Asymmetric solid-phase synthesis of 6,6-spiroketals

Article abstract of DOI:10.1002/anie.200353609

Structurally simplified spiroketals derived from natural products often retain the biological activity of the parent compound. An asymmetric solid-phase synthesis with boron-mediated aldol reactions as key stereodifferentiating transformations provides 6,

Full text of DOI:10.1002/anie.200353609

Angewandte
Chemie
libraries requires the availability of efficient and practical
methods for the multistep solid-phase synthesis (typically
more than 10 linear steps) of frameworks of biologically
promising natural products. The efficiency and selectivity of
these methods must be comparable to those of competing
solution-phase techniques. To date this goal has been attained
in only a few cases.[1,4]
Herein we report a stereoselective solid-phase synthesis of
6,6-spiroketals[5] with stereoselective aldol reactions of boron
enolates as key stereodifferentiating transformations. The
synthesis proceeds in 12 linear steps and provides access to
the desired spiroketals in preparatively viable overall yields
and with very high stereoselectivity.
6,6-Spiroketals are the prevalent underlying structural
element in a wide range of important natural products with
differing biological activity,such as the spongistatins 1 and
okadaic acid (2; Scheme 1).[6,7] Importantly,structurally
simplified spiroketals derived from natural products retain
their biological activity[7] (see Scheme 1),so that the under-
lying 6,6-spiroketal structure is suitable as a starting point for
the development of natural product derived compound
libraries. The usefulness of spiroketals in combinatorial
Asymmetric Synthesis
Asymmetric Solid-Phase Synthesis of
6,6-Spiroketals**
Okram Barun, Stefan Sommer, and Herbert Waldmann*
The solid-phase synthesis of compound libraries with a
predetermined profile of properties has evolved as a key
enabling technique in postgenomic chemical biology and
medicinal chemistry. The underlying chemical structures of
the compound libraries should have significance in nature.
Ideally they should be biologically validated[1] and/or feature
so-called privileged structures,that is,structures that enable
the library members to bind to several different proteins.[2]
The precondition of biological validation is fulfilled by
biologically active natural products,which can be regarded as
ligands selected by evolution for structurally conserved yet
genetically mobile protein domains.[1] As this insight suggests,
natural product derived compound libraries are promising
starting points for research in chemical biology and lead
development in medicinal chemistry.[1,3] The synthesis of such
[*] Dr. O. Barun, Dipl.-Chem. S. Sommer, Prof. Dr. H. Waldmann
Max-Planck-Institut für molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Universität Dortmund, Fachbereich 3, Organische Chemie
Fax: (+49)231-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
[**] This research was supported by the Max-Planck-Gesellschaft and
the Fonds der Chemischen Industrie. O.B. was supported by a
research fellowship from the Alexander von Humboldt Foundation
and S.S. by a KekulØ Fellowship from the Fonds der Chemischen
Industrie.
Scheme 1. Biologically active natural products with spiroketal substruc-
tures and structurally simplified biologically active analogues.
Angew. Chem. Int. Ed. 2004, 43, 3195 –3199
DOI: 10.1002/anie.200353609
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3195

Communications
chemistry and a method for their synthesis on solid support
both polymer-bound and soluble chiral boron enolates. A few
examples of stereoselective aldol reactions with soluble[9] and
polymer-bound[10] chiral enolates have been described. How-
ever,the use of polymer-bound chiral boron enolates in aldol
reactions has not yet been explored.
