Synthetic studies on lycopodium alkaloid, magellanine: Stereoselective construction of functionallized angular tricyclic skeletons by intramolecular Pauson-Khand reaction

Article abstract of DOI:10.1246/cl.2001.546

Angular tricyclic compounds as intermediates for total synthesis of magellanine were synthesized by stereoselective Ireland-Claisen rearrangement and intramolecular Pauson-Khand reaction of exo-methylenecyclohexylalkynes. Interestingly, remarkably differe

Full text of DOI:10.1246/cl.2001.546

546
Chemistry Letters 2001
Synthetic Studies on Lycopodium Alkaloid, Magellanine: Stereoselective Construction of
Functionallized Angular Tricyclic Skeletons by Intramolecular Pauson–Khand Reaction
Miyuki Ishizaki,* Yuka Niimi, and Osamu Hoshino*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya Funagawara-machi, Shinjuku-ku, Tokyo 162-0826
(Received March 27, 2001; CL-010277)
Angular tricyclic compounds as intermediates for total syn-
thesis of magellanine were synthesized by stereoselective
Ireland–Claisen rearrangement and intramolecular
Pauson–Khand reaction of exo-methylenecyclohexylalkynes.
Interestingly, remarkably different reactivity was observed in
the Pauson–Khand reaction of cis- and trans-disubstituted exo-
methylenecyclohexylalkynes.
Magellanine (1), which belongs to Lycopodium alkaloids,
was isolated and characterized by MacLean and co-workers.1
Magellanine possesses a unique tetracyclic skeleton, which is
constituted by angular tricyclic framework with piperidine ring.
Due to its interesting structural characteristics, magellanine
lends itself as a challenging synthetic target and several synthet-
ic approaches have been reported.2 We recently reported3
intramolecular Pauson–Khand reaction4 of various exo-cyclic
enynes to give angular tricyclic compounds. Thus, functional-
lized angular type 6-5-5 tricyclic framework of magellanine
could be constructed by the present reaction. Here, we wish to
describe stereoselective synthesis of various functionallized
angular type 6-5-5 tricyclic compounds (12, 16) directed toward
for total synthesis of magellanine (1).
Synthetic plan of angular 6-5-5 tricyclic compounds (A) is
depicted in Scheme 1. Thus, compounds (A) should be obtained
by intramolecular Pauson–Khand reaction of exo-cyclic enynes
(B), which would be synthesized by stereoselective
Ireland–Claisen rearrangement5 of siloxyallyl acetate (D) and sub-
sequent conversion via C. Synthesis of D could be performed
from E.
TIPS ether (5a) gave trans-carboxylic acid (6a) with the highest
diastereoselectivity (Table 1, entry 1). With TIPSCl as additive
instead of TBDMSCl, both the yield and diastereoselectivity were
decreased remarkably (entry 2). When HMPA was not added, the
reaction was sluggish to give the product in low yield, although
diastereoselectivity was still good (entry 3).
After separation of carboxylic acids (6a, 7a), at first, we syn-
thesized Pauson–Khand precursors (11a,b) bearing a hydroxy
group only on cyclohexane ring. Although cis-isomer (7a) was
minor product, its conversion to Pauson–Khand precursor (11b)
was also performed, because its reactivity in Pauson–Khand reac-
tion could be compared with that of 11a. Reduction of 6a and 7a
with LiAlH4 afforded alcohols (8a,b) in quantitative yield, respec-
tively. Iodination of 8a,b followed by ethynylation of resulting
iodides (9a,b) gave enynes (10a,b) in 58% and 55% yield, respec-
tively. Unfortunately, Pauson–Khand reaction of both 10a and
10b did not give corresponding cyclized products probably due to
bulkiness of TIPS group. Therefore, desilylation of 10a,b with
TBAF was carried out to afford trans- (11a) (94% yield) and cis-
alcohols (11b) (100% yield). Gratifyingly, Pauson–Khand reaction
(NMO, CH2Cl2, r.t.)8 of trans-isomer (11a) furnished angular tri-
cyclic compound (12a)9 in 52% yield, although similar reaction of
cis-isomer (11b) gave 12b9 in only 5% yield. The reaction of 11a
