First total synthesis and assignment of the stereochemistry of crispatenine

Article abstract of DOI:10.1021/jo070045j

(Figure Presented) The first racemic and enantioselective synthesis of crispatenine 1 has been achieved, which involved a few steps, enabling the assignment of the absolute and relative configurations.

Full text of DOI:10.1021/jo070045j

First Total Synthesis and Assignment of the Stereochemistry of
Crispatenine
Julien Bourdron,† Laurent Commeiras,*,† Ge´rard Audran,‡ Nicolas Vanthuyne,‡
J. C. Hubaud,§ and Jean-Luc Parrain*,†
UMR-CNRS 6178 SymBio, e´quipe Synthe`se par Voie Organome´tallique, UniVersite´ Paul Ce´zanne
(Aix-Marseille III), AVenue Escadrille Normandie Niemen, serVice 532, 13397 Marseille cedex 20, France,
UMR 6180 “Chirotechnologies: Catalyse et Biocatalyse” UniVersite´ Paul Ce´zanne (Aix-Marseille III),
France, and DIPTA (SA), zac pichaury 2, 415 rue Pierre Berthier, 13290 Aix-en-ProVence, France
laurent.commeiras@uniV-cezanne.fr; jl.parrain@uniV-cezanne.fr
ReceiVed January 9, 2007
The first racemic and enantioselective synthesis of crispatenine 1 has been achieved, which involved a
few steps, enabling the assignment of the absolute and relative configurations.
Introduction
Chemical studies from different Caribbean areas on Tridachia
() Elysia) crispata led to describe a series of polypropionates
most likely biosynthesized de noVo and accordingly to successful
experiments with the Mediterranean Elysia Viridis3 and the
Pacific Placobranchus ocellatus.4 Surprisingly, Venezualan
specimens of Elysia crispata, which average four times larger
than the Mexican individuals, contain crispatenine 1,5 a ses-
quiterpene, possessing a 1,4-diacetoxybutadiene moiety, isomer
of a metabolite C isolated from the alga Caulerpa ashmedii6
and onchidal D, together (Figure 1) with the typical polypro-
pionate metabolites. Crispatenine 1 could be envisaged as the
masked form of the aldehyde onchidal D, analogously with
caulerpenyne A, the protected form of the more reactive
oxytoxin-1 E. Interestingly, the co-occurrence in a population
of a Elysia crispata from Venezuela of both crispatenine 1 and
onchidal D (caulerpa-derived metabolites), in addition to several
polypropionates, is intriguing because two different metabolite
pathways (biosynthesis of polypropionates and biotransformation
of dietary sesquiterpenoid) seem to be active and could be
considered as the conjunction between different groups of
sacoglossans displaying different secondary metabolite path-
ways.7
Marine algae of the order Caulerpales are known for their
chemical defense against predators by producing secondary
metabolites. The majority of these often acyclic compounds are
sesquiterpenoids and diterpenoids. The terminal 1,4-diacetox-
ybutadiene moiety is a functional group common to most of
these metabolites. Nowadays, more than 30 toxins with this
moiety have been isolated from the Udoteaceae and Cauler-
paceae families such as caulerpenyne A and dihydrorhipocepha-
line B (Figure 1).1 The 1,4-diacetoxybutadiene moiety represents
an acetylated bis-enol form of the 1,4-dialdehyde system, to
which a high degree of biological activity is generally attributed.
Indeed, some of the metabolites containing this moiety have
been implicated in chemical defense against grazing fishes and
invertebrates in herbivore-rich tropical waters,2 and this has,
for example, been proposed to explain the proliferation from
Italy to Spain of Caulerpa taxifolia a tropical green seaweed
accidentally introduced in the Mediterranean sea.
* Author to whom correspondence should be addressed. Tel: 33 4 91 28 91
26. Fax: 33 4 91 28 91 26.
† UMR-CNRS 6178 SymBio, Universite´ Paul Ce´zanne (Aix-Marseille III).
‡ “Chirotechnologies: Catalyse et Biocatalyse”, Universite´ Paul Ce´zanne (Aix-
Marseille III).
(3) Gavagnin, M.; Marin, A.; Mollo, E.; Crispino, A.; Villani, G.; Cimino,
G. Comp. Biochem. Physiol. 1994, 108B, 107-115.
§ DIPTA (SA).
(1) (a) Paul, V. J.; Fenical, W. Mar. Ecol. Prog. Ser. 1986, 34, 157-
169; (b) Paul, V. J.; Fenical, W. Bioorg. Mar. Chem. 1987, 29, 1-29.
(2) Paul, V. J.; Littler, M. M.; Littler, D. S.; Fenical, W. J. Chem. Ecol.
1987, 13, 1171-1185.
(4) Ireland, C.; Scheuer, P. J. Science 1979, 205, 922-923.
(5) Gavagnin, M.; Mollo, E.; Castellucio, F.; Montanaro, D.; Ortea, J.;
Cimino, G. Nat. Prod. Lett. 1997, 10, 151-156.
