Solid-phase synthesis of [5.5]-spiroketals

Article abstract of DOI:10.1002/adsc.200800154

An efficient and reliable multi-step synthesis of 251 natural product-like [5.5]-spiroketals on solid supports has been developed. As central key step, a double intramolecular hetero-Michael (DIHMA) reaction to alkynones was applied. The sequence allows for introduction of numerous substituents on the scaffold and for variation of stereochemistry. [5.5]-Spiroketals bearing an additional ketone were obtained in high overall yields. Further diversification was achieved by reduction of the ketone and reductive amination using polymer-supported borohydride, Grignard reaction and conversion to oxime derivatives in the solution phase.

Full text of DOI:10.1002/adsc.200800154

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DOI: 10.1002/adsc.200800154
Solid-Phase Synthesis of [5.5]-Spiroketals
Stefan Sommer,a Marc Kühn,a and Herbert Waldmanna,*
a
Chemische Biologie, TU Dortmund and Max-Planck-Institut für Moleculare Physiologie, Abteilung Chemische Biologie,
Otto-Hahn-Straße 11, 44227 Dortmund, Germany
Fax : (+49)-231-133-2499; e-mail: herbert.waldmann@mpi-dortmund.mpg.de
Received: March 14, 2008; Published online: July 9, 2008
Dedicated to Professor Chi-Huey Wong on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient and reliable multi-step synthe- ketone were obtained in high overall yields. Further
sis of 251 natural product-like [5.5]-spiroketals on diversification was achieved by reduction of the
solid supports has been developed. As central key ketone and reductive amination using polymer-sup-
step,
a
double intramolecular hetero-Michael ported borohydride, Grignard reaction and conver-
(DIHMA) reaction to alkynones was applied. The sion to oxime derivatives in the solution phase.
sequence allows for introduction of numerous sub-
stituents on the scaffold and for variation of stereo- Keywords: asymmetric synthesis; chemical biology;
chemistry. [5.5]-Spiroketals bearing an additional natural products; solid-phase synthesis; spiroketals
Introduction
and -inspired compound collections in more than 10
steps on the polymeric carrier.
Biologically active small molecules have proven to be
In the context of employing natural product-in-
valuable tools for the study of biological phenomena. spired compound collections in chemical biology, we
For the synthesis of such molecules in the format of became interested in the synthesis and biological eval-
compound collections with a high degree of substitu- uation of natural product-derived molecules which
ent variation on a given scaffold,[1] in particular, diver- contain a spiroketal as scaffolding unit.
sity-oriented synthesis (DOS)[2] and biology-oriented
The spiroketal unit is a widespread substructure in
synthesis (BIOS)[3] of natural product-derived and -in- many biologically active natural products, including
spired compound collections were recently introduced steroidal saponins, polyether ionophores, macrolide
as hypothesis-generating approaches. BIOS refers to antibiotics, insect pheromones, and toxic metabolites
natural products as evolutionary selected starting from algae and fungi.[6–8]
points for compound collection synthesis. Due to their
Examples are the extraordinarily potent tubulin
biosynthetic origin and their manifold interactions polymerisation inhibiting spongistatins,[9] the protein
with proteins when exerting their functions, the char- phosphatase inhibitors okadaic acid[10] and tautomy-
acteristic structural scaffolds of natural products can cin[11] and the HIV-1 protease inhibitor integramy-
be regarded as biologically prevalidated starting cin.[12] Interestingly, structurally simplified but charac-
points in structure space for compound collection de- teristic spiroketals 1 and 2 derived from the parent
velopment.
natural
products
retain
biological
activity
For the synthesis of natural product-inspired and (Figure 1).[13] The spiroketal motifs present in okadaic
-derived compound collections solid-phase organic acid and tautomycin have an enantiomeric relation-
synthesis is a viable technology. Immobilization of the ship and the stereochemistry of the spiroketal moiet-
substrate on a polymeric carrier enables efficient and ies could be a determining factor for the affinity char-
straightforward removal of all surplus reagents re- acteristics of okadaic acid and tautomycin to the PP1
quired in the multi-step sequences typical for the syn- and PP2A phosphatases.[14] These findings validate
thesis of such compound collections and thereby facil- the choice of the [5.5]-spiroketal as underlying struc-
itates purification of the desired compounds.
tural framework for the development of promising
Thus, we[3,4] and others[1,5] have used this approach natural product-derived compound collections. The
for the synthesis of different natural product-derived usefulness of spiroketals in combinatorial chemistry[15]
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Solid-Phase Synthesis of [5.5]-Spiroketals
Figure 1. Biologically active natural products with spiroketal substructure and structurally simplified yet biologically active
analogues embodying the spiroketal substructures.
and methods for their synthesis on solid supports support by using readily accessible and enantiomeri-
have been reported earlier by us[4f,g] and the groups of cally pure building blocks and employing a double-
Ley and Paterson.[16]
hetero-Michael addition as key transformation.
Herein we describe in detail the development of an
asymmetric synthesis of [5.5]-spiroketals on a solid
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Results and Discussion
ACHTREUNG
tween the ketone and the alkyne leading to fragment
With the aim to synthesise a medium-sized library we 6, a protected 5-hexyn-1-ol, and fragment 7, a b-hy-
searched for a reliable synthesis method to construct droxy aldehyde linked to a solid phase. The aldehyde
the spiroketal scaffold. It should allow a modular ap- can be derived from homoallylic alcohols 8 or b-hy-
proach and variation of the stereochemistry. Further- droxy esters 9 and 10.
more, the building blocks should be readily accessible
The choice of the linker is crucial for every synthe-
and the method should be amenable to solid-phase sis on a solid phase. Since Forsyth and co-workers de-
synthesis to facilitate library construction. Our inter- scribed that DIHMA proceeds preferentially under
est was attracted to a method used successfully by acidic conditions[17] we decided to employ an acid-
Forsyth and co-workers which applies a double intra- labile linker to affect cleavage from the support and
molecular hetero-Michael addition (DIHMA) for spi- cyclisation in one step, and the Wang linker turned
roacetal synthesis.[17,18]
out to be the right choice.
