Establishing the absolute configuration of the asbestinins: Enantioselective total synthesis of 11-acetoxy-4-deoxyasbestinin D

Article abstract of DOI:10.1021/ja056921x

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2-C-11-cyclized cembranoid natural products. Copyright

Full text of DOI:10.1021/ja056921x

Published on Web 11/15/2005
Establishing the Absolute Configuration of the Asbestinins: Enantioselective
Total Synthesis of 11-Acetoxy-4-deoxyasbestinin D
Michael T. Crimmins* and J. Michael Ellis
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599-3290
Received October 10, 2005; E-mail: crimmins@email.unc.edu
Scheme 1. Retrosynthetic Analysis of 1
Interest in the synthesis of C-2-C-11 cyclized cembranoids has
intensified over the past decade, due to their fascinating molecular
topology and interesting biological properties.1 Various approaches
to the syntheses of the cladiellins and briarellins have been imple-
mented;2 however, none of the asbestinins have been prepared by
total synthesis, leaving some doubt regarding their absolute config-
uration and biosynthetic origin.1b,3 In 1990, Rodr´ıguez and co-
workers isolated 11-acetoxy-4-deoxyasbestinin D (1) from Briareum
asbestinum, making note of its particular cytotoxicity against CHO-
K1 cells (ED50 ) 4.82 µg/mL) and strong antimicrobial activity
against Klebsiella pneumoniae.3 The tetracyclic framework of 11-
acetoxy-4-deoxyasbestinin D includes nine contiguous stereocenters
and a fully substituted tetrahydrofuran, rendering it a formidable
and intriguing target for chemical synthesis.
We recently reported a successful strategy for the synthesis of
members of the eunicellin class of cembranoids involving the
construction of the oxonene ring through ring-closing metathesis,4-6
followed by stereoselective formation of the hydroisobenzofuran
via an intramolecular Diels-Alder cycloaddition.2k The total
synthesis of 11-acetoxy-4-deoxyasbestinin D (1) was undertaken
with the intent of validating the intramolecular Diels-Alder
approach for the synthesis of the asbestinins.7 Our synthetic plan
hinged on an asymmetric glycolate aldol reaction of oxazolidine-
thione 4 to assemble the diene 3, a precursor of the oxonene 2
(Scheme 1). This report describes the first total synthesis of an
asbestinin verifying the absolute configuration of the subclass.
The synthesis of the oxonene core began with the addition of
isoprenylmagnesium bromide to (R)-benzyl glycidyl ether (5) to
afford a secondary alcohol,8 which was O-alkylated with sodium
bromoacetate (Scheme 2). The resultant glycolic acid was coupled
with (S)-4-benzyloxazolidinethione to deliver thioimide 4. Addition
of 4-pentenal9 to the chlorotitanium enolate of thioimide 4 in the
presence of NMP5c,7 gave syn-aldol adduct 6 in good yield and
diastereoselectivity (70%, >95:5 dr).10 Reductive removal of the
chiral auxiliary and protection of the diol afforded diene 3. As
anticipated, on the basis of previous successful metathesis reactions
to form medium ring ethers,4-6 treatment of diene 3 with the Grubbs
catalyst11 led to facile formation of oxonene 7 (99% yield).
With the oxonene 7 in hand, efforts focused on construction of
the required Diels-Alder precursor. To this end, the benzyl ether
was reductively cleaved, and the resultant alcohol was oxidized to
the aldehyde under Swern conditions (Scheme 3).12 The aldehyde
was subjected to successive Wittig reactions, first using phosphorane
8,13 then methylene triphenylphosphorane to yield the requisite diene
9. Selective deprotection of the primary TBS ether was carefully
carried out in the presence of the labile enol ether.14 Oxidation12
of the alcohol provided an aldehyde, which was treated with
phosphorane 1015 at elevated temperature. After the Wittig reaction,
a spontaneous Diels-Alder cycloaddition ensued through the more
favorable exo transition state, providing adduct 11 in 80% yield as
a single diastereomer. Earlier work in related systems had dem-
Scheme 2. Synthesis of the Oxonene Ringa
a Conditions: (a) CH2dC(CH3)MgBr, CuI, THF, -40 °C, 99%; (b) NaH,
BrCH2CO2H, THF, DMF, 95%; (c) (S)-benzyl-1,3-oxazolidine-2-thione,
DCC, DMAP, CH2Cl2, 86%; (d) TiCl4, i-Pr2NEt, NMP, 4-pentenal, CH2Cl2,
-78 °C, 70%; (e) LiBH4, MeOH, Et2O, 0 °C, 95%; (f) TBSCl, imidazole,
DMAP, DMF, 50 °C, 87%; (g) Cl2(Cy3P)(IMes)RudCHPh, CH2Cl2, 40
°C, 99%.
onstrated the importance of both the C-3 configuration and the C-3
hydroxyl protecting group in controlling the diastereoselectivity of
the Diels-Alder reaction.2k,16
Ketone 11 was converted to an alkene to introduce a handle to
