A general strategy for synthesis of both (6Z)- and (6E)-cladiellin diterpenes: Total syntheses of (-)-cladiella-6,11-dien-3-ol, (+)-polyanthellin A, (-)-cladiell-11-ene-3,6,7-triol, and (-)-deacetoxyalcyonin acetate

Article abstract of DOI:10.1021/ja065782w

The first total synthesis of an (E)-cladiellin diterpene, (-)-cladiella-6,11-diene-3-ol (1), was accomplished featuring an intramolecular amide enolate alkylation-intramolecular Diels-Alder strategy. In addition, a highly stereo-, regio-, and chemoselecti

Full text of DOI:10.1021/ja065782w

Published on Web 11/15/2006
A General Strategy for Synthesis of Both (6Z)- and
(6E)-Cladiellin Diterpenes: Total Syntheses of
(-)-Cladiella-6,11-dien-3-ol, (+)-Polyanthellin A,
(-)-Cladiell-11-ene-3,6,7-triol, and (-)-Deacetoxyalcyonin
Acetate
Hyoungsu Kim, Hyunjoo Lee, Jayoung Kim, Sanghee Kim, and Deukjoon Kim*
Contribution from the Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National UniVersity, San 56-1, Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea
Received August 9, 2006; E-mail: deukjoon@snu.ac.kr
Abstract: The first total synthesis of an (E)-cladiellin diterpene, (-)-cladiella-6,11-diene-3-ol (1), was
accomplished featuring an intramolecular amide enolate alkylation-intramolecular Diels-Alder strategy.
In addition, a highly stereo-, regio-, and chemoselective synthetic strategy for other members of the cladiellin
diterpenes such as (+)-polyanthellin A (2), (-)-cladiell-11-ene-3,6,7-triol (3), and (-)-deacetoxyalcyonin
acetate (4) was developed utilizing the synthetic (E)-cladiellin 1 as a common intermediate by taking
advantage of the unique chemical properties of its C(6)-(E)-oxatricyclic skeleton.
Introduction
our intramolecular amide enolate alkylation (IAEA) methodol-
ogy,4 total synthesis of the more challenging and hitherto
The cladiellin diterpenes, the most abundant class of 2,11-
cyclized cembranoid natural products, have been isolated from
marine invertebrates.1 These medium-sized oxatricyclic marine
natural products possess a nine-membered ring, and both C(6)-
(E)- and (Z)-isomers are found in nature. Owing to their
fascinating molecular architecture and diverse biological activity,
the 2,11-cyclized cembranoids have attracted considerable
attention from the synthetic community over the past decade,
leading to the total synthesis of several members of this family2
along with a number of approaches to their synthesis.3 However,
total synthesis of the cembrane-derived diterpenes with a (6E)-
oxonene unit has not been realized to date. With the notion that
both the (6Z)- and (6E)-oxonene cores could be constructed by
inaccessible (6E)-cladiellins was undertaken. In this article, we
report an asymmetric total synthesis of (-)-cladiella-6,11-dien-
3-ol (1),5 which constitutes the first total synthesis of an (E)-
cladiellin diterpene. Furthermore, the synthetic (E)-cladiellin 1
could be transformed into other members of the cladiellin
diterpenes such as (+)-polyanthellin (2),6 (-)-cladiell-11-ene-
3,6,7-triol (3),7 and (-)-deacetoxyalcyonin acetate (4)8 in a
highly stereo-, regio-, and chemoselective fashion by taking
advantage of the unique chemical properties of its (6E)-
oxatricyclic skeleton (vide infra).
Results and Discussion
As shown in Scheme 1, we envisaged that (-)-cladiella-6,-
11-dien-3-ol (1) could be elaborated from key oxatricycle 5,
which in turn could be prepared by an intramolecular Diels-
Alder (IMDA) reaction of tetraene 6. We further envisioned
that 2,9-cis-disubstitued (E)-oxonene 7 could be secured through
an intramolecular amide enolate alkylation of chloro amide 8.
