A kiyooka aldol approach for the synthesis of the C(14)-C(23) segment of the diastereomeric analog of tedanolide C

Article abstract of DOI:10.1021/ol202515x

The challenging synthesis of a quaternary center within the highly oxygenated setting of tedanolide C can be performed via a Kiyooka aldol reaction. Here, the diastereomeric analog of tedanolide C with the configurations between C10 and C20 opposite compared to the proposed structure was chosen as the synthetic target. The tetra-substituted silyl ketene acetal provides the southern hemisphere of tedanolide C in useful selectivities, and the absolute configuration of the newly generated quaternary center was determined by NOE experiments of the corresponding acetonide.

Full text of DOI:10.1021/ol202515x

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6038–6041
A Kiyooka Aldol Approach for the
Synthesis of the C(14)ÀC(23) Segment of
the Diastereomeric Analog of Tedanolide C
€
€
Leila Bulow, Arun Naini, Jorg Fohrer, and Markus Kalesse*
€
Centre for Biomolecular Drug Research, Leibniz Universitat Hannover,
30167 Hannover, Germany
Markus.Kalesse@oci.uni-hannover.de
Received September 16, 2011
ABSTRACT
The challenging synthesis of a quaternary center within the highly oxygenated setting of tedanolide C can be performed via a Kiyooka aldol
reaction. Here, the diastereomeric analog of tedanolide C with the configurations between C10 and C20 opposite compared to the proposed
structure was chosen as the synthetic target. The tetra-substituted silyl ketene acetal provides the southern hemisphere of tedanolide C in useful
selectivities, and the absolute configuration of the newly generated quaternary center was determined by NOE experiments of the corresponding
acetonide.
In 2005 Ireland and co-workers isolated tedanolide C (1)
from the marine sponge Ircinia sp.1 It belongs to the
family of the tedanolides which includes, up to now, five
members2À4 which have attracted considerable synthetic
interest.5 Tedanolide C (1) exhibits potent cytotoxicity
against HCT-116 cells in vitro with an IC50 of 57 ng/mL.
Subsequent cell cycle analysis showed that treatment of
HCT-cells with 0.2 μg/mL tedanolide C (1) resulted in a
strong accumulation of cells in the S-phase. These results
indicate that tedanolide C (1) could be a promising lead
compound for the inhibition of protein biosynthesis.6
Tedanolide C (1) contains a highly functionalized 18-
membered macrolactone displaying 12 stereogenic centers
(Figure 1). The side chain, which bears an epoxide, is
characteristic for all members of the tedanolide family.7
(1) Ireland, C. M.; Aalbersberg, W.; Andersen, R. J.; Ayral-Kaloustian,
S.; Berlinck, R.; Bernan, V.; Carter, G.; Churchill, A. C. L.; Clardy, J.;
Concepcion, G. P.; Dilip De Silva, E.; Discafani, C.; Fojo, T.; Frost, P.;
Gibson, D.; Greenberger, L. M.; Greenstein, M.; Harper, M. K.; Mallon,
R.; Loganzo, R.; Nunes, M.; Poruchynsky, M. S.; Zask, A. Pharm Biol.
2003, 41, 15.
(2) Tedanolide: Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.;
Hossain, M. B.; van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(3) 13-Deoxytedanolide: Fusetani, N.; Sugawara, T.; Matsunaga, S.
J. Org. Chem. 1991, 56, 4971.
(4) Candidaspongiolide: Meragelman, T. L.; Willis, R. H.; Woldemichael,
C. M.; Heaton, A.; Murphy, P. T.; Snader, K. M.; Newman, D. J.; van Soest,
R.; Boyd, M. R.; Cardellina, J. H.; McKee, T. C. J. Am. Prod. 2007, 70, 1133.
(b) Whitson, E. L.; Pluchino, K. M.; Hall, M. D.; McMahon, J. B.; McKee,
T. C. Org. Lett. 2011, 13, 3518.
(5) (a) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, P.
J. Am. Chem. Soc. 2003, 125, 350. (b) Smith, A. B.; Adams, C. M.;
Barbosa, S. A. L.; Degnan, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
12042. (c) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc.
2005, 127. (d) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. J. Am.
Chem. Soc. 2006, 128, 14038. (e) Ehrlich, G.; Hassfeld, J.; Eggert, U.;
Kalesse, M. Chem.;Eur. J. 2008, 14, 2232. (f) Dunetz, J. R.; Julian,
L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 16407.
(6) Tedanolide, C; Chevallier, C.; Bugni, T. S.; Feng, X.; Harper,
M. K.; Orendt, A. M.; Ireland, C. M. J. Org. Chem. 2006, 71, 2510.
(7) (a) Taylor, R. E. Nat. Prod. Rep. 2008, 25, 854. (b) Roy, M.;
Kalesse, M. Nat. Prod. Rep. 2008, 25, 862.
r
10.1021/ol202515x
Published on Web 10/25/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Analysis of Southwest Fragment 7
Figure 1. Proposed structure of tedanolide C, 1.
Its carbon skeleton was elucidated via NMR spectro-
scopy whereas the relativeconfiguration wasdeducedfrom
a combination of molecular modeling and DFT calcula-
tions which in turn were based on the observed coupling
constants.
continuous chiral centers of which one is quaternary are
constructed within the same CÀC bond forming reaction
are rare.
The presence of a chiral quaternary center requires
substantial modifications for its synthetic startegy to con-
struct the southwest fragment as compared to tedanolide
itself. Recently, an elegant approach involving a BaylisÀ
Hillman reaction and a Sharpless dihydroxylation was put
forward by Roush et al.8
In 2002 Hayashi and co-worker used a tetra-substituted
ketene acetal for the pivotal step in the synthesis of
azaspirene.10 However, here we had to establish a protocol
that would allow for the construction of the absolute
configuration independently of the directing effects of
the inherent chiral center since we expected that this center
would not contribute significantly to the stereochemical
outcome of this transformation. Our experience with the
Kiyooka aldol reaction as the ideal transformation to
establish a secondary alcohol next to a quarternary center
was based on the synthesis of a simplified disorazole
analog.11 Even with this state of knowledge it was not
obvious if the Kiyooka aldol reaction would be suited to
establishing the chiral quaternary center and thus re-
mained as the pivotal transformation during this synthesis.
The proposed mechanism involves the complex genera-
ted from N-Ts-L-valine and BH3 to generate a chiral
oxazaborolidinone in situ. This chiral Lewis acid induces
the selective aldol process and leads to reduction of the
nascent ester moiety (Scheme 2). It is noteworthy to point
out that the use of a TBS-protected silyl ketene acetal
favors the reductive acetal formation (15) as a consequence
of their superior transition state stabilization, whereas
TMS-protected ketene acetals lead to the corresponding
β-hydroxyl esters.
Figure 2. Members of the tedanolide family.
Due to the differing configurations in the southern
hemisphere of tedanolide C (1) compared to other mem-
bers of the tedanolide family (Figure 2), we planned on the
synthesis of the diastereomeric analog of tedanolide C (6)
as our synthetic target. Our retrosynthetic analysis divides
tedanolide C into equally complex northern and southern
fragments. Focusing on the southwest fragment 7, the
synthetic plan requires the construction of a quarternary
center as the key step (Scheme 1).
Scheme 2. Proposed Mechanism for the Kiyooka Aldol Reac-
tion
To generate one additional stereogenic center at C-17 a
Kiyooka aldol reaction9 between aldehyde 9 and silyl
ketene acetal 8 was envisioned to provide the desired aldol
product with concomitant protection of the hydroxyl
group at the secondary alcohol. Examples in which two
(8) Barth, R; Roush, W. R. Org. Lett. 2010, 12, 2342.
(9) Kiyooka, S.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M.
J. Org. Chem. 1991, 56, 2276.
The aldehyde required for the construction of the south-
west fragment is derived from alcohol (16) which can be
Org. Lett., Vol. 13, No. 22, 2011
6039

