Pyranophane Transannular Diels-Alder Approach to (+)-Chatancin: A Biomimetic Asymmetric Total Synthesis

Article abstract of DOI:10.1021/jo035193y

An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that in

Full text of DOI:10.1021/jo035193y

P yr a n op h a n e Tr a n sa n n u la r Diels-Ald er Ap p r oa ch to
(+)-Ch a ta n cin : A Biom im etic Asym m etr ic Tota l Syn th esis
Pierre Soucy, Alexandre L’Heureux, Andra´s Toro´, and Pierre Deslongchamps*
Laboratoire de Synthe`se Organique, Departement de Chimie, Institut de Pharmacologie de Sherbrooke,
Universite´ de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke (Quebec) J 1H 5N4, Canada
pierre.deslongchamps@usherbrooke.ca
Received August 14, 2003
An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder
(TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route
constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It
links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize
the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles
and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction,
highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate
from (S)-citronellol and an efficient macrocyclization via a â-ketosulfoxyde/enone Michael addition.
SCHEME 1. F u r a n op h a n e TADA Ap p r oa ch
(+)-Chatancin (1) was isolated from soft coral Sarco-
phyton sp. in a screening program conducted to identify
novel platelet activating factor (PAF) antagonists from
marine organisms.1 PAF has been associated with a
variety of biological effects including platelet aggregation,
smooth muscle contraction, hypotension, and vascular
permeability. It is also implicated as a causative factor
in septic shock, inflammation, and respiratory and car-
diovascular diseases. The appealing bioactivity of diter-
pene 1 and its seven stereogenic centers dispersed on a
unique, cis-anti-cis (CAC) dodecahydrophenanthrene
framework, locked by an internal hemiketal ring, has
already inspired a racemic total synthesis.2 Beyond the
challenging structure, we were further intrigued by its
distinctive carbon functional pattern similar to that of
cembranoids isolated also from Sarcophytons as well as
from other soft corals.3 Cembranoids, diterpenes with a
14-membered macrocycle, are known to be common
intermediates in the biogenesis of a divers array of
polycyclic diterpenes. However, no transannular Diels-
Alder (TADA) reaction was ever found to be the method
of internal cyclization with cembranoids. In fact, to date,
only two biomimetic TADA syntheses are known in
natural product synthesis.4 As we have long been inter-
ested in the TADA reaction and its applications in
natural product synthesis,5 it was implicit to investigate
this type of cyclization as a biosynthetic route to 1.
In principle, two distinct biosynthetic TADA routes
may be envisaged to reach 1 from a cembranoid. The first
route, which involves artificial furanocembranoid 2, was
investigated recently by a nonenzymatic synthetic method
(Scheme 1).6 In that furanophane approach, we found
that, although 2 selectively generates TADA adduct 3 in
a reversible reaction, the extreme acid sensitivity of 1
and the strongly acidic condition required for the con-
clusive hydride shift-mediated oxygen transposition al-
lowed only for the isolation of anhydrochatancin 4.
In the alternative, pyranophane biosynthetic proposal,
the cembranoid is oxidized differently, to bicyclic 2-hy-
droxy-2H-pyrane 5a , which can cyclize to 1 directly under
very mild conditions.7 However, in an aqueous media,
pyrilium pseudobases 2-hydroxy-2H-pyranes are known
to be in a delicate, pH-dependent equilibrium with their
pyrylium ion and their open enedione forms.8 Application
of this equilibrium to the asymmetric case of 5a suggests
* To whom correspondence should be addressed. Fax: (819) 820-
6823.
(1) Sugano, M.; Shindo, T.; Sato, A.; Iijima, Y.; Oshima, T.; Kuwano,
H.; Hata, T. J . Org. Chem. 1990, 55, 5803-5805.
(2) Aigner, J .; Go¨ssinger, E.; Ka¨hlig, H.; Menz, T.; Pflugseder, K.
