Synthetic studies towards mniopetals (I). A short synthesis of a key intermediate for the total synthesis of mniopetals

Article abstract of DOI:10.1055/s-1999-2796

A short and efficient synthesis of a tricyclic core structure of mniopetals based on a new, highly diastereoselective PhSeLi induced Baylis- Hillman reaction and an endo-selective Intramolecular Diels-Alder reaction (IMDA) as key steps is presented.

Full text of DOI:10.1055/s-1999-2796

LETTER
1325
Synthetic Studies towards Mniopetals (I). A Short Synthesis of a Key
Intermediate for the Total Synthesis of Mniopetals
Johann Jauch*
Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstr. 4, D-85747 Garching, Germany
Fax (0)89-289 13 329; E-mail: jjauch@nucleus.org.chemie.tu-muenchen.de
Received 28 April 1999
egy is quite different and reaches the tricyclic core struc-
ture of the mniopetals after only seven steps from readily
available starting materials. We wish to report our synthe-
sis of an advanced key intermediate for the total synthesis
of mniopetals.
Abstract: A short and efficient synthesis of a tricyclic core struc-
ture of mniopetals based on a new, highly diastereoselective PhSeLi
induced Baylis-Hillman reaction and an endo-selective Intramolec-
ular Diels-Alder reaction (IMDA) as key steps is presented.
Key words: intramolecular Diels-Alder reaction, HIV, natural
products, terpenoids, diastereoselective Baylis-Hillman reaction
Our retrosynthetic strategy (Scheme 1) focuses on mnio-
petal F 1f. Key steps are a diastereoselective IMDA
reaction3 and a diastereoselective Baylis-Hillman reac-
tion.4 Retrosynthetic transformation of the hemi acetal of
1f from an acetal using (+)-menthol and deconjugation of
the a,b-unsaturated aldehyde followed by aldehyde reduc-
tion led to 2, which originated from trienolide 3 after
IMDA reaction. Disconnection of 3 according to the Bay-
lis-Hillman reaction led to Feringa´s butenolide 4 and di-
enal 5. Dienal 5 is retrosynthetically further simplified by
Horner-Wadsworth-Emmons reaction using thereadily
available starting materials 6 and 7.
In 1994, Anke and Steglich reported the isolation, struc-
ture elucidation, and determination of the absolute config-
uration of six new drimane type sesquiterpenes from
Mniopetalum sp. 87256, the mniopetals A-F 1a-1f (Figure
1).1
Figure 1 Structure of mniopetals A – F 1a – 1f.
It was shown that the mniopetals exhibit antibacterial and
cytotoxic activity and are novel inhibitors of reverse tran-
scriptase of several retroviruses, amongst them the HIV-
1.1 Therefore, the mniopetals are interesting targets for to-
tal synthesis.
Recently, Tadano and coworkers2 published their synthe-
sis of a tricyclic key intermediate for the total synthesis of
the mniopetals, which is based on an Intramolecular Di-
els-Alder reaction (IMDA) as a central step. Although we
too use an Intramolecular Diels-Alder approach, our strat-
Scheme 1 Retrosynthetic analysis of mniopetals
a) LiHMDS, 6, THF, -40 °C, 85%, trans:cis > 20:1; b) DIBALH,
Et2O, 0 °C, 30 min, 98%; c) TBDPSCl, Imidazole, DMF, RT, 2 h,
87%; d) 9-BBN, THF, r.t., 4 h, H2O2, NaOH, EtOH, 0 °C, 1 h, 83%;
e) PDC, MS 3 Å, CH2Cl2, r.t., 45 min, 67%; f) Ph-Se-Li, THF, 4, -40
°C to 0 °C, 8 h, 53%; g) Xylene, silylated flask, 140 °C, 60 h, 50%.
Synlett 1999, No. 8, 1325–1327 ISSN 0936-5214 © Thieme Stuttgart · New York

