Total synthesis of (+)-crocacin C using hidden symmetry

Article abstract of DOI:10.1021/jo902582w

Chemical Equetion Presentation A highly convergent and protecting-group- free synthesis of (+)-crocacin C, featuring an enzymatic enantioselective desymmetrization of a meso-diol, a base-induced ring opening of a THP ring, and a one-pot hydrostannylation/Stille coupling as the key steps, is reported. The natural product was obtained in 11 steps and 22.3% overall yield starting from readily available oxabicycle 1. Finally, a unique enantioselective step, an enzymatic desymmetrization, revealed four stereogenic centers and created one in C4 of the THP furnishing the dense building block 4 with high enantioselectivity (ee > 98%).

Full text of DOI:10.1021/jo902582w

pubs.acs.org/joc
Total Synthesis of (þ)-Crocacin C Using Hidden Symmetry
ꢀ
Mathieu Candy, Gerard Audran, Hugues Bienayme, Cyril Bressy,* and
Jean-Marc Pons*
ꢀ †
ꢀ
ꢀ
Aix-Marseille Universite, Institut des Sciences Moleculaires de Marseille,
iSm2 CNRS UMR 6263-eꢀquipe STeReꢀO, Campus Saint-Jeꢀro^me 13397 Marseille cedex 20, France.
†Current address: TARGEON, 4 Avenue de l’Observatoire, 75006 Paris, France.
cyril.bressy@univ-cezanne.fr; jean-marc.pons@univ-cezanne.fr
Received December 14, 2009
A highly convergent and protecting-group-free synthesis of (þ)-crocacin C, featuring an enzymatic
enantioselective desymmetrization of a meso-diol, a base-induced ring opening of a THP ring, and a
one-pot hydrostannylation/Stille coupling as the key steps, is reported. The natural product was obtained
in 11 steps and 22.3% overall yield starting from readily available oxabicycle 1. Finally, a unique
enantioselective step, an enzymatic desymmetrization, revealed four stereogenic centers and created one
in C4 of the THP furnishing the dense building block 4 with high enantioselectivity (ee >98%).
Introduction
possible to convert the resulting desymmetrized monoacetate
into both enantiomers of a polypropionate fragment with
complete diastereo- and enantioselectivity.
In natural product synthesis, the detection of potential hidden
symmetry can dramatically simplify retrosynthetic analysis.1 In
this context, the design of new readily available meso com-
pounds and their enantioselective desymmetrizations2 have
become important challenges for synthetic chemists.
We recently disclosed the synthesis of a new family of meso-
tetrahydropyranyl diols, which were asymmetrically desym-
metrized with a high level of enantioselectivity using Rhizo-
mucor miehei lipase.3 Moreover, we showed that it was
In the present paper, we report on the application of this
methodology to the synthesis of a biologically active natural
product, (þ)-crocacin C, which belongs to a family of four natu-
ral products (crocacins A-D), isolated from Chondromyces
crocatus and Chondromyces pediulatus4 in 1994 (Figure 1). The
structure of these natural products, elucidated by Jansen et al. in
19995 (relative configuration), was confirmed through synthe-
sis.7a Crocacins present, as a common framework, a polyenic
polypropionate structure bearing an anti-anti-syn stereotetrad.
Hence, each crocacin is recognizable by the nature of its
(1) For a review on prochiral and meso compounds bearing a mirror plan,
see: (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765–1784. (b)
Rovis T. Recent Advances in Catalytic Asymmetric Desymmetrization Reactions.
In New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.;
Wiley: New York, 2007; pp 275-312, Chapter 10. For a review on centrosym-
metric molecules, see: (c) Anstiss, M.; Holland, J. M.; Nelson, A.; Titchmarsh, J.
R. Synlett 2003, 1213–1220. Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem.
Rev. 2005, 105, 313–354.
(2) Some significant examples. Vannusal B: Nicolaou, K. C.; Zhang, H.;
Ortiz, A.; Dagneau, P. Angew. Chem., Int. Ed. 2008, 47, 8605–8610. Tamiflu:
Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73, 4895–4902.
Ionomycin: Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain,
€
(4) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 1994,
47, 881–886.
€
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Eur. J. Org. Chem. 1999, 1085–1089.
(6) Crowley, P. J.; Aspinall, I. H.; Gillen, K.; Godfrey, C. R. A.; Devillers,
I. M.; Munns, G. R.; Sageot, O. A.; Swanborough, J.; Worthington, P. A.;
Williams, J. Chimia 2003, 57, 685–691.
