A short and efficient stereoselective synthesis of the polyhydroxylated macrolactone (+)-aspicilin

Article abstract of DOI:10.1021/ol991214s

(equation presented) A short and efficient synthesis of the polyhydroxylated macrolactone (+)-aspicilin 1 using a stereoselective lithium perchlorate mediated addition of allyltributyltin to the equatorially disposed carboxaldehyde of 3 (derived from (R′,R′,R′,S) butane diacetal protected butane tetrol 2) as the key step is described. Terminal group manipulation and Masamune-Roush olefination using phosphonate ester 4 followed by macrocyclization via ring closing metathesis afforded the natural product after partial hydrogenation and global deprotection.

Full text of DOI:10.1021/ol991214s

ORGANIC
LETTERS
2000
Vol. 2, No. 2
123-125
A Short and Efficient Stereoselective
Synthesis of the Polyhydroxylated
Macrolactone (+)-Aspicilin
Darren J. Dixon, Alison C. Foster, and Steven V. Ley*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
sVl1000@cam.ac.uk
Received November 3, 1999
ABSTRACT
A short and efficient synthesis of the polyhydroxylated macrolactone (+)-aspicilin 1 using a stereoselective lithium perchlorate mediated
addition of allyltributyltin to the equatorially disposed carboxaldehyde of 3 (derived from (R′,R′,R,S) butane diacetal protected butane tetrol 2)
as the key step is described. Terminal group manipulation and Masamune−Roush olefination using phosphonate ester 4 followed by
macrocyclization via ring closing metathesis afforded the natural product after partial hydrogenation and global deprotection.
The abundance of polyhydroxylated natural products, ranging
from relatively simple sugars to more structurally complex
molecules such as polyketides which exhibit a broad range
of biological properties, continues to stimulate the develop-
ment of new methods for their stereoselective synthesis.
from Lecanoraceae lichen in 1993 by Feige and co-workers.4
Although its biological function is yet to be determined, its
structure which contains four stereogenic centers, three of
which occur as an anti,syn-triol motif, makes it an ideal
synthetic target to showcase the new methodology.
Consequently, we have recently reported the use of
dimethyl tartrate derived (R′,R′,S,S)- and (S′,S′,R,R)-2,3-
butanediacetal-protected butane tetrols as readily accessible
building blocks for polylol production.1 In addition, we
reported the preparation and utility of isomeric (R′,R′,R,S)-
2,3-butanediacetal-protected butane tetrol, derived from a C2
symmetric dimethyl tartrate through a chiral memory pro-
tocol, as a building block for anti-1,2-diols through selective
chemical differentiation of the spatially dissimilar hydroxyl
termini.2,3
The synthetic plan relied on a stereoselective addition of
a suitable allylic nucleophile to the equatorially disposed
carboxaldehyde of 3, itself readily derived from key building
block 2. It was believed that the sense of the addition would
be governed by chelation control to the ring dioxane oxygen,
mirroring our initial investigations using aldehydes derived
from (R′,R′,S,S)- and (S′,S′,R,R)-2,3-butanediacetal-protected
butane tetrols. Protection of the resulting secondary hydroxyl
and deprotection/oxidation of the axially disposed hy-
droxymethyl group followed by an olefination using phos-
phonate ester 45 should set up the desired E-R,â-unsaturated
ester. Finally, macrocyclization through a ring closing
metathesis reaction followed by partial hydrogenation and
global deprotection should afford the natural product (Scheme
1).6
Here, we describe the application of these important results
to the synthesis of the anti-1,2-diol containing polyhydroxyl-
ated macrolactone natural product aspicilin 1. Aspicilin, an
18-membered macrolactone metabolite, was first isolated
(1) Barlow, J. A.; Dixon, D. J.; Foster, A. C.; Ley, S. V.; Reynolds, D.
J. J. Chem. Soc., Perkin Trans. 1 1999, 1627-1629.
(2) Dixon, D. J.; Foster, A. C.; Ley, S. V.; Reynolds, D. J. J. Chem.
Soc., Perkin Trans. 1 1999, 1631-1633.
(4) Feige, G. B.; Lumbsch, H. T.; Huneck, S.; Elix, J. A. J. Chromatogr.
1993, 646, 417-427.
(5) Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc., Perkin Trans.
1 1987, 121-129.
(3) Dixon, D. J.; Foster, A. C.; Ley, S. V.; Reynolds, D. J. J. Chem.
Soc., Perkin Trans. 1 1999, 1635-1637.
10.1021/ol991214s CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/05/2000