DIHMA followed by reduction of the carbonyl
Polystyrene resin 11 equipped with Wang linker
group gives access to 4-hydroxy-1,7-dioxaspiro- (loading 1.1 mmolgÀ1) was activated as trichloroacet-
[5.5]undecanes. This moiety can be found in a variety
imidate,[19] which was then subjected to nucleophilic
of potent natural products reaching from structurally displacement by a chiral b-hydroxy ester or a homoal-
simple but highly toxic talaromycins to complex oligo- lylic alcohol (Scheme 2). The resin-linked esters 12
mycins, rutamycins, avermectins, milbemycins and were reduced with DIBAH and the corresponding al-
spongistatins.[6–8]
cohols were oxidised using IBX to yield the immobi-
Spiroketal 3 was traced back in the retrosynthetic lised b-hydroxy aldehydes 7. The polymer-bound ho-
sense to ketone-bearing spiroketal 4 which itself moallylic alcohols 13 were subjected to ozonolysis[20]
should be accessible from solid support-linked alkyn- and the ozonide was reduced to aldehydes 7 by addi-
Scheme 1. Retrosynthetic analysis of the [5.5]-spiroketal structures 3 and 4.
Scheme 2. Solid phase synthesis of resin-bound b-hydroxy aldehydes 7. The table shows the different buildings blocks used
in this sequence. a) Cl3CCN (19.0 equiv.), DBU (0.88 equiv.), CH2Cl2, 08C, 40 min; b) alcohol (2.50 equiv.), BF3·Et2O (0.33
equiv.), cyclohexane/CH2Cl2 =1/1, 15 min, 91% over two steps; c) O3, À788C, CH2Cl2, 7-8 min; PPh3 (5.00 equiv.), À788C to
room temperature, 16 h, 70%; d) DIBAH (5.00 equiv.), THF/toluene, room temperature, 5 h, 90%; e) IBX (5.00 equiv.),
DMSO/THF=1/1, room temperature, 16 h, 83%.
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Solid-Phase Synthesis of [5.5]-Spiroketals
Scheme 3. Solid-phase synthesis of spiroketal 29 and solution-phase synthesis of the spiroketal 32. a) alkyne (7.00 equiv.),
1 M EtMgBr in THF (7.00 equiv.), THF, room temperature, 16 h; b) IBX (5.00 equiv.), DMSO/THF=1/1, room tempera-
ture, 16 h; c) 2% MeSO3H in CH2Cl2, room temperature, 30 min; d) (i) solvent exchange to MeOH, 408C to room tempera-
ture, 30 min; (ii) solvent exchange to toluene, room temperature, 2 h, 21% over 4 steps; e) 1,3-mercaptopropane (5.00
equiv.), NaOMe (5.00 equiv.), CH2Cl2/MeOH=1/1, room temperature, 16 h; f) bis[trifluoroacetate]iodobenzene (2.50
equiv.), CH2Cl2/EtOH/H2O=2/2/1; g) TBAF (5.00 equiv.), room temperature, 16 h; h) 5% TFA in CH2Cl2, room tempera-
ture, 30 min, 18% over 6 steps; i) borohydride on Amberlite IRA 400 (~2.5 mmolgÀ1, 3”1.0 equiv.), MeOH, room tempera-
ture, 4.5 h; j) Dowex 50 X8, H+-form, MeOH, room temperature, 30 min, 80% over two steps.
tion of triphenylphosphine. A minimum of 6 min in the silyl protecting group (Scheme 3, Route C). A
ozone-saturated dichloromethane was necessary for second solvent exchange to toluene was necessary to
complete conversion of the support-bound olefin avoid 1,4-addition of methanol to the alkynone and to
while reaction times longer than 9 min already led to favor intramolecular Michael addition of the free hy-
lower aldehyde loading due to oxidative cleavage of droxy functions. Spiroketal 29 was obtained in 13%
the Wang linker. These two sequences could be con- overall yield over seven steps on the support as a
veniently monitored by FT-IR (C=O stretching band single diastereomer (determined by NMR of the
at 1721 cmÀ1). For different substrates (see below), crude product). Purification was achieved by means
resin loading at this stage was determined to be 0.65– of column chromatography.
0.75 mmolgÀ1 by application of a method which is
based on formation of the corresponding dinitrophe- by adding deprotonated 1,3-mercaptopropane to
nylhydrazone.[4a,b,21] one 28 (Scheme 3, Route D).[22] A double
alkyn
An alternative way to spiroketalisation was found
AHCTREUNG
The second part of the synthesis was optimised for hetero-Michael addition introduced the second
the sequence which led to the simple spiroketals 29 ketone protected as thioacetal. Oxidative deacetalisa-
and 32. Under inert conditions seven equivalents of tion of 30 followed by desilylation with TBAF and
metallated terminal alkyne 27 were necessary to cleavage with spontaneous cyclisation under acidic
A
responding propargylic alcohol (Scheme 3). Disap- over nine steps on the support. Although the condi-
pearance of the strong carbonyl band at 1721 cmÀ1 tions found for the second route are milder and may
and the alkyneꢁs weak vibration band at 2230 cmÀ1 in- be the appropriate choice for sensitive substrates,
dicated successful conversion. Subsequent oxidation yields were found to be in the same range as for the
with IBX proceeded smoothly to give alkynone 28 first route. Since the second route is more time-con-
(strong alkyne vibration band at 2209 cmÀ1). Metha- suming we decided for the first route to build up the
nesulfonic acid in dichloromethane effected cleavage library.
of the substrate from the Wang linker which was fol-
Reduction of spiro[5.5]ketal-4-one 29 was achieved
A
lowed by a solvent exchange to methanol to remove by treatment with polymer-bound borohydride 31.
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Scheme 4. Synthesis of homoallylic alcohols. a) (R)-configuration: (À)-crotylmenthol (1.10 equiv.), PTSA (0.10 equiv.),
CH2Cl2, room temperature, 24 h, 56–79%, ꢀ98% ee; for (S)-configuration: (+)-crotylmenthol (1.10 equiv.), PTSA (0.10
equiv.), CH2Cl2, room temperature, 24 h, 57–87%, ꢀ98% ee; b) CuI (0.05 equiv.), (vinyl)MgBr in THF (1.30 equiv.), THF,
À408C, 40 min, 90%, ꢀ98% ee.
