Catalytic asymmetric Claisen rearrangement in natural product synthesis: Synthetic studies toward (-)-xeniolide F

Article abstract of DOI:10.1021/ol052462t

(Chemical Equation Presented) The catalytic asymmetric Claisen rearrangement (CAC) of a highly substituted and functionalized α-alkoxycarbonyl-substituted allyl vinyl ether has been exploited to gain access to an advanced building block for the projected total synthesis of (-)-xeniolide F, the enantiomer of a xenicane diterpene isolated from a coral of the genus Xenia.

Full text of DOI:10.1021/ol052462t

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5705-5708
Catalytic Asymmetric Claisen
Rearrangement in Natural Product
Synthesis: Synthetic Studies toward
(−)-Xeniolide F
Annett Pollex and Martin Hiersemann*
Institut fu¨r Organische Chemie, Technische UniVersita¨t Dresden,
D-01062 Dresden, Germany
martin.hiersemann@chemie.tu-dresden.de
Received October 11, 2005
ABSTRACT
The catalytic asymmetric Claisen rearrangement (CAC) of a highly substituted and functionalized
r-alkoxycarbonyl-substituted allyl vinyl
ether has been exploited to gain access to an advanced building block for the projected total synthesis of (
a xenicane diterpene isolated from a coral of the genus Xenia.
−)-xeniolide F, the enantiomer of
Xenicane diterpenes are being isolated as bioactive natural
products from brown algae and cnidarians. Soft corals of
the genus Xenia are a particularly rich source of xenicane
and related diterpenes.1 The xenicane framework (1, Figure
1) is distinguished by the presence of a single nine membered
carbocyclic ring. (+)-Xeniolide F (2) was isolated from an
unknown Xenia species collected near Sulawesi Island
(Indonesia) in small amounts (4.7 mg from 300 g of the coral)
by Jime´nez and co-workers.2 The gross structure of xeniolide
F was determined by NMR and MS studies. The assignment
of the relative configuration was based on the analysis of
(1) For recent reports on the isolation of xenicanes from Xenia sp., see:
(a) Shen, Y.-C.; Lin, Y.-C.; Ahmed, A. F.; Kuo, Y.-H. Tetrahedron Lett.
2005, 46, 4793-4796. (b) El-Gamal, A. A. H.; Chiang, C.-Y.; Huang, S.-
H.; Wang, S.-K.; Duh, C.-Y. J. Nat. Prod. 2005, 68, 1336-1340. (c) El-
Gamal, A. A. H.; Wang, S.-K.; Duh, C.-Y. Tetrahedron Lett. 2005, 46,
6095-6096. (d) El-Gamal, A. A. H.; Wang, S.-K.; Duh, C.-Y. Tetrahedron
Lett. 2005, 46, 4499-4500. (e) El-Gamal, A. A. H.; Wang, S.-K.; Duh,
C.-Y. Org. Lett. 2005, 7, 2023-2025.
Figure 1. Basic xenicane framework (1) and the xenicane diterpene
(+)-xeniolide F (2). The depicted numbering is used throughout
the paper.
(2) Anta, C.; Gonza´lez, N.; Santafe´, G.; Rodr´ıguez, J.; Jime´nez, C. J.
Nat. Prod. 2002, 65, 766-768.
10.1021/ol052462t CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/17/2005

