Total synthesis and structural revision of callipeltoside C

Article abstract of DOI:10.1002/anie.200800086

(Chemical Equation Presented) Look again: Highlights of the 20-step synthesis of callipeltoside C include the proline-catalyzed direct aldol reaction, enantioselective α-oxyamination reaction, and rapid access to the carbohydrate framework using a de novo synthesis protocol. Based on this work the previously assigned absolute configuration of the pendent 2-O-methylevalose unit has been revised.

Full text of DOI:10.1002/anie.200800086

Communications
DOI: 10.1002/anie.200800086
Natural Products
Total Synthesis and Structural Revision of Callipeltoside C
Joseph Carpenter, Alan B. Northrup, deMichael Chung, John J. M. Wiener, Sung-Gon Kim, and
David W. C. MacMillan*
Dedicated to Professor Luigi Minale and co-workers
The continual search for new antitumor and antiviral agents
from marine sponge extracts has resulted in the identification
of a number of structurally complex and diverse natural
products with intriguing biological activity. In 1996 and 1997
Minale and co-workers reported the isolation and structural
assignment of callipeltosides A–C (Figure 1), the first three
members of a new class of marine macrolides from the
lithistid sponge Callipelta sp. indigenous to the shallow waters
off New Caledonia.[1]
Biological activity, in particular cytotoxicity, varies among
the callipeltosides, and their IC50 values range from 11.3 to
30.0 mgmLÀ1 against human bronchopulmonary NSCLC-N6
cell lines.[1] These natural isolates were shown to blockcell
proliferation in the G1 phase, but unfortunately the exact
mode of action cannot as yet be determined owing to the
prohibitively small quantities of callipeltosides A–C that have
been isolated to date (ꢀ 3.5 mg).[1] A more detailed annota-
tion of the biological mechanism will await the availability of
substantial synthetic quantities of the callipeltosides and their
analogues as the natural isolates have been consumed.[1]
In terms of structural complexity, the callipeltosides share
a common 12-membered macrocycle comprising seven ste-
reocenters and a unique dienyne chlorocyclopropane side
chain; this class is differentiated only by the composition of
the saccharide moiety. In particular, callipeltosides A and B
are characterized by the presence of two unique deoxyamino
sugars, while callipeltoside C incorporates the novel deoxy
sugar 2-O-methylevalose. Perhaps more notable, the carbo-
hydrate moieties of callipeltosides B and C were reported to
exist in the opposite enantiomeric series to that found in
callipeltoside A (callipeltosides B and C = d sugar, callipel-
toside A =l sugar).
Their stereochemical and structural complexity coupled
with their unique biological activity make the callipeltoside
family an attractive target for total synthesis. Indeed, to date,
the groups of Trost,[2] Evans,[3] Paterson,[4] and Panek[5] have
completed the asymmetric construction of callipeltoside A,
yet surprisingly callipeltosides B and C have remained
unchallenged by chemical synthesis. In this communication
we describe the first total synthesis of callipeltoside C and
present a structural revision with respect to the enantioseries
of the pendent 2-O-methylevalose carbohydrate. This syn-
thetic sequence, which is founded upon the use of organo-
catalytic and organometallic technologies, provides access to
useful quantities of callipeltoside C in 18 chemical steps and
12% overall yield.
Our disconnection of callipeltoside C into four compo-
nents 2–5 of similar complexity (Figure 2) revealed the
possibility of a convergent synthesis with broad latitude in
the sequence of fragment coupling. Inspection of fragments
2–4 brought to mind the possibility of exploiting three
asymmetric organocatalytic transformations that have
recently been developed in our laboratories.[6–9] In particular,
we proposed the use of a direct aldehyde–aldehyde aldol
coupling[6] in combination with a Semmelhackalkoxycarbon-
ylation for the rapid construction of tetrahydropyran 2.