(7) (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett. 2000, 2,
3365–3367. (b) Chakraborty, T. K.; Jayaprakash, S. Tetrahedron Lett. 2001,
42, 497–499. (c) Chakraborty, T. K.; Jayaprakash, S.; Laxman, P. Tetra-
hedron 2001, 57, 9461–9467. (d) Dias, L. C.; de Oliveira, L. G. Org. Lett.
2001, 3, 3951–3954. (e) Sirasani, G.; Paul, T.; Andrade, R. B. J. Org. Chem.
2008, 73, 6386–6388. (f) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008,
130, 14084–14085. For a general review on crocacins syntheses see:
(g) Andrade, R. B. Org. Prep. Proced. Int. 2009, 41, 359–383.
€
G. Org. Lett. 2002, 4, 1879–1882. cis-Solamin: Goksel, H.; Stark, B. W. Org.
Lett. 2006, 8, 3433–3436. Quadrigemine C and Psycholeine: Lebsack, A. D.;
Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124,
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ꢀ
(3) Candy, M.; Audran, G.; Bienayme, H.; Bressy, C.; Pons, J.-M. Org.
Lett. 2009, 11, 4950–4953.
1354 J. Org. Chem. 2010, 75, 1354–1359
Published on Web 02/03/2010
DOI: 10.1021/jo902582w
r
2010 American Chemical Society

Candy et al.
JOCFeatured Article
SCHEME 2. Synthesis of the Desymmetrized Monoacetate 5
Moreover (þ)-crocacin C could present an interest as a
pivotal scaffold for the synthesis of other members of its
family as shown by Dias et al.9
FIGURE 1. Structure of crocacins A-D.
SCHEME 1. Retrosynthetic Plan
Results and Discussion
Retrosynthetic Analysis. Our strategy for the synthesis of
(þ)-crocacin C (Scheme 1) relied on a one-pot hydrostanny-
€
lation/Stille coupling between Furstner’s intermediate al-
kyne 128b and Rizzacasa’s iodide 13,7a a base-induced ring
opening of the THP ring present in compound 10, a Julia-
type olefination involving sulfones 7 or 8, and an asymmetric
enzymatic desymmetrization of meso-THP diol 4.
Synthesis and Desymmetrization of Diol 4. meso-THP diol
4 was built in three steps on a multigram scale starting from the
easily available oxabicycle 1 (Scheme 2). This precursor was
obtained through a highly diastereoselective [4 þ 3] cycloaddi-
tion between an oxoallyl cation and furan following conditions
described by Lubineau and Bouchain.10 Hence, oxabicycle 1
was reduced in a complete diastereoselective fashion using
sodium borohydride in methanol, and the resulting alcohol
was etherified in the presence of potassium hydride and methyl
iodide in THF. The resulting methylether was then subjected to
ozonolysis [O3, MeOH/CH2Cl2 (1.5/2), -60 °C] ended by a
reductive treatment (NaBH4 in excess, -60 °C to rt) to afford
the desired meso-diol in 70% yield over three steps. The achiral
diol 4 was then desymmetrized using Rhizomucor miehei [15%
weight of the substrate,11 rt, in i-Pr2O/vinyl acetate (1/1), 18 h].
This crucial transformation could be run on two gram scale
without any noticeable loss of yield or enantioselectivity (87%,
>98% ee).3 It is worth noting that this desymmetrization step
allowed the control of five contiguous stereogenic centers, in
one single transformation, in addition to the generation of a
dense building block.
enamide side chain. Crocacins were found to exhibit moderate
antibacterial, antifungal, and cytotoxic activities; however,
crocacin D presents an important cytotoxicity against the
L929 mouse fibroblast cell culture (IC50 of 0.06 mg L-1).
Finally, a pesticide activity was recently identified for croca-
cins.6
Since the discovery of these natural products, five total
syntheses7 and four formal syntheses8 of (þ)-crocacin C were
accomplished, mainly based on aldol chemistry and using
chiral auxiliaries. Among all of these approaches, one took
advantage of the hidden symmetry of the molecule using a
desymmetrization of oxabicycle 1 (structure represented in
Scheme 2) by asymmetric hydroboration;8c however, an 18-
step sequence was still required, starting from 1, to achieve a
formal synthesis of the natural product. Concerning the
construction of the dienamide system, two approaches were
employed: olefination with Horner-Wadsworth-Emmons
reaction7a,e or Julia-type reaction8c to form the C4-C5
bond, or palladium-catalyzed cross-coupling using Stille
reaction7a,d,f or Suzuki reaction8b to form the C3-C4 bond.
Olefination by Julia-Type Reaction. Monoacetate 5 was
then oxidized under standard Swern conditions,12 and the
resulting crude aldehyde was directly submitted to a Julia-
type olefination13 (Table 1). Two different sulfones, 714
(9) Dias, L. C.; de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F. J. Org.
