Synthesis of an advanced C10-C32 spiroacetal fragment and assignment of the absolute configuration of spirangien A

Article abstract of DOI:10.1002/anie.200702735

A bit on the side: A highly convergent and flexible synthetic strategy has been developed for spirangiens A and B that made use of a common stereotetrad building block and led to an advanced C10-C32 spiroacetal fragment, thus enabling the unambiguous assi

Full text of DOI:10.1002/anie.200702735

Angewandte
Chemie
DOI: 10.1002/anie.200702735
Polyketide Synthesis
Synthesis of an Advanced C10–C32 Spiroacetal Fragment and
Assignment of the Absolute Configuration of Spirangien A**
Ian Paterson,* Alison D. Findlay, and Edward A. Anderson
Spirangiens A (1, Scheme 1) and B (2),[1] isolated by the
research group of Höfle from the epothilone-producing
As an aid to stereochemical elucidation, their controlled
chemical degradation was reported recently by Niggemann
et al.[1a] The absolute configuration at the isolated C3
stereocenter was thus determined by GC analysis of an
ozonolysis product on a chiral stationary phase. Cross-meta-
thesis of the pentaene moiety in spirangien A with ethene
generated the spiroacetal fragment 3, which enabled X-ray
crystal structure analysis. Whilst this led to the secure
determination of the relative stereochemistry, the absolute
configuration of 3, and correspondingly the C14–C28 region
of the spirangiens A and B, was unresolved. Notably, this 1,3-
diene 3 retained one tenth of the cytotoxic activity of
spirangien A (IC50 7 ngmLꢀ1 against L929), thus highlighting
the importance of the C10–C32 core to the pharmacophore.
Inspired by both the pronounced biological activity and
unique structural features associated with this novel spiroa-
cetal scaffold, we embarked on a total synthesis of the
spirangiens. Herein, we report an expedient strategy for
assembling the elaborate spiroacetal core,[3] which culminated
in the preparation of the C10–C32 fragment (+)-3, and thus
led to the assignment of the absolute configuration of
spirangiens A and B.
As outlined in Scheme 2, our retrosynthetic analysis of 3
envisaged a late-stage incorporation of the (Z)-dienyl side
chain. Careful inspection of linear spiroacetalization precur-
sor 4 reveals a repeating pattern of four contiguous stereo-
centers (C15–C18 and C25–C28) that we recognized could be
exploited to develop a modular, step-economic synthetic
strategy. In turn, this acyclic ketone 4 might arise from an
aldol coupling of aldehyde 5 with ketone 6, both of which
should be accessible from the 1,3-diol 7 as a common
stereotetrad building block.
As shown in Scheme 3, our synthesis began with the ethyl
ketone (S)-8,[4] which was converted by an aldol-reduction
sequence into the common precursor 7 with high diastereo-
selectivity (69%, > 15:1 d.r.). Multigram quantities of the 1,3-
diol 7 were readily accessed, thereby enabling two parallel
sequences of reactions to be performed to generate the
requisite C23–C32 and C13–C22 subunits, 5 and 6, respec-
tively.
Scheme 1. Spirangiens A (1) and B (2), and generation of the 1,3-diene
degradation fragment 3.
myxobacterium Sorangium cellulosum (strain So ce90), are
polyketide metabolites[2] that possess potent antifungal and
cytotoxic activity (IC50 0.7 ngmLꢀ1 against L929 mouse fibro-
blast cell line). From a structural perspective, the spirangiens
contain 14 stereocenters, and include a densely functionalized
spiroacetal core appended with a delicate pentaene side chain
that bears a terminal carboxy group. Spirangiens A and B
differ only with the presence of a methyl or ethyl substituent
at C31.
