Catalytic asymmetric aldol equivalents in the enantioselective synthesis of the apoptolidinc aglycone

Article abstract of DOI:10.1002/anie.201004925

Aldol replacement: Catalytic asymmetric ketenealdehyde cycloadditions provide surrogates for traditional aldol additions in an enantioselective synthesis of apoptolidinoneC, the aglycone of the potent apoptosis regulator apoptolidinC. Eight of apoptolidin

Full text of DOI:10.1002/anie.201004925

Communications
DOI: 10.1002/anie.201004925
Catalytic Asymmetric Synthesis
Catalytic Asymmetric Aldol Equivalents in the Enantioselective
Synthesis of the Apoptolidin C Aglycone**
Thomas R. Vargo, James S. Hale, and Scott G. Nelson*
Apoptolidins A–E are a family of macrolide natural products
that have attracted considerable attention as highly selective
apoptosis regulators.[1] The critical need for achieving greater
selectivity in cancer chemotherapeutics has stimulated efforts
to elucidate the mechanistic and structural basis for the
apoptolidinꢀs unique pharmacological profile. These efforts
include several total syntheses of apoptolidin A, each of
which has provided invaluable insights into strategies for
chemically modifying the natural product for expanded
pharmacological profiling.[2] Similar considerations inspired
our interest in developing an enantioselective synthesis of the
apoptolidins exploring the capacity of catalytic asymmetric
aldol reaction surrogates to facilitate the synthesis of these
natural products. Toward this goal, we describe herein an
enantioselective synthesis of apoptolidinone C (1), the apop-
tionalization sequence observed in biosynthetic polyketide
assembly.
A synthesis of apoptolidinone C (1) emerges from the
À
preceding analysis by disconnecting 1 across the C1 O and
À
C11 C12 bonds to reveal the mixed acetate/propionate-
derived C12–C28 fragment 2 and the extensively dehydrated
polypropionate C1–C11 fragment 3 (Scheme 1). The syn-
À
tolidin C aglycone, wherein catalytic asymmetric C C bond
constructions provide the conduit to all ten of the requisite
stereogenic centers.
Their utility in assembling acetate- or propionate-derived
polyketide architecture is among the defining characteristics
of modern aldol-based reaction technologies. There exists an
array of aldol or aldol equivalents utilizing stoichiometric
chiral controllers that provide exceptionally reliable and
predictable methods for constructing complex polyacetate
and polypropionate arrays.[3] For our purposes, the apoptoli-
din C aglycone provided a platform for evaluating whether
similar levels of operational efficiency and expediency could
be achieved in similar synthesis endeavors wherein stereo-
control would derive exclusively from catalyst-based substoi-
chiometric chiral controllers. Specifically, catalytic asymmet-
ric acyl halide–aldehyde cyclocondensation (AAC) reactions
provide highly stereoselective acetate or propionate aldol
equivalents using AlIII-based Lewis acid or cinchona alkaloid
Lewis base catalysts, respectively.[4] Complex polyketide
assemblage predicated on the AAC methodology follows a
Scheme 1. Catalytic asymmetric synthesis of apoptolidinone C (1).
À
reiterative pattern of catalyst controlled C C bond construc-
tion followed by b-lactone refunctionalization to the b-alkoxy
aldehyde required for continued chain homologation in a
sequence reminiscent of the iterative homologation–refunc-
thesis of lower fragment 2 highlights the iterative assembly of
stereodefined polyketide units enabled by the AAC method-
ology. Thus, AlIII-triamine (4)-catalyzed cyclocondensation of
acetyl bromide with methoxyacetaldehyde provided b-lac-
tone 5 as an acetate aldol equivalent (91%, ꢀ 95% ee)
(Scheme 2).[4] Converting lactone 5 to aldehyde 6 required for
continued chain elongation involved amine-mediated ring
opening (MeO(Me)NH, Me2AlCl), protection of the incipi-
ent alcohol (TBSOTf, 2,6-lutidine), and amide reduction
(iBu2AlH, THF) (94% over three steps).[5] Further homo-
[*] T. R. Vargo, J. S. Hale, Prof. S. G. Nelson
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-8611
E-mail: sgnelson@pitt.edu
[**] Generous support from the National Institutes of Health (NIGMS
R01 GM063151) is gratefully acknowledged.
logation of
6 proceeded by O-trimethylsilylquinidine
(TMSQd)-catalyzed cyclocondensation with propionyl chlo-
ride to establish the C24,C25 syn propionate aldol relation-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004925.
