Total synthesis of peloruside a through kinetic lactonization and relay ring-closing metathesis cyclization reactions

Article abstract of DOI:10.1002/anie.201002293

The other side: A convergent total synthesis of peloruside A (1) is described. The key strategic features are a diastereoselective lactonization to generate a C5-C9 valerolactone from the C2-symmetric ketone 3, and a relay ring-closing metathesis reaction to produce a dehydrovalerolactone 2. A new isomer of 1, the valerolactone isopeloruside A (iso-1), was identified. MOM=methoxymethyl.

Full text of DOI:10.1002/anie.201002293

Angewandte
Chemie
DOI: 10.1002/anie.201002293
Natural Products
Total Synthesis of Peloruside A through Kinetic Lactonization and
Relay Ring-Closing Metathesis Cyclization Reactions**
Thomas R. Hoye,* Junha Jeon, Lucas C. Kopel, Troy D. Ryba, Manomi A. Tennakoon, and
Yini Wang
The highly cytotoxic marine macrolide (+)-peloruside A (1)
was isolated from the New Zealand sponge Mycale hentscheli
by Northcote and co-workers.[1] It showed LD50 values
ranging from 6–18 nm toward H441, SH-SY5Y, and P388
cancer cell lines,[2] and has been additionally explored from a
preclinical perspective. Like paclitaxel (Taxol), peloruside A
is a microtubule stabilizer that arrests cells in the G2M phase
of the cell cycle, but it targets a different tubulin binding site
relative to paclitaxel.[3] As a consequence peloruside A (1) is a
candidate for use against paclitaxel-resistant cell lines.[4] The
therapeutic potential, low natural abundance (3 mg/170 g wet
sponge), and architectural complexity have generated signifi-
cant interest in the development of chemical syntheses of 1.
To date, four total syntheses of peloruside A have been
reported by the research groups of De Brabander, Taylor,
Ghosh, and Evans,[5–8] and related synthetic studies have been
described.[9–11]
Scheme 1. Retrosynthesis outline for accessing peloruside A (1).
À
À
a) Aldol union of C11 C12 (or C12 C13). b) RRCM. c) Desymmetriz-
ing kinetic resolution. BPS=tert-butyldiphenylsilyl, MOM=methoxy-
methyl, PMB=para-methoxybenzyl, TBS=tert-butyldimethylsilyl.
Our interest in peloruside A (1) as a target was greatly
heightened when we identified a plan that seemed ideally
matched with strategies and technologies developed earlier in
our group. In particular, it was attractive to apply a
diastereoselective kinetic lactonization of a pseudosymmetric
azelaic acid derivative[12] and to capitalize on the versatility of
relay ring-closing metathesis (RRCM)[13] reactions.
As summarized in Scheme 1 our plan for the synthesis was
to effect a late-stage aldol coupling (path a) between the
aldehyde acceptor 2 and methyl ketone donor 3 (or the
complementary ketone/aldehyde pair 2’/3’). We planned to
install the Z-trisubstituted and doubly allylically branched
ester group, would selectively provide a valerolactone/mono-
ester (i.e., 11 in Scheme 2).[16] Terminus differentiation and
À
C9 C10 bond formation would then provide access to 2
(or 2’).
The synthesis of fragment 2 is presented in Scheme 2. The
main features are: 1) synthesis of the C2-symmetric keto-
diester 4, 2) diastereoselective conversion, by desymmetrizing
kinetic lactonization, of the derived alcohol 9 into the
d-valerolactone 11, and 3) chemoselective elaboration
(including prenylation) of the lactone versus ester carbonyl
groups (C9 versus C1) in 11 to give fragment 2.
