Concerning the synthesis of the tedanolide C(13)-C(23) fragment via anti-aldol reaction

Article abstract of DOI:10.1021/ol800546g

Synthesis of C(13)-C(23) aldehyde 4, an Important Intermediate In a planned total synthesis of tedanolide, Is described. The stereoselectivity of the key anti-aldol reaction of aldehyde 5 and ketone 6 (en route to 4) perfectly tracks the enantiomeric purity of 5. It is demonstrated that aldehyde 24, a precursor of 5, undergoes facile epimerization during a Swern oxidation and stabilized ylide olefination sequence.

Full text of DOI:10.1021/ol800546g

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2059-2062
Concerning the Synthesis of the
Tedanolide C(13)-C(23) Fragment via
Anti-Aldol Reaction
Joshua R. Dunetz and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458
roush@scripps.edu
Received March 10, 2008
ABSTRACT
Synthesis of C(13)-C(23) aldehyde 4, an important intermediate in a planned total synthesis of tedanolide, is described. The stereoselectivity
of the key anti-aldol reaction of aldehyde 5 and ketone 6 (en route to 4) perfectly tracks the enantiomeric purity of 5. It is demonstrated that
aldehyde 24, a precursor of 5, undergoes facile epimerization during a Swern oxidation and stabilized ylide olefination sequence.
Tedanolide (1), isolated from the Caribbean fire sponge
Tedania ignis in 1984 by Schmitz and co-workers, displays
potent cytotoxicity against various cancer cell lines (ED50
) 250 pg/mL against human nasopharynx carcinoma; ED50
) 16 pg/mL against lymphocytic leukemia) and causes cell
arrest in the S phase.1 The closely related macrolide, 13-
deoxytedanolide (2), was isolated from the Japanese sponge
Mycale adhaerens in 1991 by Fusetani and co-workers and
demonstrates high cytotoxicity against P388 murine leukemia
cells (IC50 ) 94 pg/mL).2 The impressive biological activities
and structural complexities of the tedanolides have inspired
our laboratory3 and others4–12 to pursue their synthesis.
Kalesse (2006)4a,b and Smith (2007)5a recently reported total
syntheses of tedanolide, and a few years earlier, Smith
(2003)5c,d and our laboratory (2005)3areported total syntheses
of the 13-deoxy congener, 2.
(5) (a) Smith, A. B., III; Lee, D. J. Am. Chem. Soc. 2007, 129, 10957.
(b) Cho, C.-G.; Kim, W.-S.; Smith, A. B., III. Org. Lett. 2005, 7, 3569. (c)
Smith, A. B., III; Adams, C. M.; Lodise Barbosa, S. A.; Degnan, A. P.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12042. (d) Smith, A. B., III; Adams,
C. M.; Lodise Barbosa, S. A.; Degnan, A. P. J. Am. Chem. Soc. 2003, 125,
350. (e) Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249.
(6) (a) Jung, M. E.; Zhang, T.-h. Org. Lett. 2008, 10, 137. (b) Jung,
M. E.; Yoo, D. Tetrahedron Lett. 2008, 49, 816. (c) Jung, M. E.; Yoo, D.
Org. Lett. 2007, 9, 3543. (d) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3,
333. (e) Jung, M. E.; Lee, C. P. Tetrahedron Lett. 2000, 41, 9719. (f) Jung,
M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. (g) Jung, M. E.; Marquez, R.
Tetrahedron Lett. 1999, 40, 3129.
(7) (a) Wong, C.-M.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 4485. (b)
Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 6001. (c) Loh, T.-P.;
Feng, L.-C. Tetrahedron Lett. 2001, 42, 3223.
(8) (a) Matsui, K.; Zheng, B.-Z.; Kusaka, S.-i.; Kuroda, M.; Yoshimoto,
K.; Yamada, H.; Yonemitsu, O. Eur. J. Org. Chem. 2001, 3615. (b) Zheng,
B.-Z.; Yamauchi, M.; Dei, H.; Kusaka, S.-i.; Matsui, K.; Yonemitsu, O.
Tetrahedron Lett. 2000, 41, 6441. (c) Matsushima, T.; Nakajima, N.; Zheng,
B.-Z.; Yonemitsu, O. Chem. Pharm. Bull. 2000, 48, 855. (d) Zheng, B.-Z.;
Maeda, H.; Mori, M.; Kusaka, S.-i.; Yonemitsu, O.; Matsushima, T.;
Nakajima, N.; Uenishi, J.-i. Chem. Pharm. Bull. 1999, 47, 1288. (e)
Matsushima, T.; Mori, M.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi,
J.-i.; Yonemitsu, O. Chem. Pharm. Bull. 1999, 47, 308. (f) Matsushima,
T.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J.-i.; Yonemitsu, O.
Synlett 1999, 780. (g) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda,
H.; Uenishi, J.-i.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1335. (h)
Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett.
1996, 37, 385.
(1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.;
van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org. Chem.
1991, 56, 4971.
(3) (a) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc.
2005, 127, 6186. (b) Roush, W. R.; Newcom, J. S. Org. Lett. 2002, 4,
4739. (c) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95.
(4) (a) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. Chem. Eur. J.
2008, 14, 2232. (b) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. J. Am.
Chem. Soc. 2006, 128, 14038. (c) Hassfeld, J.; Eggert, U.; Kalesse, M.
Synthesis 2005, 1183. (d) Ehrlich, G.; Kalesse, M. Synlett 2005, 655. (e)
Hassfeld, J.; Kalesse, M. Synlett 2002, 2007
.
10.1021/ol800546g CCC: $40.75
Published on Web 04/19/2008
2008 American Chemical Society

