Oxidative cleavage in the construction of complex molecules: Synthesis of the leucascandrolide A macrolactone

Article abstract of DOI:10.1002/anie.200702999

(Chemical Equation Presented) Oxidation leads to macrolactone: Oxidative carbon-carbon bond activation is a key step in the formal synthesis of leucascandrolide A, which is formed in one step from 1. Additional features are stereoselective BiBr₃

Full text of DOI:10.1002/anie.200702999

Communications
DOI: 10.1002/anie.200702999
Natural Products
Oxidative Cleavage in the Construction of Complex Molecules:
Synthesis of the Leucascandrolide A Macrolactone**
Hyung Hoon Jung, John R. Seiders, II, and Paul E. Floreancig*
Dedicated to Professor Frederick E. Ziegler on the occasion of his retirement
Leucascandrolide A (1) is a potent cyto-
toxic and antifungal macrolide that was
isolated by Pietra and co-workers from the
New Caledonian sponge Leucascandra cav-
eolata.[1] Subsequent efforts to isolate the
natural product were unsuccessful,[2] leading
to speculation that the actual source of 1 is
an as yet unidentified bacterial symbiont.
Based on its biological activity, inaccessi-
bility from natural sources, and ample
synthetic challenges, the construction of
leucascandrolide A has generated substan-
tial interest, resulting in several total and
formal syntheses.[3] Our interest in 1 arose
from studies in which we demonstrated that
2,6-cis-dialkyltetrahydropyran-4-ones, rele-
vant to the C3–C7 portion of 1, can be
prepared through efficient oxidative cleav-
age reactions of homobenzylic ethers.[4]
Herein we report the synthesis of leucas-
candrolide A, which is the first application
of our electron-transfer-initiated cyclization
(ETIC)[5] method for natural-product syn-
Scheme 1. Retrosynthetic analysis of leucascandrolide A (1). TBS=tert-butyldimethylsilyl,
OAc=acetate, PG=protecting group, Ar=p-methoxyphenyl.
thesis. In addition, the sequence described
herein has been designed to minimize the
use of protecting groups and reagent-based
stereoinduction, resulting in an efficient
approach with respect to linear and overall step counts.
Our target in this study (Scheme 1) was phosphonate 2,
which has been converted into 1 in one step by Leighton and
co-workers.[3a] The lactone can be crafted from 3 through a
sequence in which the introduction of the C17 allylic alcohol
group required caution, owing to the presence of the labile C5
phosphonoester. We envisioned the 2,6-cis-dialkyltetrahypro-
pyran structure as arising from the single-electron oxidation,
fragmentation, and cyclization of 4. The challenging ether
linkage between C3 and C7 can be prepared through
nucleophilic opening of acetal 5. Tetrahydropyran 6, which
can be accessed from alcohol 7, was selected as the precursor
to 5. Alcohol 7 can be prepared in high enantiomeric purity
through a reported[6] three-step sequence from 1,3-propane-
diol that utilizes a Brown crotylation reaction[7] to establish
relative and absolute stereochemical control.
We explored hydroformylation reactions in an effort to
access
a tetrahydropyran group in one step from 7
(Scheme 2). As we wanted to avoid protecting groups and
harsh reaction conditions, we employed Breit and co-workersꢀ
conditions[8] (step (a) in Scheme 2) for this transformation.
This remarkably simple procedure (H2 and CO can be
introduced individually through separate balloons, obviating
the need to purchase syngas) provided lactol 8 in 90% yield.
[*] H. H. Jung, J. R. Seiders, II, Prof. Dr. P. E. Floreancig
Department of Chemistry
University of Pittsburgh
Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-8611
[9]
Exposing 8 to allyl trimethylsilane and BiBr3 at room
temperature resulted in the direct formation of tetrahydro-
pyranyl alcohol 6 as a single stereoisomer in nearly quanti-
tative yield within 20 minutes. This reaction proceeded
through the instantaneous formation of an isolable bridged
bicyclic acetal, arising from the addition of the silyloxy group
into the intermediate C15 oxocarbenium ion, followed by a
E-mail: florean@pitt.edu
[**] We thank the National Institutes of Health (GM-62924) for
generous financial support of this work.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8464
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C9 in the major product was made using the literature
precedent[12] regarding outcomes of Lewis acid-mediated
additions into b-alkoxyketones. Higher diastereocontrol
(7.8:1) was observed when the solvent was changed from
CH2Cl2 to toluene, but the overall yield was lower (50%).