The tetrol 7 was prepared from the ethylene ketal of
dimethyl acetone dicarboxylate (6)[17] by utilizing a one-pot
DIBAL-H reduction of both esters to give the intermediate
1,5-dialdehyde, and subsequent in situ double Horner–Wads-
D
16,17-alkene in 3 (or its aldehyde analogue 3’) through RRCM
(path b) of the silaketal[14] 5a or ester[15] 5b (peloruside A
skeleton numbering is used throughout). We envisioned the
main aldehyde fragment 2 (or its ketone analogue 2’) to arise
from the C2-symmetric azelaic ester precursor 4 (path c). As
detailed below, reduction of the C5 ketone in 4 from either of
its homotopic faces would give an alcohol that, through
engagement of its pro-S rather than pro-R diastereotopic
worth–Emmons
homologation
with
(EtO)2P(O)CH-
(Na)CO2 Hex.[18] The double Sharpless asymmetric dihydrox-
ylation (SAD)[19] of the bis(methyl) ester analogue was
initially studied,[16] but this transformation was plagued by
incomplete conversion into the bis(methyl)ester variant of
tetrol 7. No-D (no deuterated solvent) 1H NMR analysis[20] of
the aqueous component of the biphasic mixture indicated the
accumulation of the intermediate alkenediol. The polar
nature of this half-oxidized intermediate likely led to its
undesired partitioning into the aqueous layer and, conse-
quently, away from the active hydroxylation species. The
substantial water solubility of the desired tetrol was an
additional complication. This prompted our selection and use
n
[*] Prof. T. R. Hoye, Dr. J. Jeon, Dr. L. C. Kopel, Dr. T. D. Ryba,
Dr. M. A. Tennakoon, Y. Wang
Department of Chemistry
University of Minnesota
Minneapolis, MN 55455 (USA)
E-mail: hoye@umn.edu
[**] This investigation was supported by grants awarded by the DHHS
(GM65597 and CA76497). We thank Mr. Joseph B. Katzenmeyer for
assistance with the MS/MS measurement.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002293.
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with methanol (Oteraꢀs catalyst) smoothly gave
4
(see Scheme 1). The sequence from 6 to 4 proceeded in
over 30% yield.
Although many reagents sufficed to chemoselectively
reduce the C5 ketone in 4, most were complicated by
premature lactonization of the resulting hydroxy bis(ester)
9, with not only modest but also irreproducible levels of
diastereocontrol. Hence, neutral conditions for this reduction
that also minimized handling of 9 were sought. Use of
hydrogen gas over Raney nickel provided a convenient
solution; simple filtration and solvent removal provided the
C1-symmetric alcohol 9 (91%), which contains the new
nonstereogenic but chirotopic[24] C5-carbinol center. The
key diastereoselective cyclization of this substrate[16] pro-
ceeded with preferential engagement of the pro-S ester group
at C9 to give lactone 11 (98%, d.r. 12:1). Use of TMG
(2.0 equiv) to promote this lactonization gave reproducibly
high levels of diastereoselectivity. Interestingly, a labile
adduct of TMG with the product 11, perhaps involving a
tetrahedral intermediate in which the lactone carbonyl group
remained engaged with TMG, was generated. We found it
best to cleave this adduct by treatment with anhydrous
trifluoroacetic acid (NMR analysis) prior to aqueous workup.
The sense of the kinetic diastereocontrol observed in this
lactonization was anticipated[12] on the basis of conforma-
tional analysis; the equilibrium concentration of the reactive
conformer 10a, which could engage the C1 ester and lead to
the minor (and undesired) C5 epimer of 11, should be lower
than that of the alternative reactive conformer 10b, a
necessary intermediate en route to 11. Analogous consider-
ations equally apply to the pair of tetrahedral intermediates
derived from 10a and 10b, should it be the case that the rate-
limiting step in the lactonization is not the initial closure
implied by 10. A distinguishing feature of this symmetry
enabled approach is the rapidity and efficiency with which the
C1–C9 portion of the peloruside skeleton was established.
