Convergent total syntheses of callipeltosides A, B, and C

Article abstract of DOI:10.1002/anie.201204868

Going for the hat-trick: The synthesis of the entire callipeltoside family of natural products is described. Key to this synthesis was the coupling of the di-ene-yne and pyran fragments by a diastereoselective alkenylzinc addition allowing rapid access to the common aglycon. Attachment of each relevant L-configured sugar resulted in the first total synthesis of callipeltoside B (see scheme), and the syntheses of callipeltosides A and C.

Full text of DOI:10.1002/anie.201204868

Angewandte
Chemie
DOI: 10.1002/anie.201204868
Natural Products
Convergent Total Syntheses of Callipeltosides A, B, and C**
James R. Frost, Colin M. Pearson, Thomas N. Snaddon, Richard A. Booth, and Steven V. Ley*
Marine sponges provide a rich diversity of structurally
interesting natural products which often display a range of
useful biological activities. As part of a sustained search to
discover and identify new molecules with potential therapeu-
tic benefit, Minale and co-workers isolated callipeltosides A,
B and C (1–3) as minor metabolites from the shallow water
lithistida marine sponge Callipelta sp.[1,2] At the time, these
natural products represented a new class of polyketides that
were later joined by new members; the phorbasides, aurisides,
dolastatins and others.[3] The callipeltosides contain several
interesting features which include: 14 stereocentres, an
unusual trans-configured chlorocyclopropane ring conjugated
to a di-ene-yne unit, and a 14-membered macrolactone ring
incorporating a tetrasubstituted tetrahydropyran motif. All
callipeltosides contain a common aglycon core, and differ
only in the attached sugar unit (Figure 1), which is thought to
configuration of the sugar with respect to the natural product
skeleton. These two groups as well as the laboratories of
Evans,[6] Panek,[7] and Hoye[8] have since reported the syn-
thesis of callipeltoside A.[9] Further work by MacMillan and
co-workers culminated in the first synthesis of callipeltoside C
resulting in a structural reassignment, meaning that the l-
configured sugar moiety was present rather than the origi-
nally assigned d-configuration.[10] In spite of all these efforts,
we believed that further work was still necessary to streamline
the synthesis and complete the series by synthesizing calli-
peltoside B for the first time.
Our goal therefore was to devise a unified, efficient and
convergent strategy to all three callipeltosides A, B and C and
thereby also confirm the structure of B. While space here does
not allow us to report on all of our routes to the various
fragments of the callipeltosides, often using chemistries
invented in our laboratories, we describe only the most
successful sequence.[11]
Our analysis of the synthesis problem suggested starting
from three equally-sized components: C1–C9 pyran 4, C10–
C22 vinyl iodide 5 and the relevant sugar moiety activated as
the corresponding thioglycoside (callipeltoside A sugar 6
shown for clarity) (Figure 2). We expected that pyran 4 and
vinyl iodide 5 could be joined by a diastereoselective alkenyl
metal addition.[12] With the key C9 stereocenter in place,
further manipulations followed by macrolactonization should
provide the callipeltoside aglycon by the most convergent
process reported to date. Pyran 4 could be accessed through
the use of a catalytic AuCl3-induced cyclization protocol
previously developed by our group.[13]
Figure 1. The callipeltoside family of natural products and correspond-
Synthesis of the C1–C9 pyran fragment 4 commenced
from known (R)-Roche ester-derived aldehyde 10
(Scheme 1). Crotylboration using the Roush procedure
provided homoallylic alcohol 12 in good yield (70%) and
diastereomeric ratio (d.r. 88:12).[14] Subsequent dihydroxyla-
tion followed by sodium periodate-mediated cleavage pro-
duced the required aldehyde for propargylzinc addition. This
three-step procedure gave diol 13 in 72% overall yield, with
diastereoselectivity of 85:15 at C5 in favor of the desired 1,3-
anti-configuration; presumably by a chelation-controlled
process.[10] Protection as the acetonide followed by ynoate
formation gave pure 14 in good yield. At this juncture all
minor diastereomers could be easily and conveniently
removed by silica gel chromatography. The relative stereo-
chemistry of 14 was confirmed by single-crystal X-ray
diffraction. Removal of the acetonide provided diol 15
which, upon treatment with AuCl3 in MeOH, smoothly
cyclized to give desired pyran 16 as a single diastereomer in
an excellent 96% yield. The low catalyst loading of this
reaction is of interest, requiring just 2 mol% to deliver
product 16. Thereafter, protection of the secondary alcohol as
its TBS ether, hydrogenolysis and oxidation gave 4 in 26%
ing IC50 values against the NSCLC-N6 cell line.
play an important role in moderating cytotoxic activity
against human bronchopulmonary NSCLC-N6 (IC50 values
detailed in Figure 1) and P388 cell lines.[1] These properties
make these molecules attractive targets for synthesis.