[*] Prof. Dr. I. Paterson, A. D. Findlay, Dr. E. A. Anderson
University Chemical Laboratory
Lensfield Road, Cambridge, CB21EW (UK)
Fax: (+44)1223-336-362
E-mail: ip100@cam.ac.uk
Focusing first on aldehyde 5, previous studies[5] suggested
that the hydroboration of the 1,1-disubstituted olefin of 1,3-
diol 7 using BH3 in THF should result in installation of the
required stereocenter at C24. Following this hydration pro-
tocol, 7 generated the corresponding C24,C25-syn triol (94%,
6:1 d.r. by 1H NMR analysis) which underwent selective
silylation of the primary hydroxy group (TBSCl, imidazole),
followed by formation of the anti acetonide (2,2-dimethox-
ypropane, PPTS), to give 9 (89%, 2 steps). At this stage, the
PMB ether in 9 was cleaved by DDQ to reveal the primary
Homepage: http://www-paterson.ch.cam.ac.uk/
[**] This work was supported by the EPSRC (GR/S19929/01), Homerton
College, Cambridge (E.A.A.), and Merck Research Laboratories
(A.D.F.). We thank Dr. J. Niggemann (GBF, Braunschweig) for the
NMR spectra of degradation fragment 3 and Dr. J. P. Scott (Merck
Sharp & Dohme Research Laboratories, Hoddesdon) for discus-
sions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 2. Retrosynthetic analysis of 3 (spirangien numbering) leading
to the common precursor 7.
alcohol which was then smoothly transformed into iodide 10
(91%, 2 steps). Displacement of this leaving group with the
organolithium species 11 generated from (E)-2-bromobut-2-
ene (tBuLi, THF) was performed next. While a small amount
(around 20%) of olefin side product corresponding to E2
elimination of the iodide was observed, this was conveniently
removed by selective hydroboration of the product mixture
using 9-BBN, enabling the isolation of pure coupled product
12 in 77% yield. Cleavage of the TBS ether in 12 and Dess–
Martin oxidation[6] completed the efficient preparation of the
C23–C32 aldehyde 5 (8 steps from 7, 45% overall).
Attention was now directed to preparation of the requisite
C13–C22 aldol coupling partner 6. From the common
intermediate 7, this commenced with formation of the
anti acetonide. The PMB ether was then converted into
primary iodide 13 (70%, 3 steps). A Myers asymmetric
alkylation[7] was selected for introduction of the oxygenation
at the C20-stereocenter, where the auxiliary might then be
subsequently cleaved directly to generate the required methyl
ketone. It is recognized that the use of hydroxyacetamide 14
(prepared from (ꢀ)-pseudoephedrine and methyl glycolate)
tends to result in lower diastereoselectivities in alkylation
reactions, possibly as a consequence of the trianion that is
generated upon enolization.[7] Furthermore, reactions with b-
branched electrophiles are usually slow, thus leading to
diminished yields. In spite of these concerns, we were gratified
to find that the alkylation of the lithium enolate derived from
14 with iodide 13, followed by treatment with MeLi,
generated the desired methyl ketone 15 in high yield and
Scheme 3. Synthesis of C23–C32 aldehyde 5 and C13–C22 ketone 6.
=
a) 1. cHex2BCl, Et3N, Et2O, 08C, 1 h; H2C C(Me)CHO, ꢀ78!ꢀ278C,
16 h; 2. MeOH, pH 7 buffer, H2O2; b) Me4NHB(OAc)3, AcOH, MeCN,
ꢀ308C, 16 h; c) 1. BH3·SMe2, THF, 0!208C, 3 h; 2. MeOH, NaOH,
H2O2; d) TBSCl, imidazole, CH2Cl2, 208C, 2 h; e) 2,2-dimethoxypro-
pane, PPTS, CH2Cl2, 208C, 16 h; f) DDQ, CH2Cl2/pH 7 buffer (10:1),
CH2Cl2, 0!208C, 2 h; g) I2, PPh3, Et3N, imidazole, toluene, 0!208C,
3 h; h) 1. (E)-2-bromobut-2-ene, tBuLi, ꢀ788C; 10, THF, ꢀ78!08C,
1 h; 2. 9-BBN, THF, 0!208C, 3 h; MeOH, NaOH, H2O2; i) TBAF,
THF, 0!208C, 1 h; j) Dess–Martin periodinane, NaHCO3, CH2Cl2,
208C, 1 h; k) 2,2-dimethoxypropane, PPTS, CH2Cl2, 208C, 16 h;
l) DDQ, CH2Cl2/pH 7 buffer (10:1), CH2Cl2, 0!208C, 2 h; m) I2, PPh3,
Et3N, imidazole, toluene, 0!208C, 3 h; n) 14, LDA, THF, ꢀ78!208C,
1 h; 13, 0!208C, 16 h; o) MeLi, THF, ꢀ78!08C, 1 h; p) TESOTf, 2,6-
lutidine, CH2Cl2, ꢀ788C, 1 h. 9-BBN=9-borobicyclo[3.3.1]nonane,
cHex=cyclohexyl, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
LDA=lithium diisopropylamide, OTf=triflate=trifluoromethanesulfo-
nate, PPTS=pyridinium para-toluenesulfonate, PMB=para-methoxy-
benzyl, TBAF=tetrabutylammonium fluoride, TBS=tert-butyldimethyl-
silyl, TES=triethylsilyl.