5 and ketone 6 using conditions developed by Paterson.15
This transformation would set the C(16)- and C(17)-
stereocenters in a single operation through a transition state
believed to minimize oxygen lone pair interactions between
the enol borinate and benzyl ether.15b We were encouraged
by a report from Loh and co-workers that enol borinates
derived from ꢀ-siloxy ethyl ketones participate in the anti-
aldol reaction under Paterson’s conditions without ꢀ-elimina-
tion of the siloxy substituent. Indeed, Loh reported 85:15
selectivity for the aldol coupling of ketone 7 and aldehyde
10 (Scheme 2).7c In addition, during the preparation of this
We are pursuing a strategy toward the synthesis of
tedanolide in which the carbon skeleton is assembled in a
convergent fashion via the aldol reaction of ketone 33a and
aldehyde 4 (Scheme 1). Our selection of 4 was based on
Scheme 2.
Loh’s Anti-Aldol Reaction of ꢀ-Siloxy Ketone 77c
Scheme 1. Retrosynthetic Approach to Tedanolide
manuscript, Kalesse and co-workers reported 2:1 diastereo-
selectivity for the anti-aldol reaction of ketone 7 and aldehyde
5.4a
Both ketone 6 and aldehyde 5 are available in easily
scalable routes (Scheme 3). Addition of the lithium enolate
Scheme 3. Syntheses of Ketone 6 and Aldehyde 5
previous results from our laboratory in which we were unable
to oxidize late-stage hydroxy intermediates (e.g., 8) to the
requisite C(15)-carbonyl owing to the remarkable stability
of hemiketal 9 (eq 1). We hypothesized that inversion of
the C(15)-(R)-alcohol stereochemistry of our first-generation
intermediates (see 8) to the (S)-configuration in 4 would
destabilize the corresponding hemiketal via increased 1,3-
diaxial interactions, thereby permitting C(15)-oxidation.13,14
In planning our synthetic approach to 4 (Scheme 1), we
were intrigued by the possible anti-aldol coupling of aldehyde
(9) Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune, S.
Tetrahedron Lett. 1998, 39, 1873
.
of tert-butyl acetate to aldehyde 1216 and subsequent LiAlH4
reduction of the ester afforded 1,3-diol 13. Selective silylation
of the primary alcohol followed by Parikh-Doering oxida-
tion17 led to the targeted ketone 6. The synthesis of aldehyde
54a,d began with the Wittig olefination of aldehyde 14 and
(10) Iwata, Y.; Tanino, K.; Miyashita, M. Org. Lett. 2005, 7, 2341
.
(11) (a) Taylor, R. E.; Hearn, B. R.; Ciavarri, J. P. Org. Lett. 2002, 4,
2953. (b) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett. 1998,
39, 9361
.
(12) (a) Nyavanandi, V. K.; Nadipalli, P.; Nanduri, S.; Naidu, A.; Iqbal,
J. Tetrahedron Lett. 2007, 48, 6905. (b) Nyavanandi, V. K.; Nanduri, S.;
Dev, R. V.; Naidu, A.; Iqbal, J. Tetrahedron Lett. 2006, 47, 6667
.
2060
Org. Lett., Vol. 10, No. 10, 2008