Repeated addition of fresh reagent was required to able 3-buten-1-ol 14 and b-hydroxy esters 24a, 24b,
drive the reaction to completion.
25a and 25b[27] were appropriate starting materials.
Except for alkyne 27[28] new synthetic routes to dif-
We expected that the nucleophilic attack of the hy-
dride on the carbonyl group would occur from the ferent 5-hexyn-1-ols were developed (Scheme 5). Ad-
equatorial direction giving rise to an axial alcohol.[23] dition of allenyl-Grignard to THP-protected glycidol
However, the observed stereoselectivity was only low 43a or 43b followed by alkylation gave alkynes 44a,
(53:47 in favour of the axial alcohol). Acidic protic 44b, 45a and 45b. In a similar manner, epoxide open-
conditions may lead to isomerisation of the spiro ing of alkylated glycidol 46 or 47 with alkynyl-
carbon as described by Mori et al.[24] In this process Grignard 48, desilylation and THP-protection of the
ring opening and reclosure led to formation of the secondary alcohol gave alkynes 49 and 50. Homologa-
thermodynamically more stable equatorial alcohol 32. tion of malic acid-derived alcohol 51,[29] Swern oxida-
Upon treatment with acidic ion exchange resin in tion and alkynylation with trimethylsilyl diazome-
methanol equatorial alcohol 32 was formed in a ratio thane gave alkyne 53. Starting from (À)-b-citronel-
of 92:8. Compound 32 is a pheromone of the olive fly lene-derived alcohol 55[30] protection, bromination of
Dacus oleae.[17,24]
the double bond and double elimination gave alkyne
With a solid-phase sequence for the preparation of 56. Epoxidation of TBS-protected 3-buten-1-ol 57 fol-
spiroketals in hand, very practicable methods for the lowed by enantioselective hydrolytic kinetic resolu-
synthesis of appropriate enantiomerically pure build- tion[31] gave the chiral epoxides 58a and 58b. Ring
ing blocks in multi-gram amounts were developed.
opening with metallated trimethylsilylacetylene, desi-
For the solid-phase synthesis of the b-hydroxy alde- lylation and methylation of the secondary alcohol led
hydes 7 the chiral homoallylic alcohols 16–23[25] and to alkynes 59a and 59b.
15a and 15b[26] were synthesised following known pro-
With these building blocks in hand nearly all posi-
cedures (Scheme 4). In addition, commercially avail- tions of spiroketal 60 are addressable (Scheme 6).
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Solid-Phase Synthesis of [5.5]-Spiroketals
Scheme 5. Synthesis of protected 5-hexyn-1-ols. a) THF (2.50 equiv.), NaI (2.00 equiv.), TBSCl (1.00 equiv.), CH3CN, 558C,
ꢁ
16 h, 100%; b) LiC CH·EDTA (1.50 equiv.), pentane/DMSO=1/1, room temperature, 4 h, 88%; c) (allenyl)MgBr (2.00
equiv.), Et2O, À108C, 35 min, 92%, ꢀ98% ee[a]; d) NaH (1.50 equiv.), MeI (2.00 equiv.), THF, 08C to room temperature,
71% or NaH (1.50 equiv.), BnBr (2.00 equiv.), room temperature, 16 h, 52%; e) 48 in THF (1.30 equiv.), CuI (0.05 equiv.),
THF, À408C, 99% for epoxide 46 and 100% for epoxide 47; f) K2CO3, MeOH, room temperature, 5 h, 71% and 70%,
ꢀ98% ee[a]; g) DHP (1.35 equiv.), PTSA (0.03 equiv.), CH2Cl2, room temperature, 2 h, 94% for 49 and 100% for 50; h) aque-
ous NaOCl (1.10 equiv.), TEMPO (0.01 equiv.), KBr (0.10 equiv.), 08C, 30 min, 79%; i) Ph3P=CHCO2Me (1.00 equiv.),
CH2Cl2, room temperature, 5 h, 83%; j) DIBAH in toluene (2.50 equiv.), À788C, 1 h, 100%; k) MnO2 (22.0 equiv.), CH2Cl2,
08C to room temperature, 90 min, 80%; l) H2, Pd(OH)2/C (0.10 equiv.), EtOAc, 3.5 h, 99%; m) LDA in hexane/THF (1.20
equiv.), TMSCHN2 (1.20 equiv.), À788C, 1 h, reflux, 1 h, 75%; n) (i) O3, CH2Cl2, À788C; (ii) NaBH4 (1.50 equiv.), CH2Cl2/
MeOH, 08C to room temperature, 1 h, 91%, ꢀ98% ee[b]; o) DHP (1.35 equiv.), PTSA (0.03 equiv.), CH2Cl2, 08C to room
temperature, 3 h, 95%; p) Br2 (1.10 equiv.), CH2Cl2, À788C, 5 min, 93%; q) NaNH2 (2.50 equiv.), THF, À788C to room tem-
perature, 2 h, reflux, 19 h, 61%; r) m-CPBA (1.50 equiv.), CH2Cl2, room temperature, 8 h, 90%; s) (S,S)-(À)-N,N’-bis(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (0.005 equiv.), H2O (0.52 equiv.), AcOH (0.02 equiv.), THF, room
ꢁ
temperature, 47%; t) n-BuLi in hexane (2.50 equiv.), TMSC CH (2.50 equiv.), BF3·OEt2 (2.50 equiv.), THF, À788C, 93%;
u) K2CO3, MeOH, room temperature, 5 h, 84%, ꢀ98% ee[a]; v) NaH (1.50 equiv.), MeI (4.00 equiv.), THF, 08C, 95%.
[a]
Determined via Mosher ester. [b] Determined via chiral GC.
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Scheme 6. Building blocks and the corresponding variation of sites at the spiroketal core structure 60.