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of 5-heptynal (11)[6] with acetyl bromide provided the
enantioenriched b-lactone 12 incorporating C17 carbinol
stereocenter (75%, ꢀ 95% ee). Amine-mediated lactone
ring opening was followed by installation of the C17 p-
methoxybenzyl ether; ensuing amide reduction provided b-
alkoxy aldehyde 13 representing C12–C17 of the algycone
(58% over three steps). Alkaloid catalysis provided the
conduit to the C7–C9 propionate relationship through
TMSQn-catalyzed cyclocondensation of 3-trimethylsilylpro-
pynal (14) with propionyl chloride to generate b-lactone 15
with near perfect absolute and relative stereocontrol. In this
instance, two-step thiolate-mediated conversion of lactone 15
to the corresponding b-silyloxy aldehyde 16 (10 mol%
KHMDS, EtSH; TBSOTf then iBu2AlH) (76% for two
steps) revealed the AAC-derived b-lactone as the requisite
syn propionate aldol equivalent.
Scheme 2. Iterative catalyzed aldol additions: a) 10 mol% 4, MeCOBr,
iPr2NEt, À608C. b) Me2AlCl, (MeO)MeNH2Cl. c) TBSOTf, 2,6-lutidine,
À608C. d) iBu2AlH, THF, À788C. e) 10 mol% TMSQd, EtCOCl, LiClO4,
iPr2NEt, À788C. f) Et3SiOTf, 2,6-lutidine, À608C. g) 10 mol% TMSQn,
EtCOCl, LiI, iPr2NEt, À788C. h) MeMgBr, THF, 08C. TBS=tert-butyl
dimethylsilyl, TMSQd=O-trimethylsilylquinidine, TMSQn=O-trime-
thylsilylquinine.
Assembling the lower C12–C28 fragment 2 was predi-
cated on the aldol coupling of ketone 10 and aldehyde 13
proceeding to correctly establish the, as yet, unaddressed C17
stereocenter (Scheme 4). To this end, the kinetic enol silane
ship in providing b-lactone 7 (78%, > 95% de). The last aldol
iteration was accomplished by Weinreb amide-mediated
refunctionalization of 7 to aldehyde 8 (79% for three steps)
and ensuing propionyl chloride AAC homologation, this time
using O-trimethylsilyquinine (TMSQn) as catalyst, to provide
the syn,anti,syn b-lactone 9 as a single stereoisomer (77%,
> 95% de). The C20–C28 fragment was completed by
converting b-lactone 9 to the methyl ketone 10 using the
same amine-mediated b-lactone refunctionaliztion proce-
dure, substituting MeMgBr addition to the intervening
amide for the typical terminal reduction step (71% over
three steps).[5]
Catalytic asymmetric AAC reactions similarly served as
aldol surrogates in establishing the isolated C17–C19 acetate
and C7–C9 propionte aldol relationships embedded in the
aglycone (Scheme 3). The AlIII-catalyzed cyclocondensation
Scheme 4. Synthesis of lower fragment 2: a) NaHMDS, THF; TMSCl,
2,6-lutidine. b) 13, BF3·OEt2 (1 equiv), CH2Cl2, À788C. c) 1. TFA, 1:1
MeOH:CH2Cl2; 2. TESOTf, 2,6-lutidine, À558C. d) DDQ, 2:1
CH2Cl2:pH 7 phosphate buffer. e) Me3OBF4, proton sponge, CH2Cl2.
f) [Cp2ZrHCl], 2,6-lutidine, THF then I2. Cp=cyclopentadienyl,
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TFA=trifluoroacetic
acid.
17 derived from ketone 10 participated in highly 1,3-anti
selective Mukaiyama aldol addition to aldehyde 13
(BF3·OEt2, CH2Cl2, À788C) affording b-hydroxy ketone 18
as a single diastereomer (71%);[7] diastereoselection in this
aldol coupling is consistent with a matched pairing of
aldehyde and enolate facial biases according to the transi-
tion-state model 19.[8] Reacting 18 with acidic methanol
cleaved the C23 and C25 triethylsilyl ethers and elicited
concomitant hemiketal formation to generate pyran 20 as a
single b-anomer. Appropriately configuring both the tempo-
rary and permanent ether functionalities required for advanc-
Scheme 3. Catalytic asymmetric acetate and propionate aldols: a) 10
mol% ent-4, MeCOBr, iPr2NEt, À608C. b) Me2AlCl, (MeO)MeNH2Cl.
c) PMBOC(NH)CCl3, 15 mol% BF3·Et2O, CH2Cl2. d) iBu2AlH, THF,
À788C. e) 10 mol% TMSQd, EtCOCl, MgCl2, iPr2NEt, À788C. f) 10
mol% KHMDS, EtSH, THF then TBSOTf, 2,6-lutidine. PMB=p-
methoxybenzyl, KHMDS=potassium hexamethyldisilazide.