Furthermore, we envisioned that the stereogenicity of the
protected iodoalcohol 3 could be furnished by means of an
enantioselective formyl a-oxyamination.[7] Last, we recog-
nized the opportunity to further evaluate the versatility of our
enamine-catalyzed two-step carbohydrate synthesis[8,9] to
rapidly assemble the desired deoxy sugar 4 from simple
achiral starting materials. Moreover, we hoped that the amino
acid proline would function as a suitable organocatalyst for all
of these asymmetric processes.
Figure 1. The callipeltoside class of natural products.
[*] J. Carpenter, A. B. Northrup, Dr. dM. Chung, J. J. M. Wiener,
Dr. S.-G. Kim, Prof. D. W. C. MacMillan
Merck Center for Catalysis
Princeton University
Washington Road, Princeton NJ 08544-1009 (USA)
and
Department of Chemistry, Caltech
1200 East California Boulevard, Pasadena CA 91125 (USA)
Fax : (+1)609-258-5922
E-mail: dmacmill@princeton.edu
Assembly of the tetrahydropyran 2 and iodoalcohol
fragment 3 to give the callipeltoside aglycone was envisioned
to result from a two-point coupling strategy involving a
Homepage: http://www.princeton.edu/~dmacgr/
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Yamaguchi esterification and a diastereoselective aldehyde
vinylation, both of which could be sequentially interchanged
to serve as the macrocyclization event. Based on the studies of
Evans et al., we anticipated that attachment of the dienyne
side chain would readily be accomplished with high levels of
stereocontrol using a Horner–Wadsworth–Emmons (HWE)
olefination.[3] Finally, we recognized the importance of
forming the glycosidic linkage at a late stage to 1) establish
rapidly the absolute configuration of the callipeltose C sugar
moiety and 2) enable convenient access to a range of
callipeltoside analogues from the aglycone.
Scheme 1. Synthesis of the tetrahydropyran fragment: a) l-proline
(10 mol%), DMSO, +48C; b) HCCCH2Br, Zn, THF; c) 5% [PdCl2-
(CH3CN)2], p-benzoquinone, CO, MeOH, 08C; d) TBSCl, imidazole,
DMF; e) DDQ, CH2Cl2; f) SO3·pyridine, Et3N, CH2Cl2, DMSO.
brsm=based on recovered starting material, DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone.
Marshall and co-workers,[12b] exposure of alkynyl alcohol 8 to
the PdII catalyst in the presence of CO and MeOH did indeed
furnish the highly functionalized tetrahydropyran 9 in 75%
yield and with > 95:5 anomeric diastereocontrol. At this
stage, protection of the remaining secondary hydroxy group
as a tert-butyldimethylsilyl ether followed by cleavage of the
PMB protecting group and then Parikh–Doering oxidation[13]
provided the key tetrahydropyran coupling fragment 2 in six
steps and 44% overall yield.
Synthesis of fragment 3 began with Negishi carbometala-
tion–iodination of 4-pentynol[14] followed by Swern oxidation
to provide the trisubstituted vinyl iodide 10 with excellent
reaction efficiency and control of olefin geometry (Scheme 2).
Figure 2. Retrosynthetic analysis of callipeltoside C. PMB=para-
methoxybenzyl, TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
Scheme 2. Synthesis of the iodoalcohol fragment: a) AlMe3, [C pZrCl2],
2
I2, THF, À308C; b) (COCl)2, Et3N, DMSO, CH2Cl2, À508C ; c)l-proline
(20 mol%), PhNO, DMSO; d) NaBH4, EtOH; e) Zn, AcOH, EtOH;
f) Bu2Sn(OMe)2, PMBCl, Bu4NI, PhCH3; g) TBSCl, imidazole, DMF.