Early efforts by the Trost[4] and Paterson[5] groups towards
the synthesis of callipeltoside A defined the trans-configured
chlorocyclopropane unit, the structure of the aglycon and the
[*] J. R. Frost, Dr. C. M. Pearson, Dr. T. N. Snaddon, Dr. R. A. Booth,
Prof. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: svl1000@cam.ac.uk
[**] We gratefully acknowledge Novartis (J.R.F.), the EPSRC (C.M.P.,
T.N.S. and R.A.B.) and the B.P. 1702 Professorship endowment
(S.V.L.) for generous funding. We also thank Dr. R. Turner, Dr. J.
Davies and D. Howe for HPLC assistance, X-ray crystallography and
NMR experiments, respectively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204868.
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Figure 2. Retrosynthetic analysis of the callipeltoside family. Callipelto-
Scheme 1. Reagents and conditions: a) crotylborane 11, 4 ꢀ MS,
PhMe, ꢀ788C, 70%; b) OsO4, NMO, acetone/H2O (2:1), RT;
c) NaIO4, THF/H2O (10:1), 08C!RT; d) Zn, propargyl bromide, THF,
0!ꢀ1008C, 72% over 3 steps; e) 2,2-dimethoxypropane, (ꢁ)-CSA,
acetone, RT; f) nBuLi, THF, ꢀ40!ꢀ788C, then ClCO2Me, 73% over 2
steps; g) QP-SA, MeOH, RT, 95%; h) AuCl3 (2 mol%), MeOH, RT,
96%; i) 2,6-lutidine, TBSOTf, CH2Cl2, ꢀ788C, 91%; j) H2, Pd/C (10%
wt), EtOAc, RT, 96%; k) Dess–Martin periodinane, K2CO3, CH2Cl2, RT,
87%. NMO=N-methylmorpholine N-oxide; (ꢁ)-CSA=(ꢁ)-camphor-
sulfonic acid; QP-SA=Quadrapure sulfonic acid.
side A shown for clarity.
yield over 11 steps. This route is noteworthy for its minimal
use of chromatography.
For the synthesis of C10–C22 vinyl iodide 5, we required
large amounts of known vinyl iodide precursor 17, itself
derived from TMS-propyne in two steps by Mo-catalyzed
regioselective hydrostannylation followed by iodine
exchange.[15] Halogen–lithium exchange with tBuLi in toluene
at ꢀ788C followed by additon of PMB-protected epoxide (18)
with BF3·OEt2 proved to be the most effective means to the
desired secondary alcohol.[16] Subsequent TBS-protection and
PMB-deprotection gave primary alcohol 19. Oxidation and
Ramirez olefination[17] furnished 21 which, following Corey–
Fuchs reaction, gave the corresponding terminal alkyne.[18]
Pd-catalyzed hydrostannylation and subsequent tin–iodine
exchange proceeded with high regioselectivity to give (E)-
vinyl iodide 7 as a single diastereomer in 49% yield over 2
steps.[19] This completed the C10–C15 7 fragment in 18%
yield over 8 steps (Scheme 2).
The Stille coupling partner 8 was completed after consid-
erable optimization by treatment of known dibromide 25[7b,20]
with TBAF to give the corresponding bromoalkyne, which
was then coupled to bis-stannane 26 by a low-temperature
(ꢀ108C) Stille reaction with Ag2CO3 as an additive.[21] This
gave compound 8 exclusively, with no observation of biscou-
pled material. Fragments 7 and 8 were united by a second
Stille reaction employing [Pd(PFur3)2]Cl2 as the precatalyst[22]
to yield 27 which, following treatment with NIS, provided 5 in
a highly stereoselective fashion in 9% yield over 10 steps
(longest linear sequence).