Angew. Chem., Int. Ed. 1998, 37, 2226-2228.
(3) Rodriguez, A. D. Tetrahedron 1995, 51, 4571-4618.
(4) (a) Layton, M. E.; Morales, C. A.; Shair, M. D. J . Am. Chem.
Soc. 2002, 124, 773-775. (b) Vosburg, D. A.; Vanderwal, C. D.;
Sorensen, E. J . J . Am. Chem. Soc. 2002, 124, 4552-4553. (c) Evans,
D. A.; Starr, J . T. J . Am. Chem. Soc. 2003, 125, 13531-13540.
(5) Marsault, E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahe-
dron 2001, 57, 4243-4260.
(6) Toro´, A.; Deslongchamps, P. J . Org. Chem. 2003, 68, 6847-6852.
(7) Toro´, A.; L’Heureux, A.; Deslongchamps, P. Org. Lett. 2000, 2,
2737-2740.
(8) Williams, A. J . Am. Chem. Soc. 1971, 93, 2733-2737.
10.1021/jo035193y CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003
J . Org. Chem. 2003, 68, 9983-9987
9983

Soucy et al.
SCHEME 2. P yr a n op h a n e TADA Ap p r oa ch
SCHEME 3 a
a complex mixture of four macrocyclic diketones 6,
pyrylium ion 7, and four pseudobases 5a -d of the latter
(Scheme 2). Consequently, to test a plausible participa-
tion of a TADA reaction in the biosynthesis, all four
pseudobases 5 must be taken into account.9 Since, in
principle, every macrocyclic TADA substrate can have
four operative conformations, arising from the approach
of the diene and the dienophile via each of their respec-
tive π-faces, the four pseudobases of 5 can generate 16
potential transition states (TS). However, TSs in which
the hydroxyl group is sandwiched between the diene and
the dienophile can safely be eliminated to reduce the
number to eight. Furthermore, cis-trans-trans (CTT)
macrocycles 5a and 5b as well as TCT macrocycles 5c
and 5d can generate only the four CAC tetracycles (1 and
8-10, respectively), as in the TSs leading to the alterna-
tive four TAT tetracycles, the overlap of the diene and
the dienophile can only be perpendicular, therefore
unproductive.5 What is left behind is one quadrant of the
initial 4 × 4 TS table. To further narrow this short list
of potential TSs, their potential products should be
reviewed as the TADA reaction is presumed to have a
late TS. Thus, in these CAC tetracycles, the A.B.C[6.6.6]
ring system of 1 and 8 is expected to be favored over the
crowded A.B.C[5.6.7] ring system of 9 and 10. Finally,
inspection of the remaining two A.B.C[6.6.6] CAC tetra-
cycles shows that both peripheral alkyl groups of 1 are
equatorial, while those of 8 are axial. These selection
rules should lend a clear preference to the formation of
1 under near neutral aqueous conditions and minimal
thermal activation upon acquiring any of 5, 6, or 7. Now
we report our results on the synthetic investigation of
this hypothesis.
a
Reagents and conditions: (a) t-BuCOCl, pyridine (100%). (b)
SeO2, salicylic acid, t-BuOOH, CH2Cl2, 30 h (43%). (c) MsCl, Et3N,
THF, 0 °C then LiBr, 0 °C f rt (84%). (d) MOMCl, i-Pr2EtN,
CH2Cl2, 0 °C f rt (98%). (e) 16, n-BuLi, THF, -78 °C f -25 °C
then 14 (92%). (f) Na/Hg, Na2HPO4, MeOH/THF 1:2, 2 h then (a)
(70%). (g) HCl, i-PrOH, 55 °C, 8 h (81%). (h) TPAP, NMO, CH2Cl2
(86%).
