Total syntheses of the marine illudalanes alcyopterosin I, L, M, N, and C

Article abstract of DOI:10.1021/ol102432q

The combination of a modular assembly of enantiopure triynes and a powerful rhodium-catalyzed [2 + 2 + 2] alkyne cyclotrimerization reaction opens new and efficient entries to a set of alcyopterosins, including the first total synthesis of the alcyopteros

Full text of DOI:10.1021/ol102432q

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5644-5647
Total Syntheses of the Marine Illudalanes
Alcyopterosin I, L, M, N, and C
Tania Welsch,† Huu-Anh Tran,‡ and Bernhard Witulski*,†
Laboratoire de Chimie Mole´culaire et Thio-organique, UMR CNRS 6507, INC3M, FR 3038,
ENSICAEN and UniVersite´ de Caen, 6 BVd du Mare´chal Juin, 14050 Caen, France
bernhard.witulski@ensicaen.fr
Received October 7, 2010
ABSTRACT
The combination of a modular assembly of enantiopure triynes and a powerful rhodium-catalyzed [2 + 2 + 2] alkyne cyclotrimerization
reaction opens new and efficient entries to a set of alcyopterosins, including the first total synthesis of the alcyopterosins L, M, and C.
Illudalane sesquiterpenes comprise a group of compounds
being typical metabolites of both fungi and ferns.1 Among
these, the alcyopterosins represent a unique set of marine
illudalanes isolated from the sub-Antartic deep sea soft
coral Alcyonium paessleri (Figure 1).2 More recently, other
members of the alcyopterosin family were isolated from
the Antarctic marine soft coral Alcyonium grandis.3
Notably, the alcyopterosins represent the first ever reported
illudalanes isolated from marine sources, and alcyopterosin
E (2) and C (4) together with six other members of this
family are the first nitrate esters to be found in any natural
product. In vitro tests showed cytotoxicity toward the
human larynx carcinoma cell line for alcyopterosin E (2),
while alcyopterosin A (1) and C (4) were cytotoxic toward
the HT-29 cell line.2 Furthermore, remarkable DNA-
binding properties have been described for alcyopterosin
Figure 1. Alcyopterosins isolated from marine soft corals.
A (1) and its synthetic analogues.4
† Laboratoire de Chimie Mole´culaire et Thio-organique, UMR CNRS
6507, ENSICAEN & Universite´ de Caen.
The total synthesis of some members of the alcyopterosin
family has been reported already. The alcyopterosins A and
N have been synthesized either by a classical multistep
approach via the functionalization of a benzene core,4 or by
a titanium5 or a palladium mediated cycloaddition reaction.6
More recently, the synthesis of alcyopterosin I was reported
within a study of rhodium-catalyzed intramolecular cycliza-
tions of diynes with enones.7 However, the asymmetric
‡ Present address: Department of Chemistry, University of Alberta,
Edmonton, Canada.
(1) Fraga, B. M. Nat. Prod. Rep. 2008, 25, 1180.
(2) Palermo, J. A.; Rodriguez Brasco, M. F.; Spagnuolo, C.; Seldes,
A. M. J. Org. Chem. 2000, 65, 4482.
(3) Carbone, M.; Nunez-Pons, L.; Castelluccio, F.; Avila, C.; Gavagnin,
M. J. Nat. Prod 2009, 72, 1357.
(4) Finkielsztein, L. M.; Bruno, A. M.; Renou, S. G.; Moltrasio de
Iglesias, G. Y. Bioorg. Med. Chem. 2006, 14, 1863.
10.1021/ol102432q  2010 American Chemical Society
Published on Web 11/17/2010