Our preliminary studies suggested that the secondary nature of
C(3) and the syn relative stereochemistry of C(2) and C(3) in
key internal alkylation substrate 8 are vital for efficient
(1) (a) Rodriguez, A. D. Tetrahedron 1995, 51, 4571. (b) Bernardelli, P.;
Paquette, L. A. Heterocycles 1998, 49, 531. (c) Sung, P.-S.; Chen, M.-C.
Heterocycles 2002, 57, 1705.
(2) (a) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117,
10391. (b) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org.
Lett. 2000, 2, 1875. (c) Overman, L. E.; Pennington, L. D. Org. Lett. 2000,
2, 2683. (d) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette,
L. A.; Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135. (e) Bernardelli,
P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.; Dyck, B. P.;
Doskotch, R. W.; Lange, T.; Paquette, L. A. J. Am. Chem. Soc. 2001, 123,
9021. (f) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am.
Chem. Soc. 2001, 123, 9033. (g) Corminboeuf, O.; Overman, L. E.;
Pennington, L. D. Org. Lett. 2003, 5, 1543. (h) Molander, G. A.; St. Jean,
D. J., Jr.; Haas, J. J. Am. Chem. Soc. 2004, 126, 1642. (i) Crimmins, M.
T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126, 10264. (j) Crimmins, M.
T.; Brown, B. H.; Plake, H. R. J. Am. Chem. Soc. 2006, 128, 1371. For
total syntheses of briarellin and asbestinin diterpenes, see: (k) Corminboeuf,
O.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2003, 125, 6650.
(l) Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127, 17200.
(3) (a) Xu, Q.; Weeresakare, M.; Rainier, J. D. Tetrahedron 2001, 57, 8029.
(b) Jung, M. E.; Pontillo, J. J. Org. Chem. 2002, 67, 6848. (c) Jung, M. E.;
Pontillo, J. Tetrahedron 2003, 59, 2729. (d) Chai, Y.; Vicic, D. A.;
McIntosh, M. C. Org. Lett. 2003, 5, 1039. (e) Davidson, J. E. P.; Gilmour,
R.; Ducki, S.; Davies, J. E.; Green, R.; Burton, J. W.; Holmes, A. B. Synlett
2004, 1434. (f) Molander, G. A.; Czako, B.; St. Jean, D. J., Jr. J. Org.
Chem. 2006, 71, 1172. (g) Hutchison, J. M.; Lindsay, H. A.; Dormi, S. S.;
Jones, G. D.; Vicic, D. A.; McIntosh, M. C. Org. Lett. 2006, 8, 3663.
(4) (a) Kim, H.; Choi, W. J.; Jung, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2003, 125, 10238. (b) Lee, H.; Kim, H.; Baek, S.; Kim, S.; Kim, D.
Tetrahedron Lett. 2003, 44, 6609. (c) Baek, S.; Jo, H.; Kim, H.; Kim, H.;
Kim, S.; Kim, D. Org. Lett. 2005, 7, 75.
(5) (a) Hochlowski, J. E.; Faulkner, D. J. Tetrahedron Lett. 1980, 21, 4055.
(b) Seo, Y.; Rho, J.-R.; Cho, K. W.; Shin, J. J. Nat. Prod. 1997, 60, 171.
(6) (a) Bowden, B. F.; Coll, J. C.; Vasilescu, I. M. Aust. J. Chem. 1989, 42,
1705. (b) Ospina, C. A.; Rodriguez, A. D.; Ortega-Barria, E.; Capson, T.
L. J. Nat. Prod. 2003, 66, 357.
(7) Uchio, Y.; Nakatani, M.; Hase, T.; Kodama, M.; Usui, S.; Fukazawa, Y.
Tetrahedron Lett. 1989, 30, 3331.