(6) Paul, V. J.; Fenical, W. Bioorg. Mar. Chem. 1987, 29, 1-29.
10.1021/jo070045j CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/19/2007
3770
J. Org. Chem. 2007, 72, 3770-3775

Synthesis and Stereochemical Assignment of Crispatenine
FIGURE 1. Examples of terpenoid natural product.
To our knowledge, no synthetic route toward 1 has yet been
published, and although the structure of 1 was confidently
elucidated by NMR, mass, IR, and UV spectroscopies, the
absolute and relative configurations of crispatenine 1 remain
unknown.
alcohol function could be selectively protected as the tert-
butyldimethylsilyl ether in 64% yield over two steps.10
Synthesis of the known western fragment 3 was achieved
using Matsui’s procedure over four steps from methylcyclo-
hexanone (Scheme 2).11 First, methylcyclohexanone was con-
verted into hydroxymethylene cyclohexanone 6 by an improved
method of Bailey’s procedure. The crude alcohol 6 was next
converted into the vinyl ether 7. Reduction of crude ether 7
using sodium borohydride followed by acidic treatment yielded
an aldehyde which was subjected to another reduction with
sodium borohydride to give the desired alcohol 8 in 36% yield
from methylcyclohexanone. Finally a Claisen reaction at 220
°C in the presence of ethyl vinyl ether and pivalic acid gave
γ-homocyclogeranial 3 in 49% yield (18% over four steps).
Consequently, in order to continue our efforts in the synthesis
of terpenoids possessing a terminal 1,4-diacetoxybutadiene
moiety8 and to provide material for more extensive biological
evaluation toward, for example, the tubulin network, along with
access to novel analogues, we have undertaken total synthesis
of crispatenine 1. It was envisaged that an enantioselective
synthesis starting from a well chosen chiral building block would
allow us to determinate the absolute and relative configuration
of the two stereocenters.
The construction of the core carbon framework was next
achieved through coupling of the two fragments 4 and γ-ho-
mocyclogeranial (()-3 (Scheme 3). The coupling reaction
between west segment (()-3 and the carbanion generated by
the tin-lithium exchange reaction on the east fragment 4 gave
a 1/1 mixture of (()-9 and (()-9′ in moderate yield (58%),
which could be separated by flash chromatography on silica
gel. An X-ray crystal structure of (()-9,12 the first diastereoi-
somer eluted from flash chromatography, allowed us to attribute
the (S,S) or (R,R) configuration (Figure 2). The stereochemistry
of some natural products, isolated from Caulerpa algae (with
or without the 1,4-diacetoxybutadiene moiety) have been
previously reported. For example, the (8S) configuration was
assigned for caulerpenyne A13 and furocaulerpin F (Figure 1).14
Results and Discussion
Racemic Synthesis. In order to validate our chosen synthetic
route, a racemic synthesis was first chosen. The main structural
features of 1 are a terminal 1,4-diacetoxybutadiene moiety, an
exocyclic double bond, and two unknown chiral centers. Our
strategy for synthesizing 1 is outlined in the Scheme 1 and called
for the initial preparation of two fragments west and east. We
considered that the assembly of the complete carbon skeleton
of 1 could be obtained through a coupling reaction between
the vinylstannane 4 (east fragment) (tin-lithium exchange)
derived from butynediol and the aldehyde 3 (west fragment).
Synthesis of the key vinyl fragment 4 (Scheme 2) began by
a palladium-catalyzed hydrostannation9 of but-2-yn-1,4-diol,
giving the (E)-vinyltin reagent 5, in which the more accessible
(10) (a) Barrett, A. G. M.; Barta, T. E.; Flygare, J. A. J. Org. Chem.
1989, 54, 4246-4249; (b) Steinig, A. G.; de Meijere, A. Eur. J. Org. Chem.
1999, 1333-1344.
(11) Kawanobe, T.; Kogami, K.; Hayashi, K.; Matsui, M. Agric. Biol.
Chem. 1984, 48, 461-464.
(7) Gavagnin, M.; Mollo, E.; Montanaro, D.; Ortea, J.; Cimino, G. J.
Chem. Ecol. 2000, 26, 1563-1578.
(8) (a) Commeiras, L.; Santelli, M.; Parrain, J.-L. Org. Lett. 2001, 3,
1713-1715; (b) Commeiras, L.; Santelli, M.; Parrain, J.-L. Tetrahedron
Lett. 2003, 44, 2311-2314; (c) Commeiras, L.; Valls, R.; Santelli, M.;
Parrain, J.-L. Synlett 2003, 6, 1719-1721; (d) Commeiras, L.; Bourdron,
J.; Douillard, S.; Barbier, P.; Vanthuyne, N.; Peyrot, V.; Parrain, J.-L.
Synthesis 2006, 166-181; (e) Bourdron, J.; Commeiras, L.; Barbier, P.;
Bourgarel-Rey, V.; Pasquier, E.; Vanthuyne, N.; Peyrot, V.; Parrain, J.-L.