Our first step towards the construction of callipeltoside C
involved an enamine-catalyzed double diastereo-differentiat-
ing aldol reaction between propionaldehyde and the Roche
ester-derived aldehyde 6 (Scheme 1). This matched aldol
union provides the desired product[10] with high levels of
stereocontrol (12:1 anti/syn, > 19:1 Felkin/anti-Felkin),[11]
while affording a product carbonyl compound that can be
used directly in subsequent alkylation reactions without the
need for oxidation state adjustment.[6] Indeed, Felkin-selec-
tive chelation-controlled addition of propargyl zinc to alde-
hyde 7 afforded alkynyl diol 8 in nearly quantitative yield with
6:1 selectivity for the desired 4,5-syn diastereomer. With the
four stereogenic centers of fragment 2 in place, we sought to
employ the Semmelhackreaction to build the central
heterocyclic ring of callipeltoside C by a palladium-catalyzed
alkoxycarbonylation.[12] Using the conditions developed by
In 2003 the Zhong group, along with our own laboratory,
published a new organocatalytic transformation for the direct
and enantioselective a-oxyamination of aldehydes.[7] We
proposed that implementation of this technology with iodoal-
dehyde 10 might furnish the desired a-oxidized product with
high levels of enantioselectivity, while we hoped the mild
reaction conditions would leave the vinyl iodide moiety
intact. Indeed, deployment of iodoaldehyde 10 in a one-pot,
three-step sequence consisting of proline-catalyzed a-oxy-
amination,[7] borohydride reduction, and reductive O N bond
À
cleavage, successfully provided the diol 12 in 99% ee and
77% yield (over three steps). Selective protection of the
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resulting 1,2-diol then provided the requisite vinyl iodide 3 in
least hindered carbonyl p face. The resulting C9 hydroxy
group was then converted to a methyl ether followed by
cleavage of the PMB protecting group and oxidation of the
resultant primary hydroxyl function to furnish aldehyde 15.
Installation of the cyclopropyl dienyne side chain 5[17] using
the HWE protocol developed by Evans et al.[3a] resulted in
optimal yields in addition to excellent levels of stereoselec-
tivity (19:1 E/Z).[18] Selective removal of the C13 silyloxy
group and saponification of the methyl ester then afforded the
seco-acid 16, which is poised for macrolactonization. Yama-
guchi cyclization[16] proceeded in 83% yield, albeit with
elimination of methanol to give the dihydropyran 17.
Fortunately, treatment of the resulting cyclic enol with
triphenylphosphine hydrogen bromide introduced the requi-
site hemiacetal at C3, while subsequent exposure to acid
removed the remaining TBS group to complete the synthesis
of the callipeltoside aglycone 18 in 16 steps and 19% overall
yield. Spectral and optical rotation data for the aglycone were
in complete accord with the previous reports of Paterson
et al.[4a] and Trost et al.[2a]
In 2004 our group reported a two-step protocol for the
de novo synthesis of carbohydrates, in which we found that
Lewis acid mediated Mukaiyama aldol reactions could be
used to selectively access a variety of aldohexose sugars.[9]
Most relevant to this current report, we observed that the
MgBr2-mediated variant leads to the differentially protected
mannose architecture, a structural and stereochemical top-
ology that closely related to the callipeltoside C hexose. From
the outset we recognized the possibility that the carbohydrate
moieties of callipeltosides A–C might, in fact, be of the same
enantiomeric series (in contrast to the findings of the isolation
paper). Indeed, the recent isolation of phorbaside A,[19] which
contains l-2-O-methylevalose, provides additional support
for such a possibility. With this in mind, we thought that a de
novo carbohydrate synthesis seemed logical as it would
provide access to both enantiomers of the callipeltose C sugar
(a convenience not likely available by synthetic manipulation
of a naturally abundant carbohydrate).
57% overall yield for the seven-step sequence (Scheme 2).