Selective syn-reduction with NaBH4 and Et2BOMe[13] gave
diol 11, which could be isolated in 76% yield as a single
stereoisomer. The C1–C3 fragment was incorporated by
acetalization[14] that proceeded through the formation of the
bis(trimethylsilyl) ether of 11 followed by the addition of
aldehyde 12[15] and TMSOTf[16] to yield 13. The C4–C6 subunit
was then incorporated by a Lewis acid-mediated acetal
opening[17] in the presence of allenyltributyltin, thereby
completing the construction of the requisite ether linkage
for the oxidative cyclization reaction. Regioselective forma-
tion of the C9 hydroxy group in this reaction results from
Lewis acid chelation between the C9 and C11 oxygen atoms
and from the sterically disfavored interaction with geminal
methyl groups on the electroauxiliary that arises from Lewis
acid coordination to the C7 oxygen atom. The synthesis of
cyclization precursor 14 was completed by C9 methyl ether
formation and ruthenium-mediated Markovnikov addition of
acetic acid across the alkyne.[18]
Scheme 2. Tetrahydropyran synthesis. a) H2, CO, [Rh(CO)2acac], 6-
diphenylphosphino-2-pyridone, THF, 1 atm, RT, 90% yield. b) Allyl
trimethylsilane, BiBr3, CH3CN, RT, 99% yield. TBS=tert-butyldimethyl-
silyl, acac=acetylacetonyl.
second ionization that allowed for allyl group incorporation.
These conditions promote direct nucleophilic substitutions of
lactols and avoid cryogenic conditions without sacrificing
efficiency or stereocontrol.
The electroauxiliary for the key ETIC reaction was
introduced (Scheme 3) through a sequence of alcohol oxida-
tion and BF3·OEt2-mediated Mukaiyama aldol addition[10] of
enolsilane 9[11] to form ketone 10 as an inseparable 4.5:1
mixture of diastereomers. The stereochemical assignment at
The key ETIC reaction progressed quite smoothly, with 15
being treated with ceric ammonium nitrate at room temper-
ature to form tetrahydropyranone 17 as a single stereoisomer
(Scheme 4). This reaction proceeded through oxidative
cleavage of the benzylic carbon–carbon bond to form
oxocarbenium ion 16, with the excellent diastereoselectivity
arising from the much-precedented[19] chair transition state
for endo-cyclizations of this type.
With the two tetrahydropyran rings in place, we turned
our attention to completing the synthesis of the macrocycle
(Scheme 5). To move closer to this objective we needed to
reduce the C5 ketone. Although both diastereomers of the C5
alcohol have been converted into the natural product,[3] we
opted to proceed through the axial alcohol. Thus 17 was
reduced with l-Selectride[20] to provide 18 in 76% yield along
with 8% of the equatorial alcohol. Rather than capping the
resulting alcohol with a protecting group we converted 18 into
phosphonoacetate 19 using (CF3CH2O)2P(O)CH2CO2H[21]
Scheme 3. ETIC substrate synthesis. a) Dess–Martin periodinane, pyri-
dine, CH2Cl2. b) 9, B F·OEt2, CH2Cl2, À788C, 78% yield (two steps),
3
d.r.=4.5:1. c) NaBH4, Et2BOMe, MeOH, THF, then NaOOH, 76%
yield. d) 1) TMSOTf, 2,6-lutidine, CH2Cl2, À788C. 2) 12, TMSOTf,
CH2Cl2, À78–458C, 87% yield. e) Allenyltributyltin, TiCl4/Ti(OiPr)4
(3:1), CH2Cl2, À788C, 89% yield. f) MeOTf, 2,6-di-tert-butylpyridine,
CH2Cl2, 87% yield. g) HOAc, [Ru(p-cymene)Cl]2, (2-furyl)3P, Na2CO3,
toluene, 72% yield. TBDPS=tert-butyldiphenylsilyl, TMS=trimethyl-
silyl, Tf=trifluoromethanesulfonyl.
Scheme 4. ETIC reaction. a) Ceric ammonium nitrate, 4-Š M.S.,
NaHCO3, 1,2-dichloroethane, CH3CN, 68%.