have already been reported by Ley and co-workers.[8]
In planning the synthesis we chose compounds of the
general structure 3 as targets (Scheme 2),which were traced
The feasibility of the strategy was investigated first in
solution with the Z diisopinocampheyl borinate 11[11] and the
E enolate 13,[12] which led to the formation of the corre-
sponding syn and anti aldol adducts,respectively
(Scheme 3).[13] The absolute configuration of the aldol
Scheme 3. Solution-phase synthesis of the spiroketal 15: a) NaH (1.5 equiv),
PMBCl (1.1 equiv), DMF, 08C!RT, 24 h, 63%; b) (COCl)2 (1.5 equiv), DMSO
(2.5 equiv), Et3N (4 equiv), CH2Cl2, ꢀ78!08C, 2 h, 93%; c) 3-pentanone
(1 equiv), (ꢀ)-Ipc2BOTf (1.2 equiv), DIEA (1.5 equiv), CH2Cl2, ꢀ78!ꢀ308C,
20 h; d) 30% aqueous H2O2/MeOH/buffer (pH 7) (1.5:5:1), 08C!RT, 2 h,
69%; e) TBSCl (1.3 equiv), imidazole (2.1 equiv), DMF, room temperature,
24 h, 91%; f) (c-C6H11)2BCl (1.3 equiv), Et3N (1.5 equiv), Et2O, 08C, 4 h; g) 10
(1.4 equiv), Et2O, ꢀ78!ꢀ308C, 24 h; h) 30% aqueous H2O2/MeOH/buf-
fer (pH 7) (1.5:5:1), 08C!RT, 2 h, 89%; i) TBSCl (1.3 equiv), imidazole
(2.5 equiv), DMF, room temperature, 24 h, 92%; j) DDQ (2.8 equiv), CH2Cl2/
buffer (pH 7), 08C!RT, 3 h, 88%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone, DIEA=N,N-diisopropylethylamine, DMF=N,N-dimethylformamide,
DMSO=dimethyl sulfoxide, TBS=tert-butyldimethylsilyl, Tf=trifluoro-
methanesulfonyl.
Scheme 2. Retrosynthetic analysis of the 6,6-spiroketal struc-
tures.
back in a retrosynthetic sense to aldol adducts 4, 5,and 7. We
planned to attach one of the hydroxy groups required for
acetal formation to the solid support. The other alcohol group
was to be protected by a functional group of the same
chemical type as the anchor. Thus,final release from the
polymeric carrier would be accompanied by cleavage of the
protecting group,and under appropriate conditions by
spontaneous ketalization to give the desired spiroketals 3 in
a single step. We anticipated that these conditions would be
fulfilled by the p-methoxybenzyl (PMB) ether protecting
group and the corresponding Wang linker (Scheme 2).
Immobilized aldol intermediates 4 and 7 might be formed
by means of asymmetric boron-mediated aldol reactions with
adduct 14 was assigned based on the assumption that the
stereochemical course of the reaction is analogous to that
observed in related cases.[14] The simultaneous oxidative
cleavage of both PMB protecting groups proceeded smoothly
and was followed—as hoped—by the spontaneous formation
of the spiroketal 15,which was obtained as a single isomer.
The configuration of compound 15 was ascertained after
deprotection by means of NOE experiments and by compar-
ison of spectroscopic data with those of known compounds.
After the development of this reaction sequence in
solution we investigated whether it could be transferred to
the solid phase (Scheme 4). The Merrifield resin equipped
with the Wang linker (16; loading 1.2 mmolgꢀ1) was activated
3196
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 3195 –3199

Angewandte
Chemie
alcohol was protected as its TBS ether to yield the
immobilized aldol product 18 (monitored by FT-IR
spectroscopy).
To form the polymer-bound chiral boron enolate
required for the crucial second aldol reaction,the
ketone resin 18 was swollen in diethyl ether and then
a solution of chlorodicyclohexylborane and triethyl-
amine in diethyl ether was added to the resin at 08C.
After 6 h the resin was washed and the addition of the
reagents was repeated. As expected by analogy with
enolate formation in solution (see above and refer-
ence [12]) the E dicyclohexylboron enolate 19 was
formed on the solid support. The boron enolate resin
19 was then treated at ꢀ788C with the aldehyde 10,
and after oxidative workup as described above the
free secondary alcohol (strong absorption at
3504 cmꢀ1 and 1714 cmꢀ1 in the IR spectrum) was
protected as the TBS ether 20.
The treatment of the intermediate 20 with DDQ
in a mixture of CH2Cl2 and an aqueous buffer (pH 7)
resulted in the simultaneous cleavage of the PMB
ether,release from the Wang resin,and spiroketal-
ization. After purification by filtration through a
short column of silica gel,the spiroketal 15 was
obtained as a single stereoisomer,as determined by
1
HPLC as well as H and 13C NMR spectroscopy.[13]
NOE investigations and comparison of spectroscopic
data and the specific rotation revealed that the
product was identical to the spiroketal 15 synthesized
in solution as described above.