At this stage in our synthesis we recognized the possibility
to forge the 12-membered macrocycle by using two different
sequences that would combine fragments 2 and 3. Specifically,
we proposed that intermolecular esterification followed by
intramolecular Nozaki–Hiyama–Kishi coupling,[15] or alter-
natively, intermolecular addition of a vinyl anion to the
aldehyde prior to Yamaguchi lactonization[16] would result in
formation of the macrocycle. Initial attempts focused upon
the former route, and while macrocycle formation was
possible, all attempts at the intramolecular Nozaki–
Hiyama–Kishi reaction resulted exclusively in the production
of the undesired R alcohol stereoisomer at C9. Turning to our
latter route, we were optimistic that the correct stereochem-
istry at C9 could be delivered by diastereoselective intermo-
lecular aldehyde alkylation. Indeed, after some optimization
we found that treatment of the pyranyl aldehyde 2 with
MgBr2·Et2O prior to addition of vinyl Grignard 13 (derived in
situ from iodoalcohol 3) resulted in formation of the desired
anti-Felkin addition product 14 with excellent yield and
diastereoselectivity (98% yield, 16:1 d.r.) (Scheme 3). We
presume that the observed anti-Felkin selectivity arises from
substrate chelation to MgBr2 (through the aldehyde and
pyranyl oxygen moieties), prior to vinyl addition across the
Synthesis of the d-callipeltose sugar commenced with the
well-established d-proline-catalyzed aldol dimerization of
2-triisopropylsilanoxyacetaldehyde[8] to afford the erythrose
equivalent 19, which we hoped would participate in a
Mukaiyama aldol reaction with a nascent aldehyde enolate
according to our groupꢀs precedent (Scheme 4).[9] To our
satisfaction, reaction of the aldol dimer 19 with the triethyl-
silyl enol ether derived from 2-methoxy acetaldehyde in the
presence of MgBr2·OEt2 did indeed provide the desired
polyol-differentiated mannose 20 with excellent selectivity,
and in moderate yield (> 20:1 d.r., 47% yield). Acid-
catalyzed benzyl protection of the anomeric hydroxy group
and concomitant removal of the primary silyloxy protecting
group was accomplished prior to selective formation of the
corresponding primary phenyl thiocarbonate. Deoxygenation
following the Barton–McCombie protocol[20] and then Dess–
Martin oxidation of the secondary alcohol provided the
desired tetrahydropyranyl ketone 21 in good yield over four
Scheme 3. Coupling the iodoalcohol and tetrahydropyran:
a) MgBr2·Et2O, CH2Cl2, À788C; b) MeOTf, 2,6-DTBP, CH 2Cl2; c) DDQ,
CH2Cl2, pH 7 buffer; d) SO3·pyridine, Et3N, CH2Cl2, DMSO;
e) LiHMDS, then 5, THF, À788C; f) TBAF, THF, 0 8C;
g) Ba(OH)2·8H2O, MeOH; h) Yamaguchi: 2,4,6-Cl3C6H2COCl, iPr2EtN,
THF, DMAP, toluene, 608C; i) PPh3·HBr, H2O, CH2Cl2. j) TFA, THF,
H2O. DMAP=4-dimethylaminopyridine, 2,6-DTBP=2,6-di-tert-butylpyr-
idine, HMDS=hexamethyldisilazane, TBAF=tetrabutylammonium
fluoride, TFA=trifluoroacetic acid.
steps
(Scheme 4).
At
this
juncture,
selective
p-facial addition of a methyl group to the carbonyl of 21
would install the requisite tertiary oxy stereocenter of the
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the l antipode of the callipeltose C sugar (ent-22) to the
macrocyclic core 18. Using again the Tietze glycosylation/
TASF desilylation sequence to combine fragments 18 and ent-
22, we were delighted to find that the resulting macrolide 23
(formed as a single diastereomer) was identical to callipelto-
side C with respect to the spectroscopic data obtained for the
natural isolate.[23] On this basis we report that the structure of
callipeltoside C should be revised to that shown in
Scheme 5.[24,25]
In conclusion, a highly efficient enantioselective synthesis
of callipeltoside C has been accomplished with a longest
linear sequence of 20 steps in 11% overall yield from the
commercially available Roche ester.[26] As a result of our
synthetic efforts we also present a structural revision of the
originally reported carbohydrate stereochemistry. Highlights
of our approach include the proline-catalyzed direct aldol
reaction, enantioselective a-oxyamination reaction, and rapid
access to the carbohydrate frameworkusing a de novo
synthesis protocol.[27]
Scheme 4. De novo synthesis of a differentially protected
mannose: a) d-proline, DMF; b) MgBr2·Et2O, CH2Cl2; c) AcCl,
BnOH, 1108C; d) PhOCSCl, pyridine, CH2Cl2; e) Bu3SnH,
AIBN, toluene, 1208C; f) Dess–Martin periodinane, CH 2Cl2,
08C; g) MgBr2·Et2O, CH3MgBr, CH2Cl2; h) H2, Pd/C, EtOAc;
Cl3CCN, Cs2CO3, C HCl2; i) l-proline, DMF. AIBN=2,2’-azobi-
2
sisobutyronitrile.
