Synthesis of phoracantholide I based on stereospecific fragmentation reactions

Article abstract of DOI:10.1016/0040-4039(91)80090-S

Phoracantholide I was synthesized on the basis of silica gel-catalyzed fragmentation to the ring-enlarged lactones.

Full text of DOI:10.1016/0040-4039(91)80090-S

Tetx~edron Letters, Vol.32, No 40, pp 5585-5588, 1991
Printed m Great Britain
0040~039/91 $3 00 +
Pergamon Press plc
Synthesis of Phoracantholide I Based on
Stereospecific Fragmentation Reactions
Shinji Nagumo, Hiroshi Suemune and Kiyoshi Sakai*.
Faculty of PharmaccuUcal Sciences, Kyushu Untvcrslty, Fukuoka 812, Japan
Key words R-(-)-Phoracanthohde l; fragmentatton, epoyadatton, hydrogen bond, sdtca gel, acetal
Abstract: Phoracanthohde I was synthestzed on the basts of sthca gel-catalyzed fragmentauon to the ring- enlarged lactones
Fragmentation reactions seem to be one of the fundamental reactions to elicit the ring transformations which
provide a variety of strategies for the synthesis of a complex molecule.1 During studies on the novel ring
transformation2 developed in this laboratory, we found the fragmentation reacuon to the ring-enlarged lactone
rings,3 as shown in Scheme I. This reaction, coupled with the ready preparation of the intramolecule acetal,
seems to be widely apphed for the synthesis of natural products having the lactone moiety in the molecule.
We w:sh to report here an asymmetric synthesis of (R)-(-)-Phoracanthohde I, on the basis of facile ring
cleavage of an mtramolecule acetal to the ring-enlarged lactone. Phoracantholide I (1),4 possessing a ten-
membered lactone ring, has been isolated as defensxve secretion from the metasternal gland of the eucarypt
longlcorn, Pholacantha synonyma.
Scheme I
°oM
Scheme II
0
!
0
.,OH
~
o
!
o
o
o
o .
o.s,
>
,cooE,
R-(-)-I
1 0
4
2
The retrosynthetxc analysis of (R)-(-)-I as shown in Scheme II allows us to select the wicyclic mesylate (10) as
a key intermediate. The acetal moiety in compound 10 may be prepared from 4 via the epoxidation process with
MCPBA, because a preliminary experiment5a suggests that the epoxtdatlon of the ¢t-butenyl cyclic ketone does
not afford the epoxlde, but the internal acetal.5b
In a synthests of the chiral 4, (1R,2S)-l-ethoxycarbonyl-2-hydroxycyclohexane (2) is suitable for chiral
synthon, and can be readily prepared by a biological method.6 Alkylatton [LDA (2eq.), butenyl bromide, HMPA,
THF, -78°C, 3 h] of 2, according to Fr~iter's method,7 proceeded in a stereocontrolled fashion, and subsequent
oxidation with PCC m CH2C12 afforded (S)-4 in 35% yield. Epoxidation of (S)-4 with MCPBA in CH2C12 at
room temperature for 24 h gave two diastereomenc acetals, (+)-5 [Ct]D23 +9.95* (c 1.9, CHC13) (35%) and
(-)-6 let]D23 -67.9* (c 1.89, CHC13) (42%), wh:ch could be separated easdy by column chromatography on
5585

;586
Scheme III
9R
9S
OH
3
OOEI "1"
)-5
L ~ - COOEr
2
( - ) - 6
o
o-k-
~~co
" ~ o
"l-
( - ) - 6
7
o
r ~ o
.OH
0
0
+
O
... OH
( - ) - 6 - - ~
OCH 3 --
O
O
•;130H
9b
:1~OMs --
1
L
10b
J
°
o
,
_
_
12
1 5
O
1 6 k_../
P h o r a c a n t h o l i d e
I
13
14
R=H
Fig
I
RO4f 1 3
H
CH3.H~13 ~
CH34P' 1 3
9a
OSO2CH3
Unfavorable form
of 10a
9b (R=H)
10b (R=SO2CH3)
Unfavorable form
of 9b
sihca gel. As described above, the epoxide was not obtained under the employed reaction conditions. In both
acetals, the S configttrat~on at C6 should be retained, but the configuration at C9 remains unclear.
To solve this stereochemical problem in (+)-5 and (-)-6, we attempted to synthesize 5 and 6 using the
configuratlonally known alcohol. Alkylation of 2-ethoxycarbonylcyclohexanone with (S)-1-iodo-3,4-isopropyl-
idenedioxybutane 8 [t-BuOK, DMSO, room temp 3 h] gave the acetonide (7) m 60% yield. The S-configuration
of the side chain in 7 should be retained, although this compound is an inseparable dmstereomeric mixture.

