Total synthesis of sporochnols, fish deterrents from a marine alga

Article abstract of DOI:10.1016/S0040-4039(02)00857-2

Sporochnols, fish deterrents from a marine alga, were synthesized, using intramolecular C-H insertion of alkylidenecarbene as a key step to construct the chiral quaternary center.

Full text of DOI:10.1016/S0040-4039(02)00857-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4641–4644
Total synthesis of sporochnols, fish deterrents from a
marine alga
Susumu Ohira,* Atsuhito Kuboki, Taisuke Hasegawa, Takato Kikuchi, Tatsuhiko Kutsukake and
Maki Nomura
Department of Biological Chemistry, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005,
Japan
Received 5 April 2002; revised 1 May 2002; accepted 7 May 2002
Abstract—Sporochnols, fish deterrents from a marine alga, were synthesized, using intramolecular CꢀH insertion of alkylidenecar-
bene as a key step to construct the chiral quaternary center. © 2002 Elsevier Science Ltd. All rights reserved.
Sporochnols (1–3) are monoterpene-substituted phenols
isolated from the marine alga Sporochnus bolleanus.1
They are known to be chemical defense substances and
to exhibit feeding deterrence activity toward reef fishes.
Configuration of the asymmetric center of (+)-sporoch-
nol A (1) was determined as S by the enantioselective
synthesis of (−)-ent-1 by Ogasawara’s group in 1997.2
Each sporochnol B (2) and C (3) which includes two
stereocenters in one molecule is a 1:1 diastereomeric
mixture. Syntheses of racemic or optically active
sporochnol A (1) have recently been reported by several
groups.3 We describe here the synthesis of ( )-1 and
both enantiomers of 1, using the CꢀH insertion reaction
of alkylidenecarbene as the key step.4 (+)-1 was also
converted into 2 and 3 enriched with one of the
diastereomers to make assignment of NMR spectra of
all the diastereomers possible.
lithium aluminum hydride gave alcohol ( )-6, which
was oxidized under Swern’s conditions followed by
Wittig reaction with 1-triphenylphosphoranylidene-2-
propanone to afford a,b-unsaturated ketone ( )-7.
Hydrogenation of 7 in the presence of palladium on
charcoal gave methyl ketone ( )-8. Exposure of ( )-8
with
lithiotrimethylsilyldiazomethane5
produced
cyclopentene ( )-9 cleanly via intramolecular CꢀH
insertion of the alkylidenecarbene. It is known that the
reaction proceeds with a retention of configuration.6
The high yield (92%) of this reaction is attributable to
the low dissociation energy of the benzylic CꢀH bond
and/or the electron donating effect of p-methoxy
group.
Cyclopentene ( )-9 was subjected to epoxidation with
m-chloroperbenzoic acid to give epoxide ( )-10 as a
diastereomeric mixture. The reaction of ( )-10 with
diethylaluminum N,N-tetramethylpiperazide7 at room
temperature gave the rearranged allyl alcohol ( )-11.
The possible isomer, which contains an endo double
bond in the five-membered ring, was not produced at
all. Dihydroxylation of the double bond of ( )-11 using
OsO4 under catalytic conditions gave triol ( )-12 as a
diastereomeric mixture. The stereochemistry of ( )-10
and ( )-12 was not examined in detail because stereo-
centers except the benzylic quaternary center would
disappear in the next step. Cleavage of two CꢀC bonds
of ( )-12 occurred by treatment with excess NaIO4 via
the intermediate ( )-13 to give aldehyde ( )-14. Direct
reaction of ( )-14 with excess methylenetriphenylphos-
phorane in DMSO gave the desired product ( )-15 in
good yield. Reduction of acid ( )-15 with lithium alu-
minum hydride in THF gave alcohol ( )-16. The con-
Alkylation of the enolate of the ester
iodomethane in the presence of DMPU in THF gave
4 with
( )-5 in good yield. Reduction of ester ( )-5 with
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00857-2

