A formal synthesis of the callipeltoside aglycone

Article abstract of DOI:10.1021/ol702024b

A synthesis of the macrocyclic core structure of callipeltoside A and a C9 epimer has been achieved by applications of chiral vinylzinc or Kishi-Nozaki-Hiyama (K-N-H) additions, Roskamp homologations, and acylketene or intramolecular K-N-H macrolactonizat

Full text of DOI:10.1021/ol702024b

ORGANIC
LETTERS
2008
Vol. 10, No. 1
93-96
A Formal Synthesis of the Callipeltoside
Aglycone
James A. Marshall* and Patrick M. Eidam
Department of Chemistry, UniVersity of Virginia, P. O. Box 40019,
CharlottesVille, Virginia 22904
jam5x@Virginia.edu
Received August 17, 2007
ABSTRACT
A synthesis of the macrocyclic core structure of callipeltoside A and a C9 epimer has been achieved by applications of chiral vinylzinc or
Kishi Nozaki Hiyama (K H) additions, Roskamp homologations, and acylketene or intramolecular K H macrolactonizations as key bond-
forming steps.
−
−
−N−
−N−
The lithistid sponge metabolite callipeltoside A and its
aglycone (Figure 1) have attracted the attention of synthetic
stereochemistry, culminating in total syntheses of the natural
product. In these efforts aldol methodology played an
important role in construction of the polyketide segments.
More recently, Huang and Panek synthesized this array by
means of allylsilane reactions.5 In the present report, we
describe a formal total synthesis of the callipeltoside aglycone
and its C9 epimer from aldehyde 1, the enantiomer of which
was previously employed in our synthesis of discodermolide.6
We have recently shown that the vinylzinc bromide-N-
methylephedrine complex, prepared from vinyl iodide 2 by
the procedure of Oppolzer, reacts with aldehyde 1 to afford
the anti adduct 3 with >90:10 diastereoselectivity (Scheme
1).7 This addition efficiently introduces the key C9 stereo-
center of the callipeltoside aglycone. Our present studies were
(1) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc., 1996, 118, 11085.
(2) (a) Paterson, I.; Davies, R. D. M.; Marquez, R. Angew. Chem., Int.
Ed. 2001, 40, 603. Paterson, I.; Davies, R. D. M.; Heimann, A. C.; Marquez,
R.; Meyer, A. Org. Lett. 2003, 5, 4477.
(3) (a) Trost, B. M.; Dirat, O.; Gunzner, J. L. Angew. Chem., Int. Ed.
2002, 41, 841. (b) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J.
Am. Chem. Soc. 2002, 124, 10396.
Figure 1. Structure of callipeltoside A and retrosynthesis of the
aglycone core.
(4) Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc.
2002, 124, 5654.
(5) Huang, H.; Panek, J. S. Org. Lett. 2004, 6, 4383.
(6) Marshall, J. A.; Lu, Z.; Johns, B. A. J. Org. Chem. 1998, 63, 817.
groups since its reported isolation in 1996 by Minale and
co-workers.1 Initial synthetic work by Paterson,2 Trost,3 and
Evans4 led to the correct assignment of relative and absolute
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Surprisingly, our efforts to convert vinyl iodide 14, the
TBS ether of alcohol 13, to the zinc reagent needed for the
Oppolzer addition to aldehyde 1 were not successful.
Attempted lithiation of iodide 14 with t-BuLi, s-BuLi, or
BuLi, or by direct lithiation afforded only recovered iodide
and decomposition products.
Scheme 1
The free alcohol 13 also failed to lithiate. When the MOM
ether 15 was treated with t-BuLi, a mixture of recovered 15
and its (Z) isomer was isolated, suggestive of an OMOM-
assisted deprotonation of the vinylic hydrogen.14 This as-
sumption was verified by lithiation and subsequent D2O
quench. In separate experiments with vinyl iodide 2 we
attempted to generate the Oppolzer zinc complex by reaction
with Rieke zinc15 and subsequent addition of the lithio
N-methylephedrine followed by cyclohexane carboxaldehyde.
None of the desired adduct was produced in these experi-
ments, but we did isolate the protonolysis product derived
from the vinylzinc intermediate. Evidently the reactive zinc-
NME complex is not formed under these conditions.
An alternative route to the alcohol 17 from aldehyde 1
and vinyl iodide 16 was devised by application of the Kishi-
Nozaki-Hiyama (K-N-H) methodology,16 but the reaction
showed little stereoselectivity, affording a disappointing,
albeit separable, 60:40 mixture of alcohol adducts 17 and
18 in 84% yield (Scheme 3).17
directed toward further elaboration of this intermediate to
the macrocyclic lactone core of the natural product.
Methylation of alcohol 3 and then cleavage of the primary
DPS ether8 and Sharpless asymmetric epoxidation of the
liberated allylic alcohol 5 with the D-(-)-tartrate reagent gave
the epoxy alcohol 6.9 Upon treatment with LDA, the derived
epoxy iodide 7 underwent double elimination to afford the
alkynol 8.10
We also explored a more convergent synthesis of this
intermediate by employing the vinyl iodide 14 in which the
propargylic alcohol moiety is already present in protected
form (Scheme 2). The synthesis of this iodide commenced
Scheme 3
Scheme 2
The major alcohol adduct 17 was methylated,18 and the
primary TBS ether of the intermediate 19 was selectively
with the kinetic resolution of the racemic alcohol 9 with
Amano AK lipase and vinyl acetate in pentane,11 which
afforded a 49:47 mixture of the (S)-alcohol 10 and (R)-acetate
11 of er >95:5, as measured by Mosher ester analysis.12
Reductive cleavage of the acetate 11 and selective carboalu-
mination and iodinolysis13 of the terminal alkyne afforded
the iodo alcohol 13 in 69% yield.
(12) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(13) (a) Negishi, E.-i.; VanHorn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639. (b) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993,
32, 1068.
(14) Bonnet, B.; Ple´, G.; Duhamel, L. Synlett 1996, 221. Myers, A. I.;
Spohn, R. F. J. Org. Chem. 1985, 50, 4872.
(15) Zhu, L.; Wehmeyer, R. M.; Rieke, R. R. J. Org. Chem. 1991, 56,
1445.
(7) Marshall, J. A.; Eidam, P. M. Org. Lett. 2004, 6, 445.
(8) Shekhami, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik,
S. Tetrahedron Lett. 1990, 31 1669.
(9) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(10) (a) Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron Lett.
1988, 29, 2737. (b) Yadav, J. S.; Chander, M. C.; Rao, C. S. Tetrahedron
Lett. 1989, 30, 5455.
(16) (a) Fu¨rstner, A. Chem. ReV. 1999, 99, 991. (b) Wan, Z.-K.; Choi,
H.-w.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi, Y. Org. Lett. 2002,
4, 4431. (c) Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7,
5417. (d) Namba, K.; Wang, J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7, 5421.
(17) The stereochemistry of the alcohol center was confirmed through
mandelic ester analysis. Trost, B. M.; Belletire, J. L.; Godleski, S.;
McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello,
G. S.; Varga, S. L.; Springer, J. D. J. Org. Chem. 1986, 51, 2370.
(18) Diem, M. J.; Burow, D. F.; Fry, J. L. J. Org. Chem. 1977, 42, 1801.
(11) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129.
94
Org. Lett., Vol. 10, No. 1, 2008