selectivity (80%, 25:1 d.r.).[8] Formation of the TES ether
then completed the efficient preparation of the C13–C22
ketone 6 (6 steps from 7, 55% overall).
With aldehyde 5 and methyl ketone 6 in hand, our
attention turned to their proposed aldol coupling and
introduction of the C23-stereocenter. Preliminary studies
using LDA generated a 3.5:1 mixture of adducts 16 and 4
(Scheme 4), while the use of cHex2BCl/Et3N gave similar
results (5:1 d.r.). Pleasingly, this inherent diastereoselectivity
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Scheme 5. Completion of the synthesis of 1,3-diene 3. a) TESOTf, 2,6-
lutidine, CH2Cl2, ꢀ78!08C, 2 h; b) 1. 9-BBN, THF, 0!208C, 3 h;
2. MeOH, NaOH, H2O2; c) Dess–Martin periodinane, NaHCO3,
CH2Cl2, 208C, 1 h; d) 1. 23, CrCl2, THF, 0!208C, 1 h; 2. KOH, MeOH,
0!208C, 16 h; e) 1. 26, 4-ꢀ molecular sieves, 208C, 16 h; 2. KOH,
MeOH, 0!208C, 16 h; f) TBAF, THF, 0!208C, 3 h. TMS=trimethyl-
silyl.
Scheme 4. Aldol coupling and spiroacetalization. a) LDA, THF, ꢀ788C,
1 h; 5, ꢀ788C, 1 h; b) 1. (ꢀ)-Ipc2BCl, Et3N, Et2O, 08C, 1 h; 5, ꢀ788C,
2 h; 2. MeOH, pH 7 buffer, H2O2; c) Me3OBF4, proton sponge, CH2Cl2,
0!208C, 2 h; d) CSA, MeOH, 208C, 16 h. CSA=camphorsulfonic
acid; Ipc=isopinocampheyl.
in the undesired Felkin–Anh direction could be overturned by
employing chiral Ipc ligands on the boron enolate.[4,9] Thus,
enolization of ketone 6 with (ꢀ)-Ipc2BCl/Et3N, followed by
addition of aldehyde 5, generated the aldol adducts in 53%
yield and 2.5:1 d.r. in favor of the desired diastereomer 4. The
latter epimeric mixture was progressed to the corresponding
methyl ethers 17 and 18 using the Meerwein salt reagent
(75%).[10]
hydroboration of the disubstituted over the trisubstituted
alkene using 9-BBN, then generated the expected C14,C15-
anti alcohol 21 cleanly (70%, > 20:1 d.r.).[5,11] Subsequent
Dess–Martin oxidation gave aldehyde 22, in readiness for
installation of the (Z)-dienyl side chain. Previous studies[12]
prompted the initial examination of a Nozaki–Hiyama/
Peterson sequence using allyl silane 23. However, complica-
tions pertaining to steric factors as a result of the conforma-
tional rigidity of 22 led to a low yield (25%) of the targeted
diene 24 and isolation of the undesired regioisomeric side
product 25 (53%). An alternative procedure was therefore
sought and allyl boronate 26 was employed,[13] which was
obtained by modification of a Roush protocol.[14] Treatment
of aldehyde 22 with 26 (3m, toluene), followed by in situ
KOH-mediated Peterson elimination of the ensuing anti b-
hydroxy silanes, now produced only 24 (50%). Finally, global
deprotection of 24 with TBAF completed the synthesis of 3
(71%).