in refluxing benzene afforded 12a in 26% yield, whereas that of
11b did not give 12b at all. These results would be rationalized by
consideration of transition state of two isomers (Figure 1). The
reaction of cis-isomer (11b) would suffer severe 1,3-diaxial inter-
action between alkyne-cobalt complex moiety and hydroxy group
in transition state (TS2) and the complex might exist as TS3 rather
than TS2. On the other hand, trans-isomer (11a) does not undergo
such interaction in TS1 to furnish 12a. Inspection of Dreiding
model suggested that the reaction of alkyne-cobalt complex moiety
to olefin in TS1 would more easily occur than that in TS3.
Pauson–Khand precursors (11a,b, 15) were prepared as fol-
lows (Scheme 2). Acetylation of 2-hydroxymethyl-2-cyclo-
hexenone (2)6 followed by Luche reduction7 gave an alcohol (4).
In order to examine effect of steric factor on diastereoselectivity
of Ireland–Claisen rearrangement, various silyl ethers (5a-c) were
synthesized. Among them, Ireland–Claisen rearrangement of
Since Pauson–Khand reaction of hydroxy-exo-cyclic
enynes (11) was found to proceed, we synthesized enyne (15),
which has hydroxy groups on both cyclohexane ring and side
chain. Oxidation of alcohol (8a) with Dess–Martin periodinane
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2000
547
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3
4
afforded an aldehyde (13), which was treated with ethynylmag-
nesium bromide to furnish inseparable ca. 1:1 mixture of
propargyl alcohols (14) in 82% yield. Desilylation of 14 with
TBAF gave a diol (15) in 83% yield. Pauson–Khand reaction
of 15 followed by chromatographic separation afforded desired
angular tricyclic compounds (16a,b)10 in 23% and 30% yields,
respectively. Stereochemistry of 16a and 16b was determined
by NOE experiment. Furthermore, 16b could be converted to
16a (84% yield), which has stereochemistry of the hydroxy
group on B ring corresponding to that in 1, by Mitsunobu reac-
tion and subsequent hydrolysis.
In summary, we have investigated to synthesize various
angular type 6-5-5 tricyclic compounds (12, 16) by intramolec-
ular Pauson–Khand reaction of exo-methylenecyclohexyl-
alkynes. Among them, 16a, which has two hydroxy groups on
both A and B rings, could serve a potential key intermediate for
total synthesis of magellanine (1). Approach to 1 by the present
methodology is in progress.
5
6
S. Pereira and M. Srebnik, Aldrichimica Acta, 26, 17 (1993).
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(1979).
7
8
9
S. Shambayati, W. E. Crowe, and S. L. Schreiber, Tetrahedron
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All new compounds gave satisfactory 1H and 13C NMR, IR, and
mass spectral data.
1
10 Spectral data for 16a; mp 173–175 °C; H NMR (270 MHz,
CDCl3–CD3OD) δ 6.06 (1H, s), 5.10 (1H, d, J = 9.9 Hz), 3.57
(1H, dd, J = 3.6, 11.9 Hz), 3.80 (2H, brs), 2.69, 1.98 (each 1H,
d, J = 17.5 Hz), 2.52 (1H, dt, J = 10.9, 14.2 Hz), 2.26 (1H, dt, J
= 4, 11 Hz), 1.44–1.88 (6H, m), 1.18–1.27 (1H, m); 13C NMR
(67.5 MHz, CDCl3–CD3OD) δ 212.3, 194.4, 125.0, 69.0, 68.6,
58.9, 43.6, 43.0, 37.5, 32.0, 24.3, 20.5; IR 3360, 3327, 2934,
1689, 1630 cm–1; FAB MS m/z 209 (M++1); high-resolution
FAB mass m/z calcd for C12H17O3 (M++1) 209.1178, found:
209.1168. For 16b; mp 168–170 °C; 1H NMR (270 MHz,
CDCl3–CD3OD) δ 6.03 (1H, s), 4.85 (1H, dd, J = 5.3, 7.6 Hz),
4.02 (1H, dd, J = 3.8, 12 Hz), 3.30 (2H, brs), 2.71, 1.87 (each
1H, d, J = 17.5 Hz), 2.35 (1H, dt, J = 7.8, 13.2 Hz), 2.02 (1H, dt,
J = 5.3, 12.9 Hz), 1.85–1.88 (2H, m), 1.46–1.75 (4H, m),
1.19–1.36 (1H, m); 13C NMR (67.5 MHz, CDCl3–CD3OD) δ
212.8, 187.7, 127.6, 67.9, 67.4, 58.6, 44.0, 42.4, 38.3, 32.1, 24.1,
20.6; IR 3357, 3279, 2937, 1691, 1625 cm–1; FAB MS m/z 209
(M++1); high-resolution FAB mass m/z calcd for C12H17O3
(M++1) 209.1178, found: 209.1172.
References and Notes
1
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2