Bioorg. Med. Chem. 2006, 14, 5540-5548.
(12) Crystallographic data (excluding structure factors) for the structure
in this paper has been deposited with the Cambridge Crystallographic Data
Centre as a supplementary publication. CCDC 628567. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax +44-(0) 1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk).
(13) Amico, V.; Oriente, G.; Piatelli, M.; Tringali, C.; Fattorusso, E.;
Magno, S.; Mayol, L. Tetrahedron Lett. 1978, 38, 3593-3596.
(14) de Napoli, L.; Fattorusso, E.; Magno, S.; Mayol, L. Experentia 1981,
37, 1132.
(9) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857-1867.
J. Org. Chem, Vol. 72, No. 10, 2007 3771

Bourdron et al.
SCHEME 1. Retrosynthetic Scheme of (()-Crispatenine 1
SCHEME 2. Synthesis of East and West Fragments
Ac2O at 80 °C), and the target was obtained in 90% yield as a
47/53 mixture of two racemic diasteromers (()-1 and iso-(()-
1. The data of the synthetic (()-crispatenine (()-1 were in
excellent agreement with those reported in the literature which
confirms our prediction.5 Crispatenine isomer 12 was also
obtained (63%, over four steps from 9′) using the same
conditions described above.
To confirm without ambiguity the stereochemistry of 1, we
undertook an enantioselective total synthesis of crispatenine 1.
Enantioselective Synthesis. We chose as our starting point
the known Karahana lactone18 which was readily transformed
in four steps into the chiral aldehyde (+)-3 (Scheme 4).19
Reduction of the enantiopure Karahana lactone with DIBAL-H
gave a mixture of diastereomeric lactols 13 (and the opened
aldehydic form) in 95% yield.20 Exposure of the crude mixture
of products 13 to an excess of R-methoxy methyl triphenyl
phosphorane21 afforded 14 as a mixture of stereomers in 82%
yield. Barton-McCombie deoxygenation22 of 14 was achieved
Via the corresponding xanthate, which was reduced smoothly
with tri-n-butyltin hydride to provide 15 in an overall yield of
FIGURE 2. X-ray structure of (()-9.
Moreover, dihydopallescensin G (Figure 1),15 which has the
same cyclic structure as crispatenine and a furan ring, and which
can arise from hydrolysis of the diacetoxybutadiene moiety, has
a stereocenter with a (6S) configuration. By analogy with these
examples of natural products, we can propose that the configu-
rations of the two chiral centers of 1 are (6S) and (8S).
Consequently, we decided to pursue the synthesis of (()-1
from the diol (()-9 (Scheme 3). Esterification of diol (()-9
using standard conditions afforded diacetate (()-10 in 90%
yield. Deprotection of the silyl ether function with HF-
pyridine16 furnished the desired alcohol (()-11 in 76% yield.
Oxidation of the alcohol with Dess-Martin periodinane17 gave
the aldehyde (()-2 in 89% yield. In order to complete the
synthesis and generate the diacetoxybutadiene moiety, we
employed conditions developed in our group8b (NEt3, DMAP,
(18) Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron 2000, 56, 7477-
7481.
(19) Palombo, E.; Audran, G.; Monti, H. Tetrahedron Lett. 2003, 44,
6463-6464.
(20) Audran, G.; Galano, J.-M.; Monti, H. Eur. J. Org. Chem. 2001,
2293-2296.
(15) Kurth, M. J.; Soares, C. J. Tetrahedron Lett. 1987, 28, 1031-1034.
(16) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031-1069.
(17) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1982, 104, 902-
903; (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(21) Soderquist, J. A.; Ramos-Veguilla, J. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: Chichester,
1995; Vol. 5, pp 3363-3365.
(22) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
3772 J. Org. Chem., Vol. 72, No. 10, 2007

Synthesis and Stereochemical Assignment of Crispatenine
SCHEME 3. Synthesis of 1a
a (a) (i) MeLi.LiBr, (ii) 4 -78 °C; (b) Ac2O, DMAP, pyridine; (c) HF·pyridine, THF; (d) Dess-Martin periodinane, CH2Cl2; (e) Ac2O, DMAP, NEt3,
80 °C.
SCHEME 4. Enantioselective Synthesis of West Fragment (+)-3a
a (a) DIBAL-H, toluene, 70 °C; (b) Ph3P+CH2OMeCl-, n-BuLi, THF, rt; (c) (i) NaH, CS2, MeI, rt, THF; (ii) HSnBu3, cat. AIBN, toluene, reflux; (d) 1
M HCl/THF:1/2, rt, THF.
90% for the two steps. Subsequent hydrolysis at 0 °C with 1 M
HCl (THF/H2O) gave γ-homocyclogeranial (+)-3, [R]25D +31
(c 1.0, CHCl3)/lit23 [R]20D +29.0 (c 0.35, CH2Cl2), in 79% yield.
