Lasonolide A: Synthesis of A and B rings via a cycloetherification strategy

Article abstract of DOI:10.1055/s-2003-40323

Syntheses of tetrahydropyrans ent-2 and ent-3, substructures of the A and B rings of the enantiomer of lasonolide A (1), are described. The syntheses of ent-2 and ent-3 feature highly stereo-selective cycloetherification reactions of bis-homoallylic alcoh

Full text of DOI:10.1055/s-2003-40323

1334
LETTER
Lasonolide A: Synthesis of A and B Rings via a Cycloetherification Strategy
Lasonolide
A
avid J. Hart,* Suzanne Patterson, James P. Unch
Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, Ohio 43210, USA
Fax +1(614)2921685; E-mail: hart@chemistry.ohio-state.edu
Received 10 April 2003
This article is dedicated to the memory of Professor Ray Lemieux whose presence at The Ohio State University at an early stage of his
career is still remembered.
Abstract: Syntheses of tetrahydropyrans ent-2 and ent-3, substruc-
tures of the A and B rings of the enantiomer of lasonolide A (1), are
described. The syntheses of ent-2 and ent-3 feature highly stereo-
selective cycloetherification reactions of bis-homoallylic alcohols 7
and 8.
Key words: tetrahydropyran, cycloetherification, phenylselenenyl
chloride, lasonolide A, macrolide
The structure of lasonolide A, a marine natural product
isolated from the Caribbean sponge Forcepia sp., was ini-
tially assigned on the basis of NMR spectroscopy.1 Some
stereochemical ambiguities in the original assignment
were clarified by the Lee group through an elegant series
of studies that culminated in a total synthesis of the natural
product. These studies established the actual structure of
lasonolide A as 1 (Figure 1).2 Lasonolide A has been the
focal point of a number of synthetic studies, most likely
due to its potent activity against several tumor cell lines.3,4
We became interested in lasonolide A for this reason and
because of our interest in developing a cycloetherification
Figure 1
approach to tetrahydropyrans, a substructure that appears
in the A and B rings of 1 and many other natural products.5
This paper describes syntheses of tetrahydropyrans ent-2
and ent-3, enantiomers of intermediates in the Lee group
synthesis of 1.
An overview of the cycloetherification approach we have
developed for the synthesis of ent-2 and ent-3 is illustrated
in Equation 1. We have previously shown that treatment
of bis-homoallylic alcohols of type 4 with appropriate
electrophiles affords tetrahydropyrans of type 5 when R is
Equation 1
an appropriate carbocation stabilizing group.6 Reduction
of the electrophile (X → H) then provides a tetrahydro-
pyran of type 6. Of course there are stereochemical issues
yield.7 Conversion of 9 to nitroalkene 10 was then accom-
associated with this approach. We have addressed some
plished in 85% overall yield by a modification of litera-
of these issues in earlier work and this paper further de-
ture procedures.8 Treatment of 10 with lithium
lineates what can be expected from complex substitution
dimethylcuprate gave 11 (50–80% yield), and oxidation
patterns along the bis-homoallylic alcohol backbone.
of the derived nitronate using ozone gave carboxylic acid
12 (85%).9,10 Acid 12 was reduced with lithium aluminum
hydride, and the resulting alcohol 13 was protected as the
corresponding benzyl ether 14 (85% from 12).11 Hydroly-
sis of the exocyclic acetonide followed by treatment of the
resulting vicinal diol with triphenylphosphine-iodine gave
olefin 15 in 65% yield.12 Hydroboration-oxidation of the
olefin followed by etherification of the resulting alcohol
16 gave 17 in 77% yield. The remaining acetonide was
hydrolyzed, and Wittig olefination of the resulting hemi-
Application of this approach to the synthesis of ent-2 re-
quired the preparation and cyclization of bis-homoallylic
alcohol 7. This was accomplished as shown in Scheme 1.