Chemoselective reduction of the lactone rather than ester
functional group in 11 was achieved with l-Selectride[25] to
provide a lactol, which was treated with prenyl bromide/
indium.[26] This sequence installed the gem-dimethylated
C10 moiety, while simultaneously inducing relactonization,
Scheme 2. Synthesis of main fragment 2 via the key diastereoselective
lactonization of pseudosymmetric carbinol 9. Reagents and condi-
tions: a) 1. DIBAL-H, Et2O, À788C; then (EtO)2P(O)CH(Na)CO2nHex,
80%; 2. SAD, 08C, 88%; b) 1. 30 mol% HI, THF, 08C, 83%;
2. Me3OBF4, proton sponge, 08C to RT, 84%; c) 1. 1,2-ethanedithiol,
BF3·OEt2, 08C; 2. MOMCl, iPr2NEt, CH2Cl2, RT, 90% (2 steps); 3. I2,
NaHCO3, acetone, H2O, 08C, 91%; 4. Otera’s catalyst,[22] MeOH,
toluene, 908C, 77%; d) Raney nickel, H2, EtOH, RT, 91%; e) TMG,
C6H6, RT; then TFA, 98% (d.r. 12:1). f) 1. l-Selectride, THF, À788C,
87%; 2. prenyl bromide, indium powder, DMF, 558C, 80%; 3. AlCl3,
NaI, CH3CN, CH2Cl2, 08C, 92%; 4. (p-MeO)-PhCH(OMe)2, CSA,
CH2Cl2, M. S. (4 ꢀ), 87%; 5. MOMCl, iPr2NEt, CH2Cl2, RT, 99%;
g) 1. LAH, THF, 08C, 96%; 2. BPSCl, ImH, DMAP, DMF, RT, 92%;
3. DIBAL-H, CH2Cl2, À788C, 95%; 4. DMP, NaHCO3, CH2Cl2, RT;
5. Zn(BH4)2,[23] CH2Cl2, 08C (d.r. 3:1), 62% (2 steps); 6. TBSOTf, 2,6-
lutidine, CH2Cl2, RT, 89%; h) 1. HF·pyridine, THF, pyridine, RT, 91%;
2. DMP, NaHCO3, CH2Cl2, RT; 3. NaClO2, NaH2PO4, tBuOH, H2O,
now of the C5 OH with the C1 ester.[25] Use of the prenyl unit
=
Me2C CHMe, RT; 4. CH2N2, RT, 87%, (3 steps); 5. O3, pyridine,
À
CH2Cl2, MeOH, À788C, 75%. CSA=camphorsulfonic acid, DMAP=4-
dimethylamino-pyridine, DMF=dimethylformamide, DMP=Dess–
Martin periodinane, d.r.=diastereomeric ratio, ImH=imidazole,
LAH=lithium aluminum hydride, M.S.=molecular sieves, OTf=tri-
flate, SAD=Sharpless asymmetric dihydroxylation, TFA=trifluoroace-
tic acid, THF=tetrahydrofuran, TMG=tetramethylguanidine.
was designed to permit potential access to either the aldehyde
2 or methyl ketone 2’, but as things later developed,
implementation in the former role proved more valuable.
Removal of the two MOM groups (AlCl3, NaI), PMP acetal
À
formation, and reprotection of the C2 OH as a MOM ether
gave 12 as a single epimer at C9 (assigned to be of S
configuration,[27] consistent with aMOM-chelation controlled
addition). A series of functional/protecting group manipula-
tions (see g); Scheme 2) served to carry 12 efficiently to 13,
the precursor to fragment 2. Key among these was the
oxidation/reduction of the C8 carbinol, which had just been
revealed by a highly regioselective reductive cleavage by
DIBAL-H of the PMP acetal, to effect the required inversion
of configuration at C8. Finally, but again efficiently, the
C1 methyl ester was reinstated and the C11 aldehyde gen-
erated by ozonolysis (see h; Scheme 2) to complete the
synthesis of 2.