With the enantiopure aldehyde (+)-3 in hand, the synthesis
of (+)-crispatenine was achieved following the same synthetic
sequence described above. Thus, coupling of the two fragments
west and east was achieved Via the cross-coupling reaction
between (+)-3 and the carbanion generated by tin-lithium
exchange reaction on 4, which gave diol (+)-9 and (+)-9′ in
moderate yield (44%). At this stage, the two hydroxyl groups
of (+)-9 were protected as acetates, and desilylation of (+)-10
by the HF-pyridine complex provided (+)-11. The primary
hydroxyl group was next oxidized by Dess-Martin periodinane,
furnishing in 80% yield over three steps the enantiopure
aldehyde (+)-2. Subjected to a mixture of 3 equiv. of acetic
anhydride, 1 equiv. of dimethylaminopyridine, and triethyla-
mine at 80 °C, (+)-2 led, in 87% yield, to a 1/1 mixture of
enantiopure crispatenine (+)-1 and its isomer iso-(+)-1. More-
over, the mixture (+)-1 and iso-(+)-1 could be separated by
semipreparative HPLC to give (+)-1, iso-(+)-1 in enantiomeric
pure form. The specific rotation ([R]20 +5.2 (c 0.5, CHCl3))
D
was comparable in magnitude and exhibited the same sign as
the natural product ([R]D +5.0 (c 2.1, CHCl3)).5 The configu-
ration of the diacetoxybutadiene moiety and the structure of
(+)-1 were also confirmed by NOESY experiments (Scheme
3). This enantioselective synthesis confirmed our prediction for
the absolute configuration of the two chiral centers of 1 and
allowed us to firmly assign the absolute configuration of natural
crispatenine 1.
In conclusion, a racemic and an enantioselective synthesis
of crispatenine 1 were achieved for the first time with the
assignment of the absolute and relative configurations.
(23) Vidari, G.; Lafranchi, G.; Masciaga, F.; Morrigi, J. D. Tetrahedron
Asymmetry 1996, 7, 3009-3020.
J. Org. Chem, Vol. 72, No. 10, 2007 3773

Bourdron et al.
CH3), 0.82 (s, 3H, CH3), 0.87 (m, 9H, 3 × CH3), 0.91 (s, 3H, CH3),
1.17-1.26 (m, 1H, CH2), 1.35-1.59 (m, 3H, CH2 and CH2), 1.62-
1.67 (m, 1H, CH2), 1.75-1.81 (m, 1H, CH2), 1.84-1.89 (m, 1H,
CH), 1.94-2.09 (m, 2H, CH2), 2.01 (s, 3H, CH3), 2.02 (s, 3H, CH3),
4.27 (d, 2H, J ) 5.8 Hz, CH2), 4.48 (br s, 1H, CH), 4.56 (d, 1H,
J ) 12.5 Hz, CH), 4.63 (d, 1H, J ) 12.5 Hz, CH), 4.78 (br s, 1H,
CH), 5.02 (br d, 1H, J ) 10.8 Hz, CH), 5.76 (t, 1H, J ) 5.8 Hz,
CH); 13C NMR (75 MHz, CDCl3) δ - 5.1 (2 × CH3), 18.4 (C),
20.9 (CH3), 21.1 (CH3), 23.6 (CH2), 26.0 (3 × CH3), 26.5 (CH3),
28.3 (CH3), 31.8 (CH2), 32.2 (CH2), 34.5 (C), 36.0 (CH2), 50.1
(CH), 59.7 (CH2), 60.2 (CH2), 74.2 (CH), 110.2 (CH2), 132.9 (CH),
134.5 (C), 148.1 (C), 170.3 (C), 170.7 (C); m/z (ESI+) 470 [M +
NH4]+; HMRS found 470.3296 [M + NH4+], C25H48NO5Si requires
470.3296
Experimental Section
γ-Homocyclogeranial ((+)-3). To a solution of 15 (200 mg,
1.11 mmol) in THF (13 mL) at 0 °C was added dropwise a 1 M
HCl solution (13 mL). The reaction mixture was allowed to warm
to rt. After 12 h, the solution was diluted in ether, poured into water,
quenched by a saturated solution of NaHCO3, and extracted by
ether. The combined organic extracts were washed with water, dried,
filtered and concentrated. The residue was purified by flash
chromatography (light petroleum-Et2O, 98/2 to 95/5) to give pure
aldehyde (+)-3 ([R]25 +31.0 (c 1.0, CHCl3)) in 79% yield. H
1
D
NMR (CDCl3, 200 MHz) δ 0.78 (s, 3H, CH3), 0.98 (s, 3H, CH3),
1.25-1.66 (m, 4H, 2 × CH2), 2.0-2.09 (m, 1H, CH2), 2.15-2.23
(m, 1H, CH2), 2.41-2.50 (m, 3H, CH2 and CH), 4.52 (br s, 1H,
CH2), 4.80 (br s, 1H, CH2), 9.64 (t, 1H, J ) 2.2 Hz, CH).