cleavage of the trityl ether. Swern oxidation17 of 15 and
subsequent treatment of the ꢀ,γ-unsaturated aldehyde with
the stabilized ylide Ph3PdC(Me)CO2Et gave the unsaturated
ester 16 with excellent selectivity. DIBAL reduction of the
ester followed by oxidation of the derived primary alcohol
with MnO2 provided the requisite aldehyde 5.
Our initial exploration of the anti-aldol reaction of alde-
hyde 5 and ketone 6 under conditions developed by Paterson
(treatment of 6 with 1.5 equiv of (c-Hex)2BCl and 2.0 equiv
of Et3N in Et2O at 0 °C and then addition of 5 at -78 °C)
led to 18 as the major of two diastereomers with 80:20
selectivity (Scheme 4). Based on the aforementioned studies
assigned by conversion to acetonides 22a and 22b; both
acetals displayed identical coupling constants of J15,16 ) J16,17
) 10.4 Hz, and the 13C data of both acetonides were also
consistent with the indicated 1,3-syn stereochemistry (analy-
sis in CDCl3).19 Selective silylation of the allylic alcohols
of 20a,b followed by treatment of the mono-TES ethers with
DDQ provided benzylidene acetals 21a and 21b (deriving
1
from the major and minor aldols, respectively). H NOE
analysis of these compounds revealed that the C(14)-methine
and benzylidene acetal protons are syn and that the C(14)-H
is equatorial in both 21a and 21b. Thus, the major and minor
products from the aldol reaction of 5 and 6 have identical
stereochemistry at C(14)-C(17)sboth are anti-aldol products
with (S)-stereochemistry at C(17)-OH.
It was clear from these results that the minor aldol product
is not 19, as originally assumed. Instead, we considered that
C(20)-epimer 23 might be the minor aldol product. This
structure would arise if epimerization of the bisallylic
stereocenter of aldehyde 5 occurred during its synthesis. This
hypothesis was consistent with our observation that only a
single diastereomer is formed from the aldol reaction of
ketone 6 with methacrolein (not shown). Furthermore,
Mosher ester analysis of primary alcohol 17, the immediate
precursor of aldehyde 5, revealed this intermediate to be an
80:20 ratio of epimers at the C(20) bisallylic stereocenter
(Figure 1). This evidence confirmed our deduction that the
C(20)-epimer 23 is the minor aldol diastereomer, and not
compound 19 as suggested by previous studies.4a,7c
Scheme 4. Anti-Aldol Reaction of Ketone 6 and Aldehyde 5
by Loh7c (and also as reported by Kalesse4a after our work
was completed), we expected 19 to be the minor aldol adduct.
However, Mosher ester analysis18 of both aldol products
revealed that both haVe identical (S)-configurations for the
C(17)-alcohols. 1,3-Reduction of the two ꢀ-hydroxy ketones
with DIBAL (>95:5 dr) afforded 1,3-diols 20a and 20b. The
1,3-syn diol stereochemistry in both 20a and 20b was
Figure 1.
1H NMR spectra (400 MHz, C6D6) of the Ha and Hb
protons of Mosher esters derived from alcohol 17, the immediate
precursor to aldehyde 5.
(13) Julian, L. D. Studies toward the total synthesis of the tedanolides:
Total synthesis of 13-deoxytedanolide. Ph.D. thesis, University of Michigan,
2005.
It seemed most likely that epimerization of C(20) was
occurring during the conversion of alcohol 15 (>95:5 er as
(14) While this work was in progress, Kalesse reported experimental
evidence for this hypothesis (refs 4a and 4b).
(17) For a review, see: Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(18) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(b) For a useful explanation and examples of Mosher ester analysis, see:
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
(15) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Mechanistic discussion: Vulpetti, A.; Bernardi, A.; Gennari,
C.; Goodman, J. M.; Paterson, I. Tetrahedron 1993, 49, 685.
(16) Prepared in analogous fashion to the known p-methoxybenzyl-
protected Roche aldehyde: Organ, M. G.; Wang, J. J. Org. Chem. 2003,
68, 5568.
(19) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
Org. Lett., Vol. 10, No. 10, 2008
2061

