Synthesis of the C21-C34 fragment of antascomicin B

Article abstract of DOI:10.1016/j.tetlet.2011.09.027

The C21-C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ire-land-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 ?-

Full text of DOI:10.1016/j.tetlet.2011.09.027

Tetrahedron Letters 52 (2011) 6349–6351
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Tetrahedron Letters
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Synthesis of the C21–C34 fragment of antascomicin B
John M. Hutchison 1, Andrew S. Gibson, David T. Williams, Matthias C. McIntosh
⇑
University of Arkansas, 119 Chemistry Building, Fayetteville, AR 72701, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The C21–C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ire-
land-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters,
respectively. Directed hydrogenation installed the C29 b-configuration. The fragment possesses 7 of
the 11 fixed stereocenters contained in the natural product.
Received 1 September 2011
Accepted 6 September 2011
Available online 12 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ireland-Claisen rearrangement
Allylic diazene rearrangement
Directed hydrogenation
Natural product
The antascomicins are a small family of macrolides isolated in
China from soil bacteria of the genus Micromonospora that exhibit
very strong binding to FKBP12.1 The most potent of these, antas-
comicin B, binds with an IC50 of 0.7 nM, equivalent to that of FK-
506 and rapamycin.2–4 Unlike the latter compounds, which are
clinically used to suppress graft rejection in organ transplant pa-
tients, the antascomicins possess no immunosuppressive effects.
They lack the so-called effector domain that is responsible for
binding a second protein, calcineurin for FK-506 and mTOR for
rapamycin.
However, FKBP12 and other immunophilins have been found in
a variety of other tissues,5 including the nervous system. Small
molecule FKBP binders have been demonstrated to stimulate neu-
rite outgrowth and hence have potential for use in the treatment of
neurodegenerative diseases.6 In addition, FKBPs have multiple iso-
forms, and it may be biochemically or therapeutically useful to
selectively inhibit a particular isoform.7
Similarly, the development of inhibitors of specific peptidyl-
prolyl isomerases such as FKBP12 may find clinical applications.8
Antascomicin B offers a platform from which these issues can be
explored.
In 2008 we reported a model study of the C22–C34 fragment of
antascomicin B lacking the C31 and C32 hydroxyl groups.9 We re-
port herein the successful completion of the corresponding fully
substituted and differentially protected fragment.
reported acyclic 1,3-reductive transposition methodology10 from
hydrazone 3. The hydrazone would in turn be derived from pente-
noic acid derivative 4, which is the product of Ireland-Claisen rear-
rangement of allylic ester 5.11
The synthesis would begin with the known trihydroxy cyclo-
hexenone 6 (Scheme 2), which is available in racemic form in five
steps from benzoquinone.12 However, an efficient asymmetric
route to 6 was not available. We, therefore, undertook a racemic
synthesis of fragment 1 while simultaneously developing a practi-
cal, scalable asymmetric approach to 6. The latter has been suc-
cessfully realized.13 We report herein the racemic synthesis of
fragment 1.
Selective bis-silylation of triol 6, followed by alkene hydrogena-
tion gave hydroxy ketone 7. Although we had initially also pro-
tected the C31 hydroxyl group, additions of propynyl MgBr or Li
to the triply protected substrate were inefficient, unselective, or
selective for the undesired isomer. We noted scattered reports in
the literature describing the addition of organometallic nucleo-
philes to cyclohexanones bearing unprotected b-hydroxyl groups
that provided 1,3-syn-diols with high diastereoselectivity.14 In
those cases, however, the hydroxyl groups were fixed in an axial
position. In at least one case,14d an isomeric equatorial alcohol gave
the opposite facial selectivity. Hence enone 7 would presumably
need to adopt an all axial conformation to exhibit high diastereose-
lectivity. Gratifyingly, the addition of propynyl MgBr to b-hydroxy
ketone 7 did indeed afford a single 1,3-syn-diol diastereomer 8 in
good yield.15,16 This was in stark contrast to the propynyl MgBr
addition to the corresponding model compound lacking the C31
and C32 oxygens, which was completely unselective.9
Our approach to C21–C34 fragment 1 involves a directed hydro-
genation to install the C29 stereocenter (Scheme 1). The remote
C23 stereocenter of diene 2 would be installed via our recently
Regioselective protection of the C31 2° alcohol of diol 8 as the
t-Bu carbonate was achieved by treatment of the diol with just
over 1 equiv of n-BuLi (Scheme 3). Acylation of the 3° hydroxyl
group was performed in a similar fashion to give propargyl ester
⇑
Corresponding author.
E-mail address: mcintosh@uark.edu (M.C. McIntosh).
Current address: Auburn University Montgomery, 7061 Senators Dr., Montgom-
1
ery, AL 36117, USA.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.027