As discussed above, the three callipeltosides differ in the
attached sugar unit which, on the basis of structural inves-
tigations by others,[4–10] has resulted in callipeltoside A and C
being assigned with l-configured residues. It therefore
seemed reasonable to us that the B sugar might also be l-
configured. In an effort to synthesize appropriate carbohy-
drate coupling partners in an efficient manner, and thereby
maximize convergency, we implemented a route to all three
fragments from a common enantioenriched precursor 28.
Initial deacetylation of 28 followed by oxidation of the allylic
alcohol efficiently provided pyranone 9 in 74% over 2 steps.
Our approach to callipeltoside A and B thioglycosides 6 and
32, respectively, began by nosylation of pyranone 9 and
subsequent SN2 displacement of the nosylate with nBu4NN3.
Addition of MeLi at ꢀ1008C gave 29 as a single diastereo-
mer.[23] Having successfully installed the C4 stereocenter,
epoxidation with m-CPBA and subsequent ring opening
proceeded smoothly. Selective methylation of the secondary
alcohol was achieved by careful control of the stoichiometry
of freshly sublimed KOtBu followed by addition of MeI to
give key compound 30, allowing diversification to both the
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Scheme 2. Reagents and conditions: a) tBuLi, PhMe, ꢀ788C, then 18, BF3·OEt2, PhMe; b) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 53% over 2 steps;
c) DDQ, pH 7 phosphate buffer, CH2Cl2, 08C, 89%; d) SO3·Py, Et3N, DMSO, CH2Cl2, 08C!RT; e) PPh3, CBr4, CH2Cl2, then 20, 2,6-lutidine, CH2Cl2,
08C, 89% over 2 steps; f) nBuLi, THF, ꢀ788C, then H2O, 85%; g) Pd(PPh3)2Cl2 (3 mol%), Bu3SnH, THF, 08C; h) I2, CH2Cl2, ꢀ788C, 49% over 2
steps; i) ZnEt2, CH2I2, CH2Cl2, 08C, then 23, 22, CH2Cl2, 08C!RT, 74%; j) PCC, celite, CH2Cl2, RT; k) PPh3, CBr4, CH2Cl2, 08C, then aldehyde,
CH2Cl2, 08C!RT, 70% over 2 steps; l) TBAF, DMF, 658C; m) Pd2dba3 (10 mol%), AsPh3 (40 mol%), Ag2CO3 (1.0 equiv), THF, dark, ꢀ108C, then
26, 45% over 2 steps; n) Pd(PFur3)2Cl2 (15 mol%), DMF, dark, RT, 63%; o) NIS, MeCN, RT, 84%. DDQ=2,3-dichloro-5,6-dicyano-p-
benzoquinone; PCC=pyridinium chlorochromate; TBAF=tetrabutylammonium fluoride; NIS=N-iodosuccinimide.
callipeltoside A and B sugars.[7a,23] The callipeltoside A sugar
methoxyacetal 31 was completed following reduction of the
azide to the amine, formation of the cyclic carbamate and
triisopropylsilyl (TIPS) protection.
This was successfully activated as the thioglycoside by use
of thiophenol with BF3·OEt2 to give 6 as the single a-anomer
in 8.5% over 11 steps.[6d] Azido sugar 30 was activated and
protected in one step using TMSSPh, ZnI2 and TBAI in DCE
at 658C to provide a-configured sugar 32, a precursor to the
callipeltoside B sugar.[24] This approach meant that after
attachment of sugar 32 to the callipeltoside aglycon further
manipulation by means of azide reduction, formylation and
deprotection would be necessary to deliver 2.