not easily explained but is the subject of a more detailed
investigation that will be published later. The lithium
perchlorate activated reaction, however, is believed to
proceed via chelation control (Figure 1).
Scheme 1
Figure 1.
Because of the hindered nature of the newly formed
secondary alcohol in these reactions, Mosher analysis to
confirm the stereochemistry was not possible. However, a
single-crystal X-ray structure of the diol 7 derived from the
major product 5 (Scheme 3) confirmed that the sense of the
The synthesis began from the readily accessible diol
building block 2 which was transformed on a multigramme
scale to the desired aldehyde 3 in two steps according to the
previously established procedure.3 The stereoselective ad-
dition of an allyl group to this aldehyde was indeed possible
following similar conditions for the analogous addition to
aldehydes derived from (R′,R′,S,S)- and (S′,S′,R,R)-2,3-
butanediacetal-protected butane tetrols. Thus, 3 was dissolved
in diethyl ether, and lithium perchlorate was added until the
solution was saturated (∼5 M). Allyltributyl tin (3 equiv)
was added and the reaction left to stir overnight at room
temperature. On workup, two diastereomeric products 5 and
6 were detected in a ratio of 9:1, respectively. Chromato-
graphic purification afforded the diastereomerically pure
homoallylic alcohol 5 in 70% yield (Scheme 2).
Scheme 3a
a (a) TBAF, THF, 100%.
asymmetric induction in the lithium perchlorate mediated
reaction was consistent with addition occurring through
chelation control (Figure 1).
With these results in hand, the synthesis of both natural
and 6-epi-aspicilin was embarked upon.7 The synthesis of
both enantiomers began with protection of the homoallylic
alcohol as the methoxymethyl ether. This was possible but
required forcing conditions analogous to those used for the
protection of tertiary alcohols.8 Thus, alcohol 5 was treated
with methoxymethyl iodide (MOMI), generated via an in
situ Finkelstein reaction, and Hu¨nigs base in refluxing DME
for 13 h and afforded the desired MOM-protected material
in 72% (86%)6 yield after chromatographic purification.
Standard TBS removal and oxidation following the Swern
protocol afforded the axially disposed aldehyde 8 in 100%
(100%) yield over two steps.
Scheme 2a
a (a) 5 M LiClO4, Et2O, allyltributyltin; 9:1 (5:6) 70% of 5; (b)
ZnCl2 (3 equiv), Et2O, allyltributyltin; 1:9 (5:6) 80% of 6.
To minimize the possibility of epimerization of the axially
disposed aldehyde, the Masamune-Roush conditions9 were
chosen for the subsequent olefination reaction. Accordingly,
aldehyde 8 was treated with phosphonate ester 4, lithium
chloride, and Hu¨nigs base at room temperature for 14 h and
gave, on workup, a 10:1 mixture of E:Z isomers. Chromato-
In the course of our investigations to increase the observed
selectivity of this addition reaction, we came across an
interesting result. When zinc chloride was used as the Lewis
acid, the reaction proceeded to completion in a shorter time
and in improved yield. However, the opposite sense of
stereochemical induction was observed, giving products again
in a ratio of 9:1 (Scheme 2). This extremely useful result is
(7) Yields for the epimer synthesis given in parentheses.
(8) Narasaka, K.; Sakakura, T.; Uchimaru, T.; Guedin-Kieng, D. J. Am.
Chem. Soc. 1984, 106, 2954-2961.
(9) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(6) A similar approach was published during the course of our investiga-
tions: Nishioka, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Tetrahedron
Lett. 1998, 39, 5597-5600.
124
Org. Lett., Vol. 2, No. 2, 2000