To get access to the spiroketals in viable amounts avoided epimerisation. The stronger cleavage and cy-
the quality and the loading of the resin loaded with b- clisation conditions used initially introduced
A
a
hydroxy aldehyde was crucial. Loadings had to be CH2OMe group in the 8-position on the spiroketal
above 0.65 mmolgÀ1 and the resin had to be dried core of alkyne 53 instead of a free CH2OH group.
thoroughly.
For the cleavage and cyclisation conditions metha- vent substitution of the free alcohol by methanol.
nesulfonic acid was found to be optimal. Trifluoroace- Combination of the 5-hexyn-1-ols with the homoal-
The same changes as in the latter case helped to pre-
tic acid turned out to be too nucleophilic since tri- lylic alcohols or b-hydroxy esters led to 147 spiroke-
fluoroacetates of intermediate a,b-unsaturated ke- tals of type 60. Since most of the by-products were
tones were formed. Camphorsulfonic acid as used by rather polar in comparison to the desired cyclised
Forsyth et al. to promote DIHMA did not cleave the product, isolation could be achieved by simple
Wang linker.
column chromatography to obtain the spiroketals in
For the spiroketals derived from substrate 56 cleav- high purity of 88 to ꢀ98%. 104 of the 147 compounds
age and cyclisation conditions had to be optimised. were obtained as single diastereomers (determined by
Under initial conditions (3% MeSO3H and longer re- GC-MS) whereas the other compounds were formed
action times) epimerisation at the spiroketal a carbon as isomer mixtures with ratios ranging from 97:3 to
was observed due to enolisation.[7] Shortening reac- 50:50. The overall yield over 7 steps on the solid
tion times and reducing the amount of acid (2%) phase varied between 5 and 45% (Table 1).
Table 1. Examples for library members.
No.
Building block 1
Building block 2
Product
Yield [%][a]
dr[b]
1
45
80:20
[c]
2
12
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Solid-Phase Synthesis of [5.5]-Spiroketals
Table 1. (Continued)
No.
Building block 1
Building block 2
Product
Yield [%][a]
38
dr[b]
[c]
3
4
5
6
31
35
38
90:10
80:20
[c]
[c]
[c]
7
8
5
19
[c]
9
12
10
11
25
27
25
73:27
[c]
[c]
12
[a]
Overall yields over 7 steps on the solid phase.
Determined via GC-MS.
Only one diastereomer detected.
[b]
[c]
As determined by 2D-NMR and NOE experiments (conformer A). This was proven for these compounds
for 6 representative compounds (Scheme 7) the spiro- by the close proximity of H-2 and H-8 which resulted
ketals obtained as single diastereomers all adopted a in clear NOE signals. Additional NOE signals be-
conformation with a bisaxial arrangement of the spiro tween the isopropyl group in the 2-position and H-8
À
C O bonds leading to a double anomeric stabilisation as for spiroketal 64 or between H-2 and axially orient-
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Scheme 7. Spiroketals in four different configurations and structural assignment of six library members by NOE signals.
ed H-10 as for the compounds 62 and 63 gave further bonds was favoured (Table 1). The minor isomer is
confidence in the structural assignment. For alcohol expected to adopt configuration B or C stabilised by
65 the equatorial orientation of the OH in the 4-posi- only one anomeric effect (Scheme 7).[6,7]
tion was proven by NOE signals of the two equatori-
ally oriented protons H-3 and H-5 with axially orient- sis could not be detected. NMR experiments using
ed H-4. Eu(tfc)3 as shift reagent and chiral GC (column: Lip-
A loss of stereochemical information during synthe-
AHCTREUNG
The two isomers of the spiroketals that occurred as odex-E) showed single enantiomers. Opposing enan-
mixtures were distinguished by 13C NMR shifts: for tiomers within the library showed opposite optical ro-
spiroketals with bisaxial orientation and two anomeric tations (Table 1: entries 11 and 12, Table 2: entries 9
stabilisations the spiro carbon resonates at higher and 10).
field than for spiroketals with just one anomeric stabi-
A set of diastereomerically pure spiroketal ketones
lisation. In addition,equatorial methyl groups at the 2- was subjected to reduction to yield spiroketals similar
or 8-position appear at lower field in the 13C spectrum to 32. As reported[7] the nucleophilic attack occurs
than axial methyl groups.[32] In all mixtures the config- preferentially from the equatorial face to give alco-
À
uration with bisaxial arrangement of the spiro C O hols with preference for an axial OH group. Unfortu-
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Table 2. Examples for functionalized library members.
No.
Product
Yield[%][a]
No.
8
Product
Yield [%][a]
1
49
39
2
3
37
46
9
45
55
10
4
40
11
71
5
6
39
48
49
12
13
60
74
7
[a]
For one step starting from corresponding ketone.
nately, the diastereomeric differentiation with sup- were subjected to Grignard addition reaction, reduc-
port-bound borohydride was low and led to epimeric tive amination and oxime formation (Scheme 8).
mixtures ranging from 70:30 to 55:45 (determined by
In accordance with a literature report,[33] in the case
GC-MS) in favour of epimers with an axial hydroxy of the Grignard addition (allylMgBr, ethylMgBr,
group (Table 2: entries 1–10). Via HPLC the epimers methylMgI) in solution at lower temperature
could be separated. After separation 55 reduced spi- (À608C) the nucleophilic attack occurs preferentially
roketals were obtained in yields varying from 60 to from the equatorial face to give tertiary alcohols with
98% and 93% to ꢀ98% purity.
preference for an axial OH group (Scheme 8). The
In addition to reduction of the keto group embed- diastereomeric differentiation was substantial and led
ded into the spiroketals we sought to derivatise the to isomer ratios from 85:15 to 97:3 (determined by
scaffold further by means of solution-phase transfor- GC-MS). After purification 41 spiroketals of type 67
mation of the keto group. To this end, the ketones were obtained in yields varying from 61 to 88% and
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with 251 different members was successfully synthes-
ised.
