Kitagawa, H. Chem. Lett. 2000, 1250-
251.
25) The structure of synthetic (-)-5-epimagellanine (23) was confirmed
1
3
temperature, quenched by addition of Et N and saturated aqueous
(
by comparison with H and C NMR spectral data of the racemic 23.6
1
13
(
26) A mixture of 22 and its epimer (93:7) was recovered in 16% yield
(29) The benzoyloxy derivative could be isolated as a single isomer by
passing through a short pad of alumina with AcOEt. The C15-methyl carbon
resonated at δ 22.3 in the 13C NMR spectrum, indicating that the methyl
group should take an equatorial position rather than an axial position (see
Dalling, D. K.; Grant, D. M. J. Am. Chem. Soc. 1967, 89, 6612-6622).
Furthermore, the stereochemistry of the newly generated stereogenic center
by L-Selectride reduction could be deduced on the basis of the literature
after exposure to the Matsuo’s reagent. Thus, the chemical yield of 23 might
be described to be 52% overall yield from 21 based on the recovery of the
starting material.
(
27) The synthetic (-)-magellanine (1) was a colorless solid, mp 160-
3
0
1
1
61°C (AcOEt), and revealed [R] D -20.3 (c 0.14, CHCl3) [natural product
25
was a colorless solid, mp 165-166°C (AcOEt), and revealed M D -64.8
5
9
(
1
specific rotation was not reported); Overman’s product was a solid, mp
precedent and finally confirmed by conversion into paniculatine.
2
5
62-164°C, and revealed [R] D -11.5 (c 0.47, CHCl3)]. The structure of
synthetic magellanine was confirmed by comparison not only with spectral
(30) The synthetic (+)-paniculatine (3) was a colorless solid, mp 178-
30
179°C (acetone), and revealed [R] D +75.1 (c 0.17, CHCl3) [natural
1
13
3
data but also with H and C NMR spectra of natural (-)-magellanine.
product was a colorless solid, mp 180-181°C (acetone), and revealed MD
30
9
(
28) The synthetic (+)-magellaninone (2) was an oil and revealed [R]
D
+159.8 (specific rotation was not reported); Sha’s product was a solid,
2
26
+
82.6 (c 0.16, CHCl3) [natural product was an oil and specific rotation
mp 117-118°C, and revealed [R] D +66.0 (c 0.20, CHCl3)]. The structure
5
25
was not reported; Overman’s product was an oil and revealed [R] D +95.0
c 0.10, CHCl3)]. The structure of synthetic magellaninone was confirmed
by comparison with spectral of natural (+)-magellaninone.
of synthetic paniculatine was confirmed by comparison not only with
spectral data but also with 1H and C NMR spectra of natural (+)-
paniculatine.
13
(
10150 J. Org. Chem., Vol. 72, No. 26, 2007

StereoselectiVe Total Syntheses of Lycopodium Alkaloids
NaHCO , extracted with AcOEt, washed with water and brine,
dried, and concentrated to dryness. The residue was passed through
a short pad of silica gel with hexane-AcOEt (10:1) to give the
crude bromoacetal. To a solution of the crude bromoacetal in
benzene (210 mL) were added allyltributyltin (6.53 mL, 63.0 mmol)
and AIBN (218 mg, 2.10 mmol) at room temperature. The reaction
mixture was refluxed for 12 h. After evaporation of the solvent,
the residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to afford the crude acetal. To a solution of
3
room temperature, stirred for additional 4 h, quenched by addition
of saturated aqueous NaHCO , extracted with AcOEt, washed with
water and brine, dried, and concentrated to dryness. The residue
was passed through a short pad of silica gel with hexane-AcOEt
4
(4:1) to afford the crude lactone. To a suspension of LiAlH (21.9
mg, 0.577 mmol) in THF (2.5 mL) was added the crude lactone in
THF (1.0 mL) at 0 °C. The reaction mixture was stirred for 30
min at room temperature, quenched by addition of water, passed
through a short pad of Celite with AcOEt, and concentrated to
dryness. The residue was chromatographed on silica gel with
hexane-AcOEt (10:1) to give (+)-14 (72.5 mg, 54% from (+)-
3
the crude acetal in CH
2
Cl
2
2
(100 mL) were added mCPBA (7.00 g,
(5.20 mL, 40.6 mmol) at -40 °C. The
4
0.6 mmol) and BF ‚OEt
3
2
9
-1
reaction mixture was stirred for 1 h at the same temperature,
13) as a colorless oil: [R]
D
3
+49.7 (c 2.73, CHCl ); IR 3421 cm ;
1
quenched by addition of saturated aqueous Na
2
S O
2 3
and saturated
H NMR δ 5.65 (ddd, 1H, J ) 17.1, 10.3, 10.3 Hz), 5.10-5.02
(m, 2H), 4.63, 4.59 (ABq, 2H, J ) 6.6 Hz), 4.00-3.96 (m, 1H),
3.83-3.71 (m, 3H), 3.51-3.46 (m, 1H), 3.33 (s, 3H), 3.14-3.11
(m, 1H), 2.15-2.08 (m, 1H), 1.89-1.72 (m, 4H), 1.69-1.46 (m,
4H), 0.87 (s, 9H), 0.069 (s, 3H), 0.065 (s, 3H); 13C NMR δ 138.3,
115.9, 95.6, 82.9, 76.7, 72.2, 59.6, 56.5, 55.2, 50.6, 44.1, 36.2, 35.9,
aqueous NaHCO , extracted with CH Cl , washed with 1 N aqueous
3
2
2
NaOH, water and brine, dried, and concentrated to dryness. The
residue was chromatographed on silica gel with hexane-AcOEt
(
5:1) to give (-)-12 (4.98 g, 65% from (-)-11) as a colorless oil:
28
-1
[R]
D
-19.4 (c 2.69, CHCl
3
); IR 1788, 1763, 1740, 1641 cm ;
1
+
H NMR δ 5.91-5.82 (m, 1H), 5.15-5.07 (m, 2H), 4.43 (d, 1H,
29.5, 25.8, 21.7, 17.9, -4.3, -4.7; FAB MS m/z 401 (M + 1,
13.2). FAB HRMS calcd for C21H O Si 401.2723, found 401.2724.