Synthesis of the chiral pyranophane substrate started
with (S)-citronellol (11) (Scheme 3). After a quantitative
protection as pivalate 12, applying Sharpless’ selenium
dioxide-mediated allylic oxidation protocol functionalized
the other terminus and set the configuration of the
dienophile to afford alcohol 13 in 43% yield.10 A standard
mesylation and nucleophile bromination turned this
alcohol into allylic bromide 14 in 84% combined yield. A
typical methoxymethyl protection of alcohol 1511 gener-
ated the reagent for the introduction of the stereogenic
(10) Umbreit, M. A.; Sharpless, K. B. J . Am. Chem. Soc. 1977, 99,
(9) Although pyrylium
substrate, it was excluded based on steric arguments beyond its
aromaticity.
7
could also be considered as
a
TADA
5526-5528.
(11) Astles, P. C.; Thomas, E. J . J . Chem. Soc., Perkin Trans. 1 1997,
845-856.
9984 J . Org. Chem., Vol. 68, No. 26, 2003

Asymmetric Total Synthesis of (+)-Chatancin
SCHEME 4 a
isopropyl group. This was accomplished with an alkyla-
tion of the lithium salt of sulfone 16 with 14, followed by
a reductive desulfonylation of intermediate 17 with
sodium amalgam under buffered condition to afford 18
in a 64% combined yield.11 Preparation for further
extension on this side included a MOM deprotection to
alcohol 19 and its tetrapropylammonium perruthenate
(TPAP)-mediated oxidation to aldehyde 20 with N-
methylmorpholine N-oxide (NMO) in 71% combined
yield.12
Aldehyde 20 then served as an electrophile in the
condensation with an in situ generated lithium salt of
methylphenyl sulfoxide.13 A subsequent basic hydrolysis
completed the partial deprotection of the pivalate group
observed after condensation to isolate ultimately epimeric
diol 21 in quantitative yield. A double oxidation of this
diol to keto aldehyde 22 with Dess-Martin periodinane,14
in 83% yield, arranged one side for the macrocyclization
and prepared the other for further extension.15 Accord-
ingly, selective condensation on the aldehyde side was
achieved with 2.5 equiv of lithium salt of methyl propi-
olate to afford acetylene 23 in 84% yield.16 A catalytic
partial hydrogenation with Lindlar catalyst afforded cis-
enol 24 quantitatively,17 then a second, pyridine-buffered
Dess-Martin periodinane oxidation delivered cis-enone
25 in 83% yield.14 Finally, an iodine-catalyzed isomer-
ization of the enone system concluded the assembly of
acyclic, macrocyclization substrate trans-enone 26 by
setting the right configuration for an intramolecular
Michael reaction.
a
Reagents and conditions: (a) LDA, MeSOPh, THF then
NaOMe, MeOH (100%). (b) Dess-Martin [O], CH2Cl2 (83%). (c)
HCtCCOOMe, LDA, THF, -80 °C (84%). (d) H2, Lindlar cat.,
c-hex, CH2Cl2 (100%). (e) Dess-Martin [O], pyridine, CH2Cl2, 0
°C f rt (83%). (f) I2, Et2O, 0 °C f rt (85%).
SCHEME 5 a
Macrocyclizations are frequently the bottlenecks of
TADA syntheses. However, in this case, applying a
terminal â-keto sulfoxide as a Michael donor, a smooth
macrocyclization was observed even without slow addi-
tion and under medium dilution despite the unstable
nature of the product. Separation and purification of
these sulfoxide macrocycles 27 afforded three out of the
eight possible diastereomers in an excellent 80% com-
bined yield (Scheme 5).18 Moreover, one of them, 27c, was
crystalline and offered an easy determination of its all-R
stereochemistry by X-ray crystallography. The exact
stereochemistry of 27a and 27b was not determined due
to their instability. Pyrolysis of 27c in toluene at 115 °C
afforded a separable mixture of two diones, 6a and 6b,
out of the four possible isomers in 80% combined yield
to reach two of the targeted pyranophane substrates in
Scheme 2. Again, their exact stereochemistry was not
determined but their structure was unambiguously veri-
a
Reagents and conditions: (a) Cs2CO3, acetone, [26] ) 6.4 mM,
15 °C, 7 h (80%, 27a /27b/27c ∼ 12:59:29). (b) PhMe, 110-115 °C,
15 min (80%, 6a /6b ∼ 5:3). (c) HBF4, NaOAc, acetone, 48 h (80%).
