Total synthesis of (-)-saliniketals A and B?

Article abstract of DOI:10.1021/ol801148d

(Chemical Equation Presented) A stereocontrolled total synthesis of the orthinine decarboxylase inhibitors saliniketals A and B is described. Key features of the 17-step route include the use of two boron aldol/reduction sequences to control six of the ni

Full text of DOI:10.1021/ol801148d

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3295-3298
Total Synthesis of (-)-Saliniketals A
and B†
Ian Paterson,* Mina Razzak, and Edward A. Anderson
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ip100@cam.ac.uk
Received May 20, 2008
ABSTRACT
A stereocontrolled total synthesis of the orthinine decarboxylase inhibitors saliniketals A and B is described. Key features of the 17-step route
include the use of two boron aldol/reduction sequences to control six of the nine stereocenters, an intramolecular Wacker-type cyclization to
install the bicyclic acetal core, and a late-stage Stille coupling to append the requisite (2Z,4E)-dienamide.
Saliniketals A (1) and B (2), isolated in 2007 by Fenical
and co-workers from the marine actinomycete Salinispora
arenicola, are inhibitors of ornithine decarboxylase (ODC)
induction.1 ODC hyperactivity is a marker of tumorigenesis
and is often seen in epithelial tumors of the colon, skin,
prostate, and stomach.2 As such, ODC inhibitors may
potentially be valuable chemotherapeutic or chemopreven-
tative agents.3
The novel structures of these unusual bioactive polyketides,
comprising a 2,8-dioxabicyclo[3.2.1]octane ring featuring an
elaborate side chain at C11 that terminates in an unsaturated
primary amide, were determined mainly by 2D-NMR
spectroscopic methods, with the absolute configuration
assigned by Mosher ester analysis. Intriguingly, the salini-
ketals show a structural resemblance to the ansa chain of
the rifamycin antibiotics, which co-occur within the fermen-
tation broth. By employing our versatile boron aldol meth-
odology, we now report the first total synthesis of saliniketals
A and B, invoking a late-stage diversification strategy to
append the requisite dienamide terminus.
As outlined in Scheme 1, we envisaged that both salini-
ketal A (1) and its more oxygenated congener, saliniketal B
(2), may be accessible from the common C4-C17 interme-
diate 3. This is primed for a Stille coupling4 with either vinyl
bromide 4 or 5 to install the appropriate (2E,4Z)-dienamide.
Disconnection of the C8-C9 bond in 3 reveals aldehyde 6
and ethyl ketone (S)-7, where the use of a substrate-controlled
anti-aldol /reduction sequence5 would enable installation of
the C6-C9 stereotetrad. The dioxabicyclic core present in
6 might then be constructed by an intramolecular Wacker-
type cyclization of the olefinic 1,3-diol 8. This diol would
itself be configured using a reagent-controlled syn-aldol
reaction, now requiring the use of the enantiomeric ethyl
ketone (R)-7.
Commencing with the reagent-controlled aldol reaction of
(R)-7 (Scheme 2),5 formation of the (Z)-boron enolate6 9 ((+)-
Ipc2BOTf, i-Pr2NEt), followed by addition of 4-pentenal,
† Dedicated to the late Jonathan (Joe) Spencer, a greatly missed colleague
and friend.
(1) Williams, P. G.; Asolkar, R. N.; Kondratyuk, T.; Pezzuto, J. M.;
Jensen, P. R.; Fenical, W. J. Nat. Prod. 2007, 70, 83.
(4) (a) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(5) (a) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287. (b) Paterson, I.; Cumming,
J. G.; Ward, R. A.; Lamboley, S. Tetrahedron 1995, 51, 9393. (c) Paterson,
I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(2) (a) Saunders, L. R.; Verdin, E. Mol. Cancer Ther. 2006, 5, 2777.
(b) Thomas, T.; Thomas, T. J. Cell. Mol. Life Sci. 2001, 58, 244.
(3) (a) Basuroy, U. K.; Gerner, E. W. J. Biochem. 2006, 139, 27. (b)
Gerner, E. W., Jr Nat. ReV. Cancer 2004, 4, 781.
10.1021/ol801148d CCC: $40.75
Published on Web 06/26/2008
2008 American Chemical Society