obtained by standard transformations from the corre-
sponding Roche ester. The subsequent steps utilize the
Swern protocol and a WittigÀHorner olefination12 to
install the E-configurated R,β-unsaturated ester 17. Re-
duction to the allylic alcohol and a sequence of protecting
group manipulations were completed by DessÀMartin
oxidation. The so-obtained aldehyde is sensitive to epimer-
ization and was therefore immediately subjected to a
Wittig olefination,13 to provide skipped diene 20. Finally,
TBAF mediated TBS deprotection and MnO2 oxidation
established unsaturated aldehyde 9 (Scheme 3).
transformation proceeded in an enantiomeric ratio
>10:1.15
To complete the synthesis of ethyl ketone 7, β-hydroxy
acetal 21 was treated with NaHMDS to induce a 1,5 OfO
silyl migration followed by elimination of the methoxy
group to provide aldehyde 22. At this stage the selectivity
of the Kiyooka aldol reaction became apparent and could
be identified based on their 1H NMR signals to be 6:1.16
The final two steps include a Grignard addition using
EtMgBr followed by a TPAP oxidation to establish south-
west fragment 7 (Scheme 5).
Scheme 5. Synthesis of Ethyl Ketone 7
Scheme 3. Synthesis of Aldehyde 9
In conclusion, fragment 7 could be obtained in 15 steps
and good selectivities taking advantage of the Kiyooka
adol reaction as the pivotal transformation.
The following studies confirmed the relative configura-
tion at the quarternary center. This particular structural
motif was without literature precedent to which it could
have been compared to. We therefore decided to restrict
the conformational flexibility of the Kiyooka product
through acetonide formation and to deduce the relative
conformation from its NOE contacts. Since we had pre-
viously assigned the absolute configuration of the second-
ary alcohol at C17 using the Mosher method we would
obtain all the remaining chiral information from NMR
experiments in correlation to the secondary alcohol.17 For
practical reasons we performed the synthesis of the bis-
acetonide on aldehyde 23 (Scheme 6).
This volatile aldehyde (9) is then used in the pivotal
Kiyooka aldol reaction, with silyl ketene acetal 8 to afford
β-hydroxyacetal21ingoodyields(Scheme4).9 Silylketene
acetal 8 in turn was derived from the corresponding ester in
one step using LiHMDS, TBSCl, and HMPA.14 Gratify-
ingly, the Kiyooka aldol reaction generated the desired
product in good selectivities. The sterically demanding
quarternary center is obtained in a highly diastereoselec-
tive manner (vide infra).
Scheme 4. Kiyooka Aldol Reaction
Scheme 6. Synthesis of Kiyooka Aldol Product 24
Based on theory, the use of N-Ts-L-valine as the source
of chirality should lead to R-configured secondary alco-
hols which was confirmed for the configuration at C17
using the Mosher ester method and showed that the
β-Hydroxy acetal 24 was obtained following the Kiyooka
protocol and then carefully treated with TBAF to yield
aldehyde 25 (Scheme 7). The Kiyooka aldol reaction using
aldehyde 23 could be performed at an even higher diaster-
eomeric ratio of 10:1. Reduction of aldehyde 25 with DIBAl-
H to the corresponding diol followed by acetalization with
(10) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am.
Chem. Soc. 2002, 124, 12078.
€
(11) Schackel, R.; Hinkelmann, B.; Sasse, F.; Kalesse, M. Angew.
Chem., Int. Ed. 2010, 49, 1619.
(12) Jiao, L.; Yuan, C.; Yu, Z. J. Am. Chem. Soc. 2008, 130, 4421.
(13) Ehrlich, G.; Kalesse, M. Synlett 2005, 4, 655.
(14) Chen, C.; Namba, K.; Kishi, Y. Org. Lett. 2009, 11, 409.
(15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(16) Hillier, M. C.; Meyers, A. T. Tetrahedron Lett. 2001, 42, 5145.
(17) Kiyooka, S.-I.; Shahid, K. A. Tetrahedron: Asymmetry 2000, 11,
1537.
6040
Org. Lett., Vol. 13, No. 22, 2011