Experimental Section
General Procedure for the Activation of Wang Resin
11 as Trichloroacetimidate[19]
To a suspension of 1.00 g Wang resin 11 (1.10 mmol) in
10 mL dry dichloromethane 2.1 mL trichloroacetonitrile
(22.8 mmol, 19.0 equiv.) were added and the mixture was
stirred for 5 min at 08C. Over a time period of 5 min
0.13 mL of DBU (0.88 mmol, 0.80 equiv.) was added drop-
wise to the ice-cold suspension which changed colour from
colourless to brown. The temperature was held for 40 min.
The resin was filtered and washed successfully with CH2Cl2
(3”), DMSO (3”), THF (3”), CH2Cl2 (3”) and methanol
(3”). It was dried with air for 1 h followed by drying under
vacuum overnight to give a brown coloured trichloroaceti-
midate (TCA) resin. The FT-IR spectrum showed the disap-
pearance of the hydroxy stretching band at 3500 cmÀ1 with
the appearance of strong bands at 1665 cmÀ1 (C=N) and
Scheme 8. Functionalisation of spiroketals. a) 1 M Al-
lylMgBr in Et2O (2.00 equiv.) or 1 M EtMgBr in THF (2.00
equiv.) or 1 M MeMgI in Et2O (2.00 equiv.), THF, À788C;
10 min, À608C 3 h; b) benzylamine (2.00 equiv.), 3 Š mol
sieves, MeOH, room temperature, 24 h, borohydride on
Amberlite IRA 400 (~2.5 mmolgÀ1, 4.00 equiv.), MeOH,
room temperature, 24 h, polymer-supported benzaldehyde
(excess), MeOH, room temperature, 24 h; c) BnONH2·HCl
or MeONH2·HCl or HONH2·HCl (3.00 equiv.), EtOH, room
temperature, 3.5 h.
3339 cmÀ1 (N H). The activation of Wang resin is believed
À
to be quantitative.
General Procedure for the Loading of Homoallylic
Alcohols or b-Hydroxy Esters to Trichloroacetimidate
(TCA) Resin[19]
TCA resin (0.80 g, 0.9 mmol) was washed twice with 8 mL
of dry THF and twice with a 1:1 mixture of dry cyclohexane
and dry dichloromethane under an argon atmosphere. Cy-
clohexane/dichloromethane (4 mL) was added followed by
2.18 mmol (2.50 equiv.) of the homoallylic alcohol or b-hy-
droxy ester. Under shaking and at room temperature 45 mL
of BF3·Et2O (0.36 mmol, 0.33 equiv.) were added in one por-
tion to the suspension. A quick decolourisation was ob-
served. After 15 min shaking at room temperature the resin
was filtered and washed successfully with CH2Cl2 (3”),
THF (3”), CH2Cl2 (3”) and methanol (3”). It was dried
with air for 1 h followed by drying under vacuum overnight
to give a bright yellow coloured resin. The characteristic
bands for the TCA resin had disappeared and no IR band at
85% to 98% purity (for an example see Table 2,
entry 11).
For a reductive amination, the spiroketal was treat-
ed first with an excess of benzylamine for 24 h and
then support-bound borohydride was added. Finally
support-bound benzaldehyde was added to scavenge
the excess benzylamine and to yield spiroketal 68. In
contrast to reduction of ketones yielding mixtures of
isomers, only one diastereoisomer (determined by
GC-MS) with an axial NH group (confirmed by NOE
experiment) was found. According to this procedure
three derivatives were synthesised in viable yields of
60 to 64% (see, for example, Table 2, entry 12).
Treatment of the spiroketal ketones with hydroxyl-
3300–3500 cmÀ1 (O H) could be observed. For the resin
À
loaded with b-hydroxy ester 12 strong absorption at
1735 cmÀ1 (C=O) was perceived. The loading was deter-
mined by cleavage with 5% TFA in dichloromethane over
30 min at room temperature (1.0 mmolgÀ1, 91%).
amine and O-alkylhydroxylamines yielded spiroketals
of type 69. After purification five oximes were ob-
tained in yields of 66 to 74% (for an example see
Table 2, entry 13).
General Procedure for the Synthesis of Wang Resin
Loaded with b-Hydroxy Aldehydes 7 Starting from
Resin Loaded with Homoallylic Alcohol 13[20]
Conclusions
A suspension of 0.80 g of resin 13 loaded with homoallylic
alcohol (0.8 mmol) in 15 mL dichloromethane in a three-
necked flask was cooled to À788C. After 5 min stirring
ozone was passed via a sintered frit through the suspension.
After 1–3 min the colour changed to greenish blue indicat-
ing that saturation is reached. In general ozonolysis was
stopped after 7–8 min. Ozone was removed by flushing with
We have developed a synthesis of spiroketals on a
solid phase with varying stereogenic centres and sub-
stituents at nearly all sites of the spiroacetal core. Fur-
ther derivatisation was achieved by application of
support-bound borohydride for reduction and reduc-
tive amination, Grignard reaction and conversion to
oxime derivatives in the solution phase. A library argon until decolourisation (~1 min). At À788C 1.05 g tri-
1746
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1736 – 1750

DEDICATED CLUSTER
FULL PAPERS
Solid-Phase Synthesis of [5.5]-Spiroketals
phenylphosphine (4.00 mmol, 5.00 equiv.) were added and
the suspension was shaken for 16 h at room temperature.
The resin was filtered and washed successfully with CH2Cl2
(3”), THF (3”), CH2Cl2 (3”) and methanol (3”). The
yellow resin was dried with air for 1 h followed by thorough
drying under vacuum over 2 days. The b-hydroxy aldehyde
A solution of 1.01 g of IBX (3.6 mmol, 5.00 equiv.)[34] in a
mixture of dry DMSO:dry THF=1:1 was added to 0.80 g
resin loaded with propargylic alcohol. After 16 h shaking at
room temperature the yellow resin was filtered and washed
successfully with DMSO (3”), THF (3”), CH2Cl2 (3”) and
methanol (3”). It was dried with air for 1 h followed by
linked to resin 7 showed no IR absorption at 3300–
thorough drying under vacuum overnight. The alkynone
À1
À1
3500 cmÀ1 (O H) whereas, a strong band at 1721 cm (C= linked to resin 26 showed an IR absorption at 2209 cmÀ1
À
ꢁ
O) was observed. The loading was determined by the DNP
method (0.65–0.75 mmolgÀ1, 72–83%).[4a,b,21]
(C C) whereas, no absorption between 3300–3500 cm
could be observed.