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S. Ohira et al. / Tetrahedron Letters 43 (2002) 4641–4644
PPL in methanol to give acetate (−)-18 and alcohol
(−)-6 ([h]2D5 −16.8 (c 1.25, CHCl3) in 49% and 51% yield,
respectively (Scheme 1). Hydrolysis of (+)-18 with
aqueous KOH in methanol gave (+)-6 ([h]2D5 +16.8 (c
1.37, CHCl3) (Scheme 2). The absolute configuration of
the alcohol (6) was known10 and the enantiomeric
excess of (−)-6 and (+)-6 was calculated from NMR
spectra of MTPA esters of the alcohols as 93% ee and
95% ee, respectively. E value of the kinetic resolution
was 96.4.
version of ( )-12 to ( )-16 was achieved without chro-
matographic separation of intermediates in 65% overall
yield. Swern oxidation of alcohol ( )-16, followed by
the
Wittig
reaction
using
isopropyridenetri-
phenylphosophorane gave diene ( )-17. Although the
reaction of ( )-17 and boron tribromide gave no
desired product due to the addition of generated hydro-
gen bromide to double bonds, treatment of ( )-17 with
1
Ph2PLi8 at 50°C afforded the ( )-1 in good yield. H
NMR, 13C NMR, IR, and MS spectra of the synthetic
compound were essentially identical to those of the
natural product.1
In the same way as the synthesis of ( )-1, (+)-6 was
converted to (−)-7 and then into (+)-8. Although the
small value of the optical rotations of (−)-7 (−1.3°) and
(+)-8 (1.5°) implied occurrence of partial racemization
of the intermediate, (+)-8 was converted into the final
compound 1. The synthetic sporochnol A thus obtained
showed essentially no optical rotation. Racemization of
the aldehyde during the Wittig reaction was significant,
Establishing the pathway from ester 4 to ( )-1, our
attention then turned to the preparation of optically
active sporochnols. Since Matsumoto et al. reported the
effective enzymatic resolution of 1-acetoxy-2-
(aryl)propanes,9 we applied their conditions to acetate
( )-18, derived from ( )-6. ( )-18 was hydrolyzed with
Scheme 1. Reagent and conditions: (i) LDA; MeI, DMPU, THF, −78°C (quant.); (ii) LiAlH4, Et2O, rt (98%); (iii) DMSO (COCl)2,
Et3N, CH2Cl2, −78°C; (iv) Ph3PꢁCHCOCH3, benzene, 60°C (67% from 6); (v) H2, EtOAc, Pd/C, rt (89%); (vi) TMSC(Li)N2,
THF, 0°C (92%); (vii) mCPBA, NaHCO3, CH2Cl2, rt (91%); (viii) LTMP, Et2AlCl, toluene, 0°C (quant.); (ix) OsO4, NMO,
THF-H2O, rt (96%); (x) NaIO4, THF, H2O, rt; (xi) Ph3PꢁCH2, DMSO, 40°C; (xii) LiAlH4, (65% from 12); (xiii) DMSO, (COCl)2,
Et3N, CH2Cl2, −78°C; (xiv) Ph3PꢁC(CH3)2, DMSO, 40°C (74% from 16); (xv) Ph2PLi, THF, 50°C (85%).

S. Ohira et al. / Tetrahedron Letters 43 (2002) 4641–4644
4643
Scheme 2. Reagent and conditions: (i) PPL, MeOH, buffer, 35°C (quant.); (ii) KOH, MeOH, H2O, rt (97%).
so that modification of the route which excludes the
aldehyde as an intermediate is imperative.
natural product. (−)-1 ([h]2D5 −5.4 (c 1.48, CHCl3);
lit.3b: [h]D20 −2.5 (c 1, CHCl3)) was also obtained in the
same way from (−)-6. As the yield of each step was
good, we were able to obtain about 0.5 g of both
enantiomers of sporochnol A.
After many trials, we found that the tosylate 21
obtained from (+)-6 reacted with sodium cyanide
cleanly to give nitrile (+)-22 ([h]2D5 +8 (c 0.19, CHCl3))
(Scheme 3). (+)-22 was reduced with DIBAL to the
aldehyde that was submitted to Wordsworth–Emmons
reaction using triethyl phosphonoacetate and butyl-
lithium, giving a,b-unsaturated ester 23 as a cis–trans
mixture. After hydrolysis of the ester, the carboxylic
acid was treated with DPPA and triethylamine under
Shioiri’s conditions.11 The Curtius rearrangement
product thus obtained was hydrolyzed without isola-
tion to give methyl ketone (+)-8 ([h]2D5 +17 (c 0.29,
CHCl3). (+)-8 was transformed to (+)-1 ([h]2D5 +5.8 (c
0.95, CHCl3); lit.3a: [h]D30 +2.9 (c 1, CHCl3); natural1:
[h]D +10 (c 1, CHCl3)), using the established sequence
as shown in Scheme 1. The physical properties of
synthetic sporochnol A were identical to those of the
Conversions of (+)-1 into other sporochnols were
achieved as follows (Scheme 4). Epoxidation of (+)-1
with m-chloroperbenzoic acid gave
2 as a 1:1
diastereomeric mixture. Treatment of 2 with diethyl-
aluminum N,N-tetramethylpiperazide afforded 3 in
1
good yield. H NMR and 13C NMR spectra of 2 and
3 were identical with those of natural products. For
the complete assignment of the NMR spectra of 2 and
3, one of the diastereomers of 2 (2a, 62% de) was
prepared in three steps (protection, Shi asymmetric
epoxidation12 and deprotection). Rearrangement of 2a
afforded 3a, thus all signals of 1H NMR and 13C
NMR of
2
and
3
were assigned to each
diastereomer.13
Scheme 3. Reagent and conditions: (i) TsCl, Py, CH2Cl2, rt (93%); (ii) NaCN, DMSO, 80°C (89%); (iii) DIBAL, toluene, rt; (iv)
(EtO)2P(O)CH(Me)COOEt, BuLi, THF, rt (93% from 22); (v) KOH, H2O, MeOH, rt; (vi) DPPA, Et3N, toluene, rt; (vii) HCl,
H2O (62% from 23).
Scheme 4. Reagent and conditions: (i) mCPBA, NaHCO3, CH2Cl2, rt (quant.); (ii) LTMP, Et2AlCl, toluene, 0°C (96%); (iii)
TBDMSOTf, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, 0°C (95%); (iv) 24, oxone, n-Bu4NHSO4, buffer, dimethoxymethane, rt
(65%); (v) TBAF, THF, 0°C (98%).

