Total Synthesis of 10-lsocyano-4-cadinene and Determination of Its Absolute Configuration

Article abstract of DOI:10.1021/ol9027336

Chemical Equation Presentation The first enantloselective total synthesis of 10-isocyano-4-cadinene, a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae, was achieved. The cadinene is expected to be a novel nontoxic antifouling agent. In the synthesis, an intermolecular Diels-Alder reaction and a Sml₂-induced Barbier-type reaction were employed as key steps. The absolute configuration of 10-isocyano-4-cadinene was determined to be (1S, 6S, 7R, 10S) on the basis of the total synthesis. Antifouling activities against Balanus amphitrite with both enantiomers of 10-isocyano4-cadinene were also evaluated

Full text of DOI:10.1021/ol9027336

ORGANIC
LETTERS
2010
Vol. 12, No. 5
904-907
Total Synthesis of
10-Isocyano-4-cadinene and
Determination of Its Absolute
Configuration
Keisuke Nishikawa,† Hiroshi Nakahara,† Yousuke Shirokura,† Yasuyuki Nogata,‡
Erina Yoshimura,§ Taiki Umezawa,† Tatsufumi Okino,† and Fuyuhiko Matsuda*,†
DiVision of EnVironmental Materials Science, Graduate School of EnVironmental
Science, Hokkaido UniVersity, Sapporo 060-0810, Japan, EnVironmental Science
Research Laboratory, Central Research Institute of Electric Power Industry,
1646 Abiko, Abiko, Chiba 270-1194, Japan, and CERES, Inc., 1-6-1 Ogawa-cho,
Kanda, Chiyoda-ku, Tokyo 101-0052, Japan
fmatsuda@ees.hokudai.ac.jp
Received November 26, 2009
ABSTRACT
The first enantioselective total synthesis of 10-isocyano-4-cadinene, a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae,
was achieved. The cadinene is expected to be a novel nontoxic antifouling agent. In the synthesis, an intermolecular Diels-Alder reaction and
a SmI2-induced Barbier-type reaction were employed as key steps. The absolute configuration of 10-isocyano-4-cadinene was determined to
be (1S, 6S, 7R, 10S) on the basis of the total synthesis. Antifouling activities against Balanus amphitrite with both enantiomers of 10-isocyano-
4-cadinene were also evaluated.
10-Isocyano-4-cadinene (1), a marine sesquiterpene isolated
by Okino et al.1 from nudibranchs of the family Phyllidiidae
along with other sesquiterpenes, such as 10-isocyano-4-
amorphene (2), 2-isocyanotrachyopsane (3), and axisoni-
trile-3 (4), exhibits potent antifouling activity2 against the
larvae of the barnacle Balanus amphitrite (Figure 1). As a
fouling inhibitor, tributyltin (TBT)3 has been used widely
in ships’ hulls and fishing nets since the early 1960s.
Unfortunately, due to the toxicity of TBT, the marine
environment has been seriously compromised. For example,
TBT-exposed oysters exhibit abnormal shell development,
brittle shells, poor weight gain, and imposex.4 Thus, cadinene
1 is expected to be a novel lead compound5 for nontoxic
antifouling agents. Structurally, 1 has four continuous
stereocenters, including a quaternary carbon center with a
biologically important isocyanide group. Although the rela-
tive configuration of 1 was assigned as shown in Figure 1
(4) Horiguchi, T.; Shiraishi, H.; Shimizu, M.; Yamazaki, S.; Morita,
M. Mar. Pollut. Bull. 1995, 31, 402–405.
† Hokkaido University.
(5) (a) Kitano, Y.; Ito, T.; Suzuki, T.; Nogata, Y.; Shinshima, K.;
Yoshimura, E.; Chiba, K.; Tada, M.; Sakaguchi, I. J. Chem. Soc., Perkin
Trans. 2002, 1, 2251–2255. (b) Kitano, Y.; Yokoyama, A.; Nogata, Y.;
Shinshima, K.; Yoshimura, E.; Chiba, K.; Tada, M.; Sakaguchi, I. Biofouling
2003, 19, 187–192. (c) Nogata, Y.; Kitano, Y.; Yoshimura, E.; Shinshima,
K.; Sakaguchi, I. Biofouling 2004, 20, 87–91. (d) Kitano, Y.; Nogata, Y.;
Shinshima, K.; Yoshimura, E.; Chiba, K.; Tada, M.; Sakaguchi, I. Biofouling
2004, 20, 93–100.
‡ Central Research Institute of Electric Power Industry.
§ CERES, Inc.
(1) Okino, T.; Yoshimura, E.; Hirota, H.; Fusetani, N. Tetrahedron 1996,
52, 9447–9454.
(2) (a) Fusetani, N. Nat. Prod. Rep. 2004, 21, 94–104. (b) Garson, M. J.;
Simpson, J. S. Nat. Prod. Rep. 2004, 21, 164–179.
(3) Evans, S. M. Biofouling 1999, 14, 117–129.
10.1021/ol9027336  2010 American Chemical Society
Published on Web 02/04/2010

