Advances in the vinylogous Mukaiyama aldol reaction and its application to the synthesis of the C1-C7 subunit of oleandolide

Article abstract of DOI:10.1016/S0040-4039(02)00993-0

The synthesis of a stereo pentade of the macrolide antibiotic oleandolide is reported. The C1-C7 fragment resembles the analogous segment of Panek's total synthesis of oleandolide. The use of the vinylogous Mukaiyama aldol reaction shortens the route significantly and has the advantage of utilizing an easily accessible ketene acetal.

Full text of DOI:10.1016/S0040-4039(02)00993-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5093–5095
Advances in the vinylogous Mukaiyama aldol reaction and its
application to the synthesis of the C1ꢀC7 subunit of oleandolide
Jorma Hassfeld and Markus Kalesse*
Universita¨t Hannover, Institut fu¨r Organische Chemie, Schneiderberg 1B, 30167 Hannover, Germany
Received 14 March 2002; accepted 24 May 2002
Abstract—The synthesis of a stereo pentade of the macrolide antibiotic oleandolide is reported. The C1ꢀC7 fragment resembles
the analogous segment of Panek’s total synthesis of oleandolide. The use of the vinylogous Mukaiyama aldol reaction shortens
the route significantly and has the advantage of utilizing an easily accessible ketene acetal. © 2002 Elsevier Science Ltd. All rights
reserved.
Polyketides are a class of natural products which repre-
sent a great variety of compounds with promising
biological activities. Oleandomycin (1), a 14-membered
macrolide antibiotic, was isolated from the actino-
mycete Streptomyces antibioticus by Sobin et al.1 in
1955. In 1960 the structure was reported by Celmer,
Woodward and co-workers.2 Its absolute configuration
was determined in 19653 and independently confirmed
by X-ray analysis.4 Oleandomycin unravels its biologi-
cal activity by binding to the 50-S ribosomal subunit
and interfering with the transpeptidation or transloca-
tion reaction5 (Scheme 1).
dolide through their aldol chemistry and Panek used his
chiral crotylsilane approach for a highly convergent
total synthesis. Even though the methods utilized are
widely employed in other natural product syntheses and
characterized by their general applicability and reliabil-
ity, one would appreciate steps in which larger building
blocks can be assembled to pivotal fragments (Scheme
2).9
We could demonstrate that the vinylogous Mukaiyama
aldol reaction with ketene acetal 6 can be applied to
give good Felkin-control and syn-selectivity in the case
of aldehyde 15.10 The poor syn-selectivity (syn:anti=
1:1) observed in the addition of 9 to 7 seems to reflect
the double bond geometry of the ketene acetal. In
previous experiments with ketene acetal 6 we found
that the 3,4-Z configuration is essential not only for
obtaining good yields but also for the syn-selective
addition (Scheme 3).
Four total syntheses have been reported. Tatsuta6 et al.
reconstructed oleandomycin from its aglycon which
they derived by degradation from the natural product.
Paterson7 and Evans8 reported total syntheses of olean-
O
O
NMe2
HO
On the other hand, the addition of 6 to 7 gives exclu-
sively the all-syn diastereomer (8). The use of tris(pen-
tafluorophenyl)borane (TPPB) in the presence of
OH
R1
R2
=
=
O
Me
O
OR1
OR2
Oleandomycin 1
1 = Decosamin
2 = L-Oleandrose
+
isoproyl alcohol as a SiR3 -scavenger is essential for the
O
syn-selectivity in contrast to additions without isoproyl
alcohol in which TBS+ acts as the catalyst. As a probe
for this hypothesis we tried to catalyze the aldol reac-
tion with TBSOTf. As expected, only moderate syn-
selectivity (4.5:1) was observed, also witnessed under
isopropyl alcohol free conditions in the reaction of 6
and 7 (Scheme 4).
OMe
OH
Me
O
R
R
Oleandolide (2) R1, R2 = H
Scheme 1. Structures of oleandomycin (1) and its aglycon
oleandolide (2).
In order to demonstrate the efficiency of the vinylogous
Mukaiyama aldol reaction we report the synthesis of
the C1ꢀC7 segment of oleandolide which could be used
* Corresponding author. Tel.: +49-511-762-4643; fax: +49-511-762-
3011; e-mail: kalesse@mbox.oci.uni-hannover.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00993-0