(d) DMSO/H2O 1:1, 105-110 °C, 3-18 h, (up to 89%).
fied by NMR and MS. Interestingly, the major, kinetic
product 6a could be slowly isomerized to the thermody-
namic product 6b under buffered, acid-catalyzed condi-
tions at room temperature. Heating 6a and 6b just over
110 °C in an aqueous medium gave (+)-chatancin in 70%
and 75% yield, respectively.19 The presence of water in
the medium is essential as under the aprotic pyrolysis
conditions a step before, no TADA product was observed.
Indeed, heating any of 27 in the same aqueous medium
applied for the TADA reaction also gave 1. In fact, the
highest yield that could be achieved was with 27c.
Appearance of anhydrochatancin 4 underlines the insta-
bility of 1 and makes this tandem sequence even more
remarkable. It produces a complex polycyclic ring system
with five new stereogenic centers under exceptionally
(12) Ley, S. V.; Norman, J .; Griffith, W. P.; Marshden, S. P. Synthesis
1994, 639-666.
(13) Solladie´, G.; Rubio, A.; Carren˜o, M. C.; Ruano, J . L. G.
Tetrahedron: Asymmetry 1990, 1, 187-198.
(14) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(15) A sequence from trans-trans farnesol to keto aldehyde 22 has
already been reported in ref 7. However, as mentioned there, issues
with catalyst quality and, as a consequence, the difficulty of reproduc-
ing a crucial, enantioselective hydrogenation spurred us to develop an
alternative synthesis.
(16) Crimmins, M. T.; Nantermet, P. G.; Trotter, B. W.; Vallin, I.
M.; Watson, P. S.; McKerlie, L. A.; Reinhold, T. L.; Wai-Hing Cheung,
A.; Stetson, K. A.; Dedopoulou, D.; Gray, J . L. J . Org. Chem. 1993, 58,
1038-1047.
(17) Bernet, B.; Bishop, P. M.; Caron, M.; Kawamata, T.; Sauve´, G.;
Roy, B. L.; Ruest, L.; Soucy, P.; Deslongchamps, P. Can. J . Chem. 1985,
63, 2810-2820.
(18) Ballini, R.; Bosica, G.; Petrelli, L.; Petrini, M. Synthesis 1999,
7, 1236-1240.
(19) Durman, J .; Elliott, J .; McElroy, A. B.; Warren, S. J . J . Chem.
Soc., Perkin Trans. 1 1985, 1237-1244.
J . Org. Chem, Vol. 68, No. 26, 2003 9985

Soucy et al.
23
macrocycle 6b as a colorless oil. [R]D -57.3 (c 0.79, CHCl3);
1H NMR δ 7.22 (s, 1H), 4.93 (t, J ) 5.0 Hz, 1H), 4.07 and 3.52
(2 × d, J ) 6.2 Hz, 2H), 3.80 (s, 3H), 3.84-3.70 (m, 1H), 2.48-
0.8 (m, 12H), 1.56 (s, 3H), 0.89, 0.88, 0.87 (3 × d, J ) 6.1 and
6.8 Hz, 3 × 3H); 13C NMR δ 206.5, 204.7, 167.3, 135.4, 134.6,
134.1, 127.4, 61.1, 52.8, 48.9, 41.9, 38.0, 35.6, 29.6, 27.7, 24.0,
23.1, 21.1, 20.8, 19.1, 15.2; IR 2960, 2931, 2873, 1722, 1688,
1616, 1437, 1372, 1274, 1251 cm-1; HRMS 348.2303 ( 0.0010
(348.2300 for M+: C21H32O4).