with higher diastereoselectivity than the intermolecular
version depicted in Scheme 3. For this sequence alcohol 30,
the precursor of aldehyde 1, was acetylated and selectively
desilylated with PPTS in MeOH to afford alcohol 32.
Oxidation with the Dess-Martin periodinane reagent22 led
to aldehyde 33, the first of our coupling partners. The second,
diazo ester 29, was secured through esterification of alcohol
13 with the tosylhydrazone 28, which was converted to 29
in situ (Scheme 5).23
Scheme 4
Scheme 5
Addition of diazoacetate 29 to aldehyde 33 in the presence
of 20 mol % SnCl2 afforded the â-keto ester 35 in 50% yield
and the pyranoside 37 in 30% yield (Scheme 6). When the
Scheme 6
desilylated to afford the primary alcohol 20 (Scheme 4). The
derived aldehyde 21 was cleanly homologated to the â-keto
ester 22 by treatment with ethyl diazoacetate and SnCl2
following the Roskamp protocol.19 Cleavage of the acetate
with NaOEt and pyrolysis of the hydroxy ester 23 in
refluxing toluene to form the acylketene20 led to the
macrolide 24 in 73% yield. Oxidative cleavage of the PMB
ether with DDQ in CH2Cl2 at pH 7 led to the pyranose 25
in 96% yield. Global desilylation with TBAF in THF gave
the terminal alkyne 26 which was reduced to the vinyl
compound 27 by Lindlar hydrogenation.21 The spectral data
of 27 were in accord with those reported by Trost.3b
The favorable results from the Roskamp homologation
prompted our examination of a more elaborate version of
this reaction for an alternative approach to the callipeltoside
macrolide core. In this version the diazo ester homologation
would be employed to prepare an extended acyclic propar-
gylic ester 40 (Scheme 7) which would then be subjected to
an intramolecular K-N-H reaction to effect cyclization. It
was our hope that the intramolecular reaction would proceed
addition was conducted with added NaHCO3 we obtained
the â-keto ester 35 in 62% yield.24 However, the pyranoside
byproduct persisted. Evidently, pyranoside 37 is formed by
intramolecular attack of the PMB ether oxygen of 33 on a
SnCl2-aldehyde complex followed by cleavage of the
oxonium ether by chloride.25 In fact, when the above
Roskamp homologation was carried out on the less basic
TBS ether 34, the â-keto ester product 36 was formed in
85% yield. However, as it was desirable to differentiate the
C5 and C7 oxygens of 35/36, we decided to carry on with
(19) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
(20) Acylketene macrolactonization methodology was first described
by Boeckman and Pruit using dimethyldioxoleneones as acylketene
precursors. Boeckman, R. K.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111,
8286. The Boeckman methodology was subsequently utilized by Trost and
Gunzer4 in their syntheses of callipeltoside A and analogues. In the present
example a â-keto ester is employed as the acylketene precursor along the
lines of Greene and coworkers. Mottet, C.; Hamelin, O.; Garavel, G.; Depre´s,
J.-P., Greene, A. E. J. Org. Chem. 1999, 64, 1380.
(22) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156. (b)
Ireland, R. E.; Lin, L. J. Org. Chem. 1993, 58, 2899.
(23) (a) Corey, E. J.; Meyers, A. G. Tetrahedon Lett. 1984, 25, 3559.
(b) Blankley, C. J.; Sauter, F. J.; House, H. O. Organic Syntheses; John
Wiley: New York, 1973; Collect. Vol. V, p 258.
(24) In the absence of NaHCO3, ∼20% of the diazo ester 29 was
converted to the R-chloro ester by reaction with HCl.
(21) Lindlar, H.; Dubuis, R. Organic Syntheses; John Wiley: New York,
1973; Collect. Vol. V, p 880.
(25) Angle, S. R.; Wei, G. P.; Ko, Y. K.; Kubo, K. J. Am. Chem. Soc.
1995, 117, 8041.
Org. Lett., Vol. 10, No. 1, 2008
95