5094
J. Hassfeld, M. Kalesse / Tetrahedron Letters 43 (2002) 5093–5095
OH
O
TBSO
O
1
OTBS
OMe
TPPB, Et2O
iPrOH, 76%
TBSO
4
+
O
O
O
OP OH OH
OMe
3
5
HO
15
6
16
4,5 syn-selective
Felkin-control
3
Ph
OPMB
4
O
1
TBSO
PMB-trichloro-
Dibal-H, CH2Cl2
92%
O
O
OP
O
O
.
OMe
3
5
acetimidate, BF3 Et2O
65%
TfO
TBDPSO
I
17
4
5
Scheme 2. Retrosynthetic analysis of Panek’s oleandolide
synthesis.
OPMB
OPMB
TBSO
TBSO
(-)-DET, Ti(OiPr)4,
TBHP, CH2Cl2
OH
O
OH
18
90%
19
PMBO
OH
OH
CuCN, MeLi, THF
95%
DDQ, CH2Cl2, MS 4Å
85%
TBSO
20
PMP
PMP
22
TBSO
O
O
O
O
OH
PPh3, I2, CH2Cl2
80%
TBSO
I
21
Scheme 5. Synthesis of the C1ꢀC7-fragment of oleandolide.
with DDQ in the absence of water provided benzyli-
dene acetal 21 which was transformed into the corre-
sponding iodide (22) with I2 and PPh3.12
Scheme 3. Application of the vinylogous Mukaiyama aldol
reaction to a-chiral aldehydes with different ketene acetals.
This sequence of just seven steps starting from aldehyde
7 can be performed on large scale and constructs four
asymmetric carbons with an overall yield of 26.4%.
References
1. Sobin, B.; English, R. A.; Celmer, W. A. Antibiot. Annu.
1955, 2, 827–830.
2. Hochstein, F. A.; Els, H.; Celmer, W. D.; Shapiro, B. L.;
Woodward, R. B. J. Am. Chem. Soc. 1960, 82, 3225–
3227.
3. Celmer, W. D. J. Am. Chem. Soc. 1965, 87, 1797–1799.
4. Ogura, H.; Furuhata, K.; Harada, Y.; Iitaka, Y. J. Am.
Chem. Soc. 1978, 100, 6733–6737.
5. Wilhelm, J. M.; Oleicknick, N. L.; Corcoran, J. W.
Antimicrob. Agents Chemother. 1967, 236–250.
6. Tatsuta, K.; Kobayashi, Y.; Gunji, H.; Masuda, H. Tet-
rahedron Lett. 1988, 29, 3975–3978.
7. Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.;
Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287–11314.
8. Evans, D.; Kim, A. S.; Metternich, R.; Novack, V. J. J.
Am. Chem. Soc. 1998, 120, 5921–5942.
Scheme 4. TBSOTf-catalyzed vinylogous Mukaiyama aldol
reaction.
in Panek’s total synthesis of oleandolide. The key step
is the syn-selective Felkin-controlled addition of ketene
acetal 6 to the Roche aldehyde 15 (Scheme 5).11 The
selective addition requires tris(pentafluorophenyl)-
borane as the Lewis acid and isopropyl alcohol as a
scavenger for the Si+-species. The resulting secondary
alcohol (16) was PMB-protected with PMB–
trichloroacetimidate and BF3·Et2O. Ester reduction
with Dibal-H and subsequent Sharpless epoxidation
using (−)-DET furnished compound 19 in 90% yield.
Epoxide opening was achieved with CuCN/MeLi to
provide the stereo pentade 20 in 95% yield. Treatment
9. Hu, T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc.
1999, 121, 9229–9230.
10. (a) Hassfeld, J.; Christmann, M.; Kalesse, M. Org. Lett.
2001, 3561–3564; (b) Christmann, M.; Kalesse, M. Tetra-
hedron Lett. 2001, 42, 1269–1271; (c) Christmann, M.;
Bhatt, U.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org.
Chem. 2001, 1885–1893.