The stage was now set to investigate the pivotal spiroace-
talization reaction, where we anticipated that the acetal
center at C21 would be controlled under equilibrating
conditions as a result of double anomeric stabilization. A
range of acidic conditions were evaluated, with the best
results achieved using CSA in MeOH at ambient temper-
ature. This led to clean conversion of the C23-epimeric
bis(acetonide) 17 and 18 into the two spiroacetals 19 and 20 in
72% yield in a 2.5:1 ratio in accordance with the aldol
diastereoselectivity. Following chromatographic separation,
unequivocal assignment of their stereochemistry, including
that of the acetal center at C21, was made by NOE analysis
Gratifyingly, the spectroscopic data (1H, 13C NMR and
MS) obtained for 1,3-diene 3 were in complete accordance
with that reported for the corresponding spirangien degrada-
tion fragment.[1a,15] In addition, the measured specific rota-
tion, [a]2D0 = + 34 (c = 0.04, MeOH) agreed with the + 33.1
(c = 1.0, MeOH) reported, both in terms of magnitude and
sign, thereby leading to the confident assignment of the
1
(Scheme 4) and comparison with the H NMR data of the
spirangiens.[1a]
It now remained to install the C14-stereocenter and the
truncated spirangien side chain (Scheme 5). Silylation of the
hydroxy groups in 19 (TESOTf, 84%), followed by selective
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Communications
[3] For a synthesis of an acyclic C23–C32 fragment, see: M. Lorenz,
M. Kalesse, Tetrahedron Lett. 2007, 48, 2905 – 2907.
[4] a) I. Paterson, G. J. Florence, K. Gerlach, J. P. Scott, N. Sereinig,
J. Am. Chem. Soc. 2001, 123, 9535 – 9544; b) I. Paterson, G. J.
Florence, K. Gerlach, J. P. Scott, Angew. Chem. 2000, 112, 385 –
388; Angew. Chem. Int. Ed. 2000, 39, 377 – 380.
[5] I. Paterson, J. A. Channon, Tetrahedron Lett. 1992, 33, 797 – 800.
[6] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 – 4156.
[7] A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky,
J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496 – 6511.
[8] The configuration of the C20-stereocenter in 15 was established
by the advanced Mosher method; see: I. Ohtani, T, Kusumi, Y.
Kashman, H. Kakisawa, J. Am. Chem. Soc. 1991, 113, 4092 –
4096.
[9] I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann, C. K.
McClure, R. D. Norcross, Tetrahedron 1990, 46, 4663 – 4684.
[10] D. A. Evans, A. M. Ratz, B. E. Huff, G. S. Sheppard, Tetrahedron
Lett. 1994, 35, 7171 – 7172.
[11] W. C. Still, J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487 –
2489.
absolute configuration of the spirangiens as shown in
structures 1 and 2 in Scheme 1.
In summary, a highly convergent and flexible synthetic
strategy has been developed for spirangien A and B, which
makes use of a common stereotetrad building block to lead to
the advanced C10–C32 fragment (+)-3, thus enabling the
unambiguous assignment of the full configuration of these
bioactive polyketide metabolites. Based on the pronounced
cytotoxicity associated with this novel spiroacetal scaffold,
including that for truncated analogue 3, this synthesis opens
further SAR studies into the anticancer activity of the
spirangiens. The present work also provides a secure founda-
tion for the future completion of the total synthesis of
spirangien A.
Received: June 21, 2007
Published online: July 30, 2007
[12] I. Paterson, A. Schlapbach, Synlett 1995, 498 – 500.
[13] Treatment of allyltrimethylsilane with KOtBu and B(OiPr)3,
followed by (ꢀ)-diisopropyl tartrate, generated 26 (79%); see:
S. S. Harried, C. P. Lee, G. Yang, T. I. H. Lee, D. C. Myles, J. Org.
Chem. 2003, 68, 6646 – 6660.
[14] W. R. Roush, P. T. Grover, Tetrahedron 1992, 48, 1981 – 1998.
[15] See the Supporting Information for 1H and 13C NMR spectra and
a comparative listing of the data.
Keywords: antitumor agents · natural products · spiroacetals ·
structure elucidation · total synthesis
.
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[2] For an analysis of the biosynthetic gene cluster of this polyketide,
see: B. Frank, J. Knauber, H. Steinmetz, M. Sharfe, H. Blocker,
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