reduction of the thus obtained indanone proceeded only with
poor enantioselectivity and therefore prevented a truly
asymmetric approach to this set of natural products.
The transition metal catalyzed [2 + 2 + 2] alkyne
cycloaddition is a powerful reaction for the construction of
highly substituted benzenes.8 However, despite its versatility
and its atom- and step-economic features, applications of this
capable catalytic method in natural product synthesis still
remain rare.9 One drawback of this methodology seems to
be the often cumbersome synthesis of the functionalized
triyne serving as the cyclotrimerization precursor. However,
we have previously described the asymmetric synthesis of
alcyopterosin E (2) that gains its advantage from the
assembly of the triyne through a simple esterification.9k
We disclose here a synthetic strategy that is based on a
modular approach to gain access to a set of alcyopterosins
having either a tricyclic or a bicyclic core, and either one or
two independent asymmetric centers. We envisaged that the
alcyopterosin skeleton could be assembled through an ABC-
ring formation approach based on transition metal catalyzed
[2 + 2 + 2] cycloaddition reactions with suitable function-
alized triynes 8 (Scheme 1). Depending on the tether lengths
in 8, this strategy should provide access to the angular fused
[5-6-6]-, as well as the [5-6-5]-ring system of the
targeted alcyopterosins. In turn the cyclotrimerization precur-
sors, the triynes 8, will be obtained via operational simple
esterifications or ether formations. Furthermore, the overall
synthetic strategy will take advantage of the use of chiral
building blocks such as the diyne (S)-9, that should be
received through an enantioselective reduction of the readily
available ynone 10.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Preparation of the Key Building Block (S)-9
(5) Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 2002, 124, 9682.
(6) Nakao, Y.; Hirata, Y.; Ishihara, S.; Oda, S.; Yukawa, T.; Shirakawa,
E.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 15650.
(7) Jones, A. L.; Snyder, J. K. J. Org. Chem. 2009, 74, 2907.
(8) (a) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317.
(b) Tanaka, K. Synlett 2007, 1977. (c) Galan, B. R.; Rovis, T. Angew. Chem.,
Int. Ed. 2009, 48, 2830. (d) Agenet, N.; Buisine, O.; Slowinski, F.; Gandon,
V.; Aubert, C.; Malacria, M. Organic Reactions; Ranjan Babu, T. V., Ed.;
John Wiley & Sons: Hoboken, NJ, 2007; Vol. 68, pp 1-302. (e) Chopade,
P. R.; Louie, J. AdV. Synth. Catal. 2006, 348, 2307. (f) Saito, S.; Yamamoto,
Y. Chem. ReV. 2000, 100, 2901.
Scheme 2 summarizes the synthesis of the key building
block (S)-9. Propargylation10 of ethyl butyrate (11) with
propargyl bromide was followed by saponification and
conversion of the thus received carboxylic acid into the acid
chloride 12 with thionyl chloride. Treatment of 12 with bis-
trimethylsilyl acetylene in the presence of AlCl3 resulted in
a straightforward monoacylation of the bis-silylated acety-
lene11 to give the ynone 10 (94% yield). Enantioselective
transfer hydrogenation of 10 utilizing Noyori’s catalyst12
(1S,2S)-13 in 2-propanol afforded the corresponding chiral
alcohol with an excellent enantioselectivity (74% yield, 99%
ee).13 The thus obtained chiral propargylic alcohol was
thereafter MOM-protected to provide the desired key building
block (S)-9 in 86% yield. Other enantioselective ketone
reductions utilizing LiAlH4/Darvon alcohol (46% yield, 31%
ee),14 or BH3-SMe2 in the presence of Garcia’s (S)-
oxazoborolidine (72% yield, 88% ee),15 were less effective
with 10. These results confirm that Noyori’s catalyst has
(9) For the synthesis of natural products by transition metal mediated
[2 + 2 + 2] cycloadditions, see: (a) (() Cryptoacetalide: Zou, Y.; Deiters,
A. J. Org. Chem. 2010, 75, 5355. (b) Antiostatin A1: Alayrac, C.;
Schollmeyer, D.; Witulski, B. Chem. Commun. 2009, 1464. (c) Sporolide
B: Nicolaou, K. C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48,
3449. (d) Cannabinol: Teske, J. A.; Deiters, A. Org. Lett. 2008, 10, 2195.
(e) Illudinine: Teske, J. A.; Deiters, A. J. Org. Chem. 2008, 73, 342. (f)
(-)-Bruguierol A: Ramana, C. V.; Salian, S. R.; Gonnade, R. G. Eur. J.
Org. Chem. 2007, 5483. (g) (-)-8-O-Methyltetrangomycin: Kesenheimer,
C.; Groth, U. Org. Lett. 2006, 8, 2507. (h) (() Viridin: Anderson, E. A.;
Alexanian, E. J.; Sorensen, E. J. Angew. Chem., Int. Ed. 2004, 43, 1998.
(i) Taiwanin: Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004,
43, 2436. (j) (+)-Rubiginone: Kalogerakis, A.; Groth, U. Synlett 2003, 1886.
(k) Alcyopterosin E: Witulski, B.; Zimmermann, A.; Gowans, N. D. Chem.
Commun. 2002, 2984. (l) Clausine C and hyellazole: Witulski, B.; Alayrac,
C. Angew. Chem., Int. Ed. 2002, 41, 3281. (m) (S)-3-n-Butylphthalide:
Witulski, B.; Zimmermann, A. Synlett 2002, 1855. (n) (()-Strychnine:
Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324. (o) (()-Lysergene:
Saa, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994, 487. (p)
(()-Stemodin: Germanas, J.; Aubert, C.; Vollhardt, K. P. C. J. Am. Chem.
Soc. 1991, 113, 4006. (q) Camptothecin: Earl, R. A.; Vollhardt, K. P. C.
J. Am. Chem. Soc. 1983, 105, 6991. (r) Pterosin Z and (()-calomelano-
lactone: Neeson, S. J.; Stevenson, P. J. Tetrahedron 1989, 45, 6239. (s)
(()-Estron: Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102,
5253.
(10) Magnus, P.; Slater, M. J.; Principe, L. M. J. Org. Chem. 1989, 54,
5148.
(11) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963, 96, 3280.
(12) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. 1997, 36, 285.
(13) The ee value was determined by chiral GC (CP-Chirasil-Dex CB)
after its MOM-protection to give compound (S)-9.
Org. Lett., Vol. 12, No. 24, 2010
5645