olefination and the protected hydroxyl group at C1 should
be suitable for the formation of the δ-lactone moiety. To
ensure an efficient access to the R-keto ester 3, the enantio-
selective generation of the two nonheteroatom-substituted
stereogenic carbon atoms C2 and C10 has to be addressed.
Recognizing the Claisen rearrangement retron in the R-keto
ester 3, the achiral allyl vinyl ether 4 was selected as the
pivotal synthon.
Scheme 1. Retrosynthesis of the Key Building Block 3
It is well-known that the thermal Claisen rearrangement
of acyclic allyl vinyl ethers can be highly diastereoselective
based on the concerted nature and chairlike geometry of the
corresponding transition state.5 However, considering the
achiral nature of the allyl vinyl ether 4, an external chiral
inductor is required to control the absolute configuration of
the rearrangement product.6 Therefore, our recently imple-
mented protocol for a catalytic asymmetric Claisen rear-
rangement (CAC) should be ideally suited to solve this
problem.7 However, it was uncertain whether the highly
substituted and functionalized allyl vinyl ether 4 would be
tolerated as a substrate for our Lewis acid based CAC
protocol. Finally, a strategy that addresses the often trouble-
some diastereoselective generation of an acyclic vinyl ether
double bond was required for the synthesis of (E,Z)-4. A
convergent approach utilizing the building blocks 5-7 was
envisioned to take that synthetic hurdle.
Scheme 2 illustrates the synthesis of the Z-configured
allylic alcohol 7.
The synthesis was initiated with a Pd0-catalyzed hy-
drostannation of 2-butyne-1,4-diol 8 to afford the vinylstan-
nane 9 in excellent yield.8 Protection of the sterically less
hindered hydroxy group9 followed by iododestannation and
protection of the remaining hydroxy group as a TMS ether
provided the vinyl iodide 10. Initial attempts to perform the
subsequent cross coupling reaction in the absence of the TMS
protecting group were unsuccessful. However, the B-alkyl
Suzuki-Miyaura coupling10 between the in situ generated
borane11 from allyl benzyl ether (11) and 9-BBN12 as well
as the vinyl iodide 10 afforded the fully protected allylic
alcohol 12 along with varying amounts of the monodepro-
tected allylic alcohol 7. Complete cleavage of the TMS ether
was subsequently achieved by treatment of 12 with K2CO3
in methanol to afford the desired allylic alcohol 7 in 60%
overall yield for the cross coupling/deprotection sequence
as a single Z-configured diastereomer.
coupling constants and NOE studies. Although the absolute
configuration of xeniolide F (2) was not explicitly deter-
mined, the depicted absolute configuration at C2 and C10 is
consistent with earlier reports concerning the absolute
configuration of xenicane diterpenes from soft corals.3
Xenicanes combine unique structural features and interest-
ing biological activities with an unsolved supply issue.
However, synthetic efforts toward xenicane diterpenes are
rare.4 Therefore, we have initiated a research program aimed
at the total synthesis of members of the xenicane class of
diterpenes. Here, we report the efficient enantioselective
access to a key building block (3) in the projected total
synthesis of (-)-xeniolide F (2) and we provide a general
and enantioselective strategy for the generation of the critical
stereogenic carbon atoms C2 and C10 of the xenicane
framework.
Our retrosynthetic analysis rests on the availability of the
highly substituted acyclic R-keto ester 3 and requires the de
novo synthesis of the nine-membered carbocyclic segment
(Scheme 1). An intramolecular addition of a vinyl anion at
C7 to a carbonyl functionality at C6 may be envisioned for
this purpose. The R-keto ester function of building block 3
would be utilized to construct the C11/C12 double bond by
(5) (a) Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452. (b) Castro, A.
M. M. Chem. ReV. 2004, 104, 2939-3002.
(6) (a) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry
1996, 7, 1847-1882. (b) Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28,
43-50. (c) Nubbemeyer, U. Synthesis 2003, 961-1008.
(7) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
Int. Ed. 2001, 40, 4700-4703. (b) Hiersemann, M.; Abraham, L. Eur. J.
Org. Chem. 2002, 1461-1471. (c) Abraham, L.; Ko¨rner, M.; Schwab, P.;
Hiersemann, M. AdV. Synth. Catal. 2004, 346, 1281-1294. (d) Abraham,
L.; Ko¨rner, M.; Hiersemann, M. Tetrahedron Lett. 2004, 45, 3647-3650.
(8) Commeiras, L.; Santelli, M.; Parrain, J.-L. Org. Lett. 2001, 3, 1713-
1715.
(3) (a) Vanderah, D. J.; Steudler, P. A.; Ciereszko, L. S.; Schmitz, F. J.;
Ekstrand, J. D.; Helm, D. V. d. J. Am. Chem. Soc. 1977, 99, 5780-5784.
(b) Miyaoka, H.; Mitome, H.; Nakano, M.; Yamada, Y. Tetrahedron 2000,
56, 7737-7740. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092-4096. (c) Ohtani, I.; Kusumi, T.; Ishitsuka,
M. O.; Kakisawa, H. Tetrahedron Lett. 1989, 30, 3147-3150.
(4) For the total synthesis of (+)-coraxeniolide A, see: (a) Renneberg,
D.; Pfander, H.; Leumann, C. J. J. Org. Chem. 2000, 65, 9069-9079. (b)
Liu, G.; Smith, T. C.; Pfander, H. Tetrahedron Lett. 1995, 36, 4979-4982.
(9) Barrett, A. G. M.; Barta, T. E.; Flygare, J. A. J. Org. Chem. 1989,
54, 4246-4249.
(10) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369-6372.
(11) Bo, Z.; Schlu¨ter, A. D. J. Org. Chem. 2002, 67, 5327-5332.
(12) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc.
1974, 96, 7765-7770.
5706
Org. Lett., Vol. 7, No. 25, 2005