Acetic Acid 2-Acetoxymethyl-1-(2,2-dimethyl-6-methylene-
cyclohexylmethyl)-4-hydroxy-but-2-enyl Ester (11) To a solution
of (()-10 or (+)-10 (105 mg, 0.23 mmol) in THF (3.5 mL) was
added an excess of HF·pyridine (0.212 mL). The mixture was stirred
at room temperature and monitored by TLC. After disappearance
of the starting material, the solution was concentrated and then
purified by flash chromatography (petroleum ether-Et2O, 1/1) to
give (()-11 in 76% yield or (+)-11 ([R]22D +4.9 (c 1, CHCl3)) in
88% yield. 1H NMR (300 MHz, CDCl3) δ 0.82 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.17-1.24 (m, 1H, CH2), 1.34-1.43 (m, 1H, CH2),
1.46-1.56 (m, 2H, CH2) , 1.60-1.65 (m, 1H, CH2), 1.74-1.80
(m, 1H, CH2), 1.83-1.90 (m, 1H, CH), 1.96-2.08 (m, 2H, CH2),
2.02 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.39 (s, 1H, OH), 4.21 (d,
2H, J ) 6.8 Hz, CH2), 4.48 (br s, 1H, CH), 4.65 (s, 2H, CH2), 4.79
(br s, 1H, CH), 5.00 (br d, 1H, J ) 11.0, CH), 5.86 (t, 1H, J ) 6.8
Hz, CH); 13C NMR (75 MHz, CDCl3) δ 21.0 (CH3), 21.2 (CH3),
23.5 (CH2), 26.5 (CH3), 28.3 (CH3), 31.9 (CH2), 32.1 (CH2), 34.5
(C), 35.9 (CH2), 50.1 (CH), 58.4 (CH2), 60.0 (CH2), 74.1 (CH),
110.2 (CH2), 131.2 (CH), 136.6 (C), 148.1 (C), 170.5 (C), 171.1
2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylidene]-4-(2,2-dim-
ethyl-6-methylene-cyclohexyl)-butane-1,3-diol ((()-9 and (()-
9′ or (+)-9 and (+)-9′). To a solution of (()-3 or (+)-3 (800 mg,
1.63 mmol) in THF (25 mL), under argon, at -35 °C, was added
dropwise MeLi·LiBr (2.2 M in Et2O, 1.35 mL, 2.98 mmol). The
solution was kept at -35 °C for 2 h, and then 4 (226 mg, 1.36
mmol) was added. The solution was kept at -35 °C for 3 h and
quenched with a saturated aqueous NH4Cl solution. The aqueous
layer was extracted with ethyl acetate, and then the combined
organic layers were dried over MgSO4 and concentrated under
vacuum. The crude mixture was purified by flash chromatography
(petroleum ether-Et2O, 7/3 to 1/1) to give a 1/ 1 separated mixture
of (()-9 and (()-9′ in 58% yield or a 48/52 separated mixture of
(+)-9 ([R]22D +0.8 (c 1, CHCl3)) and (+)-9′ ([R]20D +41.4 (c 3.5,
CHCl3)) in 44% yield. (()-9 or (+)-9 was recrystallized in 1/1/1
acetonitrile/Et2O/pentane. mp ) 84 °C (for (()-9 and (+)-9). 9:
1H NMR (300 MHz, CDCl3) δ 0.08 (s, 6H, 2 × CH3), 0.83 (s, 3H,
CH3), 0.90 (s, 9H, 3 × CH3), 0.93 (s, 3H, CH3), 1.19-1.28 (m,
1H, CH2), 1.41-1.43 (m, 1H, CH2), 1.45-1.75 (m, 4H, 2 × CH2),
2.03-2.11 (m, 3H, CH2 and CH), 2.31 (br s, 1H, OH), 2.95 (s,
1H, OH), 4.11 (br d, 1H, J ) 9.8 Hz, CH), 4.19 (s, 2H, CH2), 4.28
(br d, 1H, J ) 6.0 Hz, CH2), 4.62 (br s, 1H, CH), 4.82 (br s, 1H,
CH), 5.66 (t, 1H, J ) 6.0 Hz, CH); 13C NMR (75 MHz, CDCl3) δ
- 5.1 (2 × CH3), 18.4 (C), 23.8 (CH2), 26.0 (3 × CH3), 26.4 (CH3),
28.4 (CH3), 32.6 (CH2), 33.1 (CH2), 34.8 (C), 36.2 (CH2), 49.9
(CH), 58.9 (CH2), 59.7 (CH2), 73.9 (CH), 109.7 (CH2), 127.6 (CH),
143.7 (C), 149.6 (C); m/z (ESI+) 386 [M + NH4]+; HMRS found
369.2820 [M + H]+, C21H41O3Si requires 369.2819; anal. calcd
C21H40O3Si: C, 68.42; H, 10.94 found C, 68.39; H, 11.07. 9′: 1H