cyclohexane ring of 8, Barbier-type cyclization induced by
SmI2 would be employed with aldehyde 9, derived from the
carboxylic acid 10. As mentioned above, the trans relation-
ship at C1 and C6 in 10 would be constructed by an
intermolecular Diels-Alder reaction with methyl acrylate
and the diene 11, followed by isomerization.
The synthesis commenced with the known imide 12,9
prepared via Evans alkylation with allyl bromide (Scheme
2). After the OsO4 oxidation of the olefin moiety followed
Scheme 2. Synthesis of Diene Alcohol 17
Figure 1. Sesquiterpenes from nudibranchs of the family Phylli-
diidae.
using 1D and 2D NMR experiments, the absolute configu-
ration has not been determined. Herein, we report the first
total synthesis of both enantiomers of 1 and the determination
of absolute configuration based on the enantioselective total
synthesis.
Scheme 1. Retrosynthetic Analysis of 10-Isocyano-4-cadinene
by spontaneous lactonization of the resultant diol, acetylation
of the primary alcohol gave the acetate 13, and the chiral
auxiliary was recovered.9b The acetate 13 was converted into
the alcohol 14 through LiBH4 reduction and subsequent
selective acetonide protection of the 1,2-diol moiety. Swern
oxidation of 14 and successive Horner-Wadsworth-Emmons
reaction using diethyl (2-methylallyl) phosphonate 157m,10
yielded the E-diene 16 as a single geometric isomer. The
diene 16 was then transformed to the intermolecular
Diels-Alder precursor 11 by the following sequence of
transformations: (1) one-pot deprotection of the acetonide
group and oxidative treatment with NaIO4, (2) reduction of
the resulting aldehyde (Scheme 2), and (3) acetylation
(Scheme 3). The intermolecular Diels-Alder reaction of 11
with methyl acylate in the presence of MeAlCl211 in xylene12
afforded cyclohexene 18 as a mixture of four diastereomers
Retrosynthetic analysis of 1 is shown in Scheme 1. We
envisioned the construction of the trans relationship between
C1 and C6 by intermolecular Diels-Alder reaction6 followed
by isomerization under basic conditions because it is known
that cis-decalin frameworks are selectively formed through
the corresponding intramolecular Diels-Alder reaction.7,8
The functional groups at C10 would be installed with the
ketone 8 at a later stage of the synthesis. To construct the
(7) (a) Vig, O. P.; Trehan, I. R.; Kumar, R. Indian J. Chem., Sect. B
1977, 15B, 319–321. (b) Taber, D. F.; Gunn, B. P. J. Am. Chem. Soc. 1979,
101, 3992–3993. (c) Parker, K. A.; Iqbal, T. J. Org. Chem. 1982, 47, 337–
342. (d) Katayama, M.; Marumo, S. Tetrahedron Lett. 1983, 24, 1703–
1706. (e) Vig, O. P.; Sharma, M. L.; Kiran, S.; Singh, J. Indian J. Chem.,
Sect. B 1983, 22B, 746–748. (f) Mori, K.; Waku, M. Tetrahedron 1984,
40, 305–309. (g) Parker, K. A.; Farmar, J. G. J. Org. Chem. 1986, 51,
4023–4028. (h) Davidson, B. S.; Plavcan, K. A.; Meinwald, J. J. Org. Chem.
1990, 55, 3912–3917. (i) Roush, W. R.; Champoux, J. A.; Peterson, B. C.
Tetrahedron Lett. 1996, 37, 8989–8992. (j) Tashiro, T.; Bando, M.; Mori,
K. Synthesis 2000, 1852–1862. (k) White, R. D.; Wood, J. L. Org. Lett.
2001, 3, 1825–1827. (l) Miyaoka, H.; Shida, H.; Yamada, N.; Mitome, H.;
Yamada, Y. Tetrahedron Lett. 2002, 43, 2227–2230. (m) White, R. D.;
(6) (a) Vig, O. P.; Chugh, O. P.; Matta, K. L. Indian J. Chem. 1970, 8,
29–32. (b) Kitahara, T.; Kurata, H.; Matsuoka, T.; Mori, K. Tetrahedron
1985, 41, 5475–5485.
Keaney, G. F.; Slown, C. D.; Wood, J. L. Org. Lett. 2004, 6, 1123–1126
.
Org. Lett., Vol. 12, No. 5, 2010
905