Oxidation of commercially available diacetone glucose
with PDC-acetic anhydride provided ketone 9 in 89%
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1334,1338,ftx,en;S00703ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Lasonolide A
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Scheme 1 Synthesis and cyclization of 7. Reagents: (a) CH3NO2, 0.2 N aq NaOH, Bu4NI, benzene (95%) (b) Ac2O, DMSO (90%)
(c) Me2CuLi, Et2O (50–80%) (d) 0.5 M aq NaH2PO4–1.0 M aq NaOH (1:1); aq oxone; 10% aq HCl (85%) (e) LiAlH4, THF (95%)
(f) Cl3CC(=NH)OBn, CH2Cl2–cyclohexane, CF3SO3H (90%) (g) 60% aq acetic acid, D (81%) (h) Ph3P, I2, imidazole, toluene, 80 °C (80%)
(I) 9-BBN; 2.0 N aq NaOH–30% aq H2O2 (89%) (j) BnBr, Bu4NI, NaOH (86%) (k) acidic Dowex-50, 50% aq dioxane, 80 °C (70%)
(l) Ph3PCH2(2-furyl)Br, dioxane, KO-t-Bu (86%, trans:cis = 3:1) (m) neat n-Bu3SnH, AIBN, 80 °C (99%, trans:cis = 30:1) (n) PhSeCl,
CH2Cl2 (87%) (o) n-Bu3SnH, AIBN, benzene, reflux (88%) (p) t-BuCOCl, pyridine (93%) (q) O3, MeOH (r) BH3–THF, –10 °C (64% for 2
steps) (s) t-BuPh2SiCl, DMF, imidazole (87%) (t) i-Bu2AlH, toluene (72%) (u) H2, 10% Pd on C (60%) (v) t-BuCOCl, pyridine (74%)
(w) Me2C(OMe)2, PPTS (96%) (x) n-Bu4NF, THF (87%)
acetal using (2-furyl)methylidenetriphenylphosphorane13 There are a number of ways in which 18 might be used in
gave E-olefin 7 and the isomeric Z-olefin in a 3:1 ratio, re- a synthesis of ent-lasonolide A or derivatives thereof. For
spectively. Isomerization of the mixture of olefins using characterization purposes, however, we focused on the
tri-n-butyltin radicals gave 7 (60% from hemiacetal 17) conversion of 18 to tetrahydropyran ent-2, the enantiomer
contaminated with only 3% of its geometrical isomer.14
of the Lee group intermediate in their synthesis of 1.2 This
transformation was accomplished as shown in Scheme 1.
Reduction of selenide 18 with tri-n-butyltin hydride pro-
vided 19 in 88% yield.16 Protection of the secondary hy-
droxyl group gave pivalate 20 in 93% yield. Oxidative
degradation of the furan using ozone followed by reduc-
tion of the intermediate crude carboxylic acid with bo-
rane–THF gave primary alcohol 21 in 64% yield.17
Conversion of the primary alcohol to tert-butyldiphenyl-
silyl ether 22 followed by reduction of the pivalate using
diisobutylaluminum hydride gave alcohol 23 in 63%
yield.18 Hydrogenolysis of the benzyl groups followed by
Treatment of 7 with phenylselenenyl chloride gave tet-
rahydropyran 18 as a single diastereomer in 87% yield.15
We imagine that the observed stereoselectivity is a result
of intramolecular anti addition of the electrophile and in-
cipient tetrahydropyran oxygen to the olefin via a chair
like conformation that places the C2 and C6 substituents in
equatorial sites. We have previously shown that C4 oxy-
gen substituents (TBS ethers and hydroxyl groups) exhibit
a preference for axial sites in related cycloetherifications.
This effect is consistent with the stereoselectivity ob-
served in the cyclization of 7.6
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D. J. Hart et al.