41 5
J ) 2.7 Hz), 4.28-4.25 (m, 1H), 3.03-2.99 (m, 1H), 2.71, 2.12
ABq, 2H, J ) 16.6 Hz), 2.63-2.56 (m, 1H), 2.42 (dd, 1H, J )
9.3, 8.3 Hz), 2.16-1.97 (m, 3H), 1.79-1.61 (m, 3H), 1.51-1.45
(
(1S,2S,3S,6S,8R,9R)-3-tert-Butyldimethylsilyloxy-9-ethenyl-
8-methoxymethoxy-1-(2-propynyl)-2-(2-trimethylsilylethoxy-
methoxy)bicyclo[4.3.0]nonane ((-)-15). To a solution of (+)-14
(226 mg, 0.563 mmol) and 2,6-lutidine (0.13 mL, 1.1 mmol) in
CH Cl (5.6 mL) was added AcCl (0.05 mL, 0.68 mmol) at -78
1
(
2
3
1
3
m, 1H), 0.88 (s, 9H), 0.093 (s, 3H), 0.087 (s, 3H); 13C NMR δ
15.9, 174.3, 135.8, 117.2, 80.1, 66.2, 48.4, 48.1, 42.3, 37.3, 36.6,
+
0.8, 26.7, 25.7, 21.9, 17.8, -5.0, -5.3; FAB MS m/z 365 (M +
2
2
33 4
, 27.2). FAB HRMS calcd for C20H O Si 365.2148, found
°C. The reaction mixture was stirred for 40 min at the same
temperature, quenched by addition of saturated aqueous NaHCO3,
65.2149.
(
1S,5S,6S,9S,11R,12R)-6-tert-Butyldimethylsilyloxy-11-meth-
extracted with CH
concentrated to dryness. To a solution of the residue in CH
2
Cl
2
, washed with water and brine, dried, and
Cl
2
(5.6 mL) were added Pr NEt (0.30 mL, 1.7 mmol), SEMCl (0.20
1,5
oxymethoxy-12-(2-propenyl)-4-oxatricyclo[7.3.0.0 ]dodecan-3-
one ((+)-13). To a solution of (-)-12 (204 mg, 0.559 mmol) in
MeOH (5.6 mL) was added NaBH
2
2
i
4
(106 mg, 2.80 mmol) at -50
mL, 1.1 mmol) and TBAI (229 mg, 0.620 mmol) at room
temperature. The reaction mixture was refluxed for 4 h, quenched
°
C. The reaction mixture was stirred for 1 h at the same temperature,
quenched by addition of saturated aqueous NH Cl, extracted with
AcOEt, washed with water and brine, dried, and concentrated to
4
by addition of saturated aqueous NaHCO
washed with water and brine, dried, and concentrated to dryness.
