A concise total synthesis of the lichen macrolide (+)-aspicilin

Article abstract of DOI:10.1021/ol0620287

(Figure Presented) The total synthesis of the polyhydroxylated macrolide (+)-aspicilin 5 is described using as a key step a highly diastereoselective allylation of aldehyde 6 with the uniquely functionalized allylstannane 1. (+)-Aspicilin is obtained in 1

Full text of DOI:10.1021/ol0620287

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5137-5140
A Concise Total Synthesis of the Lichen
Macrolide (+)-Aspicilin
Christophe Dubost,‡ Istva´n E. Marko´,*,‡ and Thomas Ryckmans†
UniVersite´ Catholique de LouVain, De´partement de Chimie, 1 Place Louis Pasteur,
B-1348 LouVain La NeuVe, Belgium and Pfizer Global Research and DeVelopment,
Sandwich, Kent CT13 9NJ, England
marko@chim.ucl.ac.be
Received August 17, 2006
ABSTRACT
The total synthesis of the polyhydroxylated macrolide (
aldehyde 6 with the uniquely functionalized allylstannane 1. (
+
)-aspicilin 5 is described using as a key step a highly diastereoselective allylation of
)-Aspicilin is obtained in 18 steps and 10% overall yield.
+
We have previously shown1 that enantiomerically pure syn-
anti and syn-syn configured triol units such as 3 and 4 could
be synthesized efficiently by the SnCl4-mediated allylation
of chiral R-benzyloxyaldehydes 2 with the uniquely func-
tionalized allylstannane 1. Remarkably, the relative stereo-
amount of Lewis acid employed (Scheme 1). The resulting
structures possess a stereodefined polyoxygenated triad
present in a large number of natural products. (+)-Aspicilin,
an 18-membered macrolide first isolated from Lecanoraceae
lichen in 1900 by Hesse,2 embodies a contiguous syn-anti
(1) (a) Leroy, B.; Marko´, I. E. Org. Lett. 2002, 4, 8685. (b) Dubost, C.;
Leroy, B.; Marko, I. E.; Tinant, B.; Declercq, J.-P.; Bryans, J. Tetrahedron
2004, 60, 7693.
Scheme 1
(2) (a) Hesse, O. J. Prakt. Chem. 1900, 62, 430. (b) Hesse, O. J. Prakt.
Chem. 1904, 70, 449.
(3) Quinkert, G.; Heim, N.; Bats, J. W.; Oschkinat, H.; Kessler, H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 987.
(4) (a) Dixon, D. J.; Foster, A. C.; Ley, S. V. Can. J. Chem. 2001, 79,
1668. (b) Maezaki, N.; Li, Y. X.; Ohkubo, K.; Goda, S.; Iwata, C.; Tanaka,
T. Tetrahedron 2000, 56, 4405. (c) Banwell, M. G.; McRae, K. J. Org.
Lett. 2000, 2, 3583. (d) Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett.
2000, 2, 123. (e) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K.
J. Org. Chem. 1998, 63, 7505. (f) Nishioka, T.; Iwabuchi, Y.; Irie, H.;
Hatakeyama, S. Tetrahedron Lett. 1998, 39, 5597. (g) Chenevert, R.; Lavoie,
M.; Dasser, M. Can. J. Chem. 1997, 75, 68. (h) Sinha, S. C.; Keinan, E. J.
Org. Chem. 1997, 62, 377. (i) Enders, D.; Prokopenko, O. F. Liebigs Ann.
1995, 1185. (j) Oppolzer, W.; Radinov, R. N.; de Brabander, J. Tetrahedron
Lett. 1995, 36, 2607. (k) Solladie´, G.; Fernandez, I.; Maestro, C.
Tetrahedron: Asymmetry 1991, 2, 801. (l) Quinkert, G.; Becker, H.; Du¨rner,
G. Tetrahedron Lett. 1991, 32, 7397. (m) Quinkert, G.; Fernholz, E.; Eckes,
P.; Neumann, D.; Du¨rner, G. HelV. Chim. Acta 1989, 72, 1753. (n) Quinkert,
G.; Heim, N.; Glenneberg, J.; Du¨ller, U.; Eichhorn, M.; Billhardt, U.-M.;
Schwarz, C.; Zimmermann, G.; Bats, J. W.; Du¨rner, G. HelV. Chim. Acta
1988, 71, 1719. (o) Waanders, P. P.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1987, 28, 2409.
chemistry of these adducts was governed solely by the
† Pfizer Global Research and Development.
‡ Universite´ Catholique de Louvain.
10.1021/ol0620287 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/30/2006