The spiroketal 15 was obtained in this 12-step
solid-phase synthesis in an overall yield of 16%,
which corresponds to an average yield of 86% per
step. This compares very favorably with the overall
yield of 27% recorded for the 10-step synthesis in
solution described above. The fact that the spiroketal
obtained from the solid-phase synthesis had the same
configuration as that obtained from the solution-
phase synthesis is evidence that both aldol reactions
on the polymeric support proceed by full analogy
with the corresponding asymmetric transformations
in solution. Furthermore,the degree of stereodiffer-
entiation is very similar in both cases.
Scheme 4. Solid-phase synthesis of the spiroketal 15: a) C C3Cl N (8 equiv), DBU
(3 mol%), CH2Cl2, 08C, 40 min; b) TBSO(CH2)3OH (5 equiv), BF3·Et2O
(3 mol%), cyclohexane, CH2Cl2, room temperature, 15 min; c) TBAF (8 equiv),
THF, room temperature, 14 h; d) IBX (8 equiv), DMSO, room temperature,
36 h; e) 3-pentanone (6 equiv), (ꢀ)-Ipc2BOTf (6.1 equiv), DIEA (7 equiv),
CH2Cl2, ꢀ78!08C, 20 h; filter and wash (two cycles); f) 30% aqueous H2O2/
MeOH/DMF/buffer (pH 7) (1.5:4:4:1), 08C, 8 h; g) TBSCl (10 equiv), DMAP
(1 mol%), imidazole (10 equiv), DMF/CH2Cl2 (1:1), room temperature, 24 h
(two cycles); h) (c-C6H11)2BCl (8 equiv), Et3N (9 equiv), Et2O, 08C, 24 h; filter
and wash (two cycles); i) 10 (10 equiv), E2O, ꢀ78!208C, 26 h (2 cycles);
j) 30% aqueous H2O2/MeOH/DMF/buffer (pH 7) (1.5:4:4:1), 08C, 8 h; k) TBSCl
(10 equiv), DMAP (1 mol%), imidazole (10 equiv), DMF/CH2Cl2 (1:1), room
temperature, 24 h (two cycles); l) DDQ (10 equiv), CH2Cl2/buffer (pH 7) (20:1),
08C!RT, 6 h. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP=4-dimethyl-
aminopyridine.
To demonstrate that the reaction sequence shown
in Scheme 4 is amenable to the synthesis of com-
pound libraries,three different functionalized spiro-
ketals were synthesized. Thus,the chiral aldehydes
as the corresponding trichloroacetimidate,[15] which was then
subjected to nucleophilic displacement by mono-TBS-pro-
tected 1,3-propanediol. This two-step sequence was conven-
iently monitored by FT-IR spectroscopy. After cleavage of
the TBS group the primary alcohol was oxidized to the
corresponding aldehyde 17 by 2-iodoxybenzoic acid (IBX).
At this stage resin loading was determined to be
0.75 mmolgꢀ1.[16] The polymer-bound aldehyde 17 was then
treated at ꢀ788C with the preformed Z enolate 11 in
dichloromethane,and the reaction mixture was allowed to
warm to 08C. This procedure was repeated once. After
21, 23,and 25 were prepared[17] and subjected to aldol
reactions with the boron enolate 19 (Scheme 5). After workup
and release from the solid support the spiroketals 22, 24,and
26 were obtained as single isomers in overall yields of 7,13,
and 6%,respectively.
To gain further insight into the stereoselectivity of the
asymmetric boron-mediated aldol reactions on the solid
support,we investigated whether the principle of double
diastereodifferentiation also operates in this case. To this end,
the aldehyde 27 was prepared and treated with 19 under the
aldol reaction conditions. The spiroketal 28 was obtained in
10% overall yield as an inseparable mixture with two other
ꢀ
oxidative workup to cleave the B O bond the secondary
Angew. Chem. Int. Ed. 2004, 43, 3195 –3199
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3197

Communications
[2] B. E. Evans,K. E. Rittle,M. G. Bock,R. M. DiPrado,R. M.
Freidinger,W. L. Whitter,G. F. Lundell,D. F. Veber,P. S.
Anderson,R. S. L. Chang,V. J. Lotti,D. J. Cerino,T. B. Chen,
P. J. Cling,K. A. Kunkel,J. P. Springer,J. Hershfield,
Chem. 1988, 31,2235 – 2246.