of the less polar and more well-behaved bis(n-hexyl)ester
series, which allowed isolation of 7 in 88% yield. Exposure to
a catalytic amount of aqueous hydriodic acid then promoted
ketal metathesis by engagement (and protection) of the C2
and C8 hydroxy groups to give a spirocyclic ketal as a single
diastereomer. Installation of the methyl ethers found at C3
and C7 in peloruside A (1) was achieved with Meerweinꢀs salt
to provide 8. Transketalization of 8 with ethanedithiol
(BF3·OEt2),[21] MOM-ether protection of the C2/C8 diol,
dithiolane removal (I2, aq NaHCO3), and transesterification
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To explore a metathesis-based synthesis of the hindered
Z alkene in 3 (Scheme 3), we first prepared and examined the
RCM reaction of the simple diene[14] 22a (Scheme 3), which
was an epimeric mixture at C15. This diene proved to be a
poor RCM substrate (e.g., < 20% yield of 16 using 45 mol%
of G2).[28] We turned to the RRCM substrate 5a,[29] which was
made by sequential loading of the alcohols 14[13] and 15 onto
Ph2SiCl2. RRCM proceeded to give 16 in 92% yield. For the
preparation of 5a as essentially one diastereomer, enantio-
merically enriched b-hydroxynitrile 15 was accessed by
addition of lithioacetonitrile to the enal derived from allylic
oxidation (SeO2) of (R)-citronellene, and subsequent enzy-
matic (kinetic) resolution of the resulting C15-epimeric
carbinols (Novozyme 435).[13,30] An added advantage of
adopting the RRCM strategy here was that the two epimeric
carbinols (15 and C15-epi-15) were easily discriminated by the
lipase, thereby allowing efficient resolution; the alternative
substrate 23, the precursor to 22a, has two nearly isosteric
groups and was a poor substrate for lipase resolution.
A complementary approach involving the ester 5b and its
RRCM product, the lactone 20, was also studied. Preparation
of 5b is inherently easier than that of the silaketal 5a, since it
involves simple cross-coupling of two functional groups with
complementary reactivity, namely the alcohol 15 with the acid
19. Moreover, a sample of nonracemic 19 proved to be easier
to access than one of 14. The terminal alkene in the
2-propenylated compound 18[31] was efficiently isomerized
to the more stable, internal, 1-propenyl analogue using RhCl3/
EtOH;[32,33] there was no evidence of erosion of the high d.r.
value, which implies that the branched a carbon effectively
impedes additional isomerization by b-hydride elimination of
the Ca-methine hydrogen atom. This sequential allylation/2-
to 1-propenyl isomerization/ethylene cross-metathesis degra-
dation[34] resulted in net vinylation of, in this instance, an
Evans acyloxazolidinone auxiliary (i.e., 24). We recommend
consideration of this strategy in instances when ethenylation
of carbanionic species is needed. Hydrolysis of the oxazoli-
dinone 18 gave the acid 19, which upon DCC activation was
coupled with 15 to provide 5b. This ester smoothly underwent
RRCM to give lactone 20 in 70% yield.
Efficient elaboration of either 16 or 20 into the differ-
entially protected diol derivative 17 was straightforward with
either desilylation (of 16) or reduction (of 20) and sequential
TBS and PMB installations on the promary and secondary
hydroxy groups, respectively. The choice of sodium borohy-
dride in acetic acid as the reagent for the reduction of 20 was
dictated by its base lability, which otherwise led to epimeric
mixtures of the reduced diol product. Base instability was an
even bigger obstacle in the final conversion of the nitrile in 17
into the methyl ketone in fragment 3. A solution emerged in
the form of a modified Blaise reaction, wherein the reagent
formed in situ from BrCH2CO2allyl/Zn0/Cp2TiCl2
con-
[35]
verted the nitrile into an intermediate b aminoenoate, the
hydrolysis of which was carefully monitored at pH 3
(ca. 2 days) to afford the b-ketoester 21. Attempts to effect
hydrolysis or dealkylation and decarboxylation of the methyl
ester analogue of 21 into 3 were compromised by competitive
b elimination of PMB-OH. We solved this complication by
use of the allyl ester 21, which could be smoothly decar-
balkoxylated with [Pd(PPh3)4] (HCO2H, Et3N).[36] The non-
basic conditions associated with this conversion of nitrile into
methyl ketone render this strategy applicable to other base-
sensitive nitrile substrates.
