A route for the enantioselective total synthesis of antheridic acid, the antheridium-inducing factor from anemia phyllitidis

Article abstract of DOI:10.1016/S0040-4039(00)93418-X

An effective route for the total synthesis of antheridic acid (1) has been devised in which the initial chiral intermediate 7 is generated by enantioselective catalytic reduction and transformed in a stereocontrolled fashion into key intermediates 9, 10, 13, and 2.

Full text of DOI:10.1016/S0040-4039(00)93418-X

Tetrahedron Letters, Vo1.32, No.38, pp 5025-5028, 1991
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A Route for the Enantioselective Total Synthesis of Antheridic Acid, the Antheridium-
Inducing Factor from Anemia phyllitidis
E. J. Corey and Hideo Kigoshi
Department of Chemistry, Harvard University, Cambridge, Massachusetts, 02138
Summary: An effective route for the total synthesis of antheridic acid (1) has been devised
in which the initial chiral intermediate 7 is generated by enantioselective catalytic reduction
and transformed in a stereocontrolled fashion into key intermediates 9, 10, 13, and 2.
Several years ago a total synthesis of (+)-antheridic acid, the antheridium-inducing factor of the fern
Anemia phyllitidis, was developed in these laboratoriesl, 2 which proved structure 1 for this substance.
Subsequently, a 14-step partial synthesis of 1 from gibberelin A7 (13-desoxygibberellic acid) was also
described.3 In this note we report a novel enantioselective route to the tetracyclic lactone 2 (TBMS =
t-BuMe2Si), an intermediate suitable for the synthesis of natural antheridic acid by the 10-step sequence
reported earlier.1 The new approach to chiral 1 features the establishment of the initial stereocenter by an
efficient catalytic enantioselective reaction and diastereoselective elaboration of the additional
stereocenters.
2,5-Dihydroxybenzoic acid (Aldrich) was converted to the methyl ester, mp 81-83 °C, (MeOH,
H2SO4, C1CH2CH2C1, reflux, 5 h, 67%) which upon treatment with 5 equiv of ethylene carbonate4 and
1.1 equiv of K2CO3 at 95 °C for 2 h afforded 3, mp 83-84 °C (66%) (see flowchart). Dienone ketal 4 was
synthesized from 3 as shown; iodosobenzene diacetate5 was superior to the ditrifluoroacetate or
Pb(OAc)4 for the oxidation 3 ---> 4. Enantioselective reduction of the silylated enone 6 was efficiently
accomplished using the CBS method6 to give the chiral allylic alcohol 7 (92% ee) which was obtained in
> 99% enantiomeric purity after recrystallization from hexane, mp 68-71 °C, [~x]~ +25.7° (c=l, MeOH).7,8
The use of the S catalyst for the reduction of 6 can be expected to produce the absolute configuration of 7
on the basis of considerable precedent.6 A second stereocenter was introduced stereospecifically by the
reaction of enone 8 with dimethylcopperlithium and in situ trifluoromethanesulfonation to form the vinyl
triflate derivative 9.
OH
T.M2
HOMe'e" "'~ i"1t
0
CO;zH
~O,,,'~O
5025

5026
The elaboration of 9 to 10 required 1,3-cyclohexadienyllithium, a previously unknown reagent, which
was prepared by the following sequence of reactions.
0
[ ~
1.0 KN(TMS)2
OSO2CF3
DMF-THF (2 : 1)
-78 o, 4 h; 1.0 T2f NPh,
0
o,
2
h, 56%
1.1 (Bu3Sn)2CuCNLI2
[
(T.L. 1988, 29, 4795) J
THF, -50 to -30 °, 2 h,.l
9 0 %
~r
LI
[ ~
SnBu3
[ ~
BuLl, THF,
-78 o, 1.7 h
The organocopper reagent used in the coupling reaction with vinyl triflate 9 was prepared from 1,3-
cyclohexadienyllithium and an equivalent amount of cuprous bromide methyl sulfide complex at -78 °C for
0.5 h. The coupling reaction was effected with a 3.4-fold excess of the organocopper reagent, but some
unreacted vinyl triflate 9 was invariably recovered; the yield of coupling product 10, mp 114-119 °C, was 50%
uncorrected, and 80% corrected for recovered 9.9 Other coupling procedures, e. g. Stille coupling, were less
effective. Trie~aes 10 and 11 were air sensitive and were kept under N2 with a trace of hydroquinone as
antioxidant. The conversion of diol 11 to the primary diazoacetate ester10 was accompanied by the formation of
some isomeric secondary ester (ratio ca. 3 : 1); the mixture was separated by chromatography on silica gel, and
the undesired secondary diazoacetate and other esters were recycled to diol 11 by saponification (23 °C, K2CO3
in CH3OH) (final yield of 12, 74%). The transformation of diazoacetate 12 to 13 and thence to 2 was
accomplished by the procedures developed earlier, la as shown in the flowchart.11 Tetracyclic lactone 2
produced in this way, [(~]~ +53° (c=0.3, CHC13), was found to be 96% enantiomerically pure by HPLC
analysis on a Daicel OD column (1% i-PrOH in hexane for elution; major and minor enantiomers eluted at 10.5
and 8.9 min, respectively). Slight racemization (~ 2%) evidently occurred in the conversion of 7 to 8. The chiral
tetracyclic lactone 2 was identical spectroscopically and chromatographically (silica gel) with a racemic sample
produced from the (+)-3-epimerla by the sequence: (1) desilylation (Bu4NF, THF, 23 °C, 2 h, 75%);
(2) oxidation (SO3 • CsH5N, DMSO, CH2C12, Et3N, 23 °C, 90%); (3) reduction (NaBI-In, EtOH, 0 °C, 30 m,
80%); and (4) silylation (TBMSCI, imidazole, DMF, 55 °C, 19 h, 75%). The synthetic route to the chiral
tetracyclic lactone 2 which now has been demonslxated and the transformations described earlierla constitute a
stereocontrolled and enantioselective process for the synthesis of antheridic acid.12