Chem. 2005, 70, 2225–2234.
(10) (a) Lubineau, A.; Bouchain, G. Tetrahedron Lett. 1997, 38, 8031–
8032. (b) Lautens, M.; Bouchain, G. Org. Synth. 2002, 79, 251–253.
(11) We reported previously the use of 50-60% weight of enzyme
compared to the substrate. On a larger scale, this amount could be notably
reduced without loss of reactivity or selectivity.
(12) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482.
(13) For a review on the Julia-type olefination see: Blakemore, P. R.
J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(14) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26–28.
(8) (a) Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2004, 45, 5593–5595.
€
70, 1696–1708. (c) Yadav, J. S.; Reddy, P. V.; Chandraiah, L. Tetrahedron
Lett. 2007, 48, 145–148. (d) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad,
A. R. Synlett 2007, 2049–2052.
(b) Bes-ev, M.; Brehm, C.; Furstner, A. Collect. Czech. Chem. Commun. 2005,
J. Org. Chem. Vol. 75, No. 5, 2010 1355

Candy et al.
JOCFeatured Article
TABLE 1. Swern Oxidation/Julia-Type Olefination Sequence
aDetermined by 1H NMR of the crude experiment. bIsolated yields of the E/Z mixture. cPerformed at -78 °C for 30 min then warmed up to 0 °C.
dPerformed at -60 °C for 30 min then warmed up to 0 °C. eIsolated yield of E-isomer.
SCHEME 3. Synthesis of the R-Chloromethyltetrahydropyran 10
SCHEME 4. Base-Induced Ring Opening of the Chloride 10
and 8,15 were tested changing two parameters (solvent, base)
under Barbier’s conditions (Table 1). Best results were ob-
served when performing the reaction with sulfone 8, KHM-
DS as the base, and DME as the solvent (Table 1, entries 3
and 8). The corresponding olefin 6 was thus obtained in 87%
(E/Z ratio = 87/13) yields. The two isomers were easily sepa-
rable by conventional column chromatography on silica gel
(Table 1, entry 8).
Base-Induced Ring Opening of Chloride 10. Next, treat-
ment of acetate (E)-6 with potassium carbonate in methanol
afforded alcohol 9, which was then chlorinated using stan-
dard conditions (PPh3, imidazole, CCl4, reflux) (Scheme 3).
The resulting halogenated intermediate 10 was isolated in
80% yield over two steps. A base-induced THP ring opening of
intermediate 10 allowed the formation of alkyne 11 (Scheme 4).
This methodology, which has been applied to several R-chloro-
methylcycloethers of various ring size,16 required some opti-
mization in order to obtain decent yields. Hence, when using
(16) For examples of R-chloromethylepoxides opening, see: (a) Takano,
S.; Samizu, K.; Sugihara, T.; Ogasawara, K. J. Chem. Soc., Chem Commun.
1989, 1344–1345. (b) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M.
Tetrahedron 1990, 46, 7033–7046. For examples of R-chloromethyltetrahy-
drofurans opening, see: (c) Eglinton, G.; Jones, E. R. H.; Whiting, M. C.
J. Chem Soc. 1952, 2873–2882. (d) Yadav, J. S.; Chander, M. C.; Rao, C. S.
Tetrahedron Lett. 1989, 30, 5455–5458. For examples of R-chloromethylte-
trahydropyrans opening, see: (e) Herault, V. Bull. Soc. Chim. Fr. 1963, 2105–
2113. (f) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron
Lett. 2006, 47, 4397–4401.
(15) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175–1178.
1356 J. Org. Chem. Vol. 75, No. 5, 2010

Candy et al.
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SCHEME 5. End of the synthesis
5 equiv of LDA at temperatures ranging from -78 to -30 °C,
the corresponding alkoxyalkyne 11 was obtained as the only
product in 47% yield, and 46% of the starting material was
recovered without a trace of the protonated form of intermedi-
ate vinyl chloride A. This result suggested that the elimination
step from vinyl chloride intermediate A occurred faster than its
formation through the ring-opening step. In order to optimize
this transformation, an adjustment of the amount of LDA was
operated to convert all chloride 10 during the reaction. After
close examination, it was found that 10 equiv was necessary to
observe the complete consumption of the starting material and
to obtain alkyne 11 in up to 85% yields.