6350
J. M. Hutchison et al. / Tetrahedron Letters 52 (2011) 6349–6351
Scheme 1. Retrosynthesis of C21–C34 fragment 1.
O
O
1. TBDMSCl
HO
OH
OH
OTBS
OH
imidazole, DMF
CH3CCMgBr
OTBS
OH
31
2. H2, Pd/C
MeOH, 59%
over 2 steps
THF, 0 °C to rt
80%
OH
OTBS
OTBS
6
7
8
BnO
O
Pd/BaSO4
H2 (90 psi)
1. nBuLi (1.1 eq)
ether, (BOC)2O
O
5
8
OTBS
OtBOC
pyr, EtOAc
87%
2. nBuLi, ether
ClCOCH2OBn
68% over 2 steps
OTBS
9
Scheme 2. Synthesis of allylic ester 5.
Scheme 4. Synthesis of C22–C34 fragment 1.
Weinreb amide 10.18 Addition of the Li anion of iodide 1119 pro-
vided enone 12. Conversion of enone 12 to hydrazone 3 was slug-
gish, but highly selective for the desired E-isomer.
We then sought to employ our 1,3-reductive transposition
methodology to deliver diene 2 (Scheme 4). This example would
constitute the most highly substituted and oxygenated system
thus far attempted. The conditions we employed previously largely
followed Kabalka’s protocol.20 After reduction of the hydrazone
with catecholborane was complete, solid NaOAc hydrate was
added and the mixture heated under reflux.
However, reduction of hydrazone 3 required significantly high-
er loading of catecholborane than was needed in the simpler sys-
tems. Three charges of 6 equiv each were ultimately needed to
effect the reduction.21 The high loading necessitated an intermedi-
ate wash after reduction to decompose the excess borane. The
crude isolate was then treated with NaOAc and heated under reflux
in CHCl3 to provide 1,4-syn isomer 2, presumably via allylic dia-
zene 30. The 1,4-syn configuration is a consequence of allylic strain
directed rearrangement.22,23 Cleavage of the TBS groups was best
effected sequentially, with the C30 group undergoing deprotection
upon treatment with HOAc/H2O, and the C31 TBS group requiring
Bu4NF to give alcohol 13 in good overall yield.
As in the model system, we pursued a directed hydrogenation
approach to install the C29 stereocenter, although we recognized
potential problems arising from the more highly substituted cyclo-
hexane ring. Presumably, the directed hydrogenation would need
to occur from the higher energy all axial conformation of diene
13 to selectively provide the b-configuration at C29 (Scheme 5).
Although a few examples of directed hydrogenation of alkenes pos-
sessing unprotected diols have been reported,24 it was neverthe-
Scheme 3. Synthesis of hydrazone 3.
9. Hydrogenation of alkyne 9 using Pd/BaSO4 gave Z-alkene 5 in
high yield.
Ireland-Claisen rearrangement of the highly sterically con-
gested allylic ester 5 was effected by treatment with LDA and
TMSCl at ꢀ78 °C, followed after 10 min by HOAc (Scheme 4). The
HOAc served to protonate excess base and prevent enolization of
the rearrangement product.17 The rearrangement presumably pro-
ceeded via a chair-like transition state corresponding to Z-ketene
acetal 50 in which the larger OTBS-substituted C30 carbon was ori-
ented in the pseudo-equatorial position. Pentenoic acid 4 was ob-
tained in very good yield as a single diastereomer based on 1H NMR
and 13C NMR analyses. Carboxylic acid 4 was then converted to