J. Hassfeld, M. Kalesse / Tetrahedron Letters 43 (2002) 5093–5095
5095
11. Aldehyde 15 (44 mg, 0.217 mmol) dissolved in ethyl ether
(2 mL) was cooled to −78°C under argon. Tris(penta-
fluorophenyl)borane (111 mg, 0.217 mmol) was added
and a mixture of ketene acetal 6 (100 mg, 0.438 mmol)
and isopropyl alcohol (17 mL, 0.24 mmol) dissolved in
ethyl ether (1 mL) was added over 6 h. After completion,
the cold reaction mixture was directly poured on a silica
gel column. Flash chromatography using ethyl acetate/
hexanes (1:4) as eluant afforded 52 mg (0.164 mmol,
76%) of 16 as a colorless oil: 1H NMR (400 MHz,
CDCl3) l 6.76 (dd, J=15.7, 9.3 Hz, 1H), 5.83 (dd,
J=15.7, 0.9 Hz, 1H), 3.76 (dd, J=9.8, 3.1 Hz, 1H), 3.69
(s, 3H), 3.64 (dd-like, J=8.7, 1.3 Hz, 1H), 3.62 (dd,
J=9.8, 3.9 Hz, 1H), 3.38 (broad s, 1H), 2.43 (dtq-like,
J=9.3, 6.6, 0.9 Hz, 1H), 1.57–1.66 (m, 1H), 1.12 (d,
J=6.6 Hz, 3H), 0.91 (d, J=7.0 Hz, 3H), 0.86 (s, 9H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
l 167.0, 151.1, 120.8, 77.8, 69.2, 51.4, 40.9, 26.6, 25.8,
18.1, 16.7, 9.3, −5.6, −5.7.
CH2Cl2 (0.3 mL) and the mixture was stirred at room
temperature for 17 h. Saturated aqueous Na2S2O3 (1 mL)
was added, the organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (3×5 mL). The
combined organic layers were washed with 1 M aqueous
NaHSO4 (1 mL), dried with MgSO4, filtered through
Celite and evaporated in vacuo. Flash column chro-
matography with petrol ether as eluant afforded iodide
22 (5 mg, 0.009 mmol, 80%) as a white solid. [h]D20 −9.25
1
(c=0.4, CHCl3); H NMR (400 MHz, CDCl3) l 7.41 (d,
J=8.7 Hz, 2H), 6.87 (d, 8.7 Hz, 2H), 5.46 (s, 1H), 3.78 (s,
3H), 3.59 (dd, J=9.7, 2.0 Hz, 1H), 3.57 (dd, J=10.0, 4.5
Hz, 1H), 3.51 (dd, J=9.4 Hz, 1H), 3.50 (dd, J=10.0, 4.3
Hz, 1H), 3.46 (dd, J=9.8, 2.0 Hz, 1H), 3.40 (dd, J=9.4,
2.8 Hz, 1H), 1.94–1.86 (m, 1H), 1.78 (dq-like, J=6.8, 2.0
Hz, 1H), 1.51–1.46 (m, 1H), 1.05 (d, J=6.7 Hz, 3H), 0.97
(d, J=6.8 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H), 0.88 (s, 9H),
0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
l 159.8, 131.7, 127.2, 113.5, 101.5, 84.0, 83.9, 64.5, 55.3,
36.6, 34.7, 30.9, 26.9, 25.9, 18.2, 15.8, 14.4, 7.0, −5.5,
−5.6; HRMS calcd for C24H41IO4Si: 548.1819, found:
548.1807.
12. To a stirred solution of triphenylphosphine (12 mg, 0.046
mmol) and imidazole (4 mg, 0.055 mmol) in DCM (0.5
mL) at 0°C, iodine (17 mg, 0.07 mmol) was added. After
5 min, alcohol 21 (5 mg, 0.01 mmol) was added in