triol motif3 which represents an ideal synthetic target to
benchmark our methodology.
with CBr4 and PPh3 (82%). The preparation of the corre-
sponding Grignard reagent was then accomplished in THF,
and the resulting organometallic was added to a solution of
the commercially available TBS-protected glycidol 9 and 5%
CuBr.Me2S at -25 °C. After purification over silica gel, the
desired alcohol 15 was obtained in 88% yield as a single
diastereoisomer. Subsequent protection of the free hydroxyl
with benzyl-2,2,2-trichloroacetimidate, in the presence of
triflic acid (10%), afforded the benzyl ether 16 in 89% yield
after 3 days at room temperature. Quantitative deprotection
of the TBS ether with TBAF in THF was achieved selectively
in the presence of the TBDPS ether. Finally, subjecting the
resulting primary alcohol 17 to oxidation with Dess-Martin
reagent afforded the key aldehyde 6 in 89% yield. This
aldehyde, embodying the correct functionalities and absolute
stereochemistry required for our allylation process, was
efficiently obtained in only eight steps (Scheme 3) with an
overall yield of 50%.
Though devoid of biological activity, this natural product
has attracted many synthetic chemists interested in its
challenging architecture.4 In this communication, we report
our successful total synthesis of compound 5 using a highly
diastereoselective allylation of the suitably functionalized
R-benzyloxyaldehyde 6 as a key step. This aldehyde is
readily available by condensation of a synthon equivalent
to dianion 8 with (S)-propylene oxide 7, to give the remote
alcohol required for macrocyclization, and with the TBS-
protected (S)-glycidol 9, the precursor of the R-benzyloxy-
aldehyde function of 6 (Scheme 2).
Scheme 2
On the basis of our previous studies with less elaborated
R-benzyloxyaldehydes,1b we surmised that treating 6 with
allylstannane 1,5 in the presence of 1 equiv of SnCl4, would
produce selectively the desired syn-anti triol possessing a
pendant allylsilane moiety that could be conveniently
employed for further transformations. This stereochemistry
would arise from the bicyclic transition state 19 involving
the transmetalated trichlorostannane 18 (Figure 1).
Our synthesis (Scheme 3) begins with the preparation of
the Grignard reagent derived from commercially available
1-bromooctene 10, which was added to a solution of (S)-
propylene oxide 7 and 5% CuCN in THF to afford the
desired alcohol 11 in 85% yield and as a single stereoisomer.
This compound was protected quantitatively as the TBDPS
ether 12, using standard procedure. Hydroboration of 12 with
9-BBN-H, followed by treatment with sodium hydroxide and
H2O2, gave rise to alcohol 13, in 90% yield, which was
converted to the corresponding bromide 14 upon treatment
Figure 1. Proposed transition state for allylation.
In the event, treatment of allylstannane 1 with 1 equiv of
SnCl4, at -78 °C, followed by the addition of a cold (-78
°C) solution of aldehyde 6 afforded, after purification of the
crude mixture, the desired syn-anti triol 21 as a single
diastereoisomer and in 69% yield on a multigram scale.6
Scheme 3
5138
Org. Lett., Vol. 8, No. 22, 2006