J. M. Hutchison et al. / Tetrahedron Letters 52 (2011) 6349–6351
6351
3. For an excellent review, see: Maddess, M. L.; Tackett, M. N.; Ley, S. V. Prog. Drug
Res. 2008, 66, 12–186.
4. For partial syntheses, see: (a) Fuwa, H.; Okamura, Y.; Natsugar, H. Tetrahedron
2004, 60, 5341–5352; (b) Chakraborty, T. K.; Mohan, B. K. Tetrahedron Lett.
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Tetrahedron Lett. 2006, 47, 5003–5005.
tBuO
O
R
O
HO
O
O
R
OH
OtBu
5. Barik, S. Cell. Mol. Life Sci. 2006, 63, 2889–2900.
OH
OH
6. (a) Snyder, S. H.; Lai, M. M.; Burnett, P. E. Neuron 1998, 21, 283–294; (b)
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15. The origin of the diastereoselectivity in this and related examples (Ref. 14) is
unclear. We are unaware of any computational or experimental studies that
address this phenomenon.
Scheme 5. Directed hydrogenation of 28-C29 alkene.
less a concern that the high affinity of Crabtree-type Ir(I) catalysts
for alcohols would result in sequestering of the catalyst by either
the diol or an alcohol-carbonate combination and prevent effective
reduction.
In the event, directed hydrogenation of diene 13 did provide the
desired configuration at C29,25 although a high loading of catalyst
(ca. 40 mol %) was indeed required. For the purposes of character-
ization, we found it helpful to convert diol 1 to the corresponding
bis-p-nitrobenzoate 14.
In summary, a differentially protected C21–C34 fragment of
antascomicin B has been prepared in a highly stereocontrolled se-
quence. The synthesis was 14 steps from the known trihydroxycyc-
lohexenone 6, or 19 steps from benzoquinone. Further progress
toward the antascomicins will be presented in due course.
Acknowledgments
NSF (CHE0616154, CHE0911638), NIH (P30RR031154), the
Arkansas Biosciences Institute, and the Arkansas Department of
Higher Education for a SURF fellowship (D.T.W.), and David R. Clay,
University of Arkansas, for help with data collection.
16. X-ray crystallographic analysis of a derivative confirmed the structure (see
Supplementary data).
17. Hong, S.-P.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh, M. C. J. Org. Chem.
2002, 67, 2042–2055.
Supplementary data
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21. We speculate that this is a consequence of the larger number of Lewis basic
atoms that may complex the borane.
Supplementary data (experimental procedures, characteriza-
tion data, 1H and 13C NMR spectra of all new compounds; crystal
structure and cif file of compound 90, the C31 benzyloxycarbonyl
variant of compound 9) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.09.027.
22. (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307–1370; (b)
Hoffman, R. W. Chem. Rev. 1989, 89, 1841–1860.
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M.; Valle, N. Tetrahedron Lett. 2000, 41, 4379–4382; (b) Hanessian, S.; Mainetti,
E.; Lecomte, F. Org. Lett. 2006, 8, 4047–4049; (c) Watanabe, H.; Nakada, M.
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References and notes
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Schilling, W.; Wioland, C. J. Antibiot. 1996, 49, 230–233.
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D.; McCusker, C.; Barlow, J. S.; Akiyama, R.; Yasuda, K.; Ley, S. V. Angew. Chem.,
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25. The C29 configuration was confirmed by the 10.0 Hz trans-diaxial coupling
between the C29 and C30 protons in bis-p-nitrobenzoate ester 14.