5587
Exposure (30 rain) of 7 with 10%-HC1 afforded two acetals, which could be separated by sdlca-gel column
chromatography. One is the enantlomer of above (+)-5, (-)-5 ([~]D23 -10.8" (c 2.06, CHCI3) (45%)) and the
other is identical with (-)-6 ([0t]D23 -62.0" (c 1.95, CHC13) (40%)). These results allow us to conclude that the
absolute configuration of (-)-5 can be assigned as (1R,6R,9S), (+)-5 as (1S,6S,9R), and (-)-6 as (1R,6S,9S), as
depicted in Scheme HI.
Treatment (ether, 0°C, 10 min) of (-)-6, which bears the desired S configuration at C9 for synthesis of (R)-(-)-
phoracantholide I, with MeLi afforded the ketone (8) in 84% yield. Reduction (LAH, ether, 5 min) of 8 gave, in
96% yield, a mixture (1:1.7) of the alcohols, which could be readily separated into 9a (mp 86"C) and 9b (mp 60
°C) by silica-gel column chromatography. The configuration of the alcohol at C13 m 9a,b was determined on the
basis of the 1H-NMR spectral data. The OH proton in 9a was observed at a lower field (8 4.3) than that ofgb (8
1.7), indicating the presence of a hydrogen bond.9 The presence of a hydrogen bond was also supported by the
findings that the C13-H in 9a was observed as a sharp quartet signal (8 4.36, J=6.27 Hz), in contrast to the
broad quartet in 9b (8 4.20). The absence of an intramolecule hydrogen bond in 9b is rationalized, as shown in
Fig. I (unfavorable form of 9b), by the steric repulsion between C13-Me and 1,3-diaxial hydrogen in the
cyclohexane ring which hinders the formation of a hydrogen bond. The validity of the above observation was
supported by the result of sihca-gel catalyzed-Grob type fragmentation. 10
Treatment of 9a with methanesulfonyl chloride (DMAP, pyridine, CH2C12, room temp., 24 h) and subsequent
purification by column chromatography on silica gel afforded the mesylate (10a) in 90% yield. No Grob type
fragmentation of 10a under various conchtions was observed. This may be attributable to the steric repulsion
(Fig. I, 10a) between C13-Me and 1,3 diaxial hydrogen in cyclohexane which hinders the antiperiplanar
orientation of the leaving group and oxygen required for fragmentation. Mesylation of 9b proceeded much faster
(30 min) than in the case of 9a under the same conditions. This also indicates the absence of an internal hydrogen
bond in 9b. In accordance with our expectation, 9b with the stereochemically desired antiperiplanar orientation
for fragmentation underwent facile ring cleavage to afford a mixture (80% yield) of two lactones (11 and 12)
during silica-gel column chromatography. The two lactones could be readily separated into 11 and 12 in the ratio
of 1 to 10 by column chromatography on silica gel. The geometry of the double bond in each lactone was deduced
on the basis of antiperiplaner mechanism, as depicted in Fig. 1.
Conversion of the hydroxy lactone (12) to phoracantholide I necessitates removal of the ethylidene and
hydroxy functions. Tosylation [TsCI, pyridine, CH2C12, 3 hi of the hydroxy group in 12 followed by reduction
by Ueno's method11 [NaI, Bu3SnH, AIBN, DME, reflux, 1 h] provided the methyl lactone (14) in 71% yield.
Ozonolysis of 14 followed by thioacetalization [ethanedithiol, BF3-Et20, CH2C12, room temp, 10h] afforded in
73% yield the thioacetal (16), which, upon treatment with Raney-Ni in refluxing methanol,12 afforded in 90%
yield phoracantholide I (1) [[0~]D23 -32.1" (c 0.56, CHC13)]. Spectroscopic data of the synthetic material were in
good agreement with those reported. 4
R e f e r e n c e s and n o t e s .
1. For example, see (a) Fuchs, P. L.; Clark, D. A. J. Am. Chem. Soc. 1979, 101, 3567. Co) Eschenmoser,
A.; Sternbach, D.; Shibuya, M.; Jalsli, F.; Bonetti, M. Angew. Chem., Int. Ed. Engl. 1979, 18, 634. (c)
Metivier, P.; Gushurst, A. J.; Jorgensen, W. L. J. Org. Chem. 1987, 52, 3724. (d) Wender, P. A.; Manly,
C. J. J. Am. Chem. Soc. 1990, 112, 8579, and references cited therein.
2. (a) Suemune, H.; Oda, K.; Sakai, K. Tetrahedron Lett. 1987, 28, 3373. (b) Tanaka, M.; Suemune, H.;
Sakai, K. Tetrahedron Lett. 1988, 29, 1733. (c) Nagumo, S.; Suemune, H.; Sakai, K. Tetrahedron Lett.
1988, 29, 6927. (d) Miyao, Y.; Tanaka, M.; Suemune, H.; Sakai, K. J. Chem. Soc., Chem. Commun.
1989, 1535. (e) Nagumo, S.; Suemune, H.; Sakai, K. J. Chem. Soc., Chem. Commun. 1990, 1778. (f)
Nagumo, S.; Matsukuma, A.; Inoue, F.; Yamamoto, T.; Suemune, H.; Sakai, K. J. Chem. Soc., Chem.