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Communications
ing the synthesis was accomplished by installing the C19 and
stannane 3 provided the desired E,E-diene 27 as the major
constituent of a 12:1 mixture of C10–C11 olefin isomers (10
mol% [PdCl2(MeCN)2], Ph2PO2NnBu4, DMF) (75%). Suc-
cess in this fragment coupling was critically dependent on
including tetrabutylammonium diphenylphosphinate (28) as a
scavenger for tin-derived by-products;[15] attempted Stille
couplings excluding 28 yielded extensive olefin isomeriza-
tion.[16] Saponification of the C1 carboxylate ester (LiOH, aq
THF/MeOH) was accompanied by partial, non-selective TES
ether cleavage, that produced a mixture of the expected
carboxylic acid, the regioisomeric mono TES ethers 29a/b as
well as the carboxylic acid triol 30 (78% of mixture). Reacting
this mixture with TFA completed removal of the TES ethers
to afford the carboxylic acid triol 30 (61% yield). Ensuing
chemoselective macrolactonization of triol 30 was accom-
plished using modified Yamaguchi conditions to afford the
protected aglycone 31 (57%) along with minor quantities
( ꢁ 8%) of the regioisomeric macrolactone.[17] Utilizing
Koertꢀs conditions for simultaneous ketal hydrolysis and
silyl ether removal (H2SiF6, aq CH3CN) successfully con-
verted 31 to apoptolidinone C (1).[2d]
C23 triethylsilyl ethers (TESOTf, 2,6-lutidine), removing the
C17 p-methoxybenzyl ether and methylating the resulting
alcohol (DDQ; Me3OBF4, proton sponge) to afford 21 (85%
from 18). Regioselective alkyne hydrozirconation and iodi-
À
nation of the resulting Zr C bond ([Cp2ZrHCl], 2,6-lutidine;
I2) constituted the final steps in completing the lower major
[9]
À
À
fragment 2 (72%, C12 I (2):C13 I (2’) = 18:1).
Synthesis of the C1–C11 fragment 1 representing the
dehydrated polypropionate region of apoptolidinone C
employed aldehyde 16 as a platform for constructing the
conjugated trienone array. Thus, aldehyde 16 was reacted with
CBr4/PPh3 to provide alkylidene dibromide 22 (80%)
(Scheme 5). Engaging (E,E)-5-iodo-2,4-dimethylpenta-2,4-
0
dienoate (23)[10] in Pd -catalyzed metathesis of the C I bond
À
with bis(pinacolborane) provided the alkenyl boronic ester 24
required for union with 22.[11] In the event, dibromide 22 and
boronic ester 24 were engaged in chemoselective Suzuki cross
coupling (10 mol% [Pd(PPh3)4], TlOEt) to afford the all E
trienoate 25 as a single olefin isomer (66%).[12] The less
À
reactive C Br s-bond remaining from the Suzuki reaction
was next exploited in the Negishi cross coupling with Me2Zn
(7 mol% [Pd(PtBu3)2], THF) to complete construction of the
three conjugated trisubstituted olefins in providing 26 (90%,
EC6-C7:ZC6-C7 = 6.6:1).[13] Finally, removing the terminal trime-
thylsilyl group (83%) and Pd0-catalyzed hydrostannylation of
the resulting terminal alkyne provided the alkenyl stannane 3
(68%) along with the regioisomeric 1,1-disubstituted alkenyl
stannane (20%).[14]
The final fragment coupling leading to apoptolidinone C
(1) involved the union of the major lower and upper
subsections, 2 and 3, respectively, through construction of
the conjugated C10–C13 diene (Scheme 5). For this purpose,
the Pd0-catalyzed Stille coupling of vinyl iodide 2 and alkenyl
The apoptolidinone C synthesis highlights the utility of
catalytic asymmetric aldol equivalents in the synthesis of
stereochemically complex polyketide architecture. In this
context, the catalytic asymmetric AAC-based aldol equiv-
alents complement highly successful auxiliary-based methods
for accessing polyacetate- and polypropionate-derived natu-
ral products.
Received: August 6, 2010
Published online: September 30, 2010
Keywords: aldol reaction · asymmetric synthesis ·
.
cycloadditions · homogeneous catalysis · natural products
Scheme 5. Major fragment assembly and synthesis of apoptolidinone C (1): a) CBr4, PPh3, CH2Cl2. b) (pinB)2, 3 mol% [Pd(dppf)Cl2], KOAC, DMSO,
858C. c) 24, 10 mol% [Pd(PPh3)4], TlOEt, aq THF. d) ZnMe2, 7 mol% [Pd(PtBu3)2], THF. e) nBu4NF, THF. f) nBu3SnH, 3 mol% [PdCl2(PPh3)2], THF.
g) 10 mol% [PdCl2(MeCN)2], Ph2PO2N(nBu)4, DMF. h) LiOH, 6:2:1 THF:MeOH:H2O. i) TFA. j) 2,4,6-(Cl3C6H2)COCl, DMAP, Et3N, THF. k) H2SiF6, aq
CH3CN. DMAP=4-dimethylaminopyridine, dppf=1,1’-bis(diphenylphosphino)ferrocenyl, pin=pinacol (C6H4O2).
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