(8) Uchio, Y.; Kodama, M.; Usui, S.; Fukazawa, Y. Tetrahedron Lett. 1992,
33, 1317.
9
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J. AM. CHEM. SOC. 2006, 128, 15851-15855
15851

A R T I C L E S
Kim et al.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Key (E)-Oxonene 7 by IAEAa
a Reagents and conditions: (a) n-Bu2BOTf, Et3N, CH2Cl2, -78 to -40
°C, 30 min, then 10, -78 to 0 °C, 2 h, 75%, (ds 98:2); (b) NaBH4, THF/
H2O (3:1), room temperature (rt), 2 h, 89%; (c) TBDPSCl, imidazole, 0
°C, 30 min, 92%; (d) trityl bromide, DMAP, pyridine, 100 °C, 6 h, 93%;
(e) DDQ, CH2Cl2/pH 8.0 buffer (9:1), 0 °C, 1 h, 88%; (f) ClCH2CONMe2,
NaH, THF, 0 °C to rt, 3 h, 88%; (g) SeO2, pyridine, EtOH, 80 °C, 6 h,
then NaBH4, EtOH, 0 °C, 30 min, 76% (86% BRSM); (h) Ph3P, CCl4,
pyridine, reflux, 2 h, 93%; (i) LiHMDS, THF, 45 °C, 1 h, 92%.
15 with N,N-dimethyl R-chloroacetamide afforded R-alkoxy
amide 16 (77%, two steps). Stereoselective allylic oxidation of
15
gem-dimethyl alkene 16 with SeO2 and chlorination of the
construction of strained9 (6E)-oxonenes (vide infra).10 The trityl
protecting group for the C(3) hydroxyl function in 8 was chosen
in view of the demonstrated importance of C(3) hydroxyl
protection during the IMDA step for construction of the (6Z)-
cladiellin skeleton.2i,j,l Further analysis indicated that the requisite
internal alkylation precursor 8 could be prepared from known
oxazolidinone 9 and aldehyde 10 by a glycolate aldol addition
reaction.11
To commence the synthesis, the pivotal C(3) 2°/syn stereo-
chemistry in alkylation substrate 8 was established by an aldol
reaction of the dibutylboron enolate derived from readily
available glycolate oxazolidinone 912 with known aldehyde 1013
to yield the corresponding syn-aldol adduct 11 (75%, ds 98:2,
1H NMR analysis) (Scheme 2). Reductive cleavage of the chiral
auxiliary in 11 and successive protection of the primary and
secondary hydroxyl groups in the resulting diol 12 with
TBDPSCl and trityl bromide, respectively, furnished the ap-
propriately protected triol 14 in 76% overall yield for the three
steps. Oxidative cleavage of the PMB group in 14 by the
Yonemitsu method14 and O-alkylation of the resulting alcohol
resulting (E)-allylic alcohol 17 by the Hooz protocol16 produced
(E)-allylic chloride 8 (80%, two steps), setting the stage for the
crucial internal alkylation.
To our satisfaction, treatment of C(3) 2°/syn amide 8 with
LiHMDS in THF at 45 °C for 1 h led to formation of the desired
cis-(E)-oxonene 7 as a single diastereomer in excellent yield
(92%), presumably through transition state A.17 The corre-
sponding anti-isomer of 8 did not produce any cyclization
product under comparable conditions presumably due to a
gauche effect in the transition state.
As outlined in Scheme 3, our preliminary study showed that
internal alkylation of (Z)-C(3) 3°/syn substrate 8′a proceeded
smoothly to give the desired product in good yield (80%,
unoptimized), which could be converted by a Superhydride
reduction to a known Crimmins intermediate for (-)-ophirin
B, a (6Z)-cladiellin.2i,j,18 However, cyclization of the corre-
sponding (E)-3°/syn isomer 8′b was unsatisfactory in terms of
chemical yield and reproducibility. Thus, our attempt to relieve
the possible steric crowding in the transition state of cyclization
of (E)-C(3) 3° substrate 8′b by adopting C(3) 2° amide 8 as
our cyclization precursor was rewarded. It is appropriate to
(9) Mancini, I.; Guella, G.; Zibrowius, H.; Pietra, F. HelV. Chim. Acta 2000,
83, 1561.