graphic purification afforded the isomerically pure E isomer
9 in 58% (71%) yield (Scheme 4).
Scheme 6a
Scheme 4a
a (a) Pd-BaSO4, EtOAc, 40 min, 100%; (b) TFA/H2O 9:1, 44%.
When these conditions were applied to the deprotection
of the natural diastereoisomer, the reaction gave only an
unidentifiable byproduct. However, treatment with ethanedithi-
ol and boron trifluoride etherate afforded (+)-aspicilin 1 in
73% yield. The 1H NMR, 13C NMR, IR, melting point, MS,
and specific rotation [R]28D +35.0 (c 0.20, CHCl3) [lit. [R]23
D
+37.5 (c 0.55, CHCl3)]12 of the synthesized material were
in excellent agreement with the reported data4 and that of
an authentic sample (Scheme 7).13
a (a) MOMCl, NaI, DME, Hu¨nigs base, 72% (86%); (b) TBAF,
THF, 100% (100%); (c) DMSO, (COCl)2, Et3N, DCM, -78 °C to
rt, 100% (100%); (d) LiCl, Hu¨nigs base, 4, MeCN.
Macrocyclization of triene 9 was possible using standard
ring closing metathesis conditions.10 Thus, a dilute solution
of 9 in dichloromethane at room temperature was treated
with a catalytic quantity of Grubb’s catalyst11 (10%) for 14
h and afforded the desired material 10 in 73% (45%) yield
and as a 1.5:1 mixture of Z:E isomers. The byproduct (11)
of metathesis across the double bond of the R,â-unsaturated
ester was also detected in 26% yield (Scheme 5).
Scheme 7a
a (a) Pd-BaSO4, EtOAc, 40 min, 100%; (b) (CH2SH)2, BF3‚OEt2,
DCM, 73%.
Scheme 5a
In summary, a short and efficient stereoselective synthesis
of the polyhydroxylated natural product (+)-aspicilin 1 and
the C-6 epimer has been achieved using (R′,R′,R,S)-2,3-
butanediacetal-protected butane tetrol as the starting material.
The key step relied on the stereoselective allylation of the
equatorially disposed aldehyde in 3. Terminal group ma-
nipulation and olefination using phosphonate ester 4 followed
by macrocyclization via ring closing metathesis afforded,
after partial hydrogenation and global deprotection, the target
compounds. Both diastereoisomers of aspicilin have been
submitted for biological screening.
a (a) (PCy3)2RuCl2 10 mol %, DCM, 73% of 10 (45%) and 26%
of 11.
Acknowledgment. We thank the EPSRC (to D.J.D. and
A.C.F.), Zeneca Agrochemicals (to A.C.F.), and the Novartis
Research Fellowship (to S.V.L.) for financial support and
Dr. Mike Turnbull of Zeneca Agrochemicals for useful
discussions.
Partial hydrogenation of the isomeric mixture of alkenes
10 occurred smoothly using palladium on barium sulfate in
ethyl acetate under an atmosphere of hydrogen for 40 min
to give the fully protected aspicilin in 100% (100%)6 yield.
Global deprotection using the standard conditions for BDA
removal, namely treatment with a 90% aqueous solution of
trifluoroacetic acid followed by removal of volatiles in vacuo,
proceeded smoothly on fully protected 6-epi-aspicilin to give
the triol product 12 in 44% yield.
Supporting Information Available: Characterization
data for aspicilin and 6-epi-aspicilin. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991214S
(12) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org.
Chem. 1998, 63, 7505-7515.
(13) Kindly donated by Professor Hatakeyama.
(10) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(11) Purchased from Strem Chemicals.
Org. Lett., Vol. 2, No. 2, 2000
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