To a solution of the residue in MeOH (5.6 mL) was added K CO
3
(156 mg, 1.13 mmol) at room temperature. The reaction mixture
was stirred for 4 h at the same temperature, quenched by addition
3 2 2
, extracted with CH Cl ,
afford the crude alcohol. To a solution of the crude alcohol in
2
i
2
CH Cl
2
(5.0 mL) were added Pr
2
NEt (0.30 mL, 1.7 mmol) and
MOMCl (0.08 mL, 1.1 mmol) at room temperature. The reaction
mixture was stirred for 14 h at the same temperature, quenched by
4
of saturated aqueous NH Cl, extracted with AcOEt, washed with
addition of saturated aqueous NaHCO
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed on silica gel with hexane-AcOEt
3
, extracted with CH
2
Cl
2
,
brine, dried, and concentrated to dryness. The residue was passed
through a short pad of silica gel with hexane-AcOEt (10:1) to
afford the crude alcohol. To a mixture of the crude alcohol and
IBX (316 mg, 1.13 mmol) in AcOEt (4.0 mL) was added dropwise
DMSO (4.0 mL) at room temperature. The reaction mixture was
stirred for 30 min at the same temperature, quenched by addition
(
10:1) to give (+)-13 (206 mg, 90% from (-)-12) as a colorless
29
-1
oil: [R]
D
3
+0.67 (c 9.93, CHCl ); IR 1782, 1763, 1641 cm ;
1
H NMR δ 5.83-5.73 (m, 1H), 5.04-4.92 (m, 2H), 4.51, 4.48
ABq, 2H, J ) 6.6 Hz), 4.24 (d, 1H, J ) 2.9 Hz), 4.08-4.06 (m,
(
2 2 3 3
of saturated aqueous Na S O and saturated aqueous NaHCO ,
1
1
1
1
1
3
H), 3.66-3.61 (m, 1H), 3.26 (s, 3H), 2.64-2.58 (m, 1H), 2.49,
.96 (ABq, 2H, J ) 16.6 Hz), 2.22-2.06 (m, 3H), 1.88-1.79 (m,
H), 1.67-1.62 (m, 1H), 1.56-1.53 (m, 2H), 1.47-1.40 (m, 1H),
.35-1.29 (m, 1H), 0.84 (s, 9H), 0.02 (s, 6H); 13C NMR δ 175.1,
36.9, 115.8, 95.6, 82.4, 81.2, 66.7, 55.3, 50.1, 45.9, 41.0, 37.3,
extracted with AcOEt, washed with water and brine, dried and
concentrated to afford the crude aldehyde. To a solution of the crude
aldehyde in MeOH (5.0 mL) were added dimethyl 1-diazo-2-
oxopropylphosphonate (217 mg, 1.13 mmol) and K CO (312 mg,
2 3
2.25 mmol) at room temperature. The reaction mixture was stirred
for 3 h at the same temperature, quenched by addition of saturated
5.7, 34.4, 27.1, 25.6, 22.5, 17.7, -5.2, -5.3; FAB MS m/z 411
+
(M + 1, 11.0). FAB HRMS calcd for C22
39 5
H O Si 411.2567, found
3
aqueous NaHCO , extracted with AcOEt, washed with water and
brine, dried, and concentrated to dryness. The residue was chro-
411.2575.
(
1S,2S,3S,6S,8R,9R)-3-tert-Butyldimethylsilyloxy-9-ethenyl-1-
matographed on silica gel with hexane-AcOEt (10:1) to give (-)-
2
9
(
1
0
2-hydroxyethyl)-8-methoxymethoxybicyclo[4.3.0]nonan-2-ol ((+)-
15 (258 mg, 87% from (+)-14) as a colorless oil: [R]
D
-28.1 (c
-
1 1
4). Ozone was bubbled through a solution of (+)-13 (138 mg,
3
3.55, CHCl ); IR 3306, 2114, 1637 cm ; H NMR δ 6.04-5.96
.337 mmol) in MeOH (5.0 mL) at -78 °C till the pale blue color
(m, 1H), 5.15-5.05 (m, 2H), 4.82, 4.76 (ABq, 2H, J ) 6.6 Hz),
4.66, 4.58 (ABq, 2H, J ) 6.6 Hz), 4.08-4.03 (m, 1H), 3.88-3.83
(m, 1H), 3.76-3.70 (m, 1H), 3.56-3.47 (m, 2H), 3.33 (s, 3H),
3.12 (dd, 1H, J ) 9.3, 5.1 Hz), 2.40-2.24 (m, 3H), 2.12 (dt, 1H,
J ) 13.2, 7.6 Hz), 1.97 (t, 1H, J ) 2.7 Hz), 1.80-1.53 (m, 5H),
0.95 (dd, 2H, J ) 9.0, 7.8 Hz), 0.88 (s, 9H), 0.06 (s, 6H), 0.01 (s,
9H); 13C NMR δ 138.9, 116.1, 97.6, 95.2, 84.6, 83.6, 81.3, 72.4,
70.9, 65.7, 57.0, 55.2, 50.3, 39.9, 35.9, 29.1, 25.9, 22.6, 22.0, 18.1,
persisted. Excess ozone was flushed off with nitrogen. To the
reaction mixture was added NaBH
C. The reaction mixture was stirred for 30 min at the same
temperature, quenched by addition of water, extracted with AcOEt,
washed with water and brine, dried, and concentrated to afford the
crude alcohol. To a solution of the crude alcohol in THF (1.5 mL)
were added o-NO
4
(102 mg, 2.70 mmol) at -78
°
n
2
PhSeCN (197 mg, 0.866 mmol) and Bu
3
P (0.21
+
mL, 0.87 mmol) at room temperature. After being stirred for 10 h
at the same temperature, a solution of 30% aqueous H (0.50
18.0, -1.4, -4.5, -4.7; FAB MS m/z 525 (M + 1, 3.7). FAB
O
2 2
53 5 2
HRMS calcd for C28H O Si 525.3432, found 525.3436.
mL, 4.9 mmol) in THF (3.0 mL) was added to the reaction mixture
at 0 °C. After the reaction mixture was stirred for 15 min at the
same temperature, the reaction mixture was allowed to warm to
(1S,2S,3S,6S,8R,9R,10R)-3-tert-Butyldimethylsilyloxy-8-meth-
oxymethoxy-13-trimethylsilyl-2-(2-trimethylsilylethoxymethoxy)-
1
,6 10,14
tetracyclo[7.6.0.0 .0
]pentadec-13-en-12-one ((-)-17). To a
J. Org. Chem, Vol. 72, No. 26, 2007 10151

Kozaka et al.