1326
J. Jauch
LETTER
The IMDA reaction in this letter is the first one using a
substituted Feringa-butenolide as dienophile. The abso-
lute configuration of 2 is determined by the chiral auxil-
liary (+)-menthol, which functions as a control element to
establish the correct configuration of the acetal carbon in
2 and in the mniopetals A-F 1a-1f as well as the correct
absolute configuration of the tricyclic core of the mnio-
petals. A possible transition state is shown in Fig. 2.
Figure 2 Transition state of the IMDA reaction and selected NOEs
in 14.
In summary, we developed a short and efficient synthesis
of an advanced intermediate in the total synthesis of the
mniopetals. Transformation of this key intermediate into
the natural products is currently under way and will be
published in due course.
Acknowledgement
We thank the Deutsche Forschungsgemeinschaft for financial sup-
port and BASF AG, Ludwigshafen, Germany, Pfizer AG, Karlsru-
he, Germany, Haarmann & Reimer GmbH, Holzminden, Germany,
Wacker GmbH, Burghausen, Germany, DEGUSSA AG, Frankfurt
a. M., Germany and Bayer AG, Leverkusen, Germany, for chemi-
cals and laboratory equipement.
Scheme 2 Synthesis of an advanced key intermediate 14 in the total
synthesis of mniopetals.
Our synthesis is shown in Scheme 2. First, 2,2-dimethyl-
4-pentenal5 6 is coupled with 4-(dimethylphospho-
no)methylcrotonate6 7 providing triene 8 (trans:cis >
20:1), which is reduced to alcohol 9 with DIBALH.7 Pro-
tection of the hydroxyl group as a TBDPS ether8 10 is fol-
lowed by a hydroboration/oxidation9 sequence under
standard conditions leading to dienol 11. Oxidation of the
unprotected primary alcohol with PDC in presence of mo-
lecular sieves 3Å gives aldehyde 12. Next, we planned to
couple 12 with Feringa´s butenolide10 4 in a Baylis-Hill-
man reaction.4 Since Feringa´s butenolide 4 is highly base
sensitive and Baylis-Hillman coupling under standard
conditions using DABCO as nucleophile only works well
with b-unsubstituted derivatives of acrylic acid, the origi-
nal Baylis-Hillman protocol could not be applied. Thus,
we developed a new and highly diastereoselective
variant11 of the Baylis-Hillman reaction using lithium
phenylselenide12 as nucleophile. PhSeLi is readily pre-
pared from PhSeSePh through reductive cleavage by ele-
mental lithium or by BuLi and is a very weak base and a
very good nucleophile. Reaction of PhSeLi in THF with a
mixture of aldehyde 12 and Feringa´s butenolide 4 at
–40 °C to 0 °C during 8 h gives trienolide 1313 in a highly
diastereoselective tandem-Michael-aldol-retro-Michael
reaction.14 Subsequently 13 is cyclized in an endo selec-
tive thermal IMDA reaction providing the 1-epimer 1415,16
of the core structure 2 of mniopetal F 1f in only seven
steps with a total yield of 11%.
References and Notes
(1) Kuschel, A.; Anke, T.; Velten, R.; Klostermeyer, D.; Steglich,
W.; König, B. J. Antibiot. 1994, 47, 733. Velten, R.;
Klostermeyer, D.; Steffan, B.; Steglich, W.; Kuschel, A.;
Anke, T. J. Antibiot. 1994, 47, 1017. Velten, R.; Steglich, W.;
Anke, T. Tetrahedron: Asymmetry 1994, 5, 1229.
(2) Murata, T.; Ishikawa, M.; Nishimaki, R.; Tadano, K. Synlett
1997, 1291.
(3) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, p. 513
and references cited therein. See also: Taber, D. F.; Saleh, S.
A., J. Am. Chem. Soc. 1980, 102, 5085.
(4) Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1997, Vol. 51, p. 201 and references cited
therein.
(5) Brannock, K. C. J. Am. Chem. Soc. 1959, 81, 3379. Salomon,
G.; Ghosh, S. Org. Synth. 1984, 62, 125.
(6) Baeckström, P.; Jacobsson, U.; Norin, T.; Unelius, C. R.
Tetrahedron, 1988, 44, 2541.
(7) Winterfeldt, E., Synthesis 1975, 617. Roush, W. R., J. Am.
Chem. Soc. 1980, 102, 1390.
(8) Hanessian, S.; Lavallee, P., Can. J. Chem. 1975, 53, 2975.
(9) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents;
Academic: London, UK, 1988. Kurth, M. J.; O’Brien, J.;
Hope, H.; Yanuck, M., J. Org. Chem. 1985, 50, 2626.