5588
Commun 1990, 1538. (g) Yamamoto, T.; Eki, T ; Nagumo, S.; Suemune, H.; Sakal, K Tetrahedron Lett.
1991, 32, 515.
3. Unpubhshed data.
4
For isolation: (a) Moore, B. P.; Brown, W. V. Aust. J. Chem. 1976, 29, 1365. For racemxc synthesis. (b)
Gerlach, H.; Knuzler, P.; Oertle, K. Helv. Chtm. Acta 1978, 61, 1226 (c) Ono, N., Miyake, H., Karl, A.
J. Org Chem. 84, 49, 4997 and references cited therein. For asymmetric. (d) Kitahara, T.; Koseki, K.,
Mori, K Agric. Btol. Chem. 1983, 47, 389. (e) Naoshima, Y, Hasegawa, H.; Nashlyama, T.; Nakamura,
A. Bull. Chem. Soc. Jpn. 1989, 62, 608.
5. (a) Unpublished data. (b) Pearce, G. T.; Gore, W. E.; Sdverstem, R. M J Org. Chem. 1976, 41, 2797.
6
(a) Xle, Z. -F.; Nakamura, I.; Suemune, H.; Sakai, K. J Chem Soc., Chem Commun 1988, 966 (b)
Deol, B. S.; Ridley, D. D.; Simpson, G. Aust. J. Chem. 1976, 29, 2459
7. G Fr~iter. Helv. Chim. Acta 1980, 63, 1383.
8. (S)-1-Iodo-3,4-1sopropylidenedioxybutane was synthesized by reducnon (LAH) of methyl (S)-3,4-
isopropyhdenedioxybutanoate, followed by mesylanon and substitunon with NaL For synthesis of methyl
(S)-3,4-isopropylidenedioxybutanoate: Saito, S.; Hasegawa, T.; Inaba, M., Nish~da, R, Fuji1, T., Nomizu,
S.; Monwakl, T. Chem Lett. 1984, 1389.
9. R M.Sxlverstein;"Spectrometnc identification of orgamc compounds", John Wiley & Sons Inc, New York,
1981.
10. Grob,C.A. Angew. Chem., Int. Ed Engl. 1969, 8, 535.
11. Ueno, Y ; Tanaka,C.; Okawara, M. Chem. Lett. 1983, 795.
12. Conversion of racemlc 15 into phoracantholide I had been reported by Wakamatsu, T ; Akasaka, K ; Ban, Y.
J Org Chem. 1979, 44, 2008.
S e l e c t e d s p e c t r o s c o p i c data of main products.
(+)-5. [CC]D23 (CHCI3, c = 1.9) +9.95°; IR (neat, cm"1) 2940, 1730, 1450, 1225, 1195, 1175, 1150, 1085,
1005; 1H NMR (CDC13) 8 4.55 (1 H, m), 4.18 (2 H, m), 3.87 (1 H, d, J = 6.6 Hz), 3.81 (1 H, ddd, J = 6.6,
4.6, 1.6 Hz), 2.52 (1 H, m), 2.07 (1 H, m), 1.96-1.32 (12 H, m), 1.27 (3 H, d, J = 6.9 Hz); 13C NMR
(CDC13) 8 173 75 (s), 107.98 (s), 75.22 (d), 68.12 (t), 60.26 (t), 51.96 (s), 3491 (t), 31.81 (t), 28.77 (t),
27.75 (t) 23.51 (t), 21.80 (t), 14.26 (q); MS, m/z (El, relative intensity) 240 (M+, 100), 212 (43), 195 (16),
167 (50), 108 (30), 81 (34), 67 (18), 55 (34).