NMR (300 MHz, CDCl3) δ 0.07 (s, 6H, 2 × CH3), 0.81 (s, 3H,
CH3), 0.87 (s, 3H, CH3), 0.89 (s, 9H, 3 × CH3), 1.16-1.24 (m,
1H, CH2), 1.39-1.57 (m, 3H, CH2 and CH2), 1.65-1.72 (m, 1H,
CH), 1.74-1.84 (m, 2H, CH2), 1.96-2.03 (m, 1H, CH2), 2.14-
2.25 (m, 1H, CH2), 2.95 (s, 1H, OH), 3.21 (s, 1H, OH), 4.13 (t,
1H, J ) 6.9 Hz, CH), 4.20 (s, 2H, CH2), 4.27 (d, 1H, J ) 6.0 Hz,
CH2), 4.62 (br s, 1H, CH), 4.79 (br s, 1H, CH), 5.60 (t, 1H, J )
6.0 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3) δ -5.1 (2 × CH3),
18.4 (C), 23.8 (CH2), 26.0 (3 × CH3), 26.2 (CH3), 28.2 (CH3),
32.2 (CH2), 32.8 (CH2), 35.1 (C), 36.5 (CH2), 51.2 (CH), 58.2
(CH2), 59.5 (CH2), 76.9 (CH), 109.6 (CH2), 130.4 (CH), 141.0 (C),
150.2 (C); m/z (ESI+) 386 [M + NH4]+; HMRS found 369.2810
[M + H]+, C21H41O3Si requires 369.2819.
(C); m/z (ESI+) 356 [M + NH4]+ HMRS found 356.2430 [M +
;
NH4+], C19H34NO5 requires 356.2431.
Acetic Acid 2-Acetoxymethyl-1-(2,2-dimethyl-6-methylene-
cyclohexylmethyl)-4-oxo-but-2-enyl Ester (2). To a solution of
(()-11 or (+)-11 (0.059 g, 0.17 mmol) in CH2Cl2 (4.5 mL), under
argon, at 0 °C, was added Dess-Martin periodinane (0.089 g, 0.21
mmol). The reaction mixture was stirred at room temperature and
monitored by TLC. After disappearance of the starting material,
the mixture was poured into a saturated aqueous solution of
Na2S2O3/NaHCO3 (10 mL, 1/1) and shaken vigorously for 5 min.
The aqueous layer was extracted with diethyl ether. The combined
organic layers were washed with a saturated aqueous NaHCO3
solution, dried over MgSO4, and concentrated under vacuum. The
crude product was purified by flash chromatography (petroleum
ether-Et2O, 7/3) to give (()-2 in 89% yield or (+)-2. ([R]22D +8.8
1
(c 1, CHCl3)) in 98% yield. H NMR (300 MHz, CDCl3) δ 0.85
(s, 3H, CH3), 0.93 (s, 3H, CH3), 1.19-1.28 (m, 1H, CH2), 1.36-
1.45 (m, 1H, CH2), 1.51-1.59 (m, 2H, CH2) , 1.74-1.78 (m, 2H,
CH2), 1.94-2.12 (m, 3H, CH2 and CH), 2.07 (s, 3H, CH3), 2.10
(s, 3H, CH3), 4.53 (br s, 1H, CH), 4.83 (br s, 1H, CH), 5.05-5.09
(m, 3H, CH2 and CH), 6.07 (d, 1H, J ) 7.4 Hz, CH), 10.07 (d,
1H, J ) 7.4 Hz, CH); 13C NMR (75 MHz, CDCl3) δ 20.8 (CH3),
20.9 (CH3), 23.4 (CH2), 26.9 (CH3), 28.2 (CH3), 31.7 (CH2), 31.8
(CH2), 34.6 (C), 35.6 (CH2), 50.2 (CH), 59.8 (CH2), 72.8 (CH),
110.8 (CH2), 127.9 (CH), 147.7 (C), 157.1 (C), 170.2 (C), 170.3
Acetic Acid 2-Acetoxymethyl-4-(tert-butyl-dimethyl-silany-
loxy)-1-(2,2-dimethyl-6-methylene-cyclohexylmethyl)-but-2-
enyl Ester (10). A solution of (()-9 or (+)-9 (105 mg, 0.28 mmol),
acetic anhydride (0.11 mL, 1.14 mmol), DMAP (1.7 mg), and
pyridine (4 mL) was stirred for 12 h. The mixture was quenched
with a saturated aqueous NaHCO3 solution, and the aqueous layer
was extracted with ethyl ether. The combined organic layers were
washed with saturated aqueous CuSO4 solution and water, dried
over MgSO4, and concentrated under vacuum. The crude product
was purified by flash chromatography (petroleum ether-Et2O, 8/2)
to give (()-10 in 90% yield or (+)-10 ([R]22D +2.0 (c 1, CHCl3))
(C), 190.5 (CH); m/z (ESI+) 354 [M + NH4]+ HMRS found
;
354.2276 [M + NH4+], C19H32NO5 requires 354.2274.
