Total synthesis of jimenezin via an intramolecular allylboration

Article abstract of DOI:10.1021/ol0614471

An efficient total synthesis of the annonaceous acetogenin jimenezin was achieved. The key steps used were a highly stereoselective intramolecular allylboration to establish the tetrahydropyran ring and an intramolecular Williamson reaction to close the tetrahydrofuran ring.

Full text of DOI:10.1021/ol0614471

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3829-3831
Total Synthesis of Jimenezin via an
Intramolecular Allylboration
Nina G. Bandur, David Bru1ckner, Reinhard W. Hoffmann,* and Ulrich Koert*
Fachbereich Chemie, Philipps-UniVersita¨t Marburg, Hans-Meerwein-Strasse,
35032 Marburg, Germany
koert@chemie.uni-marburg.de; rwho@chemie.uni-marburg.de
Received June 13, 2006
ABSTRACT
An efficient total synthesis of the annonaceous acetogenin jimenezin was achieved. The key steps used were a highly stereoselective
intramolecular allylboration to establish the tetrahydropyran ring and an intramolecular Williamson reaction to close the tetrahydrofuran ring.
The annonaceous acetogenins form a class of natural products
with interesting antitumor properties.1 Jimenezin was isolated
from seeds of Rollinia mucosa in 1998.2 Its structure
consisting of a tetrahydropyran (THP) ring adjacent to a
tetrahydrofuran (THF) ring was proposed using spectroscopic
techniques2 and revised after a total synthesis by Takahashi.3
Although most annonaceous acetogenins contain one to three
THF rings in the polyether part, jimenezin belongs to the
small subgroup with an additional THP ring and is structur-
ally related to mucocin.4,6 The stereocontrolled synthesis of
this THP ring represents one of the challenges of a total
synthesis of jimenezin. Takahashi3 used a chiral pool
approach from galactono-1,5-lactone to solve the THP
problem, whereas Lee5 applied a Samarium iodide-mediated
radical cyclization in his synthesis. Our synthetic plan is
shown in Scheme 1. Three CC disconnections transformed
Scheme 1. Retrosynthetic Analysis
(1) For recent reviews on annonaceous acetogenins: (a) Bermejo, A.;
Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D.
Nat. Prod. Rep. 2005, 22, 269. (b) Allali, F. Q. Allali, F. Q.; Liu, X.-X.;
McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
(2) Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61, 419.
(3) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1,
2025.
(4) For mucocin syntheses, see: (a) Neogi, P.; Doundoulakis, T.; Yazbak,
A.; Sinha, Sa. C.; Sinha, Su. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120,
11279. (b) Ba¨urle, S.; Hoppen, S.; Koert, U. Angew. Chem., Int. Ed. 1999,
38, 1263. (c) Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67, 5739 and
references therein. (d) Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem.,
Int. Ed. 2002, 41, 4751. (e) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin,
A.; Zhang, H. J. Am. Chem. Soc. 2003, 125, 14702. (f) Zhu, L.; Mootoo,
D. R. Org. Biomol. Chem. 2005, 3, 2750. (g) Crimmins, M. T.; Zhang, Y.;
Diaz, F. A. Org. Lett. 2006, 8, 2369.
(5) Hwang, C. H.; Keum, G.; Sohn, K. I.; Lee, D. H.; Lee, E. Tetrahedron
Lett. 2005, 46, 6621.
(6) Hoppen, S.; Ba¨urle, S.; Koert, U. Chem.-Eur. J. 2000, 6, 2382.
the synthetic target into three building blocks, 1, 2, and 3.
The chiral pool was intended as a source for the stereocenters
10.1021/ol0614471 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/25/2006