(-)-6' [~]D 23 (CHC13, c = 1.89) -67.9"; IR (neat, cm-1) 2940, 1730, 1450, 1230, 1160, 1140, 1060, 1040;
1H NMR (CDC13) 8 4.51 (1 H, m), 4.15 (2 H, t, J = 7.2 Hz), 3.93 (1 tl, d, J = 6.9 Hz), 3 88 (1 H, dd, J =
6 9, 1.6 Hz), 2.47 (1 H, m), 2.11-1.19 (11 H, m), 1.25 (3 H, t, J = 7.2 Hz), 13C NMR (CDCI3) 8 174.51 (s),
108.17 (s), 73.42 (d), 68.62 (t), 60.02 (t), 51.07 (s), 32.18 (t), 27.50 (t), 26.91 (t), 25.74 (t), 23.58 (t), 22 41
(t), 14.16 (q); MS, m/z (EI, relative intensity) 240 (M+, 100), 212 (49), 195 (24), 167 (55), 108 (33), 81 (49),
67 (28), 55 (45).
9a: colorless crystalline sohd, mp 85.5-86°C (from petroleum ether), [OqD26 (CHCI3, c = 1.47) -70.6°, IR
(neat, cm-1) 3440, 2930, 2870, 1450, 1050, 1010; 1H NMR (CDC13) 8 4.54 (1 H, m), 4.36 (1 H, q, J = 6.3
Hz), 4.30 (1 H, s), 3.90-3.83 (2 H, m), 2.23-1.08 (12 H, m), 1.03 (3 H, d, J = 6.3 Hz); 13C NMR (CDCI3) 8
111 89 (s), 74.04 (d), 67.98 (t), 67.79 (d), 43.09 (s), 31.46 (t), 30.44 (t), 25.42 (t), 23.67 (t), 19.70 (t), 19.61
(t), 15.66 (q); MS, m/z (El, relative intensity) 212 (M+, 0.8), 194 (1.5), 168 (I00), 111 (43), 98 (47), 81 (39),
67 (35), 55 (61), 41 (39).
9b- colorless crystalline sohd, mp 60-60.5°C (from petroleum ether); [Ot]D22 (CHCI3, c = 1.65) -56.8°, IR
(neat, cm-1) 3460, 2940, 2870, 1450, 1050, 1020; 1H NMR (CDC13) 8 4 49 (1 H, m), 4.21 (1 H, m), 3.88-
3.80 (2 H, m), 2.18-1.15 (13 H, m), 1.29 (3 H, d, J = 6.6 Hz); 13C NMR (CDC13) 8 109.75 (s), 73.24 (d),
68.62 (d), 68.21 (t), 44.99 (s), 31.47 (t), 29.78 (t), 25.62 (t), 23.58 (t), 21.24 (t), 19.77 (t), 19.19 (q); MS,
m/z (El, relative intensity) 212 (M+, 0.8), 194 (1.2), 168 (100), 111 (38), 98 (43), 81 (40), 67 (41), 55 (57).
12:[OqD26 (CHCI3, c = 0.92) +3.00", IR (neat, cm-1) 3430, 3030, 2930, 2860, 1730, 1450, 1260, 1230,
1150, 1070, 1030, 950; 1H NMR (CDC13) 8 5.24 (1 H, q, J = 6.9 Hz), 4.93 (1 H, m), 3.69 (1 H, dd, J =
11.9, 4.1 Hz), 3.63 (1 H, dd, J = 11.9, 6.3 Hz), 2.59-2.51 (2 H, m), 2.26-1.42 (11 I-t, m), 1.65 (3 H, dd, J =
69, 2 3 Hz); 13C NMR (CDCI3) 8 175.06 (s), 137.37 (s), 116.75 (d), 77.44 (d), 65.41 (t), 35.42 (t), 32.88
(t), 29.92 (t), 29.19 (t), 25.18 (t), 20.22 (t), 13.26 (q); MS, m/z (El, relative mtensity) 212 (M+, 15), 194 (26),
181 (15), 93 (100), 81 (79), 67 (76), 55 (98),41 (71).
(Received in Japan 5 June 1991)