With the cyclohexene in hand, we turned our attention to
construction of the right side cyclohexane ring and the
quaternary carbon center at C10. The carboxylic acid 10 was
transformed to the cyclization precursor 9 in 4 steps (Scheme
4). The SmI2-induced Barbier-type cyclization14 of 9 in the
Scheme 3. Diels-Alder Reaction Using the Lewis Acid
Scheme 4. Synthesis of Nitrile 22
in good yield. The mixture was equilibrated with NaOMe
in MeOH (0.08 M) to that of the two trans-esters 19 and
20. The desired ester 19 was hydrolyzed with complete
selectivity by the slow addition of 1 N HCl to the MeOH
solution at 0 °C to provide the easily separable mixture of
the desired carboxylic acid 10 and the unhydrolyzed ester
20 (10:20 ) 2:1). Separation of these two trans diastereomers
was essential for the total synthesis. After extensive studies,
we found the excellent method mentioned above.13
presence of HMPA occurred cleanly in excellent yield to
give the alcohol 21, which was oxidized with Dess-Martin
periodinane (DMP).15 To construct the quaternary carbon
center, the nitrile 22 was derived from ketone 8 with
p-toluenesulfonylmethyl isocyanide (TosMIC).7l,16 The nitrile
22 was next reduced to the aldehyde 23 (Scheme 5).17 The
alkylation of 23 with p-methoxybenzyl chloromethyl ether
2418 successfully afforded the PMB ether,19,20 which was
subjected to Wolff-Kishner conditions21 to afford the PMB
ether 25 as a single diastereomer. The PMB ether 25 was
(8) For a typical example, the intramolecular Diels-Alder reaction of
the (()-trienone 5 afforded a mixture of the (()-cis-decalins 6 and 7 in a
ratio of 89.7:10.3. Furthermore, the mixture of 6 and 7 was isomerized by
NaOMe in MeOH forming an inseparable mixture of the (()-trans-decalin
8 and 6 and 7 in a ratio of 42.7:47.2:10.1. See ref 7b.
(14) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216–
7227. (b) Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62, 2944–
2956. (c) Tamiya, H.; Goto, K.; Matsuda, F. Org. Lett. 2004, 6, 545–549.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(16) Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1973, 14,
1357–1360
.
(17) Alkylation of 22 under various conditions resulted in low yield or
a complex mixture. See ref 7l.
(9) (a) Hodgson, D. M.; Foley, A. M.; Lovell, P. J. Synlett 1999, 744–
746. (b) Ru¨eger, H.; Stutz, S.; Spindler, F.; Maibaum, J. Tetrahedron Lett.
2000, 41, 10085–10089.
(18) (a) Benneche, T.; Strande, P.; Undheim, K. Synthesis 1983, 762–
763. (b) Go´mez, C.; Macia´, B.; Lillo, V. J.; Yus, M. Tetrahedron 2006,
62, 9832–9839.
(10) Wang, Y.; West, F. G. Synthesis 2002, 99–103.
(11) (a) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402–
7403. (b) Schu¨rer, S. C.; Blechert, S. Synlett 1999, 1879–1882. (c) Roush,
W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett. 2002, 4, 1543–
1546.
(12) Among the solvents examined (xylene, toluene, benzene, and
CH2Cl2), xylene was found to be the best for yield.
(13) For example, treatment of 18 (four diastereomers) with NaOMe in
dilute MeOH solution (0.02 M) and neutralization with 1 N HCl afforded
a mixture of 19 and 20 without hydrolysis of the methyl ester moiety.
Attempted separation of 19 and 20 by silica gel chromatography failed.
(19) R-Alkylation of 23 took place from an equatorial orientation in a
completely stereoselective manner. For similar equatorial alkylations, see:
(a) Ireland, R. E.; Mander, L. N. J. Org. Chem. 1967, 32, 689–696. (b)
Ireland, R. E.; Mander, L. N. J. Org. Chem. 1969, 34, 142–152. (c)
Vishnumuthy, K.; Cheung, E.; Scheffer, J. R.; Scott, C. Org. Lett. 2002, 4,
1071–1074
.
(20) It was found that R-alkylation of 23 with MeI and t-BuOK and
Pinnick oxidation gave the 10-epimer of 26 as a sole stereoisomer, from
which 10-epi-10-isocyano-4-cadinene was synthesized following the same
synthetic scheme.
906
Org. Lett., Vol. 12, No. 5, 2010