Final Coupling. The synthesis of (þ)-crocacin C was then
achieved in two steps (Scheme 5). First, the etherification of
the free hydroxyl group of alkyne 11 was conducted under
classical conditions (NaH, MeI, THF, 0 °C to rt), affording
the desired diether 12 in 94% yield. Finally, we envisioned to
directly convert alkyne 12 into (þ)-crocacin C via a coupling
with (E)-iodoacrylamide 13.17 The synthesis of the diena-
mide moiety of the natural product involved a one-pot
palladium-catalyzed sequence involving a hydrostannyla-
tion18 and a Stille coupling.19 While a similar process had
been reported in the literature by Maleczka et al.,20 we were
surprised by the lack of application in total synthesis. This
procedure circumvented the purification of vinylstannane
intermediate 14 and, as a consequence, should prevent its
partial protodestannylation.
A set of four reaction conditions was (Scheme 5) tested to
obtain (þ)-crocacin C directly from alkyne 12. The hydrostan-
nylation step involved standard conditions [PdCl2(PPh3)2,
Bu3SnH, THF, 0 °C], which were common to all four protocols.
First, we performed the hydrostannylation using PdCl2-
(PPh3)2 followed by the Stille coupling in the presence of
Pd2(dba)3 and tri-2-furylphosphine21 (TFP) (condition A).
Under these conditions, the natural product was obtained in
a poor yield along with degradation products.
The use of PdCl2(PPh3)2 to promote both the hydrostan-
nylation and the coupling (condition B) notably improved
the yield, up to 42%, but degradation products were ob-
served.
In order to suppress the decomposition during the cou-
pling step, a microwave activation20b,22 (MW) was tested to
reduce heating time (conditions C and D). Hence, when
PdCl2(PPh3)2 and Pd(PPh3)4 were used, respectively, for
the hydrostannylation and the coupling, the natural product
(17) Vinyl iodide 13 was obtained stereoselectively using the following
sequence which involves the stannylcupration of but-2-ynoic acid (Abarbri,
^
M.; Parrain, J.-L.; Duchene, A.; Thibonnet, J. Synthesis 2006, 2951-2970),
followed by an iododestannylation, an esterification, and a transamidation:
(19) For a review on Pd-catalyzed reaction in total synthesis, see:
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44,
4442–4489.
(20) (a) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1998, 63, 9622–
9623. (b) Maleczka, R. E., Jr.; Lavis, J. M.; Clark, D. H.; Gallagher, W. P.
Org. Lett. 2000, 2, 3655–3658. (c) Maleczka, R. E., Jr.; Gallagher, W. P.;
Terstiege, I. J. Am. Chem. Soc. 2000, 122, 384–385. (d) Gallagher, W. P.;
Terstiege, I.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 2001, 123, 3194–3204.
(21) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.
(22) First example of a microwave-assisted Stille coupling: Larhed, M.;
Hallberg, A. J. Org. Chem. 1996, 61, 9582–9584.
(18) For review on hydrostannylation, see: (a) Smith, N. D.; Mancuso, J.;
Lautens, M. Chem. Rev. 2000, 100, 3257–3282. (b) Trost, B. M.; Ball, Z. T.
Synthesis 2005, 853–887. For seminal work on Pd-catalyzed hydrostannyla-
ꢀ
tion see: (c) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857–1867.
J. Org. Chem. Vol. 75, No. 5, 2010 1357

Candy et al.
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was obtained in 76% (condition C) after two irradiation
periods of 10 min each at 100 °C.
dropwise via cannula at -78 °C. After stirring for an additional
15 min, at this temperature, triethylamine (1.03 g, 1.4 mL, 10.15
mmol) was added dropwise and the reaction mixture was slowly
warmed to room temperature (30 min). It was then quenched by
adding 20 mL of a saturated aqueous solution of NH4Cl. The
aqueous layer was extracted with dichloromethane (3 ꢀ 15 mL),
and the combined organic layers were washed with water (2 ꢀ 20
mL) and brine (1 ꢀ 20 mL), dried (anhydrous MgSO4), and
concentrated in vacuo. To the crude product was added diethyl
ether (10 mL); the rest of the ammonium salts were filtered off,
and the solvent was evaporated to afford the crude aldehyde
(492 mg, 99%) as a pale yellow solid, which was used in the Julia
reaction without further purification.
A simplified procedure (condition D), with a unique catalyst
source (PdCl2(PPh3)2), gave the natural product in similar yield
after 15 min heating in a microwave oven. We were pleased
to observe that this last step proceeded with complete regio-
selectivity and stereospecificity in favor of the target molecule.
Spectroscopic data of the synthesized product were iden-
tical in all respects with those reported for the natural pro-
duct {[R]25D = þ56.2 (c = 0.5, MeOH); lit.5 [R]22D = þ52.2
(c = 0.3, MeOH)}.