With the callipeltoside A and B sugar precursors in hand,
we focused on a separate synthesis of the activated callipel-
toside C saccharide unit. This proceeded from the common
pyranone 9, through a complex-induced proximity-controlled
nucleophilic addition to give 33 as a single diastereomer.[25]
Selective TES-protection, epoxidation, ring-opening and
methylation gave 35. This was successfully converted to the
anomeric thioglycoside 36 (Scheme 3). The preparative
sequence to the callipeltoside C sugar 36 was efficient,
Scheme 3. Reagents and conditions: a) PS-Na2CO3, MeOH, RT; b) MnO2, CH2Cl2, RT, 74% over 2 steps; c) NsCl, Py, CH2Cl2, RT, 95%;
d) nBu4NN3, CH2Cl2, 08C, 72%; e) MeLi, THF, ꢀ1008C, 79%; f) m-CPBA, MeOH, 08C!RT, 52%; g) KOtBu, MeI, THF, 08C, 79%; h) H2,
Pd(OH)2, EtOAc, RT, 93%; i) triphosgene, Py, THF, ꢀ788C!RT, 72%; j) TIPSOTf, 2,6-lutidine, CH2Cl2, RT, 97%; k) PhSH, BF3·OEt2, CH2Cl2,
08C!RT, 80%; l) ZnI2, TBAI, TMSSPh, DCE, 658C, 60%; m) MeLi·LiBr, Et2O, ꢀ788C, 78%; n) TESCl, Py, DMAP, CH2Cl2, RT; o) m-CPBA, MeOH,
08C!RT, 45% over 2 steps; p) KOtBu, MeI, THF, 08C, 81%; q) ZnI2, TBAI, TMSSPh, DCE, 658C, 86%. NsCl=4-nitrobenzenesulfonyl chloride;
m-CPBA=3-chloroperbenzoic acid; TIPS=triisopropylsilyl; TMS=trimethylsilyl; TES=triethylsilyl; DMAP=4-(N,N-dimethylamino)pyridine;
TBAI=tetrabutylammonium iodide.
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proceeding in 18% yield over 7 steps.[26] With all necessary
fragments in hand, efforts to assemble the natural products
began.
We first had to address the key convergent coupling of
pyran 4 with fully assembled vinyl iodide fragment 5. Initial
investigations using the alkenylzinc nucleophile resulted in
a successful union with d.r. = 1:1 at C9. Our attention then
turned to the work of Oppolzer and Radinov,[12] and also the
elegant studies of Marshall,[27] who demonstrated that the
stereochemical information could be transferred through the
ligand-directed use of N-methylephedrine derivatives. Inspec-
tion of the proposed model revealed that (1R,2S)-(ꢀ)-N-
methylephedrine would be the reagent of choice; but in
practise, disappointing diastereoselectivity was observed
(34:66 at C9). However using the opposite enantiomer,
(1S,2R)-(+)-N-methylephedrine gave greatly improved
levels of diastereoselection (91:9). Subsequent methylation
of both C9 epimeric products using MeOTf allowed for the
interception of a known compound disclosed by MacMil-
lan.[10] This allowed for the rapid and convenient determi-
nation of the stereochemical outcomes, with the major
product of the (1S,2R)-(+)-N-methylephedrine reaction
found to be the desired product. Hence, the desired trans-
formation represents the matched case. This welcome but
unexpected result is opposite to that predicted by Noyoriꢀs
model.[28] We therefore suggest that this reaction involves
a model similar to that proposed by Myers in the synthesis of
the tetracycline antibiotics.[29] This reaction was optimized
such that only a 0.3 equivalent excess of vinyl iodide 5 was
required, allowing for maximum conversion of valuable
advanced fragments.
Scheme 4. Reagents and conditions: a) i) 5, (1.3 equiv), tBuLi, Et2O,
ꢀ788C; ii) ZnBr2, Et2O, ꢀ78!08C; iii) (1S,2R)-(+)-N-methylephedrine
(1.1 equiv), nBuLi, PhMe, 08C; iv) 4, PhMe, 08C, 48%; b) MeOTf,
DTBP, CH2Cl2, RT, 73%; c) TBAF, THF, RT, 74%; d) Ba(OH)2·8H2O,
MeOH, RT, quant.; e) 2,4,6-trichlorobenzoyl chloride, Et3N, RT, then
addition to DMAP, PhMe, 808C; f) TFA, THF/H2O (5:1), RT, 58% over
2 steps. DTBP=2,6-di-tert-butylpyridine; TFA=trifluoroacetic acid.
Thereafter, selective removal of the C13 silyl ether with
TBAF followed by saponification of the methyl ester gave
seco-acid 38. Yamaguchi macrolactonization[30] followed by
treatment with TFA in THF/H2O (5:1) installed the requisite
hemiketal and removed the remaining secondary TBS group
in a one-pot process to give the callipeltoside aglycon 39 in
58% over 2 steps (Scheme 4).
Attachment of the sugar 6 to aglycon 39 was successfully
achieved using the protocol described by Evans,[6] which, after
deprotection using TBAF furnished callipeltoside A (1).
