Studies on the synthesis of tedanolide: synthesis of the C(5)-C(21) segment via a highly stereoselective fragment assembly aldol reaction of a chiral beta,gamma-unsaturated methyl ketone.

Article abstract of DOI:10.1021/ol990572s

[formula: see text] A highly diastereoselective synthesis of 3, corresponding to the C(5)-C(21) segment of tedanolide, has been accomplished by a route utilizing the aldol reaction of aldehyde 4 and the beta,gamma-unsaturated methyl ketone 5.

Full text of DOI:10.1021/ol990572s

ORGANIC
LETTERS
1999
Vol. 1, No. 1
95-98
Studies on the Synthesis of Tedanolide:
Synthesis of the C(5)−C(21) Segment via
a Highly Stereoselective Fragment
Assembly Aldol Reaction of a Chiral
â,γ-Unsaturated Methyl Ketone
,1
William R. Roush* and Gregory C. Lane
Departments of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109, and
Indiana UniVersity, Bloomington, Indiana 47405
roush@umich.edu
Received April 9, 1999
ABSTRACT
A highly diastereoselective synthesis of 3, corresponding to the C(5)−C(21) segment of tedanolide, has been accomplished by a route utilizing
the aldol reaction of aldehyde 4 and the â,γ-unsaturated methyl ketone 5.
Tedanolide, 1, a highly cytotoxic macrolide, was isolated in
1984 from the Caribbean sponge Tedania ignis2 (Figure 1).
The structurally related macrolide 13-deoxytedanolide (2)
was subsequently isolated from Mycale adhaerens, a sponge
species from the western Pacific Ocean.3 Tedanolide displays
significant cytotoxicity against KB and PS tumor cell lines
in vivo, with ED50’s of 16 pg/mL in the PS assay and 250
pg/mL in the KB assay.2 13-Deoxytedanolide is also highly
cytotoxic, with a reported IC50 of 94 pg/mL vs P388 murine
leukemia cells.3 These potent biological properties have
stimulated interest in the synthesis of these molecules,
especially tedanolide, whose stereostructure has been deter-
mined by X-ray analysis.4-10 We report herein a highly
stereoselective synthesis of the C(5)-C(21) segment 3 of
tedanolide, via the fragment assembly aldol reaction of the
chiral aldehyde 4 and the â,γ-unsaturated methyl ketone 5.
In planning this approach to the synthesis of 3, we relied
on earlier studies from our laboratory which indicated that
the diastereofacial selectivity of 4 should favor production
of the C(13,14)-syn (i.e., Felkin) stereochemistry of 311,12
and that the intrinsic diastereofacial bias of 5, although
(5) Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron
Lett. 1996, 37, 385.
(6) Chem. Pharm. Bull. 1998, 46, 1135.
(7) Liu, J.-F.; Abiko, A.; Pei, Z. H.; Buske, D. C.; Masamune, S.
Tetrahedron Lett. 1998, 39, 1873.
(8) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett. 1998,
39, 9361.
(1) Address correspondence to this author at the Department of Chem-
istry, University of Michigan, Ann Arbor, MI 48109-1055.
(2) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.;
van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(3) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org. Chem.
1991, 56, 4971.
(9) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem. 1999, 64, 663.
(10) Matsushima, T.; Mori, M.; Zheng, B. Z.; Maeda, H.; Nakajima,
N.; Uenishi, J.; Yonemitsu, O. Chem. Pharm. Bull. 1999, 47, 308.
(11) Roush, W. R.; Bannister, T. D.; Wendt, M. D. Tetrahedron Lett.
1993, 34, 8387.
(12) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3443.
(4) Yonemitsu, O. J. Synth. Org. Chem. Jpn. 1994, 52, 946.
10.1021/ol990572s CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/24/1999

