A formal synthesis of both atropenantiomers of desertorin C

Article abstract of DOI:10.1039/a808146h

Asymmetric synthesis of both enantiomers of 1,1'-(2',4-dihydroxy-6,6'-dimethoxy-2,4'-dimethylbiphenyl-3,3'-diyl) -bisethanone allows the formal synthesis of both enantiomers of 4,4',7,7'-tetramethoxy-5,5'-dimethyl-6,8'- bicoumarin (desertorin C).

Full text of DOI:10.1039/a808146h

A formal synthesis of both atropenantiomers of desertorin C
Rekha V. Kyasnoor and Melvyn V. Sargent*
Department of Chemistry, University of Western Australia, Nedlands, Western Australia, 6907, Australia.
E-mail: mvs@chem.uwa.edu.au
Received (in Cambridge, UK) 20th October 1998, Accepted 6th November 1998
Me
Me
Asymmetric synthesis of both enantiomers of 1,1A-(2A,4-
dihydroxy-6,6A-dimethoxy-2,4A-dimethylbiphenyl-3,3A-diyl)-
bisethanone allows the formal synthesis of both enantiomers
ii–iv
of
4,4A,7,7A-tetramethoxy-5,5A-dimethyl-6,8A- bicoumarin
MeO
i
OR
MeO
OH
(desertorin C).
Br
6 R = H
7 R = THP
8
The desertorins A 1, B 2 and C 3 are a family of unsymmetrical
coumarin dimers of fungal origin which are optically active on
account of restricted rotation about their stereogenic axes.1
Scheme 1 Reagents and conditions: i, TsOH, dihydropyran, THF, 0 °C, 20
h; ii, BuLi, Ar, THF, TMEDA, 25 °C, 4 h; iii, BrCF2CF2Br, 25 °C, 1 h; iv,
H+, H2O.
O
O
OH
S
Methylation of both desertorins A and B provides desertorin C
which on base hydrolysis yields the diketone 5.1 We have
previously synthesized desertorin C in racemic form using the
(±)-diketone 5 as the key intermediate.2 Subsequently the
absolute configuration of the desertorins was established as R
by an X-ray crystal structure determination of the bis-
bromobenzoate 4.3 We now describe a synthetic approach to
both enantiomers of desertorin C.
Ac
MeO
Me
R2O
OR1
O
Me
OMe
OH
R
O
MeO
Ac
O-Methylorcinol 6 (Scheme 1) was protected as its tetra-
hydropyranyl ether 7 which on lithiation and subsequent
treatment with 1,2-dibromotetrafluoroethane and acidic work-
up gave the bromophenol 8,4 mp 71–72 °C, in 60% overall
yield. Mitsunobu reaction (Scheme 2) between this bromo-
Me
1 R1 = R2 = H
2 R1 = H, R2 = Me
3 R1 = R2 = Me
4 R1 = R2 = Bz
OMe
Me
5
Me
OMe
OMe
OMe
Br
R
R
R
S
S
S
RO
RO
O
O
O
O
S
S
OBn
OBn
OBn
OBn
OBn
v–vii
ii
iv
xi
Me
X
X
Me
OR
OR
S
S
MeO
MeO
OBn
HO
i
O
Br
Br
9 R = H
10 R = TBDMS
Me
Me
MeO
iii
Me
MeO
Me
11 R = TBDMS
12 R = H
14
15 X = OBn
16 X = OH
17 X = OTs
18 X = I
19 R = H (R)
20 R = Pri (S)
21 R = Bz (S)
viii
ix
xii
Me
Br
x
xiii
MeO
OH
OH
13
OH
OMe
OMe
Ac
OH
Ac
Ac
Ac
Ac
OPri xiv Me
OH
OH
xv, xiv
Me
OMe
OH
Me
OH
Me
MeO
OPri
xiv
xv, xiv
Me
S
+
5
R
R
S
S
OPri
HO
MeO
MeO
OH
OPri
MeO
Ac
Ac
Ac
Ac
Ac
Me
Me
Me
Me
Me
26
25
23
22
24
Scheme 2 Reagents and conditions: i, TBDMSCl, imidazole, DMF, 25 °C, 15 h, 76%; ii, 8, Bu3P, DEAD, THF, 25 °C, 24 h; iii, Bu4NF, THF, 25 °C, 1 h;
iv, 13, Bu3P, DEAD, THF, 25 °C, 48 h; v, BuLi, Ar,THF, 278 °C, 1 h; vi, CuCN, TMEDA, 278 to 240 °C, 15 min; vii, O2, 278 °C, 3 h; viii, H2, Pd/C,
EtAc, 94%; ix, TsCl, C5H5N, 0 °C, 7 h, 78%; x, NaI, Me2CO, reflux, 5 h, 91%; xi, Zn, EtOH, reflux, 1 h, 80%; xii, PriBr, K2CO3, DMF, 45 °C, 48 h, 68%;
xiii, TFAA, AcOH, CH2Cl2, 25 °C, 7h, 69%; xiv, BCl3, CH2Cl2, 0 °C, 2 h; xv, MeI, K2CO3, DMF, 40 °C, 15 h.
Chem. Commun., 1998, 2713–2714
2713