J. Med.
[3] a) W. P. Walters,M. Ajay,M. A. Murko, Curr. Opin. Chem. Biol.
1999, 3,384 – 387; b) G. W. Bemis,M. A. Murko, J. Med. Chem.
1996, 39,2887 – 2893; c) A. K. Ghose,V. N. Vishwanadhan,J. J.
Wendolosky, J. Comb. Chem. 1999, 1,55 – 68. d) M.-L. Lee,G.
Schneider, J. Comb. Chem. 2001, 3,284 – 289.
[4] For a review,see: P. Arya,R. Joseph,D. T. H. Chou, Chem. Biol.
2002, 9,145 – 156.
[5] a) F. Perron,K. F. Albizati, Chem. Rev. 1989, 89,1617 – 1661;
b) K. T. Mead,B. N. Brewer, Curr. Org. Chem. 2003, 7,227 – 256.
[6] B. A. Kulkarni,G. P. Roth,E. Lobkovsky,J. A. PorcoJ, r.,
J.
Comb. Chem. 2002, 4,56 – 72.
[7] a) H. Huang,C. Mao,S.-T. Jan,F. M. Uckun, Tetrahedron Lett.
2000, 41,1699 – 1702; b) M. Uckun,C. Mao,A. O. Vassilev,H.
Huang,S. T. Jan, Bioorg. Med. Chem. Lett. 2000, 10,541 – 545;
c) S. Mitsuhashi,H. Shima,T. Kawamura,K. Kikuchi,M.
Oikawa,A. Ichihara,H. Oikawa, Bioorg. Med. Chem. Lett. 1999,
9,2007 – 2012.
Scheme 5. Solid-phase synthesis of the spiroketals 22, 24, and 26; for reac-
tion conditions, see Scheme 4.
[8] R. Haag,A. G. Leach,S. V. Ley,M. Nettekoven,J. Schnaubelt,
Synth. Commun. 2001, 31,2965 – 2977.
[9] For iterative aldol reactions on a solid support,see: a) M.
Reggelin,V. Brenig, Tetrahedron Lett. 1996, 37,6851 – 6852;
b) C. Gennari,S. Ceccarelli,U. Piarulli,K. Aboutayab,M.
Donghi,I. Paterson, Tetrahedron 1998, 54,14999 – 15016; c) I.
isomers in a ratio of 90:7:3 (Scheme 6; determined by GC–
MS). Thus,in both aldol reactions of the chiral enolate 19 with
the enantiomeric aldehydes 23 and 27 the anti adduct is
Paterson,M. Donghi,K. Gerlach,
Angew. Chem. 2000, 112,
3453 – 3457; Angew. Chem. Int. Ed. 2000, 39,3315 – 3319; d) I.
Paterson,T. Temal-Laib, Org. Lett. 2002, 4,2473 – 2476.
[10] For the use of polymer-bound enolates in different reactions,
see: a) P. M. Worster,C. R. McArthur,C. C. Leznoff, Angew.
Chem. 1979, 91,255; Angew. Chem. Int. Ed. Engl. 1979, 18,221 –
222; b) S. M. Jelin,S. J. Shuttleworth, Tetrahedron Lett. 1996, 37,
8023 – 8026; c) K. Burgess,D. Lim, Chem. Commun. 1997,785 –
786.
[11] a) I. Paterson,J. M. Goodman,M. A. Lister,R. C. Schuman,
C. K. McClure,R. D. Norcross, Tetrahedron 1990, 46,4663 –
4684; b) I. Paterson,A. N. Hulme, J. Org. Chem. 1995, 60,
3288 – 3300.
[12] a) H. C. Brown,R. K. Dhar,R. K. Bakshi,P. K. Pandiarajan,B.
Singaran, J. Am. Chem. Soc. 1989, 111,3441 – 3442; b) D. A.
Evans,D. L. Rieger,M. T. Bilodeau,F. Urpi, J. Am. Chem. Soc.
1991, 113,1047 – 1049; c) I. Paterson,M. V. Perkins, Tetrahedron
Lett. 1992, 33,801 – 804.
Scheme 6. Double diastereodifferentiation in the aldol reaction on the
solid support.