Scheme 2. Synthesis of the Allylic Alcohol 7
Scheme 4. Catalytic Asymmetric Claisen Rearrangement
(CAC)
next (Scheme 4). After some experimentation, we found that
treatment of the E/Z ) 9/1 mixture of 4 with substoichio-
metric amounts of the chiral CuII Lewis acid [Cu{(S,S)-t-
Bu-box}](H2O)2(SbF6)2 (S,S)-1419 in the presence of freshly
activated 4 Å molecular sieves in CH2Cl2 at room temper-
ature afforded the desired rearrangement product anti-
(2S,10R)-3 in 64% yield as a single diastereo- and enantiomer
based on NMR and HPLC analysis.20 The minor (Z,Z)-
configured allyl vinyl ether 4 did not rearrange under these
conditions and was reisolated as a single double bond isomer.
Subsequent treatment of (Z,Z)-4 even with stoichiometric
amounts of (S,S)-14 did not afford the corresponding
rearrangement product but led to extensive cleavage of the
TBS ether. Significantly, the (S,S)-14-catalyzed rearrange-
ment of pure (E,Z)-4 was substantially faster and provided
anti-(2S,10R)-3 in >80% yield as a single stereoisomer. The
thermal Claisen rearrangement (1,2-dichloroethane, 80 °C,
32 h) of the E/Z ) 9/1 mixture of 4 provided the rearrange-
ment product (()-anti-3 in mediocre yield (50%) along with
unreacted (Z,Z)-4.
With the functionalized allylic alcohol 7 in hand, the allyl
vinyl ether synthesis was realized in a two-step sequence
(Scheme 3).13 In the event, a RhII-catalyzed OH-insertion14
Scheme 3. Sequential OH Insertion/Olefination13
A proposal for the stereochemical course of the rearrange-
ment and the different reactivity of (E,Z)- and (Z,Z)-4 is
depicted in Figure 2. The model rests on the previously
established privileged topicity of the (S,S)-14-catalyzed
Claisen rearrangement of 2-alkoxycarbonyl-substituted allyl
vinyl ethers.21 It is therefore feasible to assume that the
substrate 4 is coordinated to the catalyst (S,S)-14 in a
bidentate fashion and that the relative configuration of the
rearrangement product 3 is a consequence of a chairlike
transition state geometry for the catalyzed rearrangement.
A qualitative analysis of substrate-catalyst complex 15
indicates a severe 1,3-diaxial interaction between the sub-
stituents at C10 and C3. Consequently, (Z,Z)-4 did not
rearrange either in the presence of (S,S)-14 or under thermal
reaction between trimethyl diazophosphonoacetate 515 and
the alcohol 7 followed by a Horner-Wadsworth-Emmons
olefination16 of the aldehyde 617 with the resulting phospho-
nate 13 afforded the allyl vinyl ether 4 in good overall yield
as an E/Z ) 9/1 mixture of vinyl ether double-bond isomers.18
The critical CAC of the allyl vinyl ether 4 was investigated
(16) (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem.
Ber. 1959, 92, 2499-2507. (b) Wadsworth, W. S.; Emmons, W. D. J. Am.
Chem. Soc. 1961, 83, 1733-1738.
(13) The sequence of OH insertion and olefination was originally
developed and utilized by Ganem and Berchtold for the synthesis of
chorismate und its derivatives; see: (a) Ganem, B.; Ikota, N.; Muralidharan,
V. B.; Wade, W. S.; Young, S. D.; Yukimoto, Y. J. Am. Chem. Soc. 1982,
104, 6787-6788. (b) Pawlak, J. L.; Berchtold, G. A. J. Org. Chem. 1987,
52, 1765-1771. (c) Lesuisse, D.; Berchtold, G. A. J. Org. Chem. 1988,
53, 4992-4997. (d) Wood, H. B.; Buser, H. P.; Ganem, B. J. Org. Chem.
1992, 57, 178-184. (e) Mattia, K. M.; Ganem, B. J. Org. Chem. 1994, 59,
720-728.
(17) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110,
2248-2256.
(18) The E/Z diastereomers may be separated by preparative HPLC. See
the Supporting Information for details.
(19) Evans, D. A.; Miller, S. J.; Lectka, T.; Matt, P. v. J. Am. Chem.
Soc. 1999, 121, 7559-7573.
(20) A second stereoisomer could not be detected by NMR or chiral
HPLC. See the Supporting Information for details.
(21) Application of (S,S)-14 leads preferentially to a Si-face approach
of the allylic ether moiety to the (E)-configured vinyl ether double bond:
(E,S,S,Si)-topicity (E-like). See ref 7c for details.
(14) Miller, D. J.; Moody, C. J. Tetrahedron 1995, 51, 10811-10843.
(15) Prepared according to Gois, P. M. P.; Afonso, C. A. M. Eur. J.
Org. Chem. 2003, 3798-3810.
Org. Lett., Vol. 7, No. 25, 2005
5707