The final stage of the synthesis is presented in Scheme 4.
The main features are 1) the Paterson boron aldol coupling[37]
of fragments 2 and 3, 2) the regioselective macrocyclization of
the diol acid 28, and 3) the removal of protecting groups from
the penultimate intermediate 30, including our observation of
a by-product that we name here isopeloruside A (iso-1).
A number of model experiments designed to establish the
feasibility of either the 2’/3’ or 3/2 aldol donor/acceptor
Scheme 3. Synthesis of fragment 3 through the relay ring-closing
metathesis reactions of substrates 5a and 5b. Reagents and condi-
tions: a) 1. 15, Ph2SiCl2, pyridine, RT; 2. 14, pyridine, 41%; b) G2,
toluene, N2, 658C, 92%; c) 1. TBAF, THF, RT, 93%; 2. TBSCl, Et3N,
DMF, RT, 84%; 3. Cl3CC(=NH)OPMB, CSA, CH2Cl2, RT, 76%;
d) 1. RhCl3·3H2O, EtOH/H2O (10:1), 808C, 98% (E/Z=15:1);
2. LiOH, H2O2, THF/H2O (3:1), 08C, 99%; e) 15, DCC, DMAP, CH2Cl2,
08C to RT, 82%; f) G2, CH2Cl2, 458C, 70%; g) 1. NaBH4, AcOH,
EtOH, 08C to RT, 82%; 2. TBSCl, Et3N, DMAP, CH2Cl2, RT, 99%;
3. Cl3CC(=NH)OPMB, CSA, CH2Cl2, RT, 77%; h) 1. Zn0, Cp2TiCl2, allyl
2-bromoacetate, THF, 608C; 2. pH 3 buffer, iPrOH/H2O/THF (4:1:2),
=
RT; i) [Pd(PPh3)4], HCO2H, Et3N, THF, RT, 61% (3 steps). j) CH2 CH2
(15 psi), G2, PhH, 658C, quantitative. Cy=cyclohexyl, G2=second-
generation Grubbs initiator, [Ru=CHPh(Cl)2(PCy3)(H2IMes)],
Ru*=[Ru(Cl)2(H2IMes)Ln], IMes=N,N’-bis(mesityl)imidazol-2-ylidene,
TBAF=tetrabutylammonium fluoride, DCC=dicyclohexylcarbodiimide.
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Communications
Conversion of the methyl ester in 27 into the acid 28, in
preparation for the required macrolactonization, was very
slow with LiOH (aq MeOH) and was complicated by partial
epimerization at C2 when KOSiMe3 (THF) was employed.
These issues were solved by use of the more reactive and less
basic LiOOH. Yamaguchi cyclization of the diol acid
substrate 28 was uneventful; the free C9-hydoxy group gave
no evidence of interference (lactonization substrates in all
previous peloruside A syntheses and studies have had the
ketone oxidation state at C9). Oxidation of 29 into the C9-
ketone 30 was smoothly effected with the Dess–Martin
periodinane.
The silyl ether and MOM ether protecting groups were
sequentially removed by treatment first with HF·pyridine in
THF, buffered by additional pyridine, and second with 4n
aqueous HCl in THF (room temperature). The first stage
(removal of three silyl groups) was monitored by LC/MS
À
analysis. The primary C24 OH was generated quickly at
room temperature, the C5 tert-butyldiphenylsilyl ether
(OBPS) was cleaved in about a day at 608C, and the hindered
À
C8 OTBS required an additional day to completely release
À
the C5/C8/C24 triol (having the C5 OH engaged to C9 as a
hemiketal). Even though it required strongly acidic condi-
tions (aq HCl, RT), the removal of the final MOM group was
planned with confidence, given the precedent from the earlier
total syntheses. Without additional purification, the C5/C8/
C24 triol was treated with aq HCl at room temperature for
3 hours to deliver (+)-peloruside A (1) in 49% overall yield
from 30 (over 2 steps). We also observed and isolated (by
careful chromatography on SiO2, MeOH/CH2Cl2 = 5:95) a
minor (5%) and slightly more polar by-product formed
during this experiment. We deduced its structure as that of the
valerolactone derivative iso-1 based on 1H NMR and ESI MS/
MS analyses. The masses of fragments observed from the
latter (and indicated on the structure of iso-1 in Scheme 4)
were informative in suggesting the absence of a macrolactone
in this new isomeric substance. In particular, the fragmenta-
Scheme 4. Synthesis of peloruside A (1) by aldol coupling of fragments
2 and 3, macrolactonization of seco-acid 28, and deprotection.