establish the C-15 stereocenter (Scheme 4). Deprotection and
oxidation17 of the C-3 secondary alcohol followed by addition of
methylmagnesium chloride to the resultant ketone provided the
tertiary alcohol 12 in excellent yield as a single isomer.
With the required tricyclic core in place, refunctionalization of
the cyclohexane ring was undertaken. Acidic hydrolysis of the enol
1
ether yielded the R-methyl ketone (10:1 dr); however, H NMR
analysis (COSY, nOeSY) indicated the undesired isomer was the
major product. This problem was easily corrected by base-catalyzed
equilibration to the desired isomer to provide 84% of the desired
ketone after two recycles. Reduction of the ketone with L-Selectride
yielded the secondary alcohol as a single diastereomer, which was
esterified to give acetate 13.
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J. AM. CHEM. SOC. 2005, 127, 17200-17201
10.1021/ja056921x CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Intramolecular Diels-Alder Cycloadditiona
on a selective glycolate aldol addition to establish the C-2
stereocenter, a ring-closing metathesis reaction to complete the
oxonene, and an intramolecular Diels-Alder cycloaddition to
establish the relative configuration at C-1, C-10, and C-14. This
initial total synthesis of an asbestinin also serves to confirm the
absolute configuration of this family of natural products.
Acknowledgment. This work was supported by a research grant
from The National Institutes of Health (GM60567). We acknowl-
edge a generous gift of (R)-benzyl glycidyl ether from Daiso, Inc.
We also are grateful to Dr. Abimael D. Rodr´ıguez (University of
Puerto Rico, R´ıo Piedras) for his donation of an authentic sample
of the natural product.
Supporting Information Available: Experimental procedures, as
well as 1H and 13C NMR spectra for all new compounds, and synthetic
11-acetoxy-4-deoxyasbestinin D. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Conditions: (a) Na, NH3, THF, -78 °C, 86%; (b) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 to 0 °C, 94%; (c) Ph3PdC(OMe)C(O)Me (8), PhCH3,
110 °C, 84%; (d) Ph3PCH3Br, t-BuOK, THF, 0 °C, 87%; (e) NH4F, MeOH,
79%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 0 °C, 93%; (g)
Ph3PdCHC(O)Me (10), PhCH3, 110 °C, 80%.
References
Scheme 4. Completion of 11-Acetoxy-4-deoxyasbestinin Da
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THF, 0 °C, 98%; (e) HCl, CHCl3, 96%, 10:1 dr; (f) NaH, MeOH, 99%,
1:1.2 dr; (g) L-Selectride, THF, -78 °C, 94%; (h) Ac2O, Et3N, DMAP,
CH2Cl2, 99%; (i) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 80%; (j) (+)-Ipc2BH,
THF, NaOH, H2O2; (k) n-Bu4NF, THF, 64% (two steps); (l) Tf2O, 2,6-
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The final stage of the synthesis required introduction of the C-15
stereocenter and formation of the oxapane. The regioselective and
stereoselective hydroboration of the 1,1-disubstituted olefin of diene
13 proved to be a challenge. Regioselective hydroboration occurred
in high yield with 9-BBN, but the reaction was not stereoselective.18
It was speculated that increasing the steric bulk at C-3 could impede
addition from the undesired face of the alkene, improving the
diastereoselection. Accordingly, the C-3 hydroxyl was protected
as triethylsilyl ether 14, but only moderate improvement in the
diastereoselectivity (2:1 dr) was observed. Fortunately, the use of
(+)-diisopinocampheylborane delivered the desired alcohol 15 as
a single isomer after oxidative workup.19,20 The triethylsilyl ether
was subsequently cleaved to deliver the diol 16 in 64% yield over
two steps. Taking advantage of the conditions employed by
Overman in the syntheses of briarellins E and F,2i the diol 16 was
treated with triflic anhydride and 2,6-lutidine to deliver 11-acetoxy-
4-deoxyasbestinin D (1) in 66% yield. Spectroscopic data for
synthetic 1 matched the reported data for the natural product in all
regards.3 Of particular note, the specific rotation of synthetic 1 and
a purified sample of natural 1 were identical ([R]26D; CHCl3; )
-15) when measured under the same conditions.
(16) Davidson, J. E. P.; Gilmour, R.; Ducki, S.; Davies, J. E.; Green, R.; Burton,
J. W.; Holmes, A. B. Synlett 2004, 1434.
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K.; Steglich, W. Eur. J. Org. Chem. 2002, 2905. (d) Miyaoka, H.; Honda,
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In summary, a highly stereoselective synthesis of 11-acetoxy-
4-deoxyasbestinin D has been completed in 26 linear steps, hinging
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