Scheme 5. R-Keto Ester Olefination and Lactonization
R-keto ester 3 with the methylene Wittig reagent led to the
formation of an R,â-unsaturated ester which was transformed
into the δ-lactone 17 by silyl ether cleavage and subsequent
in situ lactonization. The analysis of the NOE data of the
δ-lactone 17 supports our assignment of the relative con-
figuration of the initial rearrangement product anti-(2S,10R)-3
(Scheme 5).
In summary, we have established an efficient and enan-
tioselective access to the R-keto ester building block anti-
(2S,10R)-3 utilizing the catalytic asymmetric Claisen rear-
rangement (CAC) of the highly substituted and functionalized
allyl vinyl ether (E,Z)-4. Further work aimed at the comple-
tion of the total synthesis of (-)-xeniolide F (2) and other
xenicane diterpenes is currently underway in our laboratory.
Figure 2. Stereochemical course of the CAC.
reaction conditions. The observation that the (S,S)-14-
catalyzed rearrangement of (E,Z)-4 is slower in the presence
of (Z,Z)-4 than in its absence may indicate that (S,S)-14
indeed coordinates to (Z,Z)-4. The decisive destabilizing 1,3-
diaxial interaction is absent in the complex 16 between (S,S)-
14 and (E,Z)-4 and the catalyzed Claisen rearrangement
afforded the rearrangement product anti-(2S,10R)-3. The
configuration of the rearrangement product anti-(2S,10R)-3
is a consequence of the chairlike transition-state geometry
and the privileged topicity of the (S,S)-14-catalyzed rear-
rangement of an allyl vinyl ether containing an (E)-
configured vinyl ether double bond.
Acknowledgment. Financial support from the DFG and
the FCI is gratefully acknowledged. M.H. is a Heisenberg
fellow of the DFG. We are indebted to Prof. Carloz Jime´nez
for providing NMR spectra of natural xeniolide F and a
picture of the Xenia sp. from which the natural product was
originally isolated.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Having established access to the crucial building block
anti-(2S,10R)-3 as originally envisioned, a two-step sequence
was realized in order to support the viability of our synthetic
strategy toward (-)-xeniolide F (2). Thus, treatment of the
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Org. Lett., Vol. 7, No. 25, 2005