(10) In addition, the syn stereochemistry has been shown to play a critical role
for controlling the diastereoselectivity of the intramolecular Diels-Alder
reaction for construction of the (Z)-cladiellin skeleton (see ref 3e).
(11) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(12) Jones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond, R.; Volante,
R. P.; Shinkai, I. J. Am. Chem. Soc. 1989, 111, 1157.
(15) (a) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(b) A small amount (∼5%) of overoxidized R,R′-alkenediol was obtained.
(16) Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86.
(17) (a) For previous synthesis of (E)-oxonenes, see: Pohlmann, J.; Sabater,
C.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1998, 37, 633. (b) Use of
KHMDS as base did not effect internal alkylation, leading instead to
decomposition.
(13) Kraus, G. A.; Kim, J. Org. Lett. 2004, 6, 3115.
(14) Oikawa, Y.; Yochika, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(18) Kim, J. M.S. Thesis, Seoul National University, Seoul, Korea, 2006.
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Synthesis of (6Z)- and (6E)-Cladiellin Diterpenes
A R T I C L E S
Scheme 3. Intramolecular Amide Enolate Alkylation of (6Z)- and
(6E)-C(3) 3°/syn Substratesa
Scheme 4. Completion of Total Synthesis of
(-)-Cladiella-6,11-dien-3-ol (1)a
a Reagents and conditions: (a) KHMDS, THF, rt, 10 min, 80%; (b)
Super-H, THF, rt, 2 h, 60%; (c) KHMDS, THF, rt, 10 min, ∼40%.
mention at this point that the (E)-oxonenes were found to be
quite unstable, especially under acidic conditions, and were
stored as a solution in ethyl acetate containing a small amount
of triethylamine.
With key IAEA product 7 in hand, we directed our efforts
toward construction of the hydroisobenzofuran core in the
natural product by an internal Diels-Alder strategy, which has
been elegantly documented by both Crimmins and Holmes for
the construction of (Z)-2,11-cyclized cembranoid skeleton
(Scheme 4).2i,j,l,3e To this end, we prepared IMDA substrate 6
on the basis of successive Wittig olefinations, paying particular
attention to the sensitivity of the (E)-oxonenes. The diene moiety
of IMDA precursor 6 was installed first by a three-step sequence.
Thus, partial reduction of the amide function in 7 with an ate
complex,19 followed by the Corey olefination protocol on the
resulting aldehyde with R-lithio TMS-aldimine, furnished (E)-
R,â-unsaturated aldehyde 18 (E:Z ) 5:1, 1H NMR analysis) in
68% isolated yield for the two steps.20 Wittig methylenation of
(E)-enal 18 afforded (E)-1,3-diene 19 in 97% yield. With the
diene moiety now installed, compound 19 was converted into
the required IMDA intermediate 6 by desilyation, Dess-Martin
oxidation,21 and Wittig reaction (73%, three steps). Unlike the
case of the (Z)-oxonenes,2i,j,l,3e refluxing tetraene 6 in xylene
did not effect an intramolecular Diels-Alder reaction, leading
instead to complete decomposition. However, we were pleased
to find that addition of BHT to the reaction mixture produced
the desired Diels-Alder adduct 5 in 85% yield, probably
through exo transition state B.22
a Reagents and conditions: (a) DIBAL-H/n-BuLi (1:1), THF, 0 °C to rt,
30 min; (b) CH3CH(TMS)CdN-t-Bu, n-BuLi, THF, -78 to 0 °C, 1 h, then
the aldehyde from (a), -78 °C, 1 h, then oxalic acid, rt, 1 h, 68% for two
steps, E:Z ) 5:1; (c) Ph3PdCH2, THF, -78 °C to rt, 2 h, 97%; (d) TBAF,
THF/DMF (2:1), rt, 16 h, 93%; (e) Dess-Martin periodinane, NaHCO3,
CH2Cl2, rt, 30 min; (f) Ph3PdCHCO2Me, CH2Cl2, rt, 1 h, 78% for two
steps; (g) BHT, xylene, reflux, 1 h, 85%; (h) MeLi, CeCl3, THF, -78 °C,
30 min, 89%; (i) Ac2O, DMAP, Et3N, CH2Cl2, rt, 48 h; (j) K, 18-crown-6,
t-BuNH2, THF, 1 h, 62% for two steps; (k) Dess-Martin periodinane,
pyridine, CH2Cl2, rt, 30 min; (l) MeLi, NaBF4, THF, -78 °C, 30 min, 82%
for two steps.