(10) Feringa, B. L.; de Jong, J. C. Bull. Soc. Chim. Belg. 1992, 101,
627 and references cited therein.
(11) Jauch, J. J. Org. Chem. accepted for publication.
Synlett 1999, No. 8, 1325–1327 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Short Synthesis of a Key Intermediate for the Total Synthesis of Mniopetals
1327
(12) Ley, S. V.; O’Neil, I. A.; Low, C. M. R. Tetrahedron 1986, 42,
5363. Reich, H. J.; Dykstra, R. R. Organometallics 1994, 13,
4578.
(13) 13: 374.5 mg diphenyldiselenide (1.20 mmol) are dissolved in
3.5 mL anhyd THF under nitrogen and cooled to –10 °C. 0.75
mL of 1.5 M BuLi in hexanes (1.12 mmol) are added dropwise
with stirring. After 5 min the solution is cooled to –40 °C and
a mixture of 238.8 mg 4 (1.00 mmol) and 504.8 mg 12 (1.20
mmol) in 10 mL THF is added dropwise. The reaction mixture
is stirred at this temperature for 4 h and then warmed to 0 °C
during 4 h. Then the reaction mixture is quenched with sat. aq
NH4Cl and extracted with diethyl ether. The combined
extracts are dried over MgSO4 and after evaporation of the
solvent the product is purified by flash chromatography
(pentane/diethyl ether 2:1). Yield: 349.0 mg (53%). 1H-NMR
(360 MHz, CDCl3): 7.68 (m, 4H); 7.39 (m, 6H); 6,90 (s, 1H);
6,24 (dd, 14.9 Hz, 10.4 Hz, 1H); 6.00 (s, 1H); 5.96 (dd, 15.6
Hz, 10.4 Hz, 1H); 5.69 (dt, 15.6 Hz, 4.9 Hz, 1H); 5.58 (d, 14.9
Hz, 1H); 4.46 (br s, 1H); 4.23 (d, 5.2 Hz, 2H); 3.64 (td, 4.6 Hz,
10.8 Hz, 1H); 2.12 (m, 2 H); 1.80-1.20 (m, 11H); 1.06 (s, 9H);
1.02 (s, 6H); 0.94 (d, 6.5 Hz, 3H); 0.87 (d, 7.1 Hz, 3H); 0.80
(d, 7.1 Hz, 3H). 13C-NMR (90.6 MHz, CDCl3): 170.6; 143.3;
142.9; 139.8; 135.5; 133.6; 130.3; 130.2; 129.6; 127.6; 126.3;
99.1; 79.1; 67.1; 64.2; 47.7; 40.3; 38.1; 35.7; 34.1; 31.4; 30.5;
27.2; 27.0; 26.8; 25.3; 23.1; 22.2; 20.8; 19.2; 15.8 .
(14) The configuration of the newly formed secundary alcohol is
the result of chirality transfer from the acetal carbon to the
new hydroxyl center via the sequence depicted below. The
configuration of this center is determined in the aldol step in a
Zimmermann-Traxler-like transition state and turns out to be
(R) which is epimeric to the corresponding configuration in
the natural product. This could be derived from coupling
constants in 16 (OH instead of OLi) if the reaction mixture is
quenched prior to PhSeLi elimination. It is consistent with the
configuration of the secondary hydroxyl group in 14 and is in
accordance with an X-ray structure obtained for the reaction
with benzaldehyde.11
(15) 14: 296.5 mg 13 (0.45 mmol) are dissolved in anhydrous
xylene under nitrogen in a silylated flask and heated to 140 °C
for 60 h. After cooling to room temperature the solvent is
evaporated under reduced pressure and the residue is purified
by flash chromatography (pentane/diethyl ether 7:1). Yield:
148.0 mg (50%). It is important to use a silylated flask for the
IMDA reaction, since the glass surface catalyzes the
epimerization of the acetal carbon of 13. Higher temperatures
than 140 °C increases the amount of decomposition products.
The yield given corresponds to ca. 80% conversion.
1H-NMR (360 MHz, CDCl3): 7.68 (m, 4H); 7.40 (m, 6H); 6,00
(m, 1H); 5.73 (dt, 8.6 Hz, 3.0 Hz, 1H); 5.43 (s, 1H); 3.96 (d,
7.3 Hz, 2H); 3.93-3.80 (m, 1H); 3.69 (dd, 11.0 Hz, 3.6 Hz,
1H); 3.50 (td, 10.4 Hz, 4.3 Hz, 1H); 3.20 (m, 1H); 2.64 (d, 6.7
Hz, 1H); 2.50-1.50 (m, 10 H); 1.40-1.00 (m, 3H); 1.29 (s, 3H);
1.09 (s, 9H); 0.92 (s, 3H); 0.85 (d,7.1 Hz, 3H); 0.80 (d, 6.5 Hz,
3H); 0.74 (d, 6.5 Hz, 3H). 13C-NMR (90.6 MHz, CDCl3):
175.7; 135.6; 135.5; 133.4; 133.3; 131.6; 129.9; 128.6; 127.8;
97.7; 77.8; 76.0; 63.4; 58.4; 52.0; 48.6; 47.6; 39.8; 38.9; 38.8;
34.2; 34.1; 32.0; 31.3; 27.0; 26.6; 25.0; 22.6; 22.2; 21.7; 21.1;
19.3; 15.1.
(16) Together with 14 we found small quantities of two other
products which have not yet been structurally fully
characterized.
Article Identifier:
1437-2096,E;1999,0,08,1325,1327,ftx,en;G13099ST.pdf
Synlett 1999, No. 8, 1325–1327 ISSN 0936-5214 © Thieme Stuttgart · New York