Reagents and conditions: a) cHex2BCl, Et3N, 3, Et2O, À788C to
À408C; then 2, Et2O, À788C to À208C, 64% (along with 34% of
recovered 3); b) NMe4BH(OAc)3, AcOH/MeCN (1:1), À308C, 95%
(d.r. 95:5); c) 1. Me3OBF4, 2,6-di-tBu-pyridine, CH2Cl2, 08C to RT, 82%
(after two cycles); 2. MOMCl, iPr2NEt, CH2Cl2, 08C to RT, 98%;
3. DDQ, CH2Cl2/pH 7 buffer (1:1), 08C to RT, 94% (after two cycles);
d) LiOH, H2O2, THF/MeOH/H2O (3:1.5:1), 08C to RT, ca. 100%;
e) 2,4,6-trichlorobenzoyl chloride, iPr2NEt, toluene, 08C to RT; DMAP,
PhCH3, RT, 54%; f) DMP, NaHCO3, CH2Cl2, 08C to RT, 83%;
g) 1. HF·py, THF, py, RT to 608C; 2. HCl (4n), THF, RT; 49% 1 and
5% iso-1 (2 steps). py=pyridine.
À
tion of the C10 C11 bond through a retro-aldol reaction was
evidenced by the complementary pair of sodiated ions at
À
m/z 327 and 267 and additional cleavage of the C14 C15
bond in the latter gave the ion observed at m/z of 125.
1
Additionally, H NMR data of iso-1 bore strong similarities
with the earlier described valerolactone 12. Isopeloruside A
(iso-1) presumably arose from intramolecular translactoniza-
tion within 1 by the C5-hydroxy group in the minor [and
unobserved (1H NMR)] open form of the C9 hemiketal to the
C1-carbonyl group.
pairing were carried out.[38] These eventually guided us to the
use of the dicyclohexylboron enolate derived from ketone 3,
which added to the aldehyde 2 (1.0 equiv, À78 to À208C) to
À
form the C11 C12 bond and produce the ketoalcohol 25
(64%) with essentially full control of the configuration at
C11. Presumably, the 1,5-stereoinduction keyed by the
b(C15) stereocenter in the ketone donor 3[39] is enhanced by
(i.e., matched with) that from the b(C9) stereocenter of the
a,a-gem-dimethylated aldehyde acceptor 2[40] to impart
essentially perfect diastereoselection during this powerful
cross-coupling reaction.[41] Reduction of the C13 ketone with
Me4NBH(OAc)3 proceeded to give the 1,3-anti-diol 26
(d.r. 95:5). Methylation with Meerweinꢀs salt proceeded
with near perfect regioselectivity. Installation of a MOM
ether at C11 and removal of both PMB ethers at C9 and C15
proceeded smoothly to complete the preparation of 27.
In conclusion this total synthesis of peloruside A (1)
capitalizes on the kinetic lactonization reaction of the
pseudosymmetric azelaic acid derivative 9 (to 11, Scheme 2)
and a relay ring-closing metathesis reaction to access the
trisubstituted D16.17-alkene subunit (5b to 20, Scheme 3).
Modified Blaise and net enolate ethenylation sequences are
also noteworthy. Formation of the isomeric valerolactone
iso-1 during final HCl-catalyzed removal of the MOM ethers
at C2 and C11 was observed for the first time.
Received: April 18, 2010
Published online: July 19, 2010
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