mild conditions. Consequently, to generate (+)-chatancin,
dione 6a or 6b must enter and remain in the equilibrium
shown in Scheme 2. Furthermore, the critical role of
water suggests pyrylium ion 7 as a central intermediate
in the equilibrium. These experiments verify our initial
hypothesis about a possible pyranophane TADA reaction
in the biogenesis.20
In summary, a short, asymmetric total synthesis of
(+)-chatancin was developed to investigate the bio-
genetic relationship between the cembranoids and the
target. The synthesis required bicyclic 2-hydroxy-2H-
pyrane 5a , thus the name “pyranophane approach”, as a
substrate for the conclusive TADA reaction. As 5a is a
member of a tentative multicomponent equilibrium, its
open form, 6, was targeted. Assembly of 6 started with
successive extensions of both termini of (S)-citronellol to
reach acyclic macrocyclization substrate 26 intramolecu-
lar Michael reaction, which delivered sulfoxide macro-
cycle 27 with high yield. Heating 27 or its pyrolysis
product 6 in an aqueous media indeed produced (+)-
chatancin in up to 89% yield to verify the feasibility of
this proposal.
Isom er iza tion of Ma cr ocycle 6a to Ma cr ocycle 6b.
Sodium acetate (0.7 mg, 8.6 µmol) and fluoroboric acid (0.6
µL, 7.1 µmol, 48-60% purified) were added to a solution of
macrocycle 6a (2.5 mg, 7.1 µmol) in acetone (0.7 mL) at room
temperature. After 48 h of stirring, a solution of NH4Cl
(saturated) was added and the mixture was extracted with
CH2Cl2. The residue was purified by FC (15% ether in hexane)
to yield 2.0 mg (80%) of macrocycle 6b.
(+)-Ch a ta n cin 1. (a ) F r om m a cr ocycle 6a : A solution
of macrocycle 6a (11 mg, 31.5 µmol) in a mixture of DMSO
(1.0 mL) and water (1.0 mL) was heated at 105-110 °C for
6.5 h. Upon cooling, water (15 mL) was added then the mixture
was extracted with a mixture of ether/hexane (50:50, 6 × 15
mL). The crude product was purified by FC (20 to 30% ether
in hexane) to give 7.0 mg (70%) of (+)-chatancin 1: mp 106-
107 °C; [R]23 +12.0 (c 0.980, CHCl3); H NMR (C6D6) δ 7.24
1
D
(d, J ) 3.9 Hz, 1H), 3.55 (1s, 3H), 3.04 (d, J ) 1.8 Hz, 1H),
2.61 (7 × d, J ) 6.9 and 2.2 Hz, 1H), 1.98 (ddd, J ) 10.4, 3.5,
and 2.0 Hz, 2H), 1.70-0.43 (m, H), 1.21 and 1.09 (2 × d, J )
6.9 Hz, 2 × 3H), 0.90 (d, J ) 6.0 Hz, 3H), 0.79 (s, 3H); 13C
NMR δ 165.1, 143.7, 135.9, 98.8, 75.6, 53.0, 51.2, 48.8, 47.6,
42.3, 37.7, 36.0, 34.5, 29.4, 27.2, 25.5, 24.3, 23.0, 22.2, 18.5,
18.4; IR 3597, 3011, 2956, 2930, 2873, 1714, 1631, 1456, 1436,
1272, 1214 cm-1; HRMS 348.2296 ( 0.0010 (348.2300 for M+:
Exp er im en ta l Section
(4S,11S,7E)-2-Ben zen esu lfin yl-4-isopr opyl-7,11-dim eth yl-
3,13-d ioxo-cyclotetr a d eca -7-en eca r boxylic Acid Meth yl
Ester (27). Cesium carbonate (1.442 g, 4.43 mmol) was added
to a solution of ketone 26 (1.28 g, 2.7 mmol) in acetone (420
mL) at 15 °C. After being stirred for 7 h at this temperature,
the mixture was filtered on a pad of Celite and evaporated.