General Procedure for Cleavage from the Support
and Spiroketalisation of the Alkynones
General Procedure for the Synthesis of Wang Resin
Loaded with b-Hydroxy Aldehyde 7 Starting from
Resin Loaded with b-Hydroxy Ester 12
Resin loaded with alkynone 26 (0.80 g) was treated at room
temperature with 8 mL of 2% solution of methanesulfonic
acid in dichloromethane. After shaking for 30 min the resin
was filtered and washed twice with 8 mL dichloromethane
and twice with 8 mL methanol. At 408C and under reduced
pressure dichloromethane was evaporated and the resulting
solution was shaken for 30 min at room temperature. 20 mL
toluene and 3 drops water were added and methanol was re-
moved under reduced pressure. The toluene solution was
shaken for 2 h and 0.30 mL triethylamine was added and the
solution was immediately filtered through a plug of silica.
Evaporation of the eluent gave a reddish brown oil that was
purified by column chromatography (a gradient of cyclohex-
ane/EtOAc=8/1 to 6/1 was used) to afford the desired spi-
roketals as colourless or slightly yellow oils in overall yields
ranging from 5 to 45% and 90 to ꢀ98% purity.
Resin 12 loaded with b-hydroxy ester (0.80 g, 0.8 mmol) was
washed twice with 8 mL dry THF. To the swollen resin 4 mL
of a 1M solution of DIBAH in toluene (0.40 mmol, 5.00
equiv.) were added slowly at room temperature. After 5 h
shaking at room temperature the bright, colourless resin was
filtered and washed successfully with dry THF (2”),
THF:methanol:AcOH=47:47:6 (3”), THF (3”), CH2Cl2
(3”) and methanol (3”). It was dried with air for 1 h fol-
lowed by drying under vacuum overnight. The IR absorp-
tion of the ester had disappeared while a broad band at
3433 cmÀ1 was recognised. The loading was determined via
Fmoc derivatisation, cleavage of the fluorenylmethyl group
under basic condition and quantification by UV absorption
(0.9 mmolgÀ1, 90%).
A solution of 1.01 g IBX (3.6 mmol, 5.00 equiv.)[34] in a
mixture of dry DMSO:dry THF=1:1 was added to 0.80 g
resin loaded with diol (0.72 mmol). After 16 h shaking at
room temperature the yellow resin was filtered and washed
successfully with DMSO (3”), THF (3”), CH2Cl2 (3”) and
methanol (3”). It was dried with air for 1 h followed by
thorough drying under vacuum over 2 days. The b-hydroxy
AHCTREUNG
AHCTREUNG
14.1 mg (0.046 mmol, 5%); Rf: 0.32 (cyclohexane/EtOAc=
2/1); purity: 98%; [a]2D0: 26.28 (c 0.95, CHCl3); 1H NMR
(500.1 MHz, CDCl3): d=7.14–7.30 (m, 5H, 5 ” CarH), 3.89–
3
3
3.97 (m, 1H), 3.56 (tt, J=9.1 Hz, J=2.9 Hz, 1H), 3.45 (dd,
3J=11.5 Hz, 3J=3.3 Hz, 1H), 3.39 (dd, 3J=11.7 Hz, 3J=
6.7 Hz, 1H), 2.91 (ddd, J=13.9 Hz, J=10.6 Hz, J=5.3 Hz,
1H, PhCH2), 2.68 (ddd, 3J=13.9 Hz, 3J=10.3 Hz, 3J=
6.2 Hz, 1H, PhCH2), 2.41 [s, 2H, C(5)H2], 2.38 (dd, 3J=
aldehyde linked to resin 7 showed no IR absorption at
3
3
3
3300–3500 cmÀ1 (O H) whereas, a strong band at 1721 cm
À1
À
(C=O) was observed. The loading was determined as
0.75 mmolgÀ1 (83%).[4a,b,21]
3
3
3
15.2 Hz, J=2.1 Hz, 1H), 2.23 (dd, J=14.1 Hz, J=11.3 Hz,
3
1H), 1.82–2.22 (m, 4H), 1.63–1.74 (m, 2H), 1.45 (ddd, J=
13.3 Hz, 3J=13.3 Hz, 3J=4.6 Hz, 2H), 1.28 (dddd, 3J=
12.9 Hz, 3J=12.9 Hz, 3J=12.1 Hz, 3J=4.1 Hz, 1H);
13C NMR (125.8 MHz, CDCl3): d=206.0 (s), 150.2 (s), 128.6
(d), 128.4 (d), 126.1 (d), 99.4 (s), 71.0 (d), 68.5 (d), 65.9 (t),
51.9 (t), 47.1 (t), 37.7 (t), 34.8 (t), 31.9 (t), 25.7 (t), 18.5 (t);
GC-MS(EI): tR: 7.53 min; m/z (rel. int. [%])=304 (11)
[M+], 286 (15) [M+ÀH2O], 273 (56), 199 (26), 174 (10), 155
General Procedure for Wang Resin Loaded with
Alkynone Starting from Resin Linked to b-Hydroxy
Aldehyde 7
A solution of 3.92 mmol alkyne (7.00 equiv.) in 4 mL dry
THF was treated at 08C with 3.9 mL of a 1M solution of
ethylmagnesium bromide in THF (7.00 equiv.). After 2 h
stirring at room temperature the solution was transferred
under inert conditions to 0.80 g resin loaded with b-hydroxy
aldehyde 7 that had been washed twice with dry THF and
suspended in 4 mL dry THF. The reaction mixture was
shaken for 16 h at room temperature, filtered and washed
successfully with dry THF (1”), THF:methanol:AcOH=
47:47:6 (3”), THF (3”), CH2Cl2 (3”) and methanol (3”).