LETTER
Scheme 2 Synthesis and cyclization of 8. Reagents: (a) Sn(OTf)2, N-ethylpiperidine, CH2Cl2, –70 °C; (E,E)-PMPCH=CHCH=CHCHO
(79%) (b) CH2Cl2, –10 °C, Me2AlN(OMe)Me (93%) (c) Et3SiCl, imidazole, DMF (94%) (d) n-Bu3SnCH2OCH2Ph (5 equiv), n-BuLi (3 equiv)
(55–65%) (e) CF3CO2H, THF–H2O (5:1) (f) Zn(BH4)2, toluene, Et2O, –78 °C (45–55% for 2 steps) (g) PhSeCl, CH2Cl2, –78 °C (55–65%)
(h) PhCH2Br, 10 mol% n-Bu4NI, 50% w/w aq NaOH, 60 °C, sonication (64%) (i) NBS, acetone–H2O (2:1), 0 °C → r.t. (86%) (j) n-Bu3SnH
(5 equiv), Et3B, O2, PhH, r.t. (95%) (k) Dess–Martin periodinane, CH2Cl2, r.t. (l) MCPBA, p-TsOH (cat); EtOH, H2SO4 (cat), D (65%)
esterification of the resulting triol 24 gave diol 25 in 44% others.21 Treatment of 28 with the aluminum amide de-
yield. The diol was protected as acetonide 26 (96% yield) rived from N,O-dimethylhydroxylamine gave Weinreb
and the silyl ether was removed using tetra-n-butylammo- amide 29 in 93% yield along with greater than 80% recov-
nium fluoride to give the target tetrahydropyran ent-2 in ery of the chiral auxiliary.22 Protection of the secondary
87% yield. Tetrahydropyran ent-2 was identical (1H and alcohol as TES-ether 30 was then accomplished in 94%
13C NMR) to material prepared by the Lee group.19
yield.23 After considerable experimentation it was found
that treatment of one equivalent of 30 with benzyloxy-
methyllithium (prepared from 5 equivalents of n-
Bu3SnCH2OBn and 3 equivalents of n-BuLi) gave ketone
31 in 55–65% yields along with approximately 5% each
of amide 32 (probably derived from a b-elimination reac-
tion) and a-aminoketone 33.24,25 The TES protecting
group of 31 was removed using one equivalent of trifluo-
roacetic acid in aqueous tetrahydrofuran at room temper-
ature. The resulting alcohol 34 was extremely sensitive to
both acid and base. b-Elimination and retro-aldol reac-
tions were both encountered during attempts to purify this
material. These problems were minimized when crude 34
Application of this cycloetherification approach to the
synthesis of ent-3 required the preparation and cyclization
of bis-homoallylic alcohol 8. This was accomplished as
shown in Scheme 2. Thiazolidinethione 27 was converted
to the corresponding Sn(II) enolate and reacted with E,E-
5-(4-methoxyphenyl)penta-2,4-dienal to provide aldol
product 28 in 79% yield.20,21 The diastereomeric ratio in
1
this reaction was 95:5 (based on integration of the H
NMR signals due to the C2 methyl doublets), and the ab-
solute stereochemistry was assigned by analogy with the
many examples of this process reported by Nagao and
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LETTER
Lasonolide A
1337
was immediately reduced with zinc borohydride in tolu-
ene–diethyl ether at –78 °C.26 This provided a 4:1 mixture
of cyclization substrate 8 and its C2 epimer, contaminated
with some trienol derived from b-elimination of 34 fol-
lowed by reduction. Treatment of this mixture with phe-
nylselenenyl chloride gave tetrahydropyran 35 in 48%
overall yield from 31, along with a 19% yield of 39 (pre-
sumably derived from addition of phenylselenenyl chlo-
ride to 35 followed by solvolysis of an intermediate
benzylic chloride) as a minor product. The structure of 31
was initially established by NMR spectroscopy and ulti-
mately by correlation with known material (vide infra).