Aldehyde 4 was synthesized starting from the readily
available chiral aldehyde 615 (Scheme 1). A Wittig reaction
of 6 with Ph3PdCMeCO2Et provided the targeted (E)-enoate
in 85% yield following chromatographic separation of the
minor Z isomer (97:3 selectivity). Reduction of the (E)-enoate
with DIBAL then provided 7 in 83% yield from 6.16
Diastereoselective epoxidation of 7 was performed using the
Sharpless asymmetric epoxidation,17 and the resulting epoxy
alcohol was oxidized to the aldehyde 8 in 65% overall yield
by using the Parikh-Doering procedure.18 Epoxyaldehyde
8 was elaborated to the homoallylic alcohol 10 via aldol
reaction with the chiral crotonate imide 9,19 protection of
the aldol product as a TBS ether, and then reduction of the
acyl oxazolidinone using LiBH4 (5 equiv) in THF containing
3 equiv of H2O.20 Acylation of the primary hydroxyl group
of 10 followed by oxidative cleavage of the terminal olefin
and asymmetric crotylboration21 of the resulting aldehyde
provided 12 with excellent stereoselectivity. Finally, protec-
tion of the C(15) alcohol as a TES ether followed by
oxidative cleavage of the olefin completed the synthesis of
4.
Figure 1. Retrosynthetic analysis.
Scheme 1. Synthesis of Chiral Aldehyde 4
expected to be relatively modest,13 should reinforce that of
4 in a matched double asymmetric14 fragment coupling
process using the lithium enolate of 5. However, we also
recognized that successful implementation of this strategy
would be dependent on two critical issues. The first was
whether the potentially sensitive C(10) stereocenter of â,γ-
unsaturated ketone 5 would survive the planned aldol
coupling. The second concerned the definition of a suitable
protecting group strategy for the C(15) hydroxyl group, since
our earlier studies indicated that this unit would have a
pronounced effect on the aldol reaction stereoselectivity.12
While a C(15)-OTES ether was deemed appropriate for late-
stage manipulations in our projected total synthesis, our
earlier studies suggested that a â-TES ether would not be
suitable for the proposed fragment assembly sequence.
Fortunately, as described herein, the aldol reaction of 4 and
5 proved to be a highly stereoselective and synthetically
useful transformation.
(13) For example, the chiral methyl ketones employed in the studies
summarized in refs 10 and 11, which are more structurally complex than 5
in the present work, exhibited diastereofacial preferences ranging from 60:
40 to 83:17, depending on the metal enolate employed (see footnote 10 in
ref 11).
(14) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1.
The diastereofacial selectivity of 4 and the related alde-
hydes 13a and 13b was probed by studying their aldol
reactions with enolates generated from methyl isopropyl
ketone (3-methyl-2-butanone; Table 1 and Figure 2). The
results of these reactions demonstrate once again that the
(15) Walkup, R. D.; Kane, R. R.; Boatman, P. D., Jr.; Cunningham, R.
T. Tetrahedron Lett. 1990, 52, 7587.
(16) The spectroscopic and physical properties (e.g., 1H NMR, IR, mass
spectrum and/or C,H analysis) of all new compounds were fully consistent
with the assigned structures.
(17) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
(18) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
(19) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957.
(20) Pfenning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
(21) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348.
(22) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511.
(23) The stereochemistry of all other aldols was assigned via analysis
of the characteristic ABX pattern for the C(12)-CH2 and C(13)-H
resonances, as previously described (see footnote 8 of ref 10).
96
Org. Lett., Vol. 1, No. 1, 1999

positioned relatively close to the aldehyde, where it can
destabilize the otherwise favored chairlike transition state.12
However, the gearing effects that dominate the conforma-
tional preferences of 17 are not operational, or at least are
not as prevalent in 4, since the C(18-19)-epoxide unit is
less sterically demanding than the C(8)-OTBDPS unit of
17 (the conformation of the backbone of 4 should be as
shown in Figure 3 in order to minimize gauche interactions;
Table 1. Aldol Reactions of Aldehydes 4 and 13 with
3-Methyl-2-Butanone
entry
no. RCHO
aldol reaction
yield major
conditions (-78 °C)a
(%)b product 14:15
1
2
4
4
LHMDS, THF, -78 °C
TiCl4, i-Pr2NEt, CH2Cl2,
-78 °C
Bu2BOTf, i-Pr2NEt, CH2Cl2, 86
-78 °C
83
60
14a
14a
g97:03
77:23
3
4
14a
59:41
4
5
6
7
13a
13a
13a
13a
LHMDS, THF, -78 °C
NaHMDS, THF, -78 °C
KHMDS, THF, -78 °C
TiCl4, i-Pr2NEt, CH2Cl2,
-78 °C
79
76
26
55
14b
14b
14b
14b
g95:05
90:10
80:20
85:15
8
13a
Bu2BOTf, i-Pr2NEt, CH2Cl2, 85
-78 °C
14b
55:45
9
10
11
13b
13b
13b
LHMDS, THF, -78 °C
NaHMDS, THF, -78 °C
Bu2BOTf, i-Pr2NEt, CH2Cl2, 61
-78 °C
74
54
14c
14c
14c
93:7
g95:05
33:67
a Aldol reactions were performed at -78 °C by adding 1.0 equiv of 4 or
13 to the enolate generated from 3 equiv of isopropyl methyl ketone. b The
combined yields (unoptimized) of 14 and 15 isolated chromatographically.
Figure 3. Conformational analysis of 4 and 17.
aldehyde diastereofacial selectivity is enolate metal depend-
ent, with the best selectivity for the Felkin diastereomer 14
being obtained with the lithium enolate. The stereochemistry
of 14a (R1 ) TBS, R2 ) TES) was assigned following
removal of the TES ether (TBAF, ClCH2CH2Cl) and
conversion of the resulting 1,3-diol to the 1,3-anti acetonide
16.22,23 However, in contrast to our earlier studies with
aldehydes 17a and 17b, the reaction diastereoselectivity is
not highly dependent on the identity of the C(15)-OR
protecting group.12 Our current working hypothesis is that
the bulky C(7)-OTBDPS substituent of 17 induces the C(5)-
OTBS group to adopt a conformation anti to the C(5,6)-
bond which, in turn, forces the C(3)-OTES unit to be anti to
C(3,4). In this particular conformation, the TES ether is
note also that 4 and 17 are in opposite absolute stereochem-
ical series).24 Consequently, the C(17)-OTBS ether can adopt
a position anti to the C(15,16) bond, which in turn allows
the C(15)-OTES ether to move away from aldehyde unit in
the reaction transition state.
The synthesis of the chiral â,γ-unsaturated ketone 5
commenced with enal 19, which was prepared by standard
procedures from enoate 18 (Scheme 2). The diastereoselec-
tive aldol reaction of 19 with the D-valine derived acyl
oxazolidinone 2025 provided 21 with excellent selectivity
Scheme 2. Synthesis of Chiral â,γ-Unsaturated Ketone 5 and
Its Aldol Reaction with 4
Figure 2. Structures of products of aldol reactions of aldehydes 4
and 13 with 3-methyl-2-butanone.
Org. Lett., Vol. 1, No. 1, 1999
97