The crude product was a mixture of macrocycles. Three of them
were separated and purified by FC (15% acetone in toluene)
to give 123.7 mg (9.7%) of less polar macrocycle 27a as a clear
oil, 605.4 mg (47.3%) of more polar macrocycle 27b as a clear
C
21H32O4). 1H NMR, 13C NMR, and IR spectra are identical
with those of an authentic sample of (+)-chatancin.1
(b) F r om m a cr ocycle 6b: A solution of macrocycle 6b (1.6
mg, 4.59 µmol) in a mixture of DMSO (0.4 mL) and water (0.4
mL) was heated at 105-110 °C for 18 h. After cooling, water
(10 mL) was added then the mixture was extracted with a
mixture of ether/hexane (50:50, 6 × 10 mL). The crude product
was purified by FC (20 to 30% ether in hexane) to give 1.2 mg
(75%) of (+)-chatancin 1.
(c) F r om m a cr ocycle 27c (cr ysta l): A solution of macro-
cycle 27c (272 mg, 0.574 mmol) in the mixture of DMSO (12.8
mL) and water (12.8 mL) was heated at 105-110 °C for 2.5 h.
Upon cooling, water (50 mL) was added and the mixture was
extracted with a mixture of hexanes-ether (50:50, 6 × 30 mL).
The crude product was purified by FC (7% acetone in toluene)
oil, and 289.5 g (23%) of macrocycle 27c as white crystals; mp
132-134 °C; [R]20 +217.3 (c 1.05, CHCl3); H NMR δ 7.85-
1
D
7.69 (m, 2H), 7.55-7.38 (m, 3H), 5.04 (t, J ) 5.0 Hz, 1H), 4.44
(m, 1H), 3.96 (dd, J ) 10.8 and 2.2 Hz, 1H), 3.76 (s, 3H), 3.59-
3.49 (dd, J ) 13.0 and 10.7 Hz), 2.50-1.0 (m, 14H), 1.44 (s,
3H), 0.95 (d, J ) 6.8 Hz, 3H), 0.79 (d, J ) 6.8 Hz), 0.10 (d, J
) 6.7 Hz, 3H); 13C NMR δ 208.0, 205.8, 171.2, 134.5, 131.7,
129.2, 129.1, 127.8, 126.1, 78.4, 53.8, 52.2, 50.1, 40.9, 37.8, 35.8,
35.4, 28.5, 28.4, 24.8, 21.8, 21.4, 19.1, 16.4, 14.7; IR 3047, 2874,
1741, 1714, 1697, 1444, 1380, 1225 cm-1; HRMS 475.2527 (
0.0014 (475.2518 for MH+: C27H39O5S).
