Synthetic studies towards mniopetals (II). A short synthesis of Mniopetal E

Article abstract of DOI:10.1055/s-2001-9711

A short total synthesis of Mniopetal E in thirteen steps is reported. Key steps are a new and highly diastereoselective lithium phenylselenide induced Baylis-Hillman reaction with Feringa's butenolide, an endo-selective intramolecular Diels-Alder reaction (IMDA) and a new variant of the Parikh-Doering oxidation.

Full text of DOI:10.1055/s-2001-9711

LETTER
87
Synthetic Studies towards Mniopetals (II). A Short Synthesis of Mniopetal E
Johann Jauch*
Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax (0)89-289 13 329; E-mail: Johann.Jauch@ch.tum.de
Received 17 October 2000
of trienolide 3. Compound 3 can be disconnected into al-
Abstract: A short total synthesis of Mniopetal E in thirteen steps is
dehyde 4 and Feringa´s butenolide7 5 according to a Bay-
lis-Hillman reaction. (Scheme 1).
reported. Key steps are a new and highly diastereoselective lithium
phenylselenide induced Baylis-Hillman reaction with Feringa´s
butenolide, an endo-selective intramolecular Diels-Alder reaction
(IMDA) and a new variant of the Parikh-Doering oxidation.
Key words: Baylis-Hillman reactions, Diels-Alder reactions, fura-
nones, natural products
Anke and Steglich1 reported in 1994 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).
Scheme 1 Retrosynthetic analysis of 1e
Horner-Emmons reaction8 of 79 with aldehyde 610 led to
E,E-triene ester 8 in 85% yield. DIBALH reduction11 of
the ester group followed by silylation with TBDPSCl/
imidazole12 resulted in triene 9. Next, the mono-substitut-
ed double bond was regioselectively converted by a hy-
droboration-oxidation sequence13 into a primary alcohol,
which subsequently was oxidized to aldehyde 4 with
Figure 1 Structure of mniopetals A-F 1a-1f.
TEMPO/diacetoxyiodobenzene.14 At this point, we
wished to explore the Baylis-Hillman reaction15 with Fer-
The mniopetals show various biological activities, among
which the most important is the inhibition of HIV reverse
transcriptase.1 Therefore, the mniopetals are attractive tar-
gets for synthetic chemists. The mniopetals are related to
kuehneromycin A,2,3 which also inhibits reverse tran-
scriptase of various retro viruses, and to the marasmanes.4
Tadano and coworkers5 recently reported a total synthesis
of mniopetal E using an intramolecular Diels-Alder reac-
tion (IMDA reaction). Our strategy6 is quite different and
leads to mniopetal E in a total of thirteen steps from readi-
ly available starting materials. Here we wish to report our
synthesis of mniopetal E 1e. According to our strategy 1e
is derived from 2, which is the result of an IMDA reaction
inga´s butenolide 5. Since standard conditions with DAB-
CO as nucleophile only work well with b-unsubstituted
acrylic acid derivatives and 5 and especially substituted
Feringa-butenolides such as 3 are highly base sensitive,
we had to develop a new variant of the Baylis-Hillman re-
action.16 Lithium phenylselenide17 was the nucleophile of
choice in that case because of its high nucleophilicity and
very low basicity. Michael addition of PhSeLi at -60 °C
was followed by highly diastereoselective aldol addition
of the aldehyde 4 through a Zimmermann-Traxler transi-
tion state and subsequently PhSeLi was eliminated to re-
build the a,b-unsaturated lactone.
Synlett 2001, No. 1, 87–89 ISSN 0936-5214 © Thieme Stuttgart · New York