Table 1. Optimization of the Oxidation-Olefination Sequence
afforded a syn-1,3-diol with excellent selectivity that was
silylated at the allylic alcohol position. The dimethoxybenzyl
group of 25 was then transferred to the internal C(15)-OH
through a sequence involving benzylidene acetal formation
with DDQ, followed by regioselective acetal reductive
opening with DIBAL. Finally, Dess-Martin oxidation of
alcohol 26 furnished the targeted C(13)-C(23) aldehyde 4
(Scheme 5).
entry
oxidation
Swern
Swern
Swern
Swern
Dess-Martin one-pot, R ) Me
Dess-Martin two-pot, R ) Me
Dess-Martin one-pot, R ) Me
Dess-Martin one-pot, R ) Me
ylide addition olefination enant ratioa
1
2
3
4
5
6
7
8
one-pot, R ) Et
one-pot, R ) Me
one-pot, R ) Me
two-pot, R ) Me
rt
rt
0 °C
0 °C
rt
rt
0 °C
-20 °C
80:20
80:20
85:15
90:10
90:10
90:10
94:6
94:6
a Determined by DIBAL reduction of ester 16 and Mosher ester analysis
of the resulting alcohol 17 (as shown in Figure 1).
Scheme 5. Completion of the C(13)-C(23) Fragment 4
determined by Mosher ester analysis) to the R,ꢀ-unsaturated
ester 16. This was confirmed by the studies summarized in
Table 1. We had originally employed a one-pot reaction
sequence20 in which alcohol 15 was oxidized by using the
Swern protocol (DMSO, (COCl)2, CH2Cl2, Et3N, -78 to 0
°C), followed by addition of the stabilized ylide,
Ph3PdC(Me)CO2R (R ) Me, Et), directly to the Swern
reaction mixture before the mixture was allowed to warm
to room temperature (entries 1 and 2). The isomeric purity
at C(20) was determined by DIBAL reduction of ester 16
and Mosher ester analysis of the derived alcohol 17.
Epimerization of C(20) was somewhat suppressed by main-
taining the olefination reaction at 0 °C (entry 3), and further
improvement was realized (90:10 er) when isolated aldehyde
24 (by extractive workup of the Swern oxidation) was treated
with Ph3PdC(Me)CO2Me in a two-pot sequence (entry 4).
Ultimately, the best results were obtained when the oxidation
of 15 was performed by using Dess-Martin periodinane21
(entries 5-8). In this way, 16 was obtained with optimal
enantiomeric purity of 94:6 (entries 7 and 8).
Further progress toward completion of the total synthesis
of tedanolide will be reported in due course.
Acknowledgment. Support from the National Institutes
of Health (GM 38436) is gratefully acknowledged.
Note Added after ASAP Publication. Due to a produc-
tion error, the reference to eq 2 was incorrectly printed as
eq 5 in the version published ASAP April 19, 2008; the
corrected version was published ASAP April 23, 2008. In
addition, the formula for Ph3PdC(Me)CO2R was corrected
in the version published May 8, 2008.
When aldehyde 5 (prepared from 16 of 94:6 er) was used
in the anti-aldol reaction with 6, a 94:6 mixture of aldol
diastereomers 18 and 23 was obtained (eq 2). It is striking
that the selectivity of the anti-aldol reaction tracks perfectly
with the enantiomeric purity of alcohol 17.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The synthesis of the C(13)-C(23) fragment 4 was
completed in five steps. Reduction of 18 with DIBAL
(20) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198.
(21) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
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