General Procedure for the Julia-Type Olefination: In a flame-
dried 10 mL one-necked round-bottomed flask, under an atmo-
sphere of argon, sulfone 7 or 8 (0.27 mmol, 1.3 equiv) and the
crude aldehyde (50 mg, 0.20 mmol, 1.0 equiv) were weighed out
and dried in high vacuum for 15 min. The appropriate solvent
(1.5 mL) was added, and the reaction mixture was cooled to -78
°C (-60 °C for DME). The base (0.27 mmol, 1.3 equiv) dissolved
in 1 mL of the same solvent was added dropwise at this
temperature, and the resulting orange-red mixture was stirred
for 30 min and warmed to 0 °C over a period of 30 min. It was
quenched by adding 3 mL of saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with diethyl ether (3 ꢀ
3 mL), and the combined organic layers were washed with water
(2 ꢀ 5 mL) and brine (1 ꢀ 5 mL), dried (anhydrous MgSO4), and
concentrated in vacuo. The E/Z ratio was determinated by 1H
NMR of the crude product, which was then purified by silica gel
column flash chromatography (PE/AcOEt mixture, gradient
elution: 90/10 to 85/15) to afford pure E- and Z-isomers as
colorless oils. Yields and conditions are reported in Table 1. E-
isomer (6): Rf = 0.51 (PE/EtOAc 8/2); [R]30D = þ24.5 (c = 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 2H), 7.31 (m,
2H), 7.22 (m, 1H), 6.65 (dd, J = 16.1, 1.1 Hz, 1H), 6.23 (dd, J =
16.1, 5.7 Hz, 1H), 4.23 (dd, J = 11.5, 7.7 Hz, 1H), 4.16 (dd, J =
11.5, 4.5 Hz, 1H), 4.11 (ddd, J = 5.7, 4.3, 1.1 Hz, 1H), 3.71 (ddd,
J = 7.7, 4.5, 2.6 Hz, 1H), 3.47 (t, J = 5.3 Hz, 1H), 3.37 (s, 3H),
2.15 (m, 2H), 2.08 (s, 3H), 0.96 (d, J = 7.2 Hz, 3H), 0.95 (d, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.0, 136.9, 130.3,
128.5 (2C), 128.2, 127.4, 126.4 (2C), 81.2, 80.4, 77.2, 65.2, 55.3,
36.8, 33.3, 21.0, 9.0, 8.3; HRMS (ESI TOF) calcd for
C19H30NO4 (M þ NH4)þ 336.2169, found 336.2167. Z-isomer
Conclusion
(þ)-Crocacin C has been synthesized from oxabicycle 1 in
22.3% overall yield, following a convergent protecting-
group-free23 sequence of 11 steps. In addition, the establish-
ment of the hidden symmetry of a significant portion of the
natural product has allowed a synthetic plan based on the use of
a meso compound. This non-aldol strategy offered to control
through a single enantioselective step the four contiguous
stereogenic centers of (þ)-crocacin C. Moreover, the synthesis
was achieved by the rapid building of the dienamide system
using a Pd-catalyzed one-pot sequence involving a hydro-
stannylation and microwave-assisted Stille coupling reactions.
We are currently working on the extension of this methodology
to other natural molecules bearing a polypropionate segment.
Experimental Section
(þ)-((2S,3R,4R,5S,6R)-6-(Hydroxymethyl)-4-methoxy-3,5-
dimethyltetrahydro-2H-pyran-2-yl)methyl acetate (5). Rhizomu-
cor miehei lipase (300 mg) was added to a solution of diol 4 (2.0 g,
9.79 mmol) in iPr2O (50 mL) and vinyl acetate (50 mL), and the
mixture was stirred magnetically in a hermetically stoppered one-
necked flask at room temperature (the course of the reaction
being monitored by TLC). After 18 h, the reaction mixture was
filtered through a pad of Celite, and the cake was washed with dry
Et2O. The filtratewas concentrated in vacuoandpurified bysilica
gel column flash chromatography (PE/EtOAc, gradient elu-
tion: 80/20 to 60/40) to afford 2.1 g of pure monoacetate 5 as
white crystals (87% yield): mp 80-81 °C; Rf = 0.28 (PE/EtOAc
1/1); ee >98% determined on chiral HPLC column, Sepapak-
2-HR; mobile phase, hexane/isopropanol 80/20, 1 mL/min,
temperature = 25 °C, retention time (þ)-isomer = 9.78 min,
(6): Rf = 0.66 (PE/EtOAc: 8/2); [R]30 = -82.4 (c = 1.0,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.36 to 7.28 (m, 5H),
6.70 (d, J = 11.7 Hz, 1H), 5.90 (dd, J = 11.7, 8.7 Hz, 1H), 4.23
(dd, J = 8.7, 2.6 Hz, 1H), 4.17 to 4.15 (m, 2H), 3.70 (ddd, J =
7.7, 5.3, 2.6 Hz, 1H), 3.37 (t, J = 5.3 Hz, 1H), 3.32 (s, 3H), 2.13
(m, 2H), 2.09 (s, 3H), 1.08 (d, J = 7.2 Hz, 3H), 0.97 (d, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.0, 136.7, 132.9,
128.9, 128.7 (2C), 128.3 (2C), 127.4, 80.9, 76.8, 76.1, 65.7, 55.3,
35.8, 33.2, 21.0, 8.9, 8.4; HRMS (ESI TOF) calcd for C19H26O4
(M þ H)þ 319.1904, found 319.1902.