solution of (-)-15 (65.0 mg, 0.124 mmol) in THF (1.2 mL) were
2.31-2.15 (m, 4H), 1.94-1.78 (m, 3H), 1.67-1.52 (m, 5H), 0.94-
n
13
added BuLi (1.35 M in hexane; 0.11 mL, 0.15 mmol) and HMPA
0.82 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H), 0.00 (s, 9H); C NMR δ
(0.1 mL) at -78 °C. After being stirred for 1 h at the same
135.9, 127.0, 97.5, 94.6, 82.3, 81.3, 74.7, 65.4, 60.3, 59.6, 55.1,
temperature, TMSCl (0.03 mL, 0.25 mmol) was added dropwise
to the reaction mixture. Then, the reaction mixture was allowed to
warm gradually to room temperature, stirred for additional 1 h,
49.9, 46.8, 42.7, 38.3, 36.9, 34.2, 30.0, 25.9, 22.0, 18.0 (2 × C),
+
-1.4, -4.6 (2 × C); FAB MS m/z 539 (M + 1, 1.6). FAB HRMS
55 5 2
calcd for C29H O Si 539.3588, found 539.3576.
quenched by addition of saturated aqueous NH
4
Cl, extracted with
(1S,3S,8S,9R,10R,12S,15S,16S)-15-tert-Butyldimethylsilyloxy-
AcOEt, washed with water and brine, dried, and concentrated to
dryness. To a solution of the crude enyne in 1,2-dichloroethane
10-methoxymethoxy-5-methyl-16-(2-trimethylsilylethoxymethoxy)-
3,8 1,12
5-azatetracyclo[7.7.0.0 .0 ]hexadecane ((-)-19). To a solution
(
2.4 mL) was added Co
2
(CO)
8
(50.8 mg, 0.149 mmol) at room
of (-)-18 (78.3 mg, 0.145 mmol) in MeCN (1.5 mL) were added
temperature. After being stirred for 30 min at the same temperature,
dimethyl sulfide (0.09 mL, 1.2 mmol) was added to the reaction
mixture. The reaction mixture was stirred for an additional 4 days
at 18 °C and passed through a short pad of silica gel with hexane-
AcOEt (2:1), and the filtrate was concentrated to dryness. The
residue was chromatographed on silica gel with hexane-AcOEt
NMO (34.0 mg, 0.291 mmol) and 4% aqueous OsO (0.18 mL,
4
-
2
2.9 × 10 mmol) at room temperature. The reaction mixture was
stirred for 2 h at the same temperature, quenched by addition of
saturated aqueous Na SO , stirred for 30 min, extracted with AcOEt,
2
3
washed with water and brine, dried, and concentrated to afford crude
1,2-diol. To a solution of the crude 1,2-diol in Et O (1.5 mL) and
2
(
10:1) to give (-)-17 (61.3 mg, 79% from (-)-15) as a colorless
H O (1.5 mL) was added NaIO (62.2 mg, 0.291 mmol) at room
2
4
oil and (-)-epimer of (-)-17 (12.7 mg, 16% from (-)-15) as a
temperature. The reaction mixture was stirred for 2 h at the same
30
colorless oil. Compound (-)-17: [R]
D
-70.8 (c 0.51, CHCl
3
);
temperature, extracted with Et O, washed with water and brine,
2
-
1 1
IR 1686, 1607 cm ; H NMR δ 4.85, 4.60 (ABq, 2H, J ) 7.1
Hz), 4.60 (s, 2H), 4.16 (td, 1H, J ) 7.3, 2.2 Hz), 3.52 (td, 1H, J )
dried, and concentrated to afford the crude dialdehyde. To a solution
of the crude dialdehyde was added NaBH (11.0 mg, 0.291 mmol)
4
9
9
.8, 5.9 Hz), 3.48-3.39 (m, 2H), 3.33 (s, 3H), 3.22 (td, 1H, J )
.8, 6.6 Hz), 3.01 (d, 1H, J ) 17.1 Hz), 2.77-2.71 (m, 1H), 2.60
at room temperature. The reaction mixture was stirred for 30 min