5027
OH
O
~
O
~
~ C O O M e
1. 2.0 LIBH4,
THF, 60 o, 5 h, 69%
T~
OH
1.7 t-BuMe2SICI,
O
O
OTBMS
~-
2. 1.0 PhI(OAc)2,
CH2Cl2, 23 °,
3 h, 76%
3.4 Imldazole,
DMF, 23 °
O ~ O H
'
0.5 h, 90%
5
1 atm H2, Rh-C,
EtOAc-Tol,
1
23 °, 1 h, 76%
M e . M e
H Ph
O
~
1. HOAc-H20,
23 °, 3 h, 93%
OTBMS
O
~
O
0.2
Bu
O
O
OTBMS
2. Me2CO,
0.64 BH3, THF,
37 °, 0.5 h, 87%,
92% ee
20 C u S O 4 ,
O
60 o, 4 h, 88%
~.J
7
> 99% ee after recryst.
1.2 Me2CuLI, Et20,
-20 to 0 o, 1 h;
1.3 Tf2NPh, HMPA-
THF, 0°, 2 h, 94%
Me Me
o~-o
3.4 ~ - - C u • SMe2,
H
%
•
THF, 0.1 Pd(PPh3)4
-50 o, 7 h, 80%
Me O
1 M HCI-THF,
HO"
Me,,,~O
:
(1:1),23 o,
0.5 h, 92%
OSO2CF3
9
10
11
1.3 TsNHN=CHCOCI,
2.2 PhNMe2, CH2CI2,
-25 o, 30 m; Et3N,
0 to 23 °, 30 m, 74%
1. TBMSCI, Imldazole,
O
'
~
xs Et2AICI,
~ CH2CI2, 0 o,
DMF, 23 ° (20 h),
45 o (8 h), 92%
H
TBMS
/ t-Bu HO
Me ~ O ~ O
10 m, 93%
. e
2.
O
N2
Tol, 110 °, 20 m, 76%
13
12