1
retention time (-)-isomer = 7.52 min; H NMR (300 MHz,
CDCl3) δ 4.12 (m, 2H), 3.76 (dd, J = 12.1, 9.5 Hz, 1H), 3.62 (m,
1H), 3.51 (m, 2H), 3.36 (t, J = 5.3 Hz, 1H), 3.32 (s, 3H), 2.09 (m,
2H), 2.06 (s, 3H), 0.90 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 171.0, 80.8, 80.7, 77.4, 65.2,
63.7, 55.3, 33.6, 33.2, 20.9, 8.5, 8.2; HRMS (ESI TOF) calcd for
C12H23O5 (M þ H)þ 247.1540, found 247.1543.
((2S,3R,4R,5S,6S)-4-Methoxy-3,5-dimethyl-6-((E)-styryl)-
tetrahydro-2H-pyran-2-yl)methanol (9). To a solution of acetate
6 (530 mg, 1.66 mmol) in methanol (16 mL) was added potas-
sium carbonate (460 mg, 3.32 mmol) at room temperature, and
the resulting white suspension was stirred for 30 min. It was then
quenched by adding 20 mL of a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with dichloromethane
(3 ꢀ 20 mL), and the combined organic layers were washed with
brine (2 ꢀ 10 mL), dried (anhydrous MgSO4), and concentrated
in vacuo. The crude product was purified by silica gel column
flash chromatography (PE/EtOAc mixture, gradient elution:
80/20 to 60/40) to afford 452 mg of pure alcohol 9 (99%), as
colorless oil: Rf = 0.17 (PE/EtOAc 8/2); [R]30D = þ25.5 (c =
((2S,3R,4R,5S,6S)-4-Methoxy-3,5-dimethyl-6-((E)-styryl)-
tetrahydro-2H-pyran-2-yl)methyl acetate (6).
Swern Oxidation: In a flame-dried 100 mL one-necked round-
bottomed flask, under an atmosphere of argon, dimethylsulf-
oxide (253 mg, 233 μL, 3.24 mmol) was added dropwise at -78
°C to a solution of oxalyl chloride (386 mg, 268 μL, 3.04 mmol)
in 15 mL of dry dichloromethane. The resulting colorless
solution was stirred for 5 min, and a solution of alcohol 5 (500
mg, 2.03 mmol) in 5 mL of dry dichloromethane was added
(23) In our case, the acetate group should be considered as a desymme-
trizing group. For a review on protecting-group-free syntheses, see: (a)
Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193–205. (b) Baran, P. S.;
Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404–408. (c) Hoffmann,
R. W. Synthesis 2006, 3531–3541.
1
1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.41 to 7.23 (m,
5H), 6.64 (dd, J = 16.1, 1.3 Hz, 1H), 6.23 (dd, J = 16.1, 5.7 Hz,
1358 J. Org. Chem. Vol. 75, No. 5, 2010

Candy et al.
JOCFeatured Article
1H), 4.13 (ddd, J = 5.7, 4.3, 1.3 Hz, 1H), 3.85 (dd, J = 10.4, 7.3
Hz, 1H), 3.63 to 3.54 (m, 2H), 3.47 (t, J = 5.3 Hz, 1H), 3.36 (s,
3H), 2.38 (br s, 1HOH), 2.17 (m, 1H), 2.10 (m, 1H), 0.95 (d, J =
7.2 Hz, 3H), 0.92 (d, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 136.9, 130.2, 128.5 (2C), 128.3, 127.5, 126.4 (2C), 81.3,
80.7, 80.3, 64.0, 55.3, 36.9, 33.9, 9.0, 8.7; HRMS (ESI TOF)
calcd for C17H28NO3 (M þ NH4)þ 294.2064, found 294.2059.