outstanding reactivities and enantioselectivities toward steri-
cally encumbered ynone substrates to furnish the correspond-
ing propargylic alcohols.16
With the key building block (S)-9 in hand, the synthesis
of alcyopterosin I (3) was targeted (Scheme 3).
Table 1. Cyclotrimerization Studies of 17 To Give 3 in the
Presence of 4 mol % of Catalyst
temp time yield
entry
catalyst
[Rh(PPh3)3Cl]
[Rh(PPh3)3Cl]
[Rh(PPh3)3Cl]
[Cp*Ru(COD)Cl]
[Cp*Ru(COD)Cl]
[Ir(COD)Cl]2/2 DPPE
[Rh(COD)2BF4]2/1 BINAP EtOH
[Rh(COD)2BF4]2/1 BINAP CH2Cl2
[Rh(C8H14)2Cl]2/2 BINAP EtOH
solvent (°C)
(h)
(%)
1
2
3
4
5
6
7
8
9
EtOH
CH2Cl2
PhMe
CH2Cl2
EtOH
EtOH
20
20
20
20
20
60
20
60
60
14
280
3
96
96
160
4
264
120
89
43
60
34
24
30
90
46
71
Scheme 3. Synthesis of Alcyopterosin I (3)
The spectroscopic and analytical data of 3 were in
agreement with those reported for alcyopterosin I isolated
from the soft coral Alcyonium paessleri. The optical rotation
of synthetic 3 ([R]25 +19.1 (c 2.39, CHCl3)) was in
D
conformity with that of the natural product ([R]25 +6.2 (c
D
2.59, CHCl3))2 and thereby verifying the absolute configu-
ration not only of synthetic 3, but also the absolute
configuration of (S)-9 obtained by the enantioselective
transfer hydrogenation (Scheme 2).
With the aim to emphasize on the modular approach
toward this set of natural products, the total synthesis of
alcyopterosin L (6) and M (7) was investigated next (Scheme
4). Carboxylation of the terminal alkyne moiety of (S)-9 was
Hydroxymethylation of (S)-9 followed by treatment with
CBr4/PPh3 afforded the propargyl bromide 14. Next, the
triyne 15 was assembled in 96% yield via a simple ether
formation between 14 and 3-pentyn-1-ol. At this stage, the
construction of the angular fused [5-6-6]-ring system of
alcyopterosin I via an ABC-ring formation approach was
investigated.
Scheme 4. Synthesis of Alcyopterosin L (6) and M (7)
The intramolecular [2 + 2 + 2] alkyne cyclotrimerization
of 15 was performed in ethanol at room temperature with
Wilkinson’s complex ([Rh(PPh3)3Cl]) as a catalyst to give
16 in 66% yield. Subsequently, the targeted alcyopterosin I
(3) was obtained via MOM-deprotection of 16 with HCl in
dioxane. Alternatively, the total synthesis of the natural
product 3 was accomplished by first removing the MOM
protective group from triyne 15 to give 17 (91% yield),
followed by the cyclotrimerization reaction utilizing Wilkin-
son’s complex as a catalyst in ethanol (89% yield for 3).
Other catalysts for the transformation of 17 to 3 were
examined and the results are listed in Table 1.
As can be seen, Wilkinson’s complex (entry 1) as well as
other cationic rhodium complexes (entry 6 and 7) served well
for this purpose when the reactions were carried out in
ethanol. Whereas the use of either [Cp*Ru(COD)Cl] or
[Ir(COD)Cl]2 in the presence of 2 equiv of diphenylphos-
phino ethane (DPPE) gave significantly lower yields.
(14) Darvon alcohol ) (2S,3R)-(+)-4-(dimethylamino)-3-methyl-1,2-
diphenyl-2-butanol . (a) Yamaguchi, S.; Mosher, H. S.; Pohland, A. J. Am.
Chem. Soc. 1972, 94, 9254. (b) Cohen, N.; Lopresti, R. J.; Neukom, C.;
Saucy, G. J. Org. Chem. 1980, 45, 582.
(15) Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J.
Org. Chem. 1996, 61, 9021.
accomplished in 82% yield by its deprotonation with
n-butyllithium at -78 °C followed by the addition of gaseous
carbon dioxide. Subsequently, diyne 18 was obtained in 97%
(16) (a) Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin, J. E.
Tetrahedron 2005, 61, 7219. (b) Graening, T.; Bette, V.; Neudo¨rfl, J.; Lex,
J.; Schmalz, H.-G. Org. Lett. 2005, 7, 4317.
5646
Org. Lett., Vol. 12, No. 24, 2010