at the same temperature, quenched by addition of saturated aqueous
(
1
9
dd, 1H, J ) 17.3, 6.6 Hz), 2.26 (dd, 1H, J ) 11.0, 2.2 Hz), 2.19-
NH Cl, extracted with AcOEt, washed with water and brine, dried,
4
.97 (m, 5H), 1.72-1.67 (m, 1H), 1.64-1.54 (m, 3H), 0.87 (s,
H), 0.85-0.74 (m, 2H), 0.17 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H),
and concentrated to afford crude diol. To a solution of the crude
i
diol in CH Cl (1.4 mL) were added Pr NEt (0.12 mL, 0.67 mmol)
2
2
2
-
8
0.05 (s, 9H); 13C NMR δ 213.4, 197.7, 134.5, 97.2, 95.2, 83.5,
and MsCl (0.03 mL, 0.33 mmol) at 0 °C. The reaction mixture
was stirred for 15 min at the same temperature, quenched by
addition of saturated aqueous NaHCO , extracted with CH Cl ,
1.2, 75.0, 65.4, 59.7, 58.6, 55.2, 51.4, 45.1, 42.7, 38.5, 35.3, 29.8,
2
5.8, 22.1, 17.9, -1.2, -1.4, -4.7 (2 × C); FAB MS m/z 625
3
2
2
+
(
6
M + 1, 24.7). FAB HRMS calcd for C32
H O Si
61 6 3
625.3776, found
washed with water and brine, dried, and concentrated to afford the
crude dimesylate. A mixture of the crude dimesylate and 40%
30
25.3761. (-)-Epimer of (-)-17: [R]
D
3
-17.5 (c 3.48, CHCl );
-
1 1
IR 1686, 1609 cm ; H NMR δ 5.06, 4.71 (ABq, 2H, J ) 7.1
Hz), 4.59, 4.53 (ABq, 2H, J ) 6.8 Hz), 3.81-3.75 (m, 1H), 3.58
aqueous MeNH (1.0 mL, 12 mmol) in MeOH (1.4 mL) was stirred
2
for 12 h at 85 °C in a sealed tube. The reaction mixture was
(
(
d, 1H, J ) 9.3 Hz), 3.49-3.42 (m, 3H), 3.31 (s, 3H), 3.13-3.08
m, 1H), 2.84 (d, 1H, J ) 15.4 Hz), 2.60 (dd, 1H, J ) 10.7, 7.3
extracted with AcOEt, washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed on Al O
2
3
Hz), 2.41 (dd, 1H, J ) 18.3, 7.1 Hz), 2.29-2.21 (m, 2H), 1.81-
1
(
9
6
2
with hexane-AcOEt (5:1) to give (-)-19 (76.2 mg, 92% from (-)-
18) as a colorless oil: [R]29 -40.8 (c 1.74, CHCl ); H NMR δ
1
.60 (m, 4H), 1.57-1.45 (m, 2H), 1.33-1.29 (m ,1H), 1.00-0.92
D
3
m, 2H), 0.87 (s, 9H), 0.17 (s, 9H), 0.06 (s, 6H), -0.02 (s,
5.01, 4.74 (ABq, 2H, J ) 6.6 Hz), 4.61, 4.59 (ABq, 2H, J ) 6.6
Hz), 3.86-3.78 (m, 2H), 3.56-3.50 (m, 1H), 3.45-3.37 (m, 2H),
3.33 (s, 3H), 2.56 (dd, 1H, J ) 11.5, 4.9 Hz), 2.51-2.45 (m, 1H),
2.23-1.76 (m, 9H), 2.19 (s, 3H), 1.66-1.45 (m, 6H), 1.17 (1H,
dd, J ) 12.5, 6.6 Hz), 0.93 (t, 2H, J ) 8.5 Hz), 0.86 (s, 9H), 0.03
(s, 6H), -0.01 (s, 9H); 13C NMR δ 97.4, 95.1, 83.1, 81.9, 75.2,
66.5, 57.6, 57.3, 57.2, 55.1, 54.4, 47.0, 42.6, 41.4, 38.6, 36.6, 32.0,
H); 13C NMR δ 214.7, 195.9, 136.3, 96.8, 95.4, 83.5, 77.6, 74.3,
5.7, 58.1, 55.4, 52.5, 47.3, 41.9, 38.1, 34.9, 34.1, 30.9, 25.8,
2.6, 18.1, 17.9, -0.8, -1.5, -4.7 (2 × C); FAB MS m/z 625
+
(
M + 1, 19.9). FAB HRMS calcd for C32
H O Si
61 6 3
625.3776, found
6
25.3776.
1S,2S,3S,6S,8R,9R,10S,14R)-3-tert-Butyldimethylsilyloxy-8-
methoxymethoxy-2-(2-trimethylsilylethoxymethoxy)tetracyclo-
(
31.0, 26.7, 25.9, 22.3, 18.4, 17.9, -1.4, -4.5, -4.7; EI MS m/z
1,6 10,14
+
[7.6.0.0 .0
]pentadec-12-ene ((-)-18). A mixture of (-)-17
569 (M , 5.5). EI HRMS calcd for C30
569.3928.