acetate 22 by addition of MeLi in the presence of CeCl3,
followed by acetylation of the resulting tertiary alcohol 21. After
some experimentation, we were delighted to find that, upon
subjection to dissolving metal reduction conditions (K, 18-
crown-6, t-BuNH2, THF),23 tertiary acetate 22 underwent smooth
chemoselective deoxygenation with concomitant cleavage of the
trityl ether to deliver secondary alcohol 23 in 55% yield over
three steps. Finally, Dess-Martin oxidation of alcohol 23 and
subsequent treatment of the resulting unstable ketone with MeLi
in the presence of NaBF4 by the Paquette protocol2b,e gave rise
to (-)-cladiella-6,11-dien-3-ol (1) in a stereoselective fashion,
probably by nucleophilic attack from the molecular exterior of
the preferred conformation C. The spectral characteristics and
optical rotation of the synthetic material were in agreement with
those of the natural product.5
Having successfully assembled key oxatricyclic compound
5, we embarked on the final stage of the synthesis of (-)-
cladiella-6,11-dien-3-ol (1) by addressing the manipulation of
the ester function to an isopropyl group in the presence of the
reactive (6E)-oxonene, which turned out to be a challenge. For
this purpose, ester 5 was first converted to the labile tertiary
With the initial mission accomplished, we were intrigued by
the possibility that the synthetic (E)-cladiellin 1 might serve as
a common intermediate for a highly stereo-, regio-, and
chemoselective synthesis of other members of cladiellins such
(19) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717.
(20) (a) Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 7. (b)
Attempt to isomerize the (Z)-enal under the Corey conditions was
unsuccessful, leading to decomposition. See: Corey, E. J.; Weigel, L. O.;
Floyd, D.; Bock, M. G. J. Am. Chem. Soc. 1978, 100, 2916.
(21) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (b) Use
of excess oxidant for a longer time caused allylic oxidation at the reactive
(6E)-double bond.
(23) Barrett, A. G. M.; Godfrey, C. R. A.; Hollinshead, D. M.; Prokopiou, P.
A.; Barton, D. H. R.; Boar, R. B.; Joukhadar, L.; McGhie, J. F.; Misra, S.
C. J. Chem. Soc., Perkin Trans. I 1981, 1501.
(22) The corresponding tetraene with a benzyl protecting group at C(3) furnished
the desired IMDA adduct in an inferior yield of 50%.
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A R T I C L E S
Kim et al.