(1S,3R)-3-((E)-2-Methoxy-vinyl)-2,2-dimethyl-4-methylene-cy-
clohexanol (E-14) and (1S,3R)-3-((Z)-2-Methoxy-vinyl)-2,2-dim-
ethyl-4-methylene-cyclohexanol (Z-14). (+)-Karahana lactone
(600 mg, 3.60 mmol) was dissolved in 40 mL of anhydrous toluene,
and a 1 M toluene solution of diisobutylaluminium hydride (7.2
mL, 7.20 mmol) was added dropwise at -70 °C under an argon
atmosphere. The reaction mixture was stirred for 45 min at this
temperature, quenched with Na2SO4‚10H2O (4 g) and Celite (5 g),
and allowed to rise to rt. Filtration through a pad of MgSO4,
1
in 93% yield. H NMR (300 MHz, CDCl3) δ 0.04 (s, 6H, 2 ×
3774 J. Org. Chem., Vol. 72, No. 10, 2007

Synthesis and Stereochemical Assignment of Crispatenine
concentration, and purification by flash chromatography (petroleum
ether-Et2O, 8/2 to 3/7) gave, in the same spot, a 1:1:0.5 mixture
(1H NMR determination) of lactols 13 and aldehyde 13′ in 95%
yield as a clear oil. To a suspension of (methoxymethyl)-
triphenylphosphonium chloride (3.35 g, 9.76 mmol) in THF (30
mL) at -18 °C was added a 1.6 M n-butyllithium in hexane solution
(6.00 mL, 9.60 mmol). The dark red mixture was allowed to stir
for 3 h at 0 °C. A solution of the mixture 13 and 13′ (400 mg, 2.38
mmol) in THF (7 mL) was added dropwise. After the reaction
mixture was stirred overnight at rt, the solution was diluted in ether
and poured into water. The aqueous layer was extracted with ether,
and the combined organic extracts were washed with water, dried
over MgSO4, filtered, and concentrated in vacuo. Purification of
the crude product by flash chromatography (petroleum ether-Et2O,
9/1 to 2/8) afforded in 82% yield a 20:3 mixture of E and Z isomers
of 14. 1H NMR of E-14 (300 MHz, CDCl3) δ 0.72 (s, 3H), 0.98 (s,
3H), 1.42-1.57 (m, 2H), 1.78-1.87 (m, 1H), 2.05-2.16 (m, 1H),
2.26 (br d, J ) 10.4 Hz, 1H), 2.35-2.42 (m, 1H), 3.44 (dd, J )
11.2, 4.4 Hz, 1H), 3.57 (s, 3H), 4.67 (br s, 1H), 4.77-4.84 (m, 2
× 1H), 6.24 (d, J ) 12.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
14.2 (CH3), 26.3 (CH3), 31.3 (CH2), 33.4 (CH2), 40.4 (C), 51.0
(CH), 56.2 (CH3), 77.8 (CH), 100.4 (CH), 109.4 (CH2), 148.6 (CH)
149.2 (C); Anal. Calcd for C12H20O2 (E + Z mixture) C, 73.43; H,
10.27. Found: C, 73.69; H, 10.23.
(S)-2-((E)-2-Methoxy-vinyl)-1,1-dimethyl-3-methylene-cyclo-
hexane (E-15) and (S)-2-((Z)-2-Methoxy-vinyl)-1,1-dimethyl-3-
methylene-cyclohexane (Z-15). To a suspension of sodium hydride
(141 mg, 2.94 mmol, 50% dispersion) in THF (6 mL) at 0 °C was
added a solution of E- and Z-14 (287 mg, 1.46 mmol) and carbon
disulfide (355 µL, 5.88 mmol) in THF (8 mL). The reaction mixture
was stirred for 1.5 h at rt and iodomethane (735 µL, 11.80 mmol)
was added at 0 °C. The reaction mixture was stirred overnight at
rt, diluted in ether, and carefully poured into water. After extraction
with ether, the combined organic phases were washed with water,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography to afford in 98% yield
the corresponding xanthate. This mixture was used in the next step
without further purification. To a solution of xanthate (411 mg,
1.43 mmol) in toluene (10 mL) was added a solution of tri-n-butyltin
hydride (690 µL, 2.60 mmol) and a catalytic amount of AIBN in
toluene (10 mL) under an argon atmosphere. The reaction mixture
was stirred under reflux for 1 h, cooled, and concentrated. The oily
residue was purified by flash chromatography (petroleum ether-
Et2O, 10/0 to 95/5) to give 15 (E/Z : 20/3) in 90% yield. 1H NMR
of E-15 (300 MHz, CDCl3) δ 0.76 (s, 3H), 0.89 (s, 3H), 1.22-
1.36 (m, 1H), 1.43-1.62 (m, 3H), 1.96-2.09 (m, 1H), 2.24-2.35
(m, 2H), 3.55 (s, 3H), 4.61 (br s, 1H), 4.72 (br s, 1H), 4.83 (dd, J
) 12.5, 10.2 Hz, 1H), 6.23 (d, J ) 12.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 22.8 (CH3), 23.6 (CH2), 29.9 (CH3), 35.1 (C) 35.5
(CH2), 39.6 (CH2), 53.1 (CH), 56.2 (CH3), 101.9 (CH), 108.2 (CH2),
148.0 (CH) 151.3 (C); Anal. Calcd for C12H20O (E + Z mixture):
C, 79.95; H, 11.18. Found: C, 80.22; H, 11.21.