5 2
H59NO Si 569.3932, found
(357 mg, 0.571 mmol) and Pd-C (35.7 mg) in AcOEt (5.7 mL)
was stirred under hydrogen atmosphere (1 atm) for 3 h at room
temperature. The reaction mixture was passed through a short pad
of Celite, and the filtrate was concentrated to afford the crude
(1S,3S,8S,9R,10R,12S,16R)-10-Methoxymethoxy-5-methyl-16-
3,8 1,12
(2-trimethylsilylethoxymethoxy)-5-azatetracyclo[7.7.0.0 .0 ]-
hexadec-14-ene ((-)-20). To a solution of (-)-19 (2.44 g, 4.28
mmol) in THF (4.3 mL) was added TBAF (1.0M in THF; 4.71
mL, 4.71 mmol) at room temperature. The reaction mixture was
stirred for 1.5 h at 45 °C, quenched by addition of saturated aqueous
ketone. To a solution of the crude ketone in Et
added DIBAL-H (1.0 M in hexane; 0.69 mL, 0.69 mmol) at -78
C. The reaction mixture was stirred for 30 min at the same
2
O (5.7 mL) was
°
temperature, quenched by addition of water, and passed through a
short pad of Celite with AcOEt. After evaporation of the solvent,
the filtrate was concentrated to afford the crude alcohol. To a
suspension of KH (45.8 mg, 1.14 mmol; the oil was washed off
with hexane prior to use) in THF (4.0 mL) was added dropwise a
solution of the crude alcohol obtained above in THF (1.7 mL) at
room temperature. The reaction mixture was stirred for 1 h at the
same temperature, quenched by addition of saturated aqueous
NH
and concentrated to afford the crude alcohol. To a solution of the
4
Cl, extracted with AcOEt, washed with water and brine, dried,
i
crude alcohol in CH
21 mmol), DMAP (cat.), and Ms
temperature. The reaction mixture was stirred for 1.5 h at the same
temperature, quenched by addition of saturated aqueous NaHCO
extracted with CH Cl , washed with water and brine, dried, and
2
Cl
2
2
(21.4 mL) were added Pr NEt (3.7 mL,
2
O (1.49 g, 8.57 mmol) at room
3
,
2
2
concentrated to afford the crude mesylate. A mixture of the crude
mesylate and DBU (1.92 mL, 12.8 mmol) in xylene (43 mL) was
refluxed for 12 h, quenched by addition of saturated aqueous
4
NH Cl, extracted with AcOEt, washed with water and brine, dried,
and concentrated to dryness. The residue was chromatographed on
silica gel with hexane-AcOEt (10:1) to give (-)-18 (289 mg, 94%
NaHCO
dried, and concentrated to dryness. The residue was chromato-
graphed on Al with hexane-AcOEt (5:1) to give (-)-20 (1.50
g, 80% from (-)-19) as a colorless oil: [R]
3
, extracted with AcOEt, washed with water and brine,
from (-)-17) as a colorless oil: [R]28
-61.2 (c 0.51, CHCl
); H
1
D
3
NMR δ 5.63-5.61 (m, 1H), 5.50-5.48 (m, 1H), 4.80, 4.73 (ABq,
2 3
O
27
2
H, J ) 6.8 Hz), 4.67, 4.58 (ABq, 2H, J ) 6.8 Hz), 4.14-4.10
D
-68.7 (c 0.65,
); H NMR δ 5.81-5.77 (m, 1H), 5.70-5.65 (m, 1H), 4.86,
4.76 (ABq, 2H, J ) 6.8 Hz), 4.63, 4.61 (ABq, 2H, J ) 6.8 Hz),
1
(m, 1H), 3.71-3.65 (m, 1H), 3.49 (d, 1H, J ) 9.5 Hz), 3.43-3.36
CHCl
3
(m, 2H), 3.35 (s, 3H), 3.13-3.11 (m, 1H), 2.56-2.50 (m, 1H),
10152 J. Org. Chem., Vol. 72, No. 26, 2007

StereoselectiVe Total Syntheses of Lycopodium Alkaloids
4
3
2
1
0
5
2
.04-4.01 (m, 1H), 3.79-3.74 (m, 1H), 3.69 (t, 2H, J ) 8.5 Hz),
.34 (s, 3H), 2.57-2.50 (m, 2H), 2.37-2.30 (m, 1H), 2.19 (s, 3H),
.17-2.08 (m, 3H), 2.00-1.80 (m, 6H), 1.72-1.66 (m, 1H), 1.57-
.47 (m, 2H), 1.09 (dd, 1H, J ) 12.7, 6.6 Hz), 0.98-0.91 (m, 2H),
.02 (s, 9H); 13C NMR δ 130.7, 126.8, 95.4, 94.4, 82.7, 75.6, 65.3,
7.8, 57.2, 55.7, 55.2, 54.7, 47.1, 41.6, 40.7, 39.9, 37.7, 33.1, 26.6,
(-)-Magellanine ((-)-1). To a solution of (-)-23 (8.0 mg, 2.9
2
-
× 10 mmol) in THF (0.3 mL) were added PPh
3
(76.2 mg, 0.291
mmol), benzoic acid (71.0 mg, 0.581 mmol), and DIAD (0.06
mL, 0.29 mL) at room temperature. The reaction mixture was
stirred for 10 h at the same temperature. To the reaction mixture
was added a solution of concentrated aqueous NaOH. The reac-
tion mixture was stirred for 3 h at room temperature, extracted
+
6.1, 18.1, -1.4; EI MS m/z 437 (M , 19.9). EI HRMS calcd for
C
24
4
H43NO Si 437.2961, found 437.2956.
with CHCl
trated to dryness. The residue was chromatographed on silica gel
with CHCl -MeOH (1:1) to give (-)-1 (6.0 mg, 75%) as color-
less solids: mp 160-161 °C (AcOEt); [R]
3
, washed with water and brine, dried, and concen-
(
1S,3S,8S,9R,10R,12S)-10-Methoxymethoxy-5-methyl-5-aza-
3,8 1,12
tetracyclo[7.7.0.0 .0 ]hexadec-14-en-16-on ((-)-21). A mixture
of (-)-20 (700 mg, 1.60 mmol), CsF (1.21 g, 8.00 mmol), and
MS4Å in DMF (20 mL) was refluxed for 12 h and passed through
a short pad of Celite with AcOEt to remove MS4Å, and the filtrate
was concentrated to dryness. The residue was passed through a
short pad of silica gel with hexane-AcOEt (2:1) to give the crude
3
30
D
-20.3 (c 0.14,
); IR 3418, 1651 cm ; H NMR δ 5.87 (s, 1H), 4.23-4.19
-
1 1
CHCl
3
(m, 1H), 2.77-2.60 (m, 4H), 2.51 (ddd, 1H, J ) 12.7, 6.3, 6.3
Hz), 2.32-1.88 (m, 7H), 2.20 (s, 3H), 1.93 (s, 3H), 1.71-1.52 (m,
4H); 13C NMR δ 203.3, 158.0, 125.7, 72.0, 61.0, 59.6, 56.5, 55.4,
alcohol. To a solution of the crude alcohol in CH
2
Cl
2
(20 mL) was
46.9, 41.9, 41.4, 40.3, 37.3, 37.0, 30.4, 27.0, 24.5; EI MS m/z 275
+
added Dess-Martin periodinane (919 mg, 2.17 mL) at room
temperature. The reaction mixture was stirred for 30 min at the
same temperature, quenched by addition of saturated aqueous
Na
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed on Al
(M , 100). EI HRMS calcd for C17
275.1886.