evalose saccharide ring. Semiempirical calculations
suggested that carbanion nucelophiles would approach
the low-energy pseudo-chair conformation of 21 by
means of the desired axial trajectory to avoid steric
interactions with the neighboring methoxy group,
while alleviating torsional strain in the bond-forming
event. Indeed, addition of MeMgBr to a solution of 21
and MgBr2·OEt2 in CH2Cl2 produced the desired
stereoisomer in 90% yield and 20:1 d.r. The relative
stereochemistry of 21 was confirmed by NOE analysis
and by X-ray analysis of a substance that was chemi-
cally correlated to the minor diastereomer. Palladium-
catalyzed hydrogenolysis cleanly removed the benzyl
group prior to activation of the sugar as a trichlor-
oacetimidate furnished the d-2-O-methylevalose cou-
pling partner 22 in eight steps and 14.5% overall yield
(Scheme 4). Central to our design plan, production of
the antipodal l-callipeltose sugar (ent-22) was also
accomplished using this eight-step protocol (using
catalytic l-proline in lieu of d-proline in the initial
asymmetric aldol event).
The coupling of the d-2-O-methylevalose hexose 22 and
the aglycone 18 was accomplished according to the glyco-
sylation procedure of Tietze et al (Scheme 5).[21] Silyl depro-
tection of the resulting material using tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF) in DMF at 408C
then provided a compound having the reported structure of
callipeltoside C (1) in 90% yield (Scheme 5). Unfortunately,
spectroscopic data for the macrolide 1 did not match the
characterization data reported for the natural isolate.[1,22]
With this knowledge in hand, we next focused upon linking
Scheme 5. Completion of the synthesis of callipeltoside C with structural
revision.
Received: January 8, 2008
Published online: March 31, 2008
Keywords: asymmetric synthesis · callipeltoside C·
.
carbohydrates · organocatalysis
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[17] The side chain was synthesized according to the procedure of
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[18] The HWE coupling was less effective when performed after the
macrocyclization step (84% vs. 54% yield).
[19] K. C. Skepper, J. B. MacMillan, G. Zhou, M. M. Masuno, T. F.
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[22] The macrolide 1 was formed as a 4:1 mixture of diastereomers at
the anomeric position. Spectral data for each anomer was
inconsistent with the characterization data for the natural
isolate.
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[23] We thankProfessor L. Minale and co-workers for the Herculean
taskof isolating and characterizing callipeltosides A–C. We
thankProfessor M. Valeria D ’Auria for providing comparison
spectra of natural 23 to D.W.C.M.
[24] At the present time we cannot state definitively the stereo-
chemistry of the C1’ anomeric position of callipeltoside C. Based
on the isolation studies for callipeltoside B, we tentatively
suggest that it exists as the b-equatorial anomer as shown in
Scheme 5.
[25] We anticipate that the structure of callipeltoside B will likely be
revised with respect to the enantiomer series of the pendent
deoxyamino carbohydrate.
[26] The longest linear sequence is 18 steps and 12% overall yield
from the Roche ester-derived aldehyde 6.
[13] J. R. Parikh, W. v. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505.
[14] E. Negishi, D. E. Van Horn, T. Yoshida, J. Am. Chem. Soc. 1985,
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[27] For a review on the organocatalytic synthesis of bioactive
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