Scheme 5
.
Synthesis of (+)-10-Isocyano-4-cadinene (1)
Scheme 6. Synthesis of (-)-10-Isocyano-4-cadinene (ent-1)
Therefore, the absolute configuration of (+)-1 is unambigu-
ously established as (1S, 6S, 7R, 10S).
Antifouling activities were evaluated with both (+)-1 and
(-)-ent-1. Table 1 shows EC50 values (50% effective
Table 1. Bioactivities of Synthetic (+)- and
(-)-10-Isocyano-4-cadinene
a
entry
compound
EC50
1
2
3
natural (+)-1b
synthetic (+)-1
synthetic (-)-ent-1
0.14 µg/mL
0.06 µg/mL
0.08 µg/mL
a EC50 (µg/mL): antifouling activities against Balanus amphitrite. b See
ref 1.
concentration) against cyprid larvae of the barnacle Balanus
amphitrite exposed to each compound for 48 h. Interestingly,
both compounds showed almost the same EC50 values, which
correspond to that of the natural sample. These results clearly
suggest that the absolute configuration of 10-isocyano-4-
cadinene has no effect on the antifouling activity.
In summary, the first total synthesis of (+)- and (-)-10-
isocyano-4-cadinene was completed by an intermolecular
Diels-Alder reaction and SmI2-induced Barbier-type reaction
to construct the characteristic trans-decalin framework. The
absolute configuration of natural 10-isocyano-4-cadinene was
determined to be (1S, 6S, 7R, 10S). Furthermore, it was
revealed that both enantiomers have almost the same
antifouling activities.
converted into the aldehyde by removal of the PMB group
with DDQ, followed by Dess-Martin oxidation. Pinnick
oxidation led to the carboxylic acid 26, which was subjected
to Curtius rearrangement using diphenylphosphoryl azide
(DPPA)7l,22 to give the isocyanate. The isocyanato group
was converted into an isonitrile group in two steps by NaBH4
reduction22 and dehydration of 10-formamido-4-cadinene
(27)23 to achieve the total synthesis of 1. All spectroscopic
data (1H and 13C NMR, MS, IR) of synthetic 1 are identical
to those of natural 1. The optical rotation of synthetic (+)-
23
1, [R]D +59.8 (c 0.65, CHCl3), is similar to that of the
23
natural product, [R]D +63.6 (c 0.60, CHCl3).1 We also
synthesized the enantiomer, (-)-10-isocyano-4-cadinene (ent-
1), from the (+)-imide ent-12 via the (-)-carboxylic acid
ent-10 by using the same synthetic procedure (Scheme 6).
23
Acknowledgment. We thank the 21st Century COE
Research Assistantship for doctoral candidates and the Global
COE Research Assistantship for doctoral candidates (to
K. N.) and a Global COE Research grant for young scientists
(to T. U. and K. N.).
The optical rotation of (-)-ent-1, [R]D -58.2 (c 0.68,
CHCl3), is opposite in sign to that of the natural product.
(21) (a) Miyaoka, H.; Yamanishi, M.; Kajiwara, Y.; Yamada, Y. J. Org.
Chem. 2003, 68, 3476–3479. (b) Shimazawa, R.; Suzuki, T.; Dodo, K.;
Shirai, R. Bioorg. Med. Chem. Lett. 2004, 14, 3291–3294
(22) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; D´ıaz, C. G.
Synlett 2000, 1561–1564
.
Supporting Information Available: Experimental pro-
.
1
cedures and copies of H NMR and 13C NMR spectra of
(23) 10-Formamido-4-cadinene (27), a natural product isolated from the
sponge Acanthella caVernosa, exhibits antifouling activity against the larvae
of the barnacle Balanus amphitrite (EC50 0.50 µg/mL). All data (1H and
13C NMR, MS) of the synthetic 27 were identical with those in the literature.
See: Nogata, Y.; Yoshimura, E.; Shinshima, K.; Kitano, Y.; Sakaguchi, I.
Biofouling 2003, 19, 193-196.
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL9027336
Org. Lett., Vol. 12, No. 5, 2010
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