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using the Hoveyda–Grubbs catalyst[26] provided allylic alco-
hol 22 in 70% yield. Adding p-benzoquinone to this reaction
proved to be useful in suppressing ketone formation through
alkene isomerization.[27] At this stage allylic alcohol trans-
position was required prior to macrolide formation. While 22
and the product of its transposition are both secondary allylic
alcohols, we postulated that the desired transposed product
would be formed preferentially under equilibrating condi-
tions. This assertion was based on the capacity for the
transposed hydroxy group to engage in hydrogen bonding
with the tetrahydropyranyl ether and, in consideration of
Kozmin and co-workersꢀ report[3f] of the unexpected stability
of the leucascandrolide macrolactol, for its potential to add
into the pendent C1 carbonyl group. Thus we exposed 22 to
Re2O7 in Et2O, conditions shown by Lee and Hansen[28] to
promote suprafacial migration, thereby transposing the allylic
alcohol group and forming lactol 23 directly in 69% yield.
Notably, we observed that subjecting the C19-epimer of 22,
prepared through the cross metathesis of 20 with the
enantiomer of 21, to the transposition conditions provided
23 in 49% yield. This result suggests that epimerization can
occur during the transposition and that resolving 21 prior to
metathesis is not necessary. While the reason for the
epimerization has yet to be determined, we speculate that
the transposition is rapid and reversible, and that rearrange-
ment occasionally proceeds through a boat-like rather than a
chair-like transition state. Oxidizing 23 with PCC completed
the synthesis of leucascandrolide macrolactone 24. Since 24
has been converted in one step into leucascandrolide A by the
Leighton group, this completes a formal synthesis. Cleaving
the phosphonoacetate group (Na2CO3, MeOH) provided a C5
alcohol that is spectroscopically identical to material that was
derived from cleaving the ester side chain from 1,[1] thereby
confirming the structural assignment.
We have completed a concise formal synthesis of leucas-
candrolide A through a sequence in which our ETIC method
was employed for the stereoselective formation of a key
tetrahydropyran ring from an advanced intermediate, thereby
establishing the utility of the method in the context of
complex molecule construction. Additional noteworthy
advances include the minimization of protecting group
manipulations (only two steps in the longest linear sequence
were solely devoted to functional group protection or
deprotection), the use of BiBr3 in a mild and efficient lactol
functionalization, the extensive use of substrate-derived
stereocontrol, and the utilization of macrolactol formation
as a thermodynamic driving force for allylic alcohol trans-
position. The sequence proceeds in 17 linear steps from the
known alcohol 7 (20 steps from commercially available
material) and in 4.5% yield, making this route quite
competitive with the most efficient enantioselective routes
to leucascandrolide A.
Scheme 5. Completion of the synthesis. a) l-Selectride, THF, À908C,
76%. b) (CF3CH2O)2P(O)CH2CO2H, EDC, HOBt, CH2Cl2, 92%. c) HCl,
MeOH, 98%. d) Dess-Martin periodinane, CH2Cl2, 95%. e) 21, Hov-
eyda–Grubbs catalyst, 1,4-benzoquinone, CH2Cl2, reflux, 70%.
f) Re2O7, Et2O, 69%. g) PCC, CH2Cl2, 81%. EDC=1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride, HOBt=1-hydroxybenzotri-
azole, PCC=pyridinium trioxochlorochromate, R=OCH2CF3.
and EDC with the expectation that this group would
ultimately be used for the construction of the C5 side chain
through a Still–Gennari reaction.[22] The presence of the
electrophilic phosphonate group, however, required us to
complete the synthesis under very mild conditions. Silyl group
cleavage was achieved with hydrochloric acid in methanol,
with no phosphonate transesterification being observed.
Notably, attempts to conduct this reaction with fluoride
sources promoted the cleavage of one trifluoroethoxy group
from the phosphonate group. Oxidation of the resulting
alcohol with the Dess–Martin periodinane[23] yielded alde-
hyde 20. A cross-metathesis reaction[24] between 20 and 21[25]
Received: July 5, 2007
Revised: August 7, 2007
Published online: September 26, 2007
Keywords: leucascandrolide A · natural products · radical ions ·
.
rearrangement · stereoselectivity
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