yield after removal of the trimethylsilyl protective group with
tetrabutylammonium fluoride (TBAF) in THF. The dicyclo-
hexylcarbodiimide (DCC) mediated esterification of 18 with
the readily available propargylic alcohol (R)-1917 proceeded
with retention of the absolute configuration, to give the thus
assembled enantiopure triyne ester 20 (65% yield).
Scheme 5.
Synthesis of Alcyopterosin N (5) and C (4)20
Gratifyingly, the intramolecular cyclotrimerization of the
exceedingly functionalized triyne ester 20 mediated by
Wilkinson’s catalyst proceeded at 40 °C and secured the
assembly of the angular [5-6-5]-ring system of compound
21 (69% yield). The conversion of 21 into alcyopterosin L
(6) commenced with the nucleophilic substitution of the tosyl
ester against a chlorine atom using LiCl/NH4Cl in DMF. This
was followed by cleavage of the MOM-ether with CBr4 to
furnish 6, in 65% yield. Likewise, the total synthesis of
alcyopterosin M (7) was accomplished in 36% yield over
two steps by first displacing in 21 the tosyl ester against the
nitrate ester functionality,18 followed by a MOM-deprotection
with CBr4.
opterosin C (4) was accomplished by converting 5 into its
mesyl ester followed by nucleophilic displacement of the
mesyl group against the nitrate ester functionality.
To examine the feasibility of the ABC-ring formation
approach to gain access to the bicyclic members of the
alcyopterosin family, we next focused on the synthesis of
alcyopterosin N (5) and C (4) (Scheme 5). Therefore, (()-3
was oxidized to the indanone 22 (85% yield) by means of
diacetoxy iodobenzene (DIB) and catalytic amounts of
2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) at room tem-
perature.19 The use of the hypervalent iodine reagent in
combination with TEMPO was chosen here as the environ-
mentally benign alternative to heavy metal based oxidizers.
The completely regiospecific cleavage of the C ring of 22
was achieved by using BBr3 in CH2Cl2 to provide compound
23 in 84% yield. The reduction of the benzylic bromide
moiety in 23 with tributyltin hydride gave alcyopterosin N
(5) (93% yield). Finally, the first total synthesis of alcy-
In conclusion, we have completed the enantioselective total
synthesis of alcyopterosin I (3) within 11 steps (29% overall
yield), as well as the first enantioselective total syntheses of
alcyopterosin L (6) and M (7) within 12 steps each (10%
and 6% overall yield, respectively). The efficiency of the
synthetic sequences results from a modular assembly of the
enantiopure triynes 17 and 20 and powerful metal-catalyzed
intramolecular [2 + 2 + 2] cycloaddition reactions. This
strategy was also successful for the total synthesis of the
bicyclic alcyopterosins N (5) (14 steps, 19% overall yield)
and C (4) (16 steps, 13% overall yield).
Acknowledgment. The financial support of the French
Agence Nationale de la Recherche (ANR 08-CEXC NCHIR)
is gratefully acknowledged.
(17) Compound (R)-19 was synthesized from (S)-2,3-O-isopropylidene
glyceraldehyde in four steps, see: (a) Reference 9k. (S)-2,3-O-Isopropylidene
glyceraldehyde is a widely used chiral building block that is accessible
through a one-step preparation starting from commercially available (R)-
2,3-O-isopropylideneglycerol, see: (b) Ermolenko, L.; Sasaki, N. A.; Potier,
P. Synlett 2001, 1565.
Supporting Information Available: Experimental pro-
cedures and spectral data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102432Q
(18) Hwu, J. R.; Vyas, K. A.; Patel, H. V.; Lin, C.-H.; Yang, J.-C.
Synthesis 1994, 471.
(19) (a) Schmiech, L.; Alayrac, C.; Witulski, B.; Hofmann, T. J. Agric.
Food Chem. 2009, 57, 11030. (b) De Mico, A.; Margarita, R.; Parlanti, L.;
Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
(20) Racemic (()-3 was obtained by the same sequence as for (+)-3
with the exception that 10 was reduced with LiAlH4 to give (()-9 after
MOM protection.
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