2,2-dimethoxy propane generated acetonide 26 which was
used for NOE studies.
contacts can be rationalized with the C16ÀC17 syn rela-
tionshipof thediol moiety. Inthecaseof theantiisomerthe
protons H-8a and H-8b should not exhibit NOE contacts
to H-17. Additionally, these results are consistent with the
configurational analysis reported by Kiyooka et al.17
To show that this is a general protocol allowing for the
generation of a variety of different tertiary alcohols,
aliphatic, unsaturated, and aromatic aldehydes were em-
ployed as well (Table 2). It became apparent that the
diasteriomeric ratios range from 6:1 to 10:1 as observed
in the two above-mentioned cases and the enantiomeric
ratio was higher than 10:1.18
Scheme 7. Synthesis of Acetonide 26
Table 2. Kiyooka Protocol Using Different Aldehydes
The observed NOE contacts are shown in Table 1 and
allow the unambiguous assignment of the relative config-
uration of the quarternary center.
Table 1. Indicative NOE Contacts (displayed in red)a
entry
R
yield (%)
dr
er
1
2
3
Phenyl
83
80
40
6:1
10:1
10:1
>10:1
>10:1
>10:1
Cinnamyl
Valeryl
In summary, we developed a diastereoselective synthesis
of the southwest fragment of tedanolide C in 15 steps,
involving the construction of the quarternary center and
the adjacent secondary alcohol. Among the different con-
ditions validated in the pivotal aldol step, the Kiyooka
protocol not only provided the highest yields and selectiv-
ities but also allowed for the efficient assembly of the ethyl
ketone, required for further transformations.
a Tedanolide C numbering is used.
It can be seen that proton H-17 has contact with proton
H-15a and with both protons H-8a, H-8b) at the CH2-
group of the five-membered acetonide. Proton H-8b shows
contacts to proton H-17 and to the CH2-protons H-15a
and H-15b. In contrast proton H-8a has NOE contacts
to the protons H-19, H-18, H-17, and Me-9. All these
Supporting Information Available. Full experimental
procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(18) See Supporting Information.
Org. Lett., Vol. 13, No. 22, 2011
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