Scheme 5. Transformation of (-)-Cladiella-6,11-dien-3-ol (1) to Other Cladiellinsa
a Reagents and conditions: (a) BF3‚Et2O, Et2O, rt, 30 min, 84%; (b) Hg(OAc)2, THF/H2O (1:1), rt, 1 h, then Et3B, NaBH4, 62% (88% BRSM); (c)
Hg(OAc)2, THF, rt, 30 min, then Hg(OAc)2, H2O to THF/H2O (1:1), 1 h, then Et3B, NaBH4, -20 °C to rt, overnight, 69%; (d) Ac2O, DMAP, Et3N, CH2Cl2,
rt, 24 h, 78%; (e) OsO4, NMO, THF/H2O (3:1), 0 °C, 1 h, 94%; (f) TESOTf, CH2Cl2, rt, 30 min, 97%; (g) OsO4, NMO, THF/H2O (3:1), 0 °C, 5 h, 99%;
(h) Ac2O, DMAP, Et3N, CH2Cl2, 0 °C, 30 min, 97%; (i) Burgess salt, toluene, 70 °C, 30 min; (j) TBAF, THF, 50 °C, 3 h, 92% for two steps.
as (+)-polyanthellin A (2), (-)-cladiell-11-ene-3,6,7-triol (3),
and (-)-deacetoxyalcyonin acetate (4) as shown in Scheme 5.
This attractive strategy relies on the following reasoning: (1)
the trisubstituted (6E)-oxonene double bond in 1 might be more
susceptible to electrophilic attack than the trisubstituted C(11)
cyclohexene double bond, possibly due to a transannular
interaction with the ring oxygen atom and ring strain9,17,24 and
(2) the (E)-oxonene moiety of the oxatricyclic skeleton is
conformationally more rigid compared to that of the corre-
sponding (Z)-oxonene, which should render peripheral attack
in a highly stereoselective manner.2e,9
First, synthesis of (+)-polyanthellin A (2) was pursued along
this line. A stereo- and regioselective oxymercuration-demer-
curation of oxatetracycle 24, the known BF3‚Et2O-mediated
cyclization product of 1,5a in the presence of triethylborane25a
to suppress â-elimination, furnished tertiary â-alcohol 25 (62%,
88% BRSM).26 The observed stereochemical outcome could be
rationalized by considering that the electrophile approaches from
the R-face of the hexahydroisobenzofuran moiety to avoid steric
interference from the pseudoaxially oriented C(14) isopropyl
group. To our delight, exploration of a direct route to 25 led to
an efficient one-pot protocol that consisted of sequential
oxymercuration25b of the synthetic (E)-cladiellin 1 and exhaus-
tive demercuration to furnish the desired tertiary â-alcohol in
69% optimized yield in a stereo- and regioselective manner.
Acetylation of tertiary alcohol 25, which is itself a natural
product, furnished (+)-polyanthellin A (2). Both enantiomers
of polyanthellin A have been found in nature, and the present
synthesis establishes the absolute stereochemistry of the natural
products. The enantiomer isolated by Bowden et al. corresponds
to our synthetic (+)-polyanthellin A.6
For synthesis of (-)-cladiell-11-ene-3,6,7-triol (3), treatment
of (-)-cladiella-6,11-dien-3-ol (1) with osmium tetroxide
delivered the desired triol 3 in a highly stereo- and chemose-
lective fashion by peripheral attack by the electrophile on the
preferred conformation D onto the more nucleophilic (6E)-
double bond in 94% yield.27-29
Finally, protection of the hindered tertiary hydroxyl group
of the sensitive (6E)-oxatricycle 1 with TESOTf and subsequent
treatment of the resulting silyl ether with osmium tetroxide in
a similar fashion provided diol 26 (96%, two steps).30 Selective
acetylation of the secondary hydroxyl group of diol 26 provided
(24) Shea, K. J.; Kim, J.-S. J. Am. Chem. Soc. 1992, 114, 3044.
(25) (a) Kang, S. H.; Lee, J. H.; Lee, S. B. Tetrahedron Lett. 1998, 39, 59. (b)
Mercuriocyclization-demercuration of a related (6Z)-oxatricycle was shown
to be completely nonregioselective (see ref 2e).
(26) In an exploratory experiment, oxatetracycle 24 could be converted to tertiary
â-alcohol 25 in a conventional manner by successive treatment of 24 with
aqueous NBS and methanolic K2CO3, followed by regioselective LiAlH4
opening of the resultant â-epoxide (see ref 3f).