The yellow resin was dried with air for 1 h followed by thor-
ough drying under vacuum overnight. Completeness of the
reaction was assumed when no IR absorption at 1721 cmÀ1
(C=O) could be observed anymore and a weak band at
(23), 128 (37), 117 (47), 91 (100) [Bn+]; LC-MS
(ESI): tR:
A
8.39 min; m/z=305.17 [M+H]+; HR-MS (FAB: 3-NBA):
m/z=305.1734, calcd. for C18H24O4 [M+H]+: 304.1675.
Representative Procedure for the Reduction of
Spiroketals with Support-Bound Borohydride in
Solution Phase
AHCTREUNG
A
ACHTREUNG
was placed in a small vial and dissolved in 0.5 mL dry meth-
anol. Three times after every 1.5 h 51 mg polymer-supported
borohydride (~0.38 mmol, borohydride on Amberlite IRA
2230 cmÀ1 (CꢁC) and a broad band at 3432 cmÀ1 (O H)
À
could be observed.
Adv. Synth. Catal. 2008, 350, 1736 – 1750
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1747

DEDICATED CLUSTER
FULL PAPERS
Stefan Sommer et al.
400, ~2.5 mmolgÀ1
;
Aldrich Cat. No. 32,864–2) were
47.7, 43.6, 42.6, 39.5, 30.0, 29.1, 26.6, 26.2, 26.1, 21.4; GC-
MS(EI): tR: 8.20 min; m/z (rel. int. [%])=283 (81), 253 (15),
223 (7), 171 (28), 153 (100), 131 (91), 99 (75), 71 (64), 55
(48), 41 (48); HR-MS (EI): m/z=325.2399, calcd. for
C19H32O4 [M+H]+: 324.2301.
added.[27] After 4.5 h completion of the reduction was con-
trolled by TLC (cyclohexane/EtOAc=1/1). The suspension
was filtered and the eluent was evaporated to dryness. Pu-
rification and separation of the two epimers was achieved
by means of HPLC.
(2R,4S,6R,9R)-2-[(Benzyloxy)methyl]-9-methoxy-1,7-di-
Representative Procedure for the Reductive
Amination of Spiroketals in Solution Phase
N
A
(0.050 mmol, 39%); Rf: 0.44 (cyclohexane/EtOAc=1/1);
purity: 94%; [a]D20: À22.88 (c 1.73, CHCl3); 1H NMR
(500.1 MHz, CDCl3): d=7.22–7.35 (m, 5H, 5 ” CarH), 4.58
To a solution of (3S,6R)-3-methyl-1,7-dioxaspiro
A
AHCTREUNG
3
mine (19.4 mg, 0.105 mmol, 2.00 equiv.) in 2.0 mL dry
MeOH was added 3 Š mol sieves and this suspension was
stirred for 24 h. Then 72 mg polymer-supported borohydride
(~0.58 mmol, borohydride on Amberlite IRA 400,
~2.5 mmolgÀ1; Aldrich Cat. No. 32,864–2) were added.[27]
After 24 h an excess polymer-supported benzaldehyde was
added to scavenge the excess amine. This suspension was
stirred for further 24 h. The suspension was filtered. The
eluent was evaporated to dryness to afford (3R,4R,6R)-N-
(s, 2H, CH23Ph), 4.05–4.13 (m, 2H), 3.75 (ddd, J=10.2 Hz,
3
3J=4.8 Hz, J=2.2 Hz, 1H), 3.53 (d, J=1.8 Hz, 1H), 3.52
3
(d, J=2.8 Hz, 1H), 3.35 (s, 3H, OCH3), 3.23–3.33 (m, 1H),
3
1.86–1.94 (m, 1H), 1.71–1.83 (m, 4H), 1.67 (d, J=3.5 Hz,
3
3
1H), 1.62 (dd, J=10.7 Hz, J=3.1 Hz, 1H), 1.50–1.59 (m,
2H); GC-MS(EI): tR:7.52 min; m/z (rel. int. [%])=322 (1)
[M+], 304 (2) [M+ÀH2O], 216 (10), 201 (15), 183 (24), 157
(27), 129 (24), 107 (26), 91 (100) [Bn+]; HR-MS (FAB: 3-
NBA): m/z=323.1875, calcd. for C18H26O5 [M+H]+:
322.1780.
benzyl-3-methyl-1,7-dioxaspiro[5.5]undecan-4-amine
N
(Table 2: entry 12); yield: 17.6 mg (0.064 mmol, 60%); Rf:
(2R,4R,6R,9R)-2-[(Benzyloxy)methyl]-9-methoxy-1,7-di-
0.30 (cyclohexane/EtOAc=1/1); purity: 87%; [a]2D0: À1.18 (c
U
A
1
1.73, CHCl3); H NMR (400 MHz, CDCl3): d=7.38–7.20 (m,
(0.047 mmol, 37%); Rf: 0.53 (cyclohexane/EtOAc=1/1);
purity: 98%; purity: 94%; [a]2D0: À10.48 (c 1.65, CHCl3);
1H NMR (500.1 MHz, CDCl3): d=7.23–7.36 (m, 5H, 5 ”
CarH), 4.57 (s, 2H, CH2Ph), 4.08 (sept, 3J=5.4 Hz, 1H),
5H, 5 ” CarH), 3.98 (d, 3J=13.4 Hz, 1H), 3.67 (d, 3J=
13.6 Hz, 2H), 3.58–3.51 (m, 2H), 3.39–3.33 (m, 1H), 2.60
(dd, 3J=6.8 Hz, 3J=3.6 Hz, 1H), 2.52–2.36 (m, 1H), 2.00
3
3
3
(dd, J=14.0 Hz, J=2.7 Hz, 1H), 1.86–1.76 (m, 2H), 1.59–
1.41 (m, 6H), 0.89 (d, 3J=6.9 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3): d=141.5, 128.3, 128.0, 126.5, 96.3, 62.0,
60.2, 53.6, 52.3, 37.7, 35.4, 34.2, 25.0, 18.3, 13.6; GC-MS
(EI): tR: 7.67 min; m/z (rel. int. [%])=275 (5), 232 (1), 216
(68), 176 (11), 160 (11), 132 (34), 106 (46), 91 (100), 65 (9),
55 (10).