their elegant synthesis of endo-brevicomin, Grigg and co-
workers10 first demonstrated that Wacker oxidation conditions
(catalytic Pd(II) with Cu(II) as the reoxidant) could be used to
convert olefinic 1,3-diols into cyclic acetals.11 Hence, an
intramolecular Wacker-type12 cyclization of the 1,3-diol 8 was
examined, with the aim of installing the C16 oxygenation in a
regio- and stereocontrolled manner. After screening several
reaction conditions (Table 1, entries 1-3), the use of catalytic
Scheme 1
Table 1. Conditions for Intramolecular Wacker Oxidation of 8
entry
X
solvent
temp. (°C)
yield (%)a
1
2
3
4
NO3
OAc
Cl
THF
THF
20
20
20
0
48b
50b
23b
88
DMA/THF/H2Oc
THF
Cl
a Isolated yield. b Several byproducts were also formed. c 7:2:1.
PdCl2 and CuCl2 in THF under an atmosphere of oxygen at 0
°C was found to give a good yield (88%) of the acetal 11 (entry
generated the syn adduct 10 in 92% yield with the expected
high diastereoselectivity (dr >20:1).7 Installation of the C11
Scheme 3
Scheme 2
4). The desired [3.2.1]-dioxabicycle 11 likely arises from the
expected 5-exo attack of the C13 hydroxyl onto the palladium-
stereocenter was next achieved by a 1,3-anti reduction.
Evans-Tischenko8 conditions (SmI2, EtCHO) were selected
which, following K2CO3-mediated solvolysis of the ensuing
ester, afforded the 1,3-diol 8 cleanly (98%, dr ) 99:1).7,9
Formation of the characteristic 2,8-dioxabicyclo-[3.2.1]-
octane ring system of the saliniketals was now addressed. In
(9) Confirmation of the desired C11-C13 and C7-C9 stereochemistry
was provided by preparation of the acetonides and 13C NMR analysis: (a)
Rychnovsky, S. D.; Skalitzky, D. J Tetrahedron Lett. 1990, 31, 945. (b)
Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099.
(10) Byrom, N. T.; Grigg, R.; Kongkathip, B. J. Chem. Soc., Chem.
Commun. 1976, 6, 216.
(11) Subsequently, similar acetals have been installed using slightly
modified conditions in syntheses of various insect pheromones and terrestrial
natural products. For examples, see: (a) Kongkathip, B.; Kongkathip, N.
Tetrahedron Lett. 1984, 25, 2175. (b) Mori, K.; Seu, Y.-B. Tetrahedron
1985, 41, 3429. (c) Bulman Page, P. C; Rayner, C. M.; Sutherland, I. O.
Tetrahedron Lett. 1986, 27, 3535. (d) Ploysuk, C.; Kongkathip, B.;
Kongkathip, N. Synth. Commun. 2007, 37, 1463.
(6) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Paterson,
I.; Lister, M. A. Tetrahedron Lett. 1988, 29, 585.
(7) See the Supporting Information for details of stereochemical
assignments.
(8) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
3296
Org. Lett., Vol. 10, No. 15, 2008