2
H25NO 275.1885, found
(+)-Magellaninone ((+)-2). To a solution of (-)-23 (18.2 mg,
-
2
2
S O
2 3
and saturated aqueous NaHCO
3
, extracted with CH
2
Cl
2
,
6.61 × 10 mmol) in CH
2 2
Cl (0.7 mL) was added Dess-Martin
periodinane (56.1 mg, 0.132 mmol) at room temperature. The
reaction mixture was stirred for 1 h at the same temperature,
2
O
3
with hexane-AcOEt
(
[
5:1) to give (-)-21 (319 mg, 65% from (-)-20) as a colorless oil:
quenched by addition of saturated aqueous Na
aqueous NaHCO , extracted with CHCl , washed with water and
brine, dried, and concentrated to dryness. The residue was chro-
matographed on Al with hexane-AcOEt (1:1) to give (+)-2
(15.3 mg, 85%) as a colorless oil: [R]
2 2 3
S O and saturated
29
-1 1
R]
D
-40.0 (c 1.08, CHCl
3
); IR 1661 cm ; H NMR δ 6.77-
3
3
6
9
1
3
.72 (m, 1H), 6.01-5.97 (m, 1H), 4.58 (s, 2H), 3.67 (dt, 1H, J )
.5, 5.9 Hz), 3.30 (s, 3H), 2.63-2.55 (m, 3H), 2.52-2.49 (m,
H), 2.32 (dd, 1H, J ) 19.8, 5.9 Hz), 2.24-2.11 (m, 3H), 2.18 (s,
H), 2.03-1.95 (m, 3H), 1.85-1.76 (m, 2H), 1.68-1.59 (m, 3H);
C NMR δ 202.4, 145.9, 128.6, 95.6, 82.4, 60.8, 60.0, 56.5, 55.2,
2
O
3
30
D
3
+82.6 (c 0.16, CHCl );
-
1 1
IR 1734, 1655 cm ; H NMR δ 6.00 (s, 1H), 3.02 (d, 1H, J ) 6.6
Hz), 2.77 (dddd, 1H, J ) 19.1, 6.4, 2.5, 1.2 Hz), 2.64-1.71 (m,
14H), 2.24 (s, 3H), 1.99 (s, 3H); 13C NMR δ 216.4, 200.7, 158.1,
125.7, 60.4, 58.5, 56.5, 52.9, 46.6, 44.8, 40.6 39.8, 39.6, 39.2, 29.8,
26.2, 24.6; EI MS m/z 273 (M , 100). EI HRMS calcd for C17
13
5
4.5, 46.8, 42.4, 40.2, 39.8, 38.5, 38.0, 26.4, 25.0; EI MS m/z 305
+
(M , 97.3). EI HRMS calcd for C18
H
27
3
O N 305.1991, found
+
3
05.1992.
-)-5-Epimagellanine ((-)-23). To a suspension of CuCN (66.0
mg, 0.737 mmol) in Et O (10 mL) was added MeLi (1.0 M in Et O;
.3 mL, 1.3 mmol) at 0 °C. The reaction mixture was stirred for
5 min at the same temperature. To the reaction mixture were added
O (5.0 mL) and
TMEDA (0.1 mL) at -40 °C. The reaction mixture was stirred for
2 h at the same temperature, quenched by addition of saturated
aqueous NH Cl, and passed through a short pad of Celite with
AcOEt. The filtrate was extracted with Et O, washed with water
H
23
-
(
2
NO 273.1729, found 273.1729.
2
2
(+)-Paniculatine ((+)-3): According to the procedure described
for preparation of (-)-23 from (-)-21, the crude C14-methylated
1
1
-
2
ketone 22 was obtained from (-)-21 (24.6 mg, 7.65 × 10
a solution of (-)-21 (45.0 mg, 0.147 mmol) in Et
2
mmol). To a solution of the crude ketone 22 in THF (0.8 mL) was
added dropwise L-Selectride (1.0 M in THF; 0.38 mL, 0.38
mmol) at -10 °C. The reaction mixture was stirred for 3 h at
the same temperature, quenched by addition of water, extracted
1
4
2
with CHCl
trated to dryness. The residue was passed through a short pad of
Al with AcOEt to give the crude alcohol. To a solution of the
3
, washed with water and brine, dried, and concen-
and brine, dried, and concentrated to afford the crude ketone 22.