88
J. Jauch
LETTER
Thus, we arrived at trienolide 3, which was the starting
material for the IMDA reaction.18 Cyclization of 3 to form
10 proceeded smoothly at 140 °C in xylene in a silylated
flask to reduce epimerization at the acetal center. In the
following steps 10 was transformed into mniopetal E 1e.
First, the secondary alcohol (which has the opposite con-
figuration at C1 in comparison to the mniopetals) was
transformed into triflate 11 using trifluoromethanesulfon-
ic anhydride and DMAP as base. Elimination of the tri-
flate group was accomplished in 2,6-lutidine at 100 °C
leading to 2. Removal of the silyl protecting group with
TBAF12 was straightforward leading to the b,g-unsaturat-
ed alcohol 12 which had to be converted into an a,b-unsat-
urated aldehyde 13. This oxidation was best carried out
with pyridine-SO3 complex in DMSO with NEt3 as base
(Parikh-Doering oxidation19). To obtain reproducible
good results it was important to run the reaction under in-
ert atmosphere and to add the pyridine-SO3 complex dis-
solved in DMSO very slowly via syringe pump overnight.
Now, the two double bonds had different electronic prop-
erties and it was possible to transform the more electron-
rich double bond between C1 and C2 stereoselectively
from the si-face into the cis-diol 14 (the only stereoisomer
found) with OsO4/NMO.20 In the final step, the menthyl
residue was removed by action of TFA/H2O/acetone
(1:1:1) overnight. The product obtained was identical in
all respects with the natural mniopetal E.21 The complete
synthesis is shown in Scheme 2. Starting from aldehyde 6
and phosphonate 7, we were able to synthesize mniopetal
E 1e in only thirteen steps in a total yield of 16% through
efficient combination of a new variant of the Baylis-Hill-
man reaction, the powerful IMDA reaction, a new variant
of the Parikh-Doering oxidation and a chemo- and stereo-
selective cis-hydroxylation.
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 equipment. The author gratefully acknowledges
Habilitation grants from the Deutsche Forschungsgemeinschaft and
the Fazit-Stiftung. We thank Prof. W. Steglich, Ludwig-Maximili-
ans-Universität München, for 600 MHz spectra of natural mniopetal
E.
References and Notes
a) LiHMDS, THF, -40 °C, 85%, trans:cis > 20:1; b) DIBALH, Et2O,
0 °C, 30 min, 98%; c) TBDPSCl, Imidazole, DMF, RT, 2 h, quant.; d)
9-BBN, THF, RT, 4 h, H2O2, NaOH, EtOH, 0 °C, 1 h, 91%; e) TEM-
PO/PhI(OAc)2, RT, 2h, 98%; f) Ph-Se-Li, THF, 5, -60 °C, 6 h, 88%;
g) Xylene, silylated flask, 140 °C, 60 h, 69%; h) Tf2O, DMAP, 0 °C,
2 h, 98%; i) 2,6-lutidine, 100 °C, 4 h, 84%; j) TBAF, THF, RT, 2 h,
90%; k) DMSO, NEt3, RT, add pyridine-SO3 in DMSO via syringe
pump during 16 h, 79%; l) cat. OsO4, NMO, THF/H2O, 0 °C, 168 h,
62%; m) TFA/H2O/acetone 1:1:1, RT, 24 h, quant.
(1) (a) Kuschel, A.; Anke, T.; Velten, R.; Klostermeyer, D.;
Steglich, W.; König, B. J. Antibiot. 1994, 47, 733. (b) Velten,
R.; Klostermeyer, D.; Steffan, B.; Steglich, W.; Kuschel, A.;
Anke, T. J. Antibiot. 1994, 47, 1017. (c) Velten, R.; Steglich,
W.; Anke, T. Tetrahedron: Asymmetry 1994, 5, 1229.
(d) Inchausti, A., Yaluff, G., De Arias, A. R., Ferreira, M. E.,
Nakayama, H., Schinini, A., Lorenzen, K., Anke, T., Fournet,
A., Phytother. Res. 1997, 11, 193.
(2) Erkel, G.; Lorenzen, K.; Anke, T.; Velten, R.; Gimenez, A.;
Steglich, W. Z. Naturforsch. C 1995, 50, 1.
Scheme 2 Synthesis of mniopetal E 1e.
(3) Jauch, J. Angew. Chem. 2000, 112, 2874; Angew. Chem. Int.
Ed. 2000, 39, 2764.
Synlett 2001, No. 1, 87–89 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Studies towards Mniopetals (II)
89
(4) (a) Ayer, W. A.; Craw, P. A.; Stout, T. J.; Clardy, J. Can. J.
Chem. 1989, 67, 773. (b) Ayer, W. A.; Craw, P. A. Can. J.
Chem. 1989, 67, 1371.
(5) (a) Murata, T.; Ishikawa, M.; Nishimaki, R.; Tadano, K.
Synlett 1997, 1291. (b) Suzuki, Y.; Nishimaki, R.; Ishikawa,
M.; Murata, T.; Takao, K.; Tadano, K. Tetrahedron Lett.
1999, 40, 7835.
(6) Jauch, J. Synlett 1999, 1325.
(7) Feringa, B. L.; de Jong, J. C. Bull. Soc. Chim. Belg. 1992, 101,
627 and references cited therein.
To run the reaction with acceptable chemoselectivity, we had