Application of the same glycosylation procedure provided
protected callipeltoside C. Deprotection using TASF deliv-
ered callipeltoside C (3); identical to the natural product and
that described by MacMillan (Scheme 5).[10]
With callipeltosides A and C in hand, our next concern
was to address the synthesis of callipeltoside B. Following
attachment using thioglycoside 32, we faced the prospect of
having to reduce the azide in the presence of multiple
unsaturated functional groups. Pleasingly, this was achieved
using 1,3-propanedithiol in aqueous pyridine/Et3N.[31] Formy-
lation using a large excess of reagent 40,[32] and desilylation
using TASF gave callipeltoside B (2) (Scheme 6) as a 4:1
mixture of formamide rotamers identical in all respects to the
natural product. This therefore confirms that all members of
the callipeltoside family contain l-configured sugars.[33]
In conclusion, we have developed a highly convergent
approach to the entire callipeltoside family, which has
resulted in the first total synthesis of callipeltoside B (2).
Scheme 5. Reagents and conditions: a) 39, 6, 4 ꢀ MS, CH2Cl2, DTBMP,
RT, 50 min, then ꢀ158C, NIS, TfOH, ꢀ158C!RT; b) TBAF, THF, 83%
over 2 steps; c) 39, 36, 4 ꢀ MS, CH2Cl2, DTBMP, RT, 50 min, then
ꢀ158C, NIS, TfOH, ꢀ158C!RT; d) TASF, DMF, 408C, 57% over 2
steps. DTBMP=2,6-di-tert-butyl-4-methylpyridine; TfOH=trifluorome-
thanesulfonic acid; TASF=tris(dimethylamino)sulfonium difluorotri-
methylsilicate.
4
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Scheme 6. Reagents and conditions: a) 39, 32, 4 ꢀ MS, CH2Cl2,
DTBMP, RT, 50 min, then ꢀ158C, NIS, TfOH, ꢀ158C!RT, 56%;
b) 1,3-propanedithiol, Et3N, Py/H2O (10:1), RT; c) 40, CHCl3, RT;
d) TASF, DMF, 408C, 52% over 3 steps.
This has been achieved by 1) a high yielding approach to the
pyran core 4, which benefitted from our own AuCl3-induced
cyclization methodology[13] and required minimal chromatog-
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manner by sequential Stille reactions; and 3) union of 4 and 5
by means of a highly convergent and diastereoselective
Oppolzer–Radinov alkenylzinc addition. An extensive
account of our efforts towards these targets will be presented
in full at a later date.
Received: June 21, 2012
Published online: && &&, &&&&
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Keywords: callipeltoside · chlorocyclopropane · gold catalysis ·
Oppolzer–Radinov addition · Stille cross coupling
.
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[1] a) A. Zampella, M. V. DꢀAuria, L. Minale, C. Debitus, C. J.
Roussakis, J. Am. Chem. Soc. 1996, 118, 11085 – 11088; b) A.
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[2] The depicted structures differ from those drawn in the original
isolation paper and are the result of previous synthetic efforts
and the work detailed in this Communication. Whilst the a-
glycosidic linkage of callipeltoside A is well known, that of
callipeltoside B and C has not been rigorously established.
Despite the same method being used to unite each sugar
fragment with the callipeltoside aglycon, analysis of NOESY
data for callipeltosides B and C has led us to assign respective a-
and b-configurations at the glycosidic linkage (see Schemes 5, 6
and the Supporting Information). At this stage it is not known
why the opposite configurations are obtained.
[3] K.-S. Yeung, I. Paterson, Chem. Rev. 2005, 105, 4237 – 4313.
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[22] a) C. M. Hettrick, W. J. Scott, J. Am. Chem. Soc. 1991, 113,
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synthesis.
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[33] For completion the d-configured sugar was also attached to
aglycon 39. It was found that the 1H NMR spectrum was
significantly different to the l-configured series and did not
match the natural product.
6
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Angewandte
Chemie
Communications
Natural Products
Going for the hat-trick: The synthesis of
the entire callipeltoside family of natural
products is described. Key to this syn-
thesis was the coupling of the di-ene-yne
and pyran fragments by a diastereoselec-
tive alkenylzinc addition allowing rapid
access to the common aglycon. Attach-
ment of each relevant l-configured sugar
resulted in the first total synthesis of
callipeltoside B (see scheme), and the
syntheses of callipeltosides A and C.
J. R. Frost, C. M. Pearson, T. N. Snaddon,
R. A. Booth, S. V. Ley*
&&&& — &&&&
Convergent Total Syntheses of
Callipeltosides A, B, and C
Angew. Chem. Int. Ed. 2012, 51, 1 – 7
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