C19 (malic acid), C15 (glycidol), and C36 (propene oxide).
The C4 stereocenter is accessible via known aldehyde 3 with
97% ee.6 Stereocenters C16, C20, C23, and C24 remain as
a task in stereoselective synthesis.
The generation of (E)-γ-alkoxyallylboronates and their
intramolecular addition to aldehydes provide a highly ste-
reocontrolled entry into substituted THP rings.7,8 Here, we
report on the successful use of this intramolecular allylbo-
ration in a total synthesis of jimenezin.
99:1. After TBS protection of the primary OH group, the
remaining secondary hydroxy function was transformed into
the ynol ether 6 following Greene’s procedure.11 The triple
bond in 6 was converted by a zirconium-mediated hydrobo-
ration12 into an E-vinyl boronate, which was homologized
into the E-allyl boronate 7 by treatment with chlorometh-
yllithium.7,13
With 7 in hand, the stage was set for the intramolecular
allylboration provided that conditions were found to trans-
form the acetal in 7 into an aldehyde function without side
reactions at the sensitive allylboronate (7 f 8 f 9). A
screening of several deprotection conditions revealed that
The synthesis of the THP ring is outlined in Scheme 2.
The starting point was the R-hydroxy lactone 49 which was
14
15
LiBF4 or Yb(OTf)3 in acetonitrile with 2% water led to
the desired allylboration product 9. Unexpectedly, the
reaction was associated with the desilylation of the primary
TBS ether. A chairlike transition state of type 8 with all-
equatorial substituents can explain the exclusive formation
of the desired stereoisomer.
Scheme 2. Synthesis of the THP Ring
With the successful assembly of the THP ring, the
C25-34 aliphatic side chain was addressed next. After TBS
protection, the hydroformylation of the terminal alkene 9 with
the reliable Rh(CO)2acac/BIPHEPHOS catalyst16 led to the
corresponding aldehyde, which was subsequently trans-
formed into the alkene 10 by a Wittig olefination. Cleavage
of the primary TBS ether and conversion of the alcohol into
an iodide led to compound 11.
The attachment of the THF ring to the THP fragment
required the preparation of the aldehyde 15 (Scheme 3). To
this end, TES-protected (S)-glycidol 1217 was allowed to react
with the Grignard reagent 1318 to produce the corresponding
Scheme 3. Synthesis of the THF Ring
benzylated and subsequently reduced to the lactol 5. Addition
of 3 equiv of (MeO)2CH(CH2)2MgBr prepared in THF10 to
5 dissolved in CH2Cl2 in the presence of 1.1 equiv of MgBr2
gave the corresponding diol with a diastereoselectivity of
(7) Hoffmann, R. W.; Hense, A.; Mu¨nster, I.; Kru¨ger, J.; Bru¨ckner, D.;
Gerusz, V. ACS Symposium Series 783; American Chemical Society:
Washington, DC, 2001; p 160.
(8) Hoffmann, R. W.; Kru¨ger, J.; Bru¨ckner, D. New J. Chem. 2001, 25,
102.
(9) Schinzer, D.; Bauer, A.; Schieber, J. Chem.-Eur. J. 1999, 5, 2492.
(10) Molander, G. A.; Losada, C. P. Tetrahedron 1998, 54, 5819.
3830
Org. Lett., Vol. 8, No. 17, 2006

secondary alcohol which was TBS protected to yield com-
pound 14. After a selective TES deprotection, a Dess-Martin
oxidation of the resulting alcohol gave the aldehyde 15.
An iodine-lithium exchange reaction of 11 gave the
corresponding organolithium compound which added to the
aldehyde 15 with a modest Felkin-Anh selectivity of 5:2.
The desired stereoisomer 16 was obtained in 53% yield after
chromatographic separation. Tosylation of the secondary
hydroxy group in 16 opened the THF ring-closure sequence.
The following hydrogenation cleaved two benzyl ethers and
hydrogenated the double bond in the C25-34 side chain.
Refluxing the product of this sequence in pyridine initiated
the intramolecular Williamson reaction to produce compound
17 in quantitative yield.
Scheme 4. Attachment of the Butenolide
Having completed the synthesis of the THP-THF sub-
structure, we turned our attention to the final part of the
synthesis, the attachment of the butenolide fragment (Scheme
4). At first, the alcohol 17 was converted into the 1-phenyl-
1H-tetrazol-5-yl (PT) sulfone 18. A Julia-Kocienski olefi-
nation19 of the sulfone 18 with the aldehyde 196 gave the
alkene 20 as an inseparable E/Z-mixture. A chemoselective
hydrogenation of the isolated double bond in 20 using
Wilkinson’s catalyst20 led to tris-TBS-protected jimenezin.
Cleavage of all three silyl ethers with HF in acetonitrile
provided (-)-jimenezin ([R]D ) -10.4, c ) 0.75 in MeOH)
which was found to be identical to the natural product with
respect to the spectroscopic data.
In summary, the enantioselective synthesis of (-)-jime-
nezin has been completed in 3.8% yield for the longest linear
sequence of 24 steps starting from commercially available
(S)-glycidol. Our strategy highlights the intramolecular allyl-
boration as a highly stereocontrolled access to the THP part
of jimenezin.
Acknowledgment. U.K. and R.W.H. gratefully acknowl-
edge generous support by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie.
(11) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987,
52, 2919.
(12) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
(13) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(14) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267.
(15) Inanga, J.; Yokoyama, Y.; Hanamoto, T. Tetrahedron Lett. 1993,
34, 2791.
(16) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999.
(17) Mori, Y.; Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron 1995,
51, 5299.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds and
synthetic (-)-jimenezin. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0614471
(18) The corresponding bromide is described in: Yang, L.-M.; Huang,
L.-F.; Luh, T.-Y. Org. Lett. 2004, 6, 1461.
(19) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(20) Avedissian, H.; Sinha, S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha,
S. C.; Keinan, E. J. Org. Chem. 2000, 65, 6035.
Org. Lett., Vol. 8, No. 17, 2006
3831