Though we were quite pleased to obtain 21 with a good yield,
we tried to further improve the reaction and discovered that
using a higher dilution was beneficial. A careful control of
the temperature also had to be exercised. For example,
diluting the reaction 10 times and using a diethylether/N2
cooling bath led to 21 in a gratifying 85% yield7 (Scheme
4).
A Sakurai reaction between 23 and 2-methoxy-1,3-
dioxolane, mediated by ZnCl2‚Et2O, was then successfully
used to introduce an acetal moiety. Even though the reaction
proceeded sluggishly, we were able to obtain the desired
product 24 in 99% yield and 69% conversion after 72 h.
The starting material could easily be recycled, and after three
runs, the overall yield in 24 was almost quantitative.
Ozonolysis of 24 in a mixture of DCM and MeOH, at
-78 °C, followed by addition of NaBH4 to quench the
ozonide, produced smoothly a mixture of two diastereoiso-
meric alcohols 25 in 88% yield. At this stage the removal
of the TBDPS protecting group was successfully ac-
complished using TBAF in refluxing THF (99% yield) to
give 26 ready for a one-pot deprotection of the acetal/
dehydration sequence to produce the trans-unsaturated al-
dehyde 27. In the event, treating 26 with PTSA in acetone,
initially at room temperature and then at 40 °C for 2 h, gave
27 in a decent 65% yield as the sole (E)-double bond isomer.
Scheme 4
With product 21 in hand, we next focused on the
conversion of the allylsilane moiety into the required
unsaturated carbonyl system. Preliminary model studies
indicated that the carbamate protecting group had to be
removed as soon as possible because the harsh reducing
conditions required for its deprotection (LiAlH4 in refluxing
THF) would be troublesome with the unsaturated carbonyl
we aimed to introduce. Interestingly, treatment of 21 with
LiAlH4 in refluxing THF afforded smoothly the unprotected
diol 22 in 99% yield (Scheme 5). Foreseeing a final global
deprotection in one step, diol 22 was protected as the
corresponding benzyl ether. The first attempts, using a
sequential deprotonation with NaH followed by addition of
benzyl bromide in the presence of Bu4NI, were disappointing
since only the desilylated starting material was observed. We
assumed that a possible 5- or 6-membered “ate” complex
could be formed by attack of an alkoxide on the TMS group
of 22. This activated allylsilane would then react with a
proton during acidic aqueous workup. This problem was
solved by mixing 22, a large excess of benzyl bromide and
Bu4NI in THF, and adding NaH portionwise so that the
formed alkoxide was immediately trapped by the alkylating
agent. This procedure afforded the desired tri-benzylated
product 23 in 79% yield along with some desilylated starting
material.
With the recent improvements made in the field of tandem
oxidation processes using MnO2, we envisaged completing
our approach with an ambitious tandem oxidation/macrocy-
clization8 combination. Thus, 27 was submitted to Corey’s
procedure for the one-pot oxidation of allylic aldehydes to
unsaturated esters9 using 20 equiv of MnO2 in the presence
of 5 equiv of KCN in THF. Although the starting material
was totally consumed within 24 h, our first attempts showed
only small traces of the desired macrocycle 29, even at reflux.
We assumed that the acyl-cyanide, generated in situ, was
not reactive enough to promote the macrocyclization. There-
fore, the reaction was performed in toluene, at room
temperature, and the excess of MnO2 was filtered once all
the starting material had disappeared by TLC. This solution
was added to a refluxing solution of DMAP in toluene, using
a syringe pump, over 2 h. With this improved protocol, we
were pleased to obtain a modest 18% yield of macrocycle
29 after purification (Scheme 6). In parallel, we also oxidized
27 to acid 28, using Pinnick’s10 protocol, in quantitative yield
and submitted this compound to Yamaguchi’s macrocycliza-
tion.11 This reaction had already been reported in previous
total syntheses but with less robust protecting groups than
benzyl ethers. In our case, we were delighted to obtain the
macrocyclized adduct 29 in 92% yield using 2,4,6-trichlo-
Scheme 5
Org. Lett., Vol. 8, No. 22, 2006
5139

recrystallization from ether. The synthetic sample displayed
spectral data in perfect agreement with those reported in the
literature (Scheme 7).
Scheme 6
Scheme 7
robenzoyl chloride to prepare the mixed anhydride and
DMAP in refluxing toluene as the promoter.
In summary, we have achieved the total synthesis of (+)-
aspicilin in 18 steps and 10% overall yield. This synthesis
compares favorably with other approaches already reported.
We have also demonstrated that the allylation protocol
developed in our laboratory is efficient and reliable in a
multistep sequence and in large scale. Moreover, the
preliminary results of a tandem oxidation/macrolactonization
sequence are described for the first time. Although a modest
yield is obtained at present, subsequent optimization might
lead to an improved and shorter synthesis of (+)-aspicilin.
The final step required the deprotection of three benzyl
ethers at once. Our initial attempts implied hydrogenations
with Pd/C at room temperature. These conditions produced
a mixture of monobenzylated products and saturated mac-
rocycles, formed by hydrogenation of the CdC double bond.
We then focused on the use of Lewis acid-mediated
deprotections. While FeCl3 in DCM proved to be unreactive,
treating 29 with a solution of BCl3 in DCM12 at -78 °C for
11 h, followed by quenching with MeOH, afforded (+)-
aspicilin 5 (65%) as a white solid, after purification and
(5) See reference 1b for preparation of this product in a three-step
procedure.
(6) Enantiomeric purity of 21 was determined to be 97.2 % by chiral
HPLC (Chirex AD-H; hexane/i-PrOH, 99.55:0.45, 1 mL/min).
(7) The increase in yield is partly explained by the partial suppression
of a possible migration of the trichlorotin residue at the R position of the
carbamate.
(8) For comprehensive review on TOP with MnO2, see: Taylor, R. J.
K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851.
(9) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968,
90, 5616.
(10) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
Acknowledgment. Financial support for this work by the
Universite´ Catholique de Louvain and Pfizer Ltd. (student-
ship to C.D.) and SHIMADZU Benelux (financial support
for the acquisition of a FTIR-8400S spectrometer) is grate-
fully acknowledged.
Supporting Information Available: Characterization,
procedures, and full spectral data (including NMR spectra)
for all intermediates and (+)-aspicilin. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(12) Williams, D. R.; Brown, D. R.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923.
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