1
(89% yield). Protection of the hydroxyl group as a TBS ether
(96%) followed by reduction of the acyl unit (62%) and
protection of the primary hydroxyl group as a TES ether
then provided 22 in 95% yield. The BOM ether was then
removed via reduction with lithium naphthalenide (87%).26
The primary alcohol was oxidized to the sensitive â,γ-
unsaturated enal by using catalytic TPAP and NMO (96%
yield),27 which was dissolved in THF and added to a solution
of MeLi in Et2O at -78 °C. The resulting secondary alcohol
was then oxidized, again by using the catalytic TPAP
protocol,27 to give the targeted methyl ketone 5 in 67%
overall yield for this final four-step sequence.
To our considerable delight, treatment of 1.9 equiv of 5
with 2.1 equiv of LiHMDS in THF at -78 °C followed by
addition of 1.0 equiv of aldehyde 4 provided aldol 3 in 53%
yield, as the only obserVed aldol diastereomer. In addition,
28% of aldehyde 4 and 36% of â,γ-unsaturated ketone 5
were recovered, along with ca. 8% of a compound tentatively
identified as the aldol dimer of 5. The stereochemistry of
the newly formed C(13) hydroxyl group of 3 was assigned
by spectroscopic correlation with 14a, using the characteristic
and diagnostic11,23 ABX pattern for the C(12)-C(13) spin
system in the H NMR spectrum as a specific point of
comparison. Remarkably, both methyl ketone 5 and aldol 3
are stable to silica gel chromatography, and the potentially
sensitive C(10) stereocenter exhibits no tendency to epimer-
ize under normal handling conditions.28
In conclusion, we have demonstrated that the aldol reaction
of aldehyde 4 and the chiral â,γ-unsaturated methyl ketone
5 is a synthetically viable strategy for construction of the
C(5)-C(21) segment of tedanolide. Further progress toward
completion of a total synthesis of this highly bioactive marine
macrolide will be reported in due course.
Acknowledgment. Support provided by the National
Institutes of Health (Grant No. GM 38436) is gratefully
acknowledged.
1
Supporting Information Available: Figures giving H
NMR spectra of 3, 14a-c, and 15a-c. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL990572S
(28) A mixture of C(10) epimers of 3 was observed in one initial aldol
experiment in which a sub-stoichiometric amount of LiHDMS was
accidentally used. A small amount (ca. 10%) of epimerization of C(10) of
recovered methyl ketone 5 is also observed if the aldol reactions are
quenched by addition of saturated aqueous NH4Cl to the -78 °C reaction
mixture (the NH4Cl solution immediately freezes). However, if the -78
°C reaction mixture is poured directly into aqueous NH4Cl solution at
ambient temperature, recovered 5 is completely stereochemically homo-
geneous. Epimerization of the aldol product 3 was not observed under either
of these sets of workup conditions.
(24) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1992, 31, 1124.
(25) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(26) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(27) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
98
Org. Lett., Vol. 1, No. 1, 1999