(2S,3R,4R,5S,6S,7E)-2-(Chloromethyl)-4-methoxy-3,5-di-
methyl-6-styryltetrahydro-2H-pyran (10). In a 25 mL one-
necked round-bottomed flask, equipped with a reflux conden-
ser, alcohol 9 (200 mg, 0.72 mmol) was dissolved in 4 mL of
carbon tetrachloride. Triphenylphosphine (569 mg, 2.17 mmol)
was added followed by imidazole (147 mg, 2.17 mmol), and the
resulting light yellow solution was stirred at 70 °C for 2 h. After
being cooled to room temperature, the reaction mixture was
quenched by adding 10 mL of a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with dichloromethane
(3 ꢀ 10 mL), and the combined organic layers were washed with
brine (2 ꢀ 10 mL), dried (anhydrous MgSO4), and concentrated
in vacuo. The crude product was purified by silica gel column
flash chromatography using solid deposit (3 g of silica) (PE/
EtOAc mixture, gradient elution: 98/2 to 95/5) to afford 168 mg
of pure chloride 10 (80%), as a colorless oil: Rf = 0.66 (PE/
solution was added portionwise sodium hydride (60% disper-
sion in mineral oil) (43 mg, 1.82 mmol) at 0 °C. The resulting
light yellow alcoholate was stirred at room temperature for 30
min; iodomethane (77 μL, 173 mg, 1.22 mmol) was added
dropwise, and the reaction mixture was stirred for 12 h at room
temperature. The reaction was then quenched by adding 10 mL
of a saturated aqueous solution of NH4Cl. The aqueous layer
was extracted with diethyl ether (3 ꢀ 10 mL), and the combined
organic layers were washed with brine (2 ꢀ 10 mL), dried
(anhydrous MgSO4), and concentrated in vacuo. The crude
product was purified by silica gel column flash chromatography
(PE/EtOAc mixture, gradient elution: 95/5 to 90/10) to afford
156 mg of pure alkyne 12 (94%), as a white solid: mp 55-56 °C;
Rf = 0.62 (PE/EtOAc 9/1); [R]30D = þ24.8 (c = 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.39 (m, 2H), 7.33 (m, 2H), 7.24 (m,
1H), 6.62 (d, J = 16.1 Hz, 1H), 6.21 (dd, J = 16.1, 7.2 Hz, 1H),
4.16 (ddd, J = 7.2, 2.3, 1.0 Hz, 1H), 3.57 (s, 3H), 3.33 (s, 3H),
3.17 (dd, J = 9.8, 2.5 Hz, 1H), 2.78 (qt, J = 7.0, 2.5 Hz, 1H), 2.07
(d, J = 2.5 Hz, 1H), 1.96 (m, 1H), 1.36 (d, J = 7.2 Hz, 3H), 0.95
(d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 136.8, 132.0,
129.2, 128.6 (2C), 127.5, 126.4 (2C), 85.1, 84.8, 80.9, 69.9, 61.4,
56.4, 42.8, 29.4, 18.2, 9.9; HRMS (ESI TOF) calcd for
C18H24O2Na (M þ Na)þ 295.1669, found 295.1667.
1
EtOAc 9/1); [R]30D = þ40.5 (c = 1.0, CHCl3); H NMR (300
(þ)-Crocacin C. In a flame-dried 10 mL MW vial, under an
atmosphere of argon, alkyne 12 (40 mg, 0.147 mmol) was
dissolved in 2 mL of dry THF. The solvent was degassed
(three freeze-pump-thaw degassing cycles), and PdCl2(PPh3)2
(5 mg, 7.3 μmol) was added followed by tributyltin hydride
(44 μL, 47 mg, 0.161 mmol) at 0 °C over a period of 15 min. The
reaction mixture was stirred at this temperature, and the for-
mation of the stannane was monitored by TLC (15 min). Vinyl
iodide 13 (34 mg, 0.161 mmol) was added in one portion, and the
tube was submitted to MW irradiation (15 min at 100 °C). The
reaction mixture was filtered through a short pad of silica,
washed with ethyl acetate, and the resulting filtrate was con-
centrated in vacuo. The residue was purified by two consecutive
silica gel columns flash chromatography (PE/EtOAc mixture,
gradient elution: 50/50 to 30/70) to afford 39 mg of (þ)-crocacin
MHz, CDCl3) δ 7.41 to 7.23 (m, 5H), 6.66 (dd, J = 16.1, 1.1 Hz,
1H), 6.21 (dd, J=16.1, 5.6 Hz, 1H), 4.13 (ddd, J = 5.6, 4.3, 1.1
Hz, 1H), 3.67 (m, 2H), 3.53 (m, 1H), 3.47 (t, J = 5.3 Hz, 1H),
3.38 (s, 3H), 2.30 (m, 1H), 2.17 (m, 1H), 0.96 (d, J = 7.2 Hz, 3H),
0.95 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 136.9,
130.4, 128.5 (2C), 127.9, 127.5, 126.4 (2C), 81.2, 80.6, 79.4, 55.4,
43.6, 36.7, 32.9, 9.0, 8.7; HRMS (ESI TOF) calcd for
C17H24O2Cl (M þ H)þ 295.1459, found 295.1456.