To a solution of the crude ketone 22 in THF (1.0 mL) were added
LDA (0.4 M in THF; 0.5 mL, 0.2 mmol) and HMPA (0.1 mL) at
2
O
3
crude alcohol in pyridine (0.5 mL) was added benzoyl chloride
(0.02 mL, 0.16 mmol) at room temperature. The reaction mix-
ture was stirred for 10 h at 50 °C, quenched by addition of satu-
-
20 °C. The reaction mixture was stirred for 1 h at the same
temperature. To the reaction mixture was added a solution of N-tert-
butylbenzenesulfinimidoyl chloride (95.4 mg, 0.442 mmol) in THF
3 3
rated aqueous NaHCO , extracted with CHCl , washed with water
(
-
1
0.5 mL) at -20 °C. The reaction mixture was stirred for 3 h at
and brine, dried, and concentrated to give crude benzoate. The
mixture of the crude benzoate and 10% aqueous HCl (0.10 mL,
0.27 mmol) in MeOH (0.5 mL) was stirred for 17 h at 45 °C,
20 °C, allowed to warm gradually to 0 °C, stirred for additional
h at 0 °C, quenched by addition of saturated aqueous NH Cl,
O, washed with water and brine, dried, and
4
extracted with Et
2
quenched by addition of saturated aqueous NaHCO
CHCl , washed with water and brine, dried, and concentrated
to dryness. The residue was passed through a short pad of silica
gel with CHCl -MeOH (10:1) to give crude alcohol. To a solu-
tion of the crude alcohol in CH Cl (0.5 mL) was added Dess-
3
, extracted with
concentrated to dryness. The residue was chromatographed on a
short pad of silica gel with AcOEt-MeOH (1:1) to recover the
ketone (7.4 mg, recovered yield 16%) and with MeOH to give the
crude R,â-unsaturated ketone. To a solution of R,â-unsaturated
ketone in MeOH (1.5 mL) was added 10% aqueous HCl at room
temperature. The reaction mixture was stirred for 2 h at 45 °C,
3
3
2
2
Martin periodinane (46.2 mg, 0.109 mmol) at room tempera-
ture. The reaction mixture was stirred for 40 min at the same
quenched by addition of saturated aqueous NaHCO
AcOEt, washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed on Al with AcOEt-
MeOH (10:1) to give (-)-23 (17.7 mg, 44% from (-)-21) as a
3
, extracted with
temperature, quenched by addition of saturated aqueous Na
and saturated aqueous NaHCO , extracted with CHCl , washed
with water and brine, dried, and concentrated to give crude ketone.
The mixture of the crude ketone and conc. aqueous NaOH (0.1
mL) in MeOH (0.5 mL) was stirred for 1.5 h at room temper-
2 2 3
S O
3
3
2
O
3
30
-1
colorless oil: [R]
D
3
-15.9 (c 0.23, CHCl ); IR 3421, 1651 cm ;
1
H NMR δ 5.88 (s, 1H), 3.80 (ddd, 1H, J ) 9.5, 5.9, 5.9 Hz),
ature. The reaction mixture was extracted with CHCl
with water and brine, dried, and concentrated to dryness. The resi-
due was chromatographed on Al with CHCl -MeOH (5:1) to
give (+)-3 (11.6 mg, 55% from (-)-20) as colorless solids: mp
3
, washed
2
(
1
5
.70-2.53 (m, 3H), 2.39-2.34 (m, 1H), 2.26-1.79 (m, 9H), 2.21
s, 3H), 1.93 (s, 3H), 1.69-1.60 (m, 2H), 1.54 (ddd, 1H, J ) 13.7,
2
O
3
3
1.7, 9.8 Hz); 13C NMR δ 202.8, 157.8, 125.3, 77.9, 62.9, 60.0,
3
0
6.5, 54.5, 46.7, 42.2, 41.3, 40.9, 39.8, 38.2, 30.3, 26.5, 24.5; EI
178-179 °C (acetone); [R]
D
3
+75.1 (c 0.17, CHCl ); IR 3408,
+
-1 1
MS m/z 275 (M , 100). EI HRMS calcd for C17
H25NO
2
275.1885,
1722 cm ; H NMR δ 3.83 (br s, 1H), 2.81-2.71 (m, 2H), 2.56-
1.68 (m, 13H), 2.31 (s, 3H), 1.34-1.22(m, 4H), 0.93 (d, 3H, J )
found 275.1885.
J. Org. Chem, Vol. 72, No. 26, 2007 10153

Kozaka et al.
6
4
.6 Hz); 13C NMR δ 220.4, 75.5, 58.5, 57.5, 53.4, 51.9, 46.3, 44.0,
Education, Culture, Sports, Science and Technology, Japan, for
which we are grateful.
Supporting Information Available: 1H and 13C NMR spectra
for compounds 1-3, 11-15, 17-21, and 23. This material is
available free of charge via the Internet at http://pubs.acs.org.
1.2, 40.2, 39.7, 39.4, 38.0, 32.3, 25.6, 22.1, 19.1; EI MS m/z 277
+
(M , 90.1). EI HRMS calcd for C17
H27NO
2
277.2042, found
2
77.2042.
Acknowledgment. This work was supported in part by a
Grant-in Aid for Scientific Research from the Ministry of
JO702136B
10154 J. Org. Chem., Vol. 72, No. 26, 2007