(27) A similar reaction of (-)-cladiellin, which possesses an exo-methylene-
disubstituted double bond at C(11), with OsO4 was reported: Kazlauskas,
R.; Murphy, P. T.; Wells, R. J.; Scho¨nholzer, P. Tetrahedron Lett. 1977,
4643.
(28) Osmylation of a related (6Z)-oxatricycle was shown to be nonstereoselective
(see refs 2d,e).
(29) The present synthesis also constitutes a formal synthesis of (-)-sclerophytin
A (see ref 2f).
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Synthesis of (6Z)- and (6E)-Cladiellin Diterpenes
A R T I C L E S
tertiary alcohol 27 for the crucial elimination step. After a
considerable amount of experimentation, tertiary alcohol 27
furnished the desired exo-methylene regioisomer 28 upon
exposure to Burgess salt31 in excellent yield in a highly
regioselective manner (∆7,19/∆7,8 ) 20:1, 1H NMR analysis).32
Finally, desilylation of 28 with TBAF led to (-)-deacetoxyal-
cyonin acetate (4) whose spectral data and rotation were in good
agreement with those of the natural material.
and chemoselective fashion into (+)-polyanthellin A (2), (-)-
cladiell-11-ene-3,6,7-triol (3), and (-)-deacetoxyalcyonin acetate
(4) by taking advantage of the unique properties of the (E)-
oxonene moiety of 1. Application of the present strategy to total
synthesis of a variety of other 2,11-cyclized cembranoids is in
progress in our laboratories.
Acknowledgment. This article is dedicated to Professor
Steven M. Weinreb on the occasion of his 65th birthday. We
thank Professors J. Shin (Seoul National University), A. D.
Rodr´ıguez (University of Puerto Rico), B. F. Bowden (James
Cook University), and L. E. Overman (University of California,
Irvine) for providing spectra of (-)-cladiella-6,11-dien-3-ol (1),
(-)-polyanthellin A (2), (+)-(2) and (+)-deacetylpolyanthellin
A (25), and natural and synthetic (-)-cladiell-11-ene-3,6,7-triol
(3), respectively. This research was supported by the Korea
Research Foundation Grant (KRF-2004-015-C00272) and the
Brain Korea Project in 2005 and 2006.
Conclusion
In conclusion, an asymmetric total synthesis of (-)-cladiella-
6,11-dien-3-ol (1) was accomplished in 21 steps in 6% overall
yield from readily available starting materials 9 and 10 in a
completely substrate-controlled manner, employing an intramo-
lecular amide enolate alkylation and an intramolecular Diels-
Alder reaction as key steps. This work constitutes the first total
synthesis of an (E)-cladiellin. In addition, synthetic (-)-cladiella-
6,11-dien-3-ol (1) was transformed in a highly stereo-, regio-,
(30) In view of the fact that C(3) hydroxyl groups of a considerable number of
(6E)-cladiellins are acylated, our extensive attempt to acylate the C(3)
hydroxyl function of (6E)-cladiellin 1 was unsuccessful unlike the case of
(6Z)-cladiellins,2e,i,j possibly due to steric interference from C(7) methyl
group in conformation D. For instance, treatment of 1 with acetic anhydride
in the presence of Bi(OTf)3 produced oxatetracycle 24 as the major product.
(31) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38,
26 and references therein.
Supporting Information Available: General experimental
procedures, including spectroscopic and analytical data for all
new compounds and copies of the 1H and 13C NMR spectra for
1-8, 11-21, and 23-28. This material is available free of
charge via the Internet at http://pubs.acs.org.
(32) Treatment of tertiary alcohol 27 with thionyl chloride furnished the
corresponding ∆7,19- and ∆7,8-regioisomer in a roughly equal amount by
1H NMR analysis.
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