to decrease the reaction temperature to 0 °C.
(8) Roush, W. R. J. Am. Chem. Soc. 1980, 102, 1390.
(9) Baeckström, P.; Jacobsson, U.; Norin, T.; Unelius, C. R.
Tetrahedron 1988, 44, 2541.
(10) (a) Brannock, K. C. J. Am. Chem. Soc. 1959, 81, 3379.
(b) Salomon, G.; Ghosh, S. Org. Synth. 1984, 62, 125.
(11) Winterfeldt, E. Synthesis 1975, 617.
(12) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975.
(13) (a) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents;
Academic Press: London, UK, 1988. (b) Kurth, M. J.;
O’Brien, J.; Hope, H.; Yanuck, M. J. Org. Chem. 1985, 50,
2626.
(14) De Mico, A., Margarita, R., Parlanti, L., Vescovi, A.,
Piacantelli, G. J. Org. Chem. 1997, 62, 6974.
(15) Ciganek, E. in Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1997, Vol. 51, p. 201 and references cited
therein.
A typical procedure is as follows: 20 mg 13 (50 mmol) were
dissolved in 0.4 mL THF and 0.1 mL water. The solution was
cooled to 0 °C and 3 mL of a 1 M solution of OsO4 (3 mmol) in
acetone and 7 mg NMO (50 mmol) were added. The reaction
mixture was stirred at 0 °C for one week, then saturated
aqueous NaHCO3 solution (2 mL) and saturated aqueous
Na2S2O3 solution (1 mL) was added and the reaction mixture
was allowed to reach room temperature. Extraction with
AcOEt, drying with MgSO4 and purification by preparative
TLC (diethyl ether/pentane 2:1 (v:v), silica, Rf = 0.2) gave 13
mg (62%) of 14. 1H NMR (360 MHz, CDCl3, d rel. to TMS):
9.48 (s, 1H); 7.12 (d, br, 6.6 Hz, 1H); 5.28 (s, 1H); 4.32 (d, br,
2.2 Hz, 1H); 4.18 (ddd, 12.4 Hz, 4.4 Hz, 2.6 Hz, 1H); 3.72 (s,
br, 1H); 3.47 (td, 10.6 Hz, 4.0 Hz, 1H); 2.47 (ddd, 18.6 Hz, 7.5
Hz, 4.0 Hz, 1H); 2.28-2.17 (m, 3H); 2.06 (septd, 7.1 Hz, 3.1
Hz, 1H); 1.79 (t, 12.8 Hz, 1H); 1.67 (dm, 12.8 Hz, 2H); 1.53
(dd, 12.4 Hz, 4.0 Hz, 1H); 1.28 (s, 3H); 1.10-0.8 (m, 7H,
superimposed by the following signals); 1.03 (s, 3H); 0.95 (d,
(16) Jauch, J. J. Org. Chem., in press.
(17) (a) Ley, S. V.; O’Neil, I. A.; Low, C. M. R. Tetrahedron 1986,
42, 5363. (b) Reich, H. J.; Dykstra, R. R. Organometallics
1994, 13, 4578.
(18) 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.
6.6 Hz, 3H); 0.90 (d, 7.1 Hz, 3H); 0.76 (d, 7.1 Hz, 3H). 13
C
NMR (90.3 MHz, CDCl3, d rel. to TMS): 193.0; 176.0; 154.7;
138.7; 102.3; 79.0; 71.0; 65.9; 53.4; 47.6; 46.2; 41.6; 39.8;
39.6; 34.3; 33.6; 33.4; 31.5; 25.8; 24.7; 23.3; 22.7; 22.2; 21.1;
15.2; [a]D20 = +27 (c = 0.8, CHCl3).
(21) A typical procedure is as follows: To 10 mg of 14 (23 mmol)
was added a mixture of TFA and water (1:1 v/v, 2 mL). Then
1 mL of acetone was added to dissolve 14 and the mixture was
stirred at room temperature overnight. Then the mixture was
evaporated to dryness at reduced pressure and the residue was
purified by preparative TLC (toluene/acetone/acetic acid
70:30:1 (v/v), silica, Rf = 0.25). Yield: 6.8 mg (quant.). 1H
NMR (360 MHz, D4-methanol, d rel. to TMS): 9.49 (s, 1H);
7.26 (d, br, J = 6.6 Hz, 1H); 5.44 (s, 1H); 4.39 (s, br, 1H); 4.14
(dd, J = 12.4Hz, 2.9 Hz, 1H); 3.77 (s, br, 1H); 2.55 (dm,
J = 17.7 Hz, 1H); 2.17 (m, 1H); 1.92 (t, J = 12.4, 1H); 1.69
(dd. J = 12.8 Hz, 3.5 Hz, 1H); 1.45 (dd, J = 12.8 Hz, 4.0 Hz,
1H); 1.31 (s, 3H); 1.07 (s, 3H). 13C NMR (90.3 MHz, D4-
methanol, d rel. to TMS): 195.1; 178.9; 156.3; 140.3; 101.8;
72.3; 66.8; 55.5; 47.9; 42.2; 41.0; 34.4; 33.9; 25.9; 24.0.
[d]D20 = - 59 (c = 0.1, CH3OH); Lit.1b: [d]D20 = –57 (c = 0.1,
CH3OH).
For details of the described IMDA reaction of 3 see Reiser, U.;
Jauch, J.; Herdtweck, E. Tetrahedron: Asymmetry 2000, 11,
3345.
(19) Tidwell, T. T. in Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1991, Vol. 39, p. 297 and references cited
therein.
(20) (a) Altenbach, H.-J., Voss, B. Vogel, E. Angew. Chem. 1983,
95, 424; Angew. Chem. Int. Ed. 1983, 22, 424. (b) Van
Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
First, we studied the cis-hydroxylation with OsO4 cat./NMO,
THF/water, 18 h, r.t. However, under these conditions 13 gave
a mixture of 14 (35%) and the regio-isomer 15 (35%).
Article Identifier:
1437-2096,E;2001,0,01,0087,0089,ftx,en;G22000ST.pdf
Synlett 2001, No. 1, 87–89 ISSN 0936-5214 © Thieme Stuttgart · New York