3.74–3.82 (m, 1H), 3.63–3.69 (m, 1H), 3.53 (dd, J=10.3 Hz,
3J=5.3 Hz, 1H), 3.49 (dd, 3J=10.3 Hz, 3J=4.8 Hz, 1H),
3.22–3.37 (m, 2H), 3.34 (s, 3H, CH3), 1.87–2.01 (m, 3H),
1.69–1.86 (m, 2H), 1.53–1.60 (m, 2H), 1.28 (quint, 3J=
12.0 Hz, 2H); GC-MS(EI): tR: 7.61 min; m/z (rel. int. [%])=
322 (1) [M+], 304 (2) [M+ÀH2O], 216 (41), 201 (19), 183
(61), 157 (50), 129 (34), 107 (30), 91 (100) [Bn+]; HR-MS
(FAB: 3-NBA): m/z=323.1885, calcd. for C18H26O5 [M+
H]+: 322.1780.
Representative Procedure for the Oxime Formation
of Spiroketals in Solution Phase
A
G
(19.4
Representative Procedure for the Grignard Reaction
of Spiroketals in Solution Phase
mg, 0.105 mmol, 1.00 equiv.) and 22 mg hydroxylamine hy-
drochloride (0.315 mmol, 3.00 equiv.) were stirred in 1.5 mL
dry EtOH. After 3.5 h completion was controlled by TLC
(cyclohexane/EtOAc=2/1). The suspension was filtered and
the eluent was evaporated to dryness. The residue was puri-
fied by column chromatography to afford (3S,6R)-3-methyl-
A
N
decan-4-one (10.7 mg, 0.038 mmol, 1.00 equiv.) was placed
in a small vial and dissolved in 1.5 mL dry THF and cooled
to À788C. A 1M solution of allylmagnesium bromide in
Et2O (80 mL, 0.076 mmol, 2.00 equiv.) was added slowly at
À788C and stirred then further 3 h at À608C. The reaction
was quenched with saturated, aqueous ammonium chloride
solution (2 mL). The biphasic mixture was separated, the
aqueous layer was extracted with diethyl ether (3”10 mL),
the combined organic layers were washed with brine
(10 mL), dried (MgSO4) and concentrated. The residue was
purified by column chromatography to give (2R,4S,6S,9S)-4-
1,7-dioxaspiro[5.5]undecan-4-one-O-methyl oxime (Table 2:
A
entry 13); yield: 16.6 mg (0.078 mmol, 74%); Rf =0.29 (cy-
clohexane/EtOAc=2/1); purity=89%; [a]2D0: 2.18 (c=0.89,
1
CHCl3); H NMR (400 MHz, CDCl3): d=3.83 (s, 3H), 3.69
3
3
3
(dd, J=10.8 Hz, J=5.8 Hz, 1H), 3.60 (d, J=2.5 Hz, 1H),
3
3
3.59–3.56 (m, 1H), 3.45 (t, J=11.1 Hz, 1H), 3.29 (d, J=
14.5 Hz, 1H), 2.52–2.41 (m, 1H), 1.83–1.76 (m, 2H), 1.74–
3
1.69 (m, 1H), 1.61–1.52 (m, 4H), 1.02 (d, J=6.6 Hz, 3H);
13C NMR (100.6 MHz, CDCl3): d=156.0, 97.2, 66.1, 61.3,
60.3, 36.0, 35.6, 34.8, 24.5, 18.6, 10.7; GC-MS(EI): tR:
6.35 min; m/z (rel. int. [%])=213 (2), 183 (3), 169 (21), 152
(20), 113 (100), 98 (18), 83 (33), 68 (56), 55 (41), 41 (53);
HR-MS (EI): m/z=214.1454, calcd. for C11H19NO3 [M+
H]+: 213.1365.
allyl-2-cyclohexyl-9-methoxy-1,7-dioxaspiro[5.5]un-decan-4-
U
ol (Table 2: entry 11): yield: 8.7 mg (0.027 mmol, 71%); Rf:
0.42 (cyclohexane/EtOAc=2/1); purity: 91%; [a]2D0: À50.08
1
(c 0.87, CHCl3); H NMR (400 MHz, CDCl3): d=5.89–5.73
(m, 1H), 4.98 (m, 2H), 4.22 (s, 1H), 3.71–3.60 (m, 2H), 3.47
3
3
3
(ddd, J=11.8 Hz, J=7.3 Hz, J=2.2 Hz, 1H), 3.30–3.28 (s,
3H, OCH3), 3.20–3.15 (m, 1H), 2.17–2.02 (m, 2H), 2.01–
1.96 (m, 1H), 1.95–1.87 (m, 1H), 1.85–1.54 (m, 8H), 1.38–
1.09 (m, 7H), 0.95–0.87 (m, 2H); 13C NMR (100.6 MHz,
CDCl3): d=133.8, 117.6, 97.5, 72.7, 70.0, 69.8, 61.8, 56.1,
1748
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1736 – 1750

DEDICATED CLUSTER
FULL PAPERS
Solid-Phase Synthesis of [5.5]-Spiroketals
CorrÞa Jr. , A. Nçren-Müller, H.-D. Ambrosi, S. Jaku-
povic, K. Saxena, H. Schwalbe, M. Kaiser, H. Wald-
mann, Chem. As. J. 2007, 9, 1109–1126; p) M. Scheck,
M. Koch, H. Waldmann, Tetrahedron 2008, 64, 4792–
4801.
Acknowledgements
This research was supported by the Max-Planck-Gesellschaft
and the Fonds der Chemischen Industrie. S. S. was supported
by a KekulØ-Fellowship of the Fonds der Chemischen Indus-
trie.
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Opin. Chem. Biol. 2004, 8, 281–286; c) R. Balamuru-
gan, F. J. Dekker, H. Waldmann, Mol. BioSyst. 2005, 1,
36–45, and references cited therein.
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