the former, pending evaluation of the intramolecular K-N-H
cyclization. As an aside, we did not observe a lactol
byproduct analogous to 37 in reactions of aldehyde 21 with
excess ethyl diazoacetate and SnCl2 (Scheme 4).
the larger R-substituent. This mode of attack would introduce
torsional strain between the C9 oxygen and the C8 methyl
group in the transition state (Figure 2, A). If, on the other
The PMB ether 35 was converted to the pyranose 38 in
69% yield with DDQ (Scheme 7). Cleavage of the acetate
Scheme 7
Figure 2. Torsional interactions in cyclization transition states for
aldehyde 40.
hand, the aldehyde carbonyl is rotated by 180°, the corre-
sponding transition state would involve only lower energy
O/H and CH3/H interactions en route to the observed trans-
adduct (Figure 2, B). Thus, although both inter- and
intramolecular carbonyl additions are controlled by transition
state considerations, the intramolecular nature of the latter
prevents the attacking group from approaching the carbonyl
syn to the smaller alpha substituent.26
In summary, the present synthesis of the callipeltoside
aglycone utilizes novel Oppolzer and Roskamp methodolo-
gies for polyketide synthesis. Our inability to lithiate vinylic
iodides 13, 14, and 15 is noteworthy, suggesting certain
limitations of this typically trivial synthetic operation. The
use of the complex diazo ester 29 for the â-keto ester
homologation represents a new application of the heretofore
little used Roskamp methodology.
with ethanolic NaOEt and oxidation of the alcohol 39 with
the Dess-Martin periodinane reagent afforded aldehyde 40.
Treatment of this aldehyde with CrCl2 and NiCl2(dppp)2 in
DMSO and DMS then afforded the macro lactone 41 as a
single diastereomer in 71% yield.17
In our initial consideration of the intramolecular K-N-H
reaction we carried out a molecular mechanics analysis of a
truncated methyl ester analogue of the aldehyde 40. The
analysis indicated that the carbonyl oxygen is oriented anti
with respect to the C7 hydrogen in a Felkin-Anh conforma-
tion (see the Supporting Information). This arrangement
would afford the cis-adduct with the desired callipeltoside
stereochemistry. However, the formation of the trans isomer
41 as the sole adduct must result from an anti-Felkin-Ahn
conformation. A possible explanation emerges from a
consideration of the likely transition states for the two
alternative additions. The 1,3-disposition of the C6 and C8
methyl groups strictly limits rotation of the C7/C8 bond to
minimize a potential 1,3 eclipsing interaction, but the C8/
C9 bond suffers no such constraints. While the calculated
conformation of the truncated aldehyde 40 conforms to the
Felkin-Anh arrangement, the intramolecular nature of the
addition requires attack of the vinylic Cr moiety to be cis to
Acknowledgment. We are indebted to Martin Herold for
his assistance in NMR data analysis and for helpful discus-
sions of various experimental procedures and to Jesse
Sabatini for his valuable assistance in additional studies on
the zincation of vinylic iodides 13 and 15.
Supporting Information Available: Experimental de-
tails, spectral data for new compounds, and a minimized
structure representation for aldehyde 40. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL702024B
(26) It should be noted that anti-Felkin-Anh attack on the non-Felkin-
Anh conformation of aldehyde 40 affords the same product (trans) that
would be produced from Felkin-Anh addition to the Felkin-Anh confor-
mation. However, steric constraints would expectedly disfavor this latter
pathway in the present case.
96
Org. Lett., Vol. 10, No. 1, 2008