The structure of 39 was established by X-ray crystallo-
graphic analysis of diol 40, prepared in 89% yield by re-
duction of 39 with tri-n-butyltin hydride.27 The
stereochemical course of the cyclization of 8 to 35 (and
the tetrahydropyran portion of 39) can once again be ratio-
nalized by anti addition of the electrophile and incipient
tetrahydropyran oxygen across the double bond via a
chair-like transition state in which the C2 and C6 substitu-
ents occupy equatorial sites. This cyclization transition
state would require that the incipient C3 methyl and C4 hy-
droxyl groups occupy axial sites in the cyclization transi-
tion state. We note that although no other tetrahydropyran
stereoisomers were detected, the mass balance for the
conversion of 31 to 35 and 39 suggests that minor stereo-
isomers may have been produced.28
Acknowledgment
We thank the Graduate School at OSU for a fellowship to SP.
References
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Once again, although we imagine there may be a number
of ways in which 35 might be used in a synthesis of ent-
lasonolide A, we focused on correlation of this material
with compound ent-3, the enantiomer of the intermediate
used by the Lee group in their approach to 1. Thus, protec-
tion of the secondary hydroxyl group as a benzyl ether
(35 → 36 in 64% yield) followed by bromohydrin forma-
tion (NBS in aqueous DMSO) gave a mixture of 37 and
the Ca-Cb diastereomer in 86% yield.29 This mixture was
reduced with tri-n-butyltin hydride to provide a mixture of
38 and its Ca epimer in 95% yield.30 Oxidation of this mix-
ture with the Dess–Martin periodinane gave ketone 41 in
89% yield.31 Bayer–Villiger oxidation of 41 using m-
chloroperoxybenzoic acid, followed by ethanolysis of the
resulting aryl ester, gave tetrahydropyran ent-3 in 65%
overall yield.32 Tetrahydropyran ent-3 was spectroscopi-
cally identical (1H and 13C NMR) to material prepared by
the Lee.19
(10) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Epifano, F.;
Rosati, O. Synth. Commun. 1998, 28, 3057.
(11) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun.
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(15) For seminalstudies on PhSeCl-initiated cycloetherifications,
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(19) We thank Professor Lee for providing us with copies of 1H
and 13C NMR spectra of 2 and 3.
(20) (a) Lewis, N.; McKen, P. W.; Taylor, R. J. K. Synlett 1991,
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In summary, it has been shown that the cycloetherification
strategy outlined in Equation 1 can be used to prepare the
enantiomers of both the A-ring and B-ring intermediates
(2 and 3) in Lee’s synthesis of lasonolide A (1). The key
cycloetherifications proceed with excellent levels of dia-
stereoselectivity and the overall length of the syntheses of
ent-2 and ent-3 are similar to the Lee syntheses of the cor-
responding enantiomers. Nonetheless, the syntheses are
longer than desirable and improvements are needed be-
fore this chemistry will provide a practical route to la-
sonolide A (1) and derivatives thereof.33
(23) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1990, 31, 601.
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D. J. Hart et al.
LETTER
the exception of the benzyloxymethyl group (axially
(27) We thank Dr. Judith C. Gallucci for determining the
structure of 40 at the OSU Chemistry Department
Crystallographic Facility.
(28) During the course of this work we have examined
cyclizations of several structures related to 8 (replace C6
p-methoxystyryl group with phenyl, 2-furyl, styryl). In all
cases the structure corresponding to 35 was the major
product in 60–70% yield. In one case (styryl) a minor
diastereomer (5%) was detected in which all substituents
were equatorially disposed on the tetrahydropyran ring with
disposed).
(29) Dalton, D. R.; Dutta, V. P.; Jones, D. G. J. Am. Chem. Soc.
1968, 90, 5498.
(30) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima,
K.; Utimoto, K. Bull Chem. Soc. Jpn. 1989, 62, 143.
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(32) Ha, D. C.; Hart, D. J. J. Antibiotics 1987, 40, 309.
(33) Some of the reagents used in Schemes 1 and 2 are toxic (for
example PhSeCl). Appropriate care should be used in the
handling and disposal of these materials.
Synlett 2003, No. 9, 1334–1338 ISSN 1234-567-89 © Thieme Stuttgart · New York