Crispatenine (1). In a dry Schlenk tube, a solution of (()-2 or
(+)-2 (30 mg, 0.089 mmol), DMAP (11 mg, 0.089 mmol), NEt3
(0.67 mL), and acetic anhydride (0.025 mL, 0.27 mmol) was stirred
under argon at 80 °C and monitored by TLC. After disappearance
of the starting material, the mixture was concentrated under vacuum.
The crude product was then purified by flash chromatography
(petroleum ether-Et2O, 8/2) to give a mixture (47/53 E,Z/Z,Z) of
two isomers (()-1 and iso-(()-1 in 90% yield or a mixture (1/1
E,Z/Z,Z) of (+)-1 ([R]20 +5.2 (c 0.5, CHCl3)) and iso-(+)-1 in
D
87% yield. m/z (ESI+) 396 [M + NH4]+ 1H NMR of 1 (500 MHz,
;
CDCl3) δ 0.84 (s, 3H, CH3), 0.95 (s, 3H, CH3), 1.18-1.28 (m, 1H,
CH2), 1.38-1-44 (m, 1H, CH2), 1.49-1.60 (m, 4H, 2 × CH2),
1.92-1.97 (br d, 1H, J ) 11.5 Hz, CH), 2.03-2.11 (m, 2H, CH2),
2.06 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.17 (s, 3H, CH3), 4.56 (br
s, 1H, CH), 4.83 (br s, 1H, CH), 5.68 (br d, 1H, J ) 11.3 Hz, CH),
5.78 (d, 1H, J ) 12.6 Hz, CH), 7.17 (s, 1H, CH), 7.60 (d, 1H, J )
12.6 Hz, CH); 13C NMR (75 MHz, CDCl3) δ 20.8 (CH3), 20.83
(CH3), 21.0 (CH3), 23.7 (CH2), 26.2 (CH3), 28.4 (CH3), 30.5 (CH2),
32.4 (CH2), 34.7 (C), 36.2 (CH2), 49.8 (CH), 68.8 (CH), 109.7 (CH),
110.0 (CH2), 121.0 (C), 133.1 (CH), 136.9 (CH), 148.2 (C), 167.2
(C), 168.0 (C), 170.2 (C); HMRS found 396.2380 [M + NH4+],
C21H34NO6 requires 396.2380. 1H NMR of iso-1 (300 MHz, CDCl3)
δ 0.84 (s, 3H, CH3), 0.94 (s, 3H, CH3), 1.18-1.28 (m, 1H, CH2),
1.38-1.58 (m, 4H, CH2 and 2 × CH2), 1.88-1.99 (m, 2H, CH
and CH2), 2.03 (s, 3H, CH3), 2.05-2.14 (m, 2H, CH2), 2.19 (s,
3H, CH3), 2.21 (s, 3H, CH3), 4.56 (br s, 1H, CH), 4.83 (br s, 1H,
CH), 5.15 (d, 1H, J ) 7.4 Hz, CH), 5.70-5.76 (m, 1H, CH), 7.21
(d, 1H, J ) 7.4 Hz, CH), 7.78 (s, 1H, CH), 13C NMR (75 MHz,
CDCl3) δ 20.9 (CH3), 21.0 (CH3), 21.1 (CH3), 23.7 (CH2), 26.2
(CH3), 28.5 (CH3), 30.9 (CH2), 32.5 (CH2), 34.7 (C), 36.3 (CH2),
49.8 (CH), 68.7 (CH), 103.7 (CH), 109.8 (CH2), 119.1 (C), 135.1
(CH), 136.5 (CH), 148.4 (C), 167.3 (C), 167.5 (C), 170.2 (C);
HMRS found 396.2380 [M + NH4+], C21H34NO6 requires 396.2380.
Acknowledgment. J.B. thanks Re´gion PACA and DIPTA
for providing financial support, Michel Giorgi for X-ray
structure, and John E. Moses for carefully reading of the paper.
Supporting Information Available: Synthesis procedures of
known compounds (()-3, (()-4, (()-5, (()-6, (()-7, (()-8, copies
of 1H NMR and 13C NMR spectra, and CIF file of (()-9 are
available free of charge via the Internet at http://pubs.acs.org.
JO070045J
J. Org. Chem, Vol. 72, No. 10, 2007 3775