(3S,4R,5S,6S,1E)-5-Methoxy-4,6-dimethyl-1-phenyloct-1-en-
7-yn-3-ol (11). In a flame-dried 25 mL one-necked round-
bottomed flask, under an atmosphere of argon, a solution of
chloride 10 (140 mg, 0.47 mmol) in dry THF (2 mL) was added
dropwise at -78 °C to a solution of LDA (freshly prepared by
adding 1.9 mL (4.7 mmol) of n-BuLi (2.5 M in hexanes) to
diisopropylamine (665 μL, 480 mg, 4.7 mmol)) in 3 mL of dry
THF. The resulting yellow solution was warmed to -30 °C and
stirred for 2 h at this temperature. After completion of the
reaction (TLC check), it was quenched by adding 10 mL of a
saturated aqueous solution of NH4Cl. The aqueous layer was
extracted with diethyl ether (3 ꢀ 10 mL), and the combined
organic layers were washed with brine (2 ꢀ 10 mL), dried
(anhydrous MgSO4), and concentrated in vacuo. The crude
product was purified by silica gel column flash chromatography
(PE/EtOAc mixture, gradient elution: 90/10 to 70/30) to afford
105 mg of pure alkyne 11 (85%), as a white solid: mp 81-82 °C;
Rf = 0.25 (PE/EtOAc 9/1); [R]30D = þ0.5 (c = 2.0, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.38 (m, 2H), 7.32 (m, 2H), 7.23 (m,
1H), 6.69 (dd, J = 16.1, 1.7 Hz, 1H), 6.29 (dd, J = 16.1, 5.1 Hz,
1H), 4.64 (m, 1H), 3.58 (s, 3H), 3.23 (dd, J = 7.7, 4.2 Hz, 1H),
2.86 (br s, 1HOH), 2.84 (m, 1H), 2.12 (d, J = 2.6 Hz, 1H), 2.10
C (73%), as a white solid: mp 87-88 °C; Rf = 0.25 (PE/EtOAc
1
1/1); [R]25 = þ56.2 (c = 0.5, MeOH); H NMR (300 MHz,
D
CDCl3) δ 7.38 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 6.59 (d, J =
16.1 Hz, 1H), 6.17 (dd, J = 16.1, 7.2 Hz, 1H), 6.09 to 5.99 (m,
2H), 5.63 (s, 1H), 5.37 (br s, 2HNH), 4.09 (dd, J = 7.2, 1.3 Hz,
1H), 3.54 (s, 3H), 3.32 (s, 3H), 3.20 (dd, J = 10.0, 2.2 Hz, 1H),
2.55 (m, 1H), 2.25 (d, J = 1.0 Hz, 3H), 1.54 (m, 1H), 1.20 (d, J =
6.8 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 169.1, 149.7, 137.2, 136.7, 133.9, 132.0, 129.2, 128.6
(2C), 127.6, 126.4 (2C), 119.40, 86.4, 81.0, 61.9, 56.4, 42.6, 40.0,
18.7, 13.8, 9.7; HRMS (ESI TOF) calcd for C22H31NO3Na (M þ
Na)þ 380.2196, found 380.2188.
Acknowledgment. We gratefully thank Dr. Laurent Com-
ꢀ
meiras (University Paul Cezanne) for helpful discussions.
The University Paul Cezanne, the CNRS and the Conseil
(m, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H); 13
C
ꢀ
NMR (75 MHz, CDCl3) δ 137.0, 131.1, 129.8, 128.5 (2C), 127.4,
126.3 (2C), 87.1, 85.5, 72.6, 70.1, 61.2, 41.1, 29.3, 17.6, 11.6;
HRMS (ESI TOF) calcd for C17H22O2Na (M þ Na)þ 281.1512,
found 281.1513.
ꢀ ꢀ
General des Bouches du Rhone are also gratefully acknowl-
edged. Finally, M.C. thanks the CNRS and the Region
^
Provence Alpes Cotes d’Azur for a fellowship.
^
ꢀ
((3S,4R,5S,6S,7E)-3,5-Dimethoxy-4,6-dimethyloct-1-en-7-
ynyl)benzene (12). In a flame-dried 25 mL one-necked round-
bottomed flask, under an atmosphere of argon, alkyne 11 (157
mg, 0.61 mmol) was dissolved in 5 mL of dry THF. To this
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1359