5028
References and Notes
Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574-5576. (b) Corey, E. J., Myers, A. G.;
Takahashi, N.; Yamane, H.; Schraudolf, H. Tetrahedron Lett. 1986, 27, 5083-5084.
1.
For background literature see (a) Nakanishi, K.; Endo, M.; N~, U.; Johnson, L. F. J. Am. Chem. Soc.
1971, 93, 5579-5581. (b) N~f, U.; Nakanishi, K.; Endo, M. Bot. Rev. 1975, 41,315-359.
Furber, M.; Mander, L. N. J. Am. Chem. Soc. 1987, 109, 6389-6396.
See, Morgan, M. S.; Cretcher, L. H. J. Am. Chem. Soc. 1946, 68, 781-784.
(a) Lewis, N.; Wallbank, P. Synthesis, 1987, 1103-1106. (b) Pelter, A.; Elgendy, S. Tetrahedron
Lett. 1988, 29, 677-680.
2.
3.
4.
5.
(a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551-3. (b) Corey, E. J.;
Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-6. (c) Corey,
E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861-3. (d) Corey, E. J. Proceedings 31st
National Organic Chemistry Symposium; American Chemical Society: Washington, D.C.; 1989; p 1.
(e) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275-8. (f) Corey, E. J.; Bakshi, R. K.
Tetrahedron Lett. 1990, 31,611-14. (g) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209-16.
The enantiomeric purity (ee) was determined by conversion to the MTPA ester (Dale, J.; Mosher,
H.S.J. Am. Chem. Soc. 1973, 95, 512) followed by IH NMR analysis at 500 MHz in C6D6 solution.
The following optical rotations were measured for key intermediates: for 8 [CC]2D3 +68.3° (c=1.2,
CHC13); for 9 [Ct]2D3 -70° (c=1.2, CHC13); for 10, mp 114-119 °C, [t~]~ -183° (c=1.5, CHC13); for 13,
[Ct]2D3 0% [Ct]235 -47° (C=0.3, CHC13); for 2, [t~]2D3 +53° (C=0.3, CHC13).
6.
7.
8.
9.
The stereochemistry of 10 was confirmed by NOE experiments (500 MHz, C6D6) which showed a
positive NOE effect between the angular methyl of 10 and the vicinal carbinol C-H (3.7%).
Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559-62.
1H NMR data at 500 MHz for intermediates 5, 8, 9, 10, 13, and 2 are as follows:
For 5: (in CDC13) 8 6.66-6.62 (m, 2H), 6.14 (d, 1H, J = 9.8 Hz), 4.42 (d, 2H, J = 2.0 Hz), 4.19-4.13
10.
11.
(m, 4H), 0.93 (s, 9H), 0.09 (s, 6H); For 8: (in C6D6) ~ 5.46 (s, 1H), 4.05 (m, 1H), 3.89 (br s, 2H),
2.22 (dt, 1H, J = 16.6, 2.6 Hz), 1.87-1.62 (m, 3H), 1.30 (s, 3H), 1.22 (s, 3H);
For 9: (in CDC13) 8
5.49 (br s, 1H), 3.85 (m, 1H, Wl/2 = 7 Hz), 3.74 (d, 1H, J = 11.9 Hz), 3.51 (d, 1H, J = 11.9 Hz), 2.62
(dddd, 1H, J = 17.7, 10.1, 7.7, 2.3 Hz), 2.15 (m, 1H), 1.98-1.88 (m, 2H), 1.45 (s, 3H), 1.34 (s, 3H),
0.93 (s, 3H); For 10: (in C6D6) 8 6.06-6.01 (m, 2H), 5.76 (dt, 1H, J = 10.1, 4.4 Hz), 5.54 (s, 1H),
3.71 (m, 1H, W1/2 = 8 Hz), 3.54 (d, 1H, J = 11.5 Hz), 3.46 (d, 1H, J = 11.5 Hz), 2.61 (m, 1H), 2.40-
2.27 (m, 2H), 2.12 (dd, 1H, J = 16.5, 6.1 Hz), 2.10-2.02 (m, 2H), 1.85 (dt, 1H, J = 13.9, 4.5 Hz), 1.62
(dddd, 1H, J = 13.9, 12.0, 6.2, 2.0 Hz), 1.42 (s, 3H), 1.33 (s, 3H), 0.66 (s, 3H); For 13: (in CDC13)
5.87 (dd, 1H, J = 9.4, 5.4 Hz), 5.77 (d, 1H, J = 5.4 Hz), 5.72 (m, 1H), 4.50 (d, 1H, J = 10.9 Hz), 3.89
(d, 1H, J = 10.9 Hz), 3.48 (dd, 1H, J = 12.5, 4.9 Hz), 2.23 (dd, 1H, J = 14.7, 6.4 Hz), 2.20-2.11 (m,
4H), 1.97 (ddd, 1H, J = 14.7, 12.8, 7.8 Hz), 1.71 (d, 1H, J = 8.2 Hz), 1.70 (ddt, 1H, J = 14.1, 6.4, 12.8
Hz), 1.58 (d, 1H, J = 8.2 Hz), 1.55 (m, 1H), 1.14 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H);
For 2: (in CDC13) ~ 5.78 (br d, 1H, J = 10.3 Hz), 5.72 (m, 1H), 4.19 (d, 1H, J = 10.6 Hz), 3.97 (dd,
1H, J = 10.6, 2.4 Hz), 3.69 (br d, 1H, J = 11.1 Hz), 3.65 (dd, 1H, J = 11.9, 4.8 Hz), 3.49 (dd, 1H, J =
11.1, 8.8 Hz), 2.78 (br d, 1H, J = 8.8 Hz), 2.60-2.54 (m, 2H), 2.27 (m, 1H), 2.12 (m, 1H), 2.04 (m,
1H), 1.84 (m, 1H), 1.77 (m, 1H), 1.31 (ddt, 1H, J = 11.9, 4.5, 13.1 Hz), 1.15 (s, 3H), 0.87 (s, 9H),
0.08 (s, 3H), 0.05 (s, 3H).
12.
This research was assisted financially by grants from the National Science Foundation and the
National Institutes of Health.
(Received in USA 30 May 1991)