[13] The syn configuration of the aldol adduct 12 was assigned based
on the coupling constant of J = 4.7 Hz for CH(OH)CH(CH3)
and CH(OH)CH(CH3) of the deprotected adduct and compar-
ison with literature values.[11] The diastereomeric ratio was
determined by HPLC of the crude product; the ee value by GC
on a chiral phase and by NMR spectroscopy in the presence of a
chiral europium shift reagent. The anti configuration of the aldol
adduct 14 was assigned based on the coupling constant of J =
9.7 Hz for CH(OH)CH(CH3) and CH(OH)CH(CH3) and com-
parison with literature values.[12] The diastereomeric ratio was
formed as the major product. In accordance with related
findings[18] the combination of 19 with 23 represents the
matched case and the combination of 19 with 27 the
mismatched case.
Received: December 22,2003 [Z53609]
1
determined by HPLC and H NMR spectroscopy of the crude
reaction mixture (see Supporting Information). Analysis of the
crude product 15 (Scheme 4) by GC–MS showed only one
spiroketal stereoisomer. Analytical data for compound 15: Rf =
Keywords: asymmetric synthesis · chemical biology ·
.
natural products · solid-phase synthesis · spiro compounds
0.34 (silica gel,cyclohexane),[ a]2D0 = +104.4 (c = 0.80,CHCl 3),
ꢀ1
IR (KBr): n˜max = 3015,2859,1255 cm
;
1H NMR (400 MHz,
CDCl3): d = 4.27 (dt, J1 = 11.5, J2 = 4.9 Hz,1H),3.70–3.59 (m,
4H),3.53–3.50 (m,1H),2.17–2.10 (m,1H),1.82–1.45 (m,4H),
1.39–1.34 (m,1H),1.15 (d, J = 6.6 Hz,3H),1.03 (d, J = 6.8 Hz,
3H),0.89 (s,9H),0.88 (s,9H),0.51 (s,3H),0.04 ppm (s,9H);
13C NMR (100 MHz,CDCl 3): d = 102.7,72.7,66.9,59.3,58.0,
[1] R. Breinbauer,I. Vetter,H. Waldmann, Angew. Chem. 2002, 114,
3002 – 3150; Angew. Chem. Int. Ed. 2002, 41,2878 – 2890,and
references therein.
3198
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 3195 –3199

Angewandte
Chemie
44.4,43.4,35.5,29.6,26.1,26.1,18.4,18.3,14.0,9.6,
ꢀ3.9, ꢀ4.2,
[16] D. Brohm,N. Philippe,S. Metzger,A. Bhargava,O. Müller,F.
ꢀ4.4, ꢀ4.4 ppm; GC–MS (m/z,%): 444 ( M+,8),387 ([ Mꢀ57]+,
15); HRMS (EI,70 eV) calcd for C 23H48O4Si2: 444.3091,found:
404.3099.
Lieb,H. Waldmann, J. Am. Chem. Soc. 2002, 124,13171 – 13178.
[17] a) I. Paterson,C. Savi,M. Tudge, Org. Lett. 2001, 3,3149 – 3152;
b) A. B. Smith III,T. J. Beauchamp,M. J. LaMarche,M. D.
Kaufman,Y. Qiu,H. Arimoto,D. R. Jones,K. Kobayashi, J. Am.
Chem. Soc. 2000, 122,8654 – 8664; c) J. Nokami,K. Nomiyama,
S. Matsuda,N. Imai,K. Kataoka, Angew. Chem. 2003, 115,1311 –
1314; Angew. Chem. Int. Ed. 2003, 42,1273 – 1276.
[14] a) K. C. Nicolaou,J. Xu,F. Murphy,S. Barluenga,O. Baudoin,
H. Wei,D. L. F. Gray,T. Ohshima, Angew. Chem. 1999, 111,
2599 – 2604; Angew. Chem. Int. Ed. 1999, 38,2447 – 2451; b) A.
Vulpetti,A. Bernardi,C. Gennari,J. M. Goodman,I. Paterson,
Tetrahedron 1993, 49,685 – 696.
[18] D. A. Evans,M. J. Dart,J. L. Duffy,D. L. Rieger, J. Am. Chem.
Soc. 1995, 117,9073 – 9074.
[15] S. Hanessian,F. Xie, Tetrahedron Lett. 1998, 39,733 – 736.
Angew. Chem. Int. Ed. 2004, 43, 3195 –3199
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3199