Scheme 4
alkene complex 12 (Scheme 3), followed by ꢀ-hydride elimina-
tion and acid-catalyzed acetal formation. Owing to its skeletal
which (PdCl2(PPh3)2, Bu3SnH)16 then provided the vinyl
stannane 3 (77%).
rigidity linked with the avoidance of syn-pentane interactions,
With the common C4-C17 stannane 3 in hand, attention
now turned to the preparation of the requisite Stille coupling
partners 4 and 5 for saliniketal A and B, respectively (Scheme
5). In the former case, this proved relatively straightforward
1
the H and 13C NMR data for the bicyclic acetal 11 matched
well with that for the corresponding region of saliniketal A.7
With the correctly configured ring system in hand,
elaboration of the saliniketal side chain was now required
(Scheme 4). Debenzylation of 11 (Pd/C, H2) and Dess-Martin
oxidation gave the aldehyde 6 (88%), primed for a substrate-
controlled anti-aldol reaction with the ethyl ketone (S)-7.4,13
Using our standard conditions (c-Hex2BCl, Et3N),13 eno-
lization of (S)-7 generated the (E)-boron enolate 13, and
addition of aldehyde 6 gave the desired anti-adduct 14 in
80% yield.7 Despite the significant steric demands of the
aldehyde component, this mismatched aldol coupling pro-
ceeded efficiently (dr ) 13:1) due to the excellent 1,4-syn
stereoinduction arising from the enolate 13.
Scheme 5
A sequence of Evans-Tischenko reduction of the ꢀ-hy-
droxy ketone 14,8 ester solvolysis, and acetonide formation
then gave 15 (92%, dr ) 85:1).7,9 While initial attempts to
cleave the benzyl ether in 15 using standard Pd/C hydro-
genolysis conditions led to acetonide migration, the use of
Raney Ni afforded the desired primary alcohol cleanly.
Oxidation with Dess-Martin periodinane then gave aldehyde
16 (99%) which was then progressed to the alkyne, initially
using the Ohira-Bestmann conditions.14 However, this
resulted in significant epimerization of the C6 stereocenter.
To circumvent this problem, the Corey-Fuchs procedure was
employed.15 By buffering with Et3N, conversion of 16 to
the corresponding vinyl dibromide proceeded in good yield
(81%) without any epimerization. Treatment with n-BuLi
afforded the alkyne, Pd-catalyzed syn-hydrostannation of
by chromatographic separation of a commercially available
mixture of (E)- and (Z)-3-bromo-2-methylacrylonitrile. The
more polar (Z)-isomer17 17 was then hydrolyzed under
oxidative conditions (K2CO3, H2O2)18 to give the corre-
sponding primary amide 4. Owing to the additional oxygen-
ation present in saliniketal B, the synthesis of the required
amide 5 proved more involved. Starting from phosphonate
18, a base-mediated addition to formaldehyde and elimination
(12) Tsuji, J. Synthesis 1984, 369.
(16) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
(13) (a) Paterson, I.; Scott, J. P. J. Chem. Soc., Perkin Trans. 1 1999,
1003. (b) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
(17) Based on analogous results for a similar system, the desired isomer
was assumed to be the major product and was separated from the mixture
by flash chromatography: Han, Q.; Wiemer, D. F J. Am. Chem. Soc. 1992,
114, 7692.
30, 7121
.
(14) (a) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett.
1996, 6, 521. (b) Ohira, S. Synth. Commun. 1989, 19, 561.
(15) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(18) Crowley, B. M.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 2885.
Org. Lett., Vol. 10, No. 15, 2008
3297

afforded the allylic alcohol 19.19 Following TBS ether
formation, bromination of the alkene and treatment with
DBU then led to the vinyl bromide 20 (2:1 E/Z).17 Unex-
pectedly, the nitrile in (E)-20 proved to be resistant to
hydrolysis, and although low yielding, this was achieved
using NH3/H2O2 to afford amide 5.
With the vinyl bromides 4 and 5 both available, it was
now an appropriate time to explore the endgame exploiting
the Stille coupling reaction4 of the stannane 3 (Scheme 6).
Cleavage of the acetonide was then performed with Dowex
50Wx8 acidic resin in MeOH. Gratifyingly, the spectroscopic
data (1H, 13C NMR, and MS) obtained and the measured
20
specific rotation, [R]D -10.0 (c 0.10, MeOH), cf. -13.7
(c 0.133, MeOH), correlated with that reported for natural
(-)-saliniketal A (1), thus corroborating the stereostructure
assigned by the Fenical group.1 Similarly, Stille coupling
between 3 and the bromide 5 also proceeded smoothly to
give the (2Z,3E)-diene 22 (69%), the final intermediate
enroute to saliniketal B. This was easily deprotected using
the same conditions as before to give 2 (92%) which had
20
spectroscopic data and a specific rotation, [R]D -10.8 (c
Scheme 6
0.12, MeOH), cf. -22.4 (c 0.107 MeOH), in accord with
that reported for natural (-)-saliniketal B.1
In conclusion, we have completed the first total synthesis
of saliniketals A and B, novel polyketide inhibitors of
ornithine decarboxylase isolated from the marine actino-
mycete Salinispora arenicola, and validated their full
configurational assignment. By using our versatile boron
aldol methodology, (-)-saliniketal A was prepared in 17
steps (longest linear sequence) from ketone (R)-7 in an
overall yield of 18.4%, while (-)-saliniketal B was com-
pleted in 18.6% yield. This work should provide a platform
for the facile evaluation of side chain analogues of the
saliniketals as potential anticancer agents.
Acknowledgment. We thank the EPSRC (EP/C541677/
1), the Tertiary Education Commission of New Zealand
(M.R.), and Merck Research Laboratories for support.
Supporting Information Available: Experimental details,
For saliniketal A (1), this proceeded well with catalytic
Pd2(dba)3 in toluene at 80 °C, leading to cross-coupling with
the bromide 4 to produce the (2Z,3E)-diene 21 in 70% yield.
1
spectroscopic data, and copies of H and 13C NMR spectra
for new compounds and synthetic 1 and 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Csuk, R.; Ho¨ring, U.; Schaade, M. Tetrahedron 1996, 52, 9759.
OL801148D
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Org. Lett., Vol. 10, No. 15, 2008