to afford 177 mg (89%) of (+)-chatancin and 11.7 mg (6.2%) of
(4S,11S)-4-Isop r op yl-7,11-d im eth yl-3,13-d ioxo-cyclotet-
r a d eca -1,7-d ien eca r boxylic Acid Meth yl Ester or (5S,-
12S)-12-Isopr opyl-5,9-dim eth yl-3,13-dioxo-cyclotetr adeca-
1,8-d ien eca r boxylic Acid Meth yl Ester (m a cr ocycles 6a
a n d 6b). A solution of macrocycle 27c (73 mg, 0.154 mmol) in
toluene (2.0 mL) was heated at 110-115 °C for 15 min. After
evaporation of the mixture, a crystallization from ether/hexane
1
anhydrochatancin 4: [R]20 110 (c 1.05, CH2Cl2); H NMR δ
D
7.18 (s, 1H), 5.87 (s, 1H), 3.73 (s, 3H), 3.34 (s, 1H), 2.3-1.10
(m, 12H), 1.00 (d, J ) 7.0 Hz, 3H), 0.91 (d, J ) 6.8 Hz, 3H),
0.84 (d, J ) 6.7 Hz, 3H), 0.83 (s, 3H); 13C NMR δ 209.9, 167.8,
142.7, 139.6, 134.2, 124.1, 59.2, 56.2, 51.7, 41.8, 36.6, 34.6, 31.9,
31.2, 25.9, 23.9, 22.8, 22.1, 21.3, 21.2, 18.6; IR 2931, 1721, 1631,
1256 cm-1; HRMS 330.2188 ( 0.0010 (330.2195 for M+:
gave 26 mg (50.6%) of macrocycle 6a as white crystals: mp
C
21H30O3). 1H NMR, 13C NMR, and IR spectra are identical
95-97 °C; [R]20 -132.1 (c 1.355, CHCl3); H NMR δ 6.24 (s,
1
D
with those of anhydrochatancin 4, kindly supplied by E.
Go¨ssinger.
1H), 5.01 (t, J ) 5.0 Hz, 1H), 3.81 (1s, 3H), 3.23 (s, 2H), 3.02
(dd, J ) 13.6 and 4.9 Hz, 1H), 2.35-1.20 (m, 12H), 1.40 (s,
3H), 0.93, 0.91 and 0.88 (3 × d, J ) 6.2 and 7.2 Hz, 3 × 3H);
13C NMR δ 206.2, 199.9, 169.1, 138.5, 136.6, 132.7, 127.1, 58.2,
52.4, 48.7, 48.3, 40.0, 36.0, 31.4, 28.3, 26.1, 23.5, 20.6, 20.4,
19.8, 15.0; IR 2959, 2929, 1732, 1710, 1692, 1620, 1436, 1371,
1246 cm-1; HRMS 348.2303 ( 0.0010 (348.2300 for M+:
(d ) F r om m a cr ocycle 27a : A solution of macrocycle 27a
(120 mg, 0.253 mmol) in a mixture of DMSO (2.0 mL) and
water (0.5 mL) was heated at 105-110 °C for 3 h. Upon
cooling, water (20 mL) was added then the mixture was
extracted with a mixture of ether/hexane (50:50, 6 × 30 mL).
The crude product was purified by FC (20 to 30% ether in
hexane) to afford 26 mg (30%) of (+)-chatancin 1 and 37 mg
(40%) of anhydrochatancin 4.
C
21H32O4). The supernatant of the crystallization was purified
by FC (10, 20, 30% ether in hexane) to give 15.8 mg (29.5%) of
(e) F r om m a cr ocycle 27b: A solution of macrocycle 27b
(605 mg, 1.276 mmol) in a mixture of DMSO (7.0 mL) and
water (4.0 mL) was heated at 105-110 °C for 3 h. Similar
workup as for 27a afforded 82 mg (15%) of (+)-chatancin 1
and 139.4 mg (25%) of anhydrochatancin 4.
(20) Further, categorical evidence could be obtained by incubation
of isotopically labeled 6 with a cell culture of soft coral Sarcophyton
sp. The nonphysiological temperature of the chemosynthetic TADA
reaction may also suggest an enzymatic assistance from a TADA-ase
in the biosynthesis.
9986 J . Org. Chem., Vol. 68, No. 26, 2003

Asymmetric Total Synthesis of (+)-Chatancin
NMR spectra for all compounds, and X-ray crystal structure
data for compound 27c in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
The crystal structure for 27c has been deposited at the
Cambridge Crystallographic Data Centre (CCDC 217495).
Ack n ow led gm en t. We wish to thank Dr. Aiya Sato
for an authentic sample of (+)-chatancin and Prof. Edda
Go¨ssinger for thoughtful discussions and for supplying
analytical and spectroscopic data for (()-4.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
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