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S. Ohira et al. / Tetrahedron Letters 43 (2002) 4641–4644
9. Matsumoto, T.; Takeda, Y.; Terao, H.; Takahashi, T.;
Acknowledgements
Wada, M. Chem. Pharm. Bull. 1993, 41, 1459–1461.
10. Senanayake, C. H.; Larsen, R. D.; Bill, T. J.; Corley, E.
G.; Reider, P. J. Synlett 1994, 199–200.
The authors are grateful to Professor W. Fenical, Uni-
versity of California—San Diego, for kindly providing
the 1H NMR and 13C NMR spectra of natural
sporochnols.
11. Yamada, S.; Ninomiya, K.; Shioiri, T. Tetrahedron Lett.
1973, 1595–1598.
12. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J.
Am. Chem. Soc. 1997, 119, 11224–11235.
1
13. 2a: H NMR (500 MHz, CDCl3) l 7.166 (2H, d, J=8.7
Hz), 6.769 (2H, d, J=8.7 Hz), 5.987 (1H, dd, J=10.7,
17.4 Hz), 5.086 (1H, dd, J=10.7, 1.2 Hz), 5.035 (1H, dd,
J=17.4, 1.2 Hz), 2.691 (1H, t, J=6.3 Hz), 1.909 (1H, dt,
J=12.8, 4.6 Hz), 1.805 (1H, dt, J=12.8, 4.9 Hz), 1.24–
1.50 (2H, m), 1.347 (3H, s), 1.284 (3H, s), 1.170 (3H, s);
13C NMR (125 MHz, CDCl3) l 153.66, 146.81, 138.98,
127.77, 114.88, 111.73, 64.81, 58.70, 43.39, 37.46, 24.87,
24.83, 24.21, 18.61. 2b (diastereomer of 2a): 1H NMR
(500 MHz, CDCl3) l 7.166 (2H, d, J=8.7 Hz), 6.769 (2H,
d, J=8.7 Hz), 5.980 (1H, dd, J=10.7, 17.4 Hz), 5.105
(1H, dd, J=10.7, 1.2 Hz), 5.045 (1H, dd, J=17.4, 1.2
Hz), 2.694 (1H, t, J=6.3 Hz), 1.994 (1H, ddd, J=13.4,
9.6, 7.6 Hz), 1.723 (1H, ddd, J=13.4, 9.4, 7.4 Hz),
1.24–1.50 (2H, m), 1.342 (3H, s), 1.293 (3H, s), 1.206 (3H,
s); 13C NMR (125 MHz, CDCl3) l 153.68, 146.56, 139.15,
127.69, 114.90, 111.96, 64.81, 58.70, 43.37, 37.38, 24.87,
24.98, 24.25, 18.56. 3a: 1H NMR (500 MHz, CDCl3) l
7.147 (2H, d, J=8.3 Hz), 6.746 (2H, d, J=8.3 Hz), 5.984
(1H, dd, J=10.7, 6.7 Hz), 5.070 (1H, d, J=12.2 Hz),
5.012 (1H, d, J=17.7 Hz), 4.915 (1H, bs), 4.834 (1H, bs),
4.012 (1H, t, J=6.4 Hz), 1.764 (1H, dt, J=13.0, 4.9 Hz),
1.670 (1H, dt, J=13.0, 4.9 Hz), 1.34–1.51 (2H, m), 1.621
(3H, s), 1.329 (3H, s); 13C NMR (125 MHz, CDCl3) l
153.70, 147.03, 147.02, 139.13, 127.74, 114.91 111.60,
111.50, 76.58, 43.26, 36.64, 29.60, 25.08, 17.35. 3b
(diastereomer of 3a): 1H NMR (500 MHz, CDCl3) l
7.147 (2H, d, J=8.3 Hz), 6.746 (2H, d, J=8.3 Hz), 5.977
(1H, dd, J=10.7, 6.7 Hz), 5.070 (1H, d, J=12.2 Hz),
5.012 (1H, d, J=17.7 Hz), 4.915 (1H, bs), 4.834 (1H, bs),
4.012 (1H, t, J=6.4 Hz), 1.853 (1H, dt, J=12.9, 4.6 Hz),
1.587 (1H, dt, J=12.9, 4.6 Hz), 1.34–1.51 (2H, m), 1.648
(3H, s), 1.329 (3H, s); 13C NMR (125 MHz, CDCl3) l
153.71, 147.03, 147.00, 139.18, 127.73, 114.91, 111.64,
111.47, 76.60, 43.26, 36.64, 29.64, 25.01, 17.40.
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