phenol 8 and the mono(tert-butyldimethylsilyl)ether 10 of
1,4-di-O-benzyl-
-threitol 95 gave the ether 11 (68%) which on
deprotection afforded the alcohol 12 (90%). This alcohol was
diketones 22 and 23. Selective dealkylation of this mixture with
BCl3 yielded the tetrol 24 (30%), mp 198–200 °C, [a]D20 32.8
(c 0.86, Me2CO), dOH(CDCl3) 8.46, 8.54, 11.80 and 13.42, and
the triol 25 (35%), mp 120 °C decomp., [a]D 261.0 (c 1.05,
L
20
caused to react in another Mitsunobu reaction with the
bromophenol 13.6 The resultant
D-threitol derivative 14, mp
Me2CO), dOH(CDCl3) 8.36, 11.87 and 12.45. Methylation and
selective demethylation of the tetrol 24 gave the (S)-diketone 5
(69%), mp 147–149 °C (lit.,1 149–150 °C), [a]D20 34.0 (c 0.94,
Me2CO),10 which had previously been obtained by basic
hydrolysis of desertorin C.1 The (R)-diketone 26 (82%), mp
54–56 °C (45%), was subjected sequentially to lithiation,
copper( ) cyanide and dry oxygen after the manner of Lipschutz
I
et al.,7 which gave the cyclized product 15 (40%). Deprotection
was achieved by hydrogenolytic debenzylation and tosylation
of the resultant diol 16. The tosylate 17 was converted into the
iodide 18, mp 155–157 °C, which on reductive elimination with
20
145–146 °C, [a]D 253.0 (c 0.80, Me2CO),11 was obtained in
a similar fashion from the triol 25. Since the racemic diketone
has been converted into desertorin C this constitutes a formal
synthesis of both of the enantiomers of this metabolite.
Both the synthetic diketone 5 and the degradation product 5
appear to have undergone some racemisation, the former
presumably at the tetrol stage, and the latter under the harsh
conditions of the hydrolysis.
20
activated zinc supplied the diol 19, mp 134–136 °C, [a]D 227
(c 0.67, CHCl3).
In order for the intramolecular coupling 14?15 to occur the
aryloxy substituents in the intermediate higher order cyano-
cuprate7 are predicted to adopt, on account of the anomeric
effect, the gauche conformation depicted in Fig. 1. Hence the
axial configuration of the intermediate cyclic compound 15 is S
and that of the diol 19 is R. The diol appeared to be
enantiomerically pure since it was not resolved on HPLC on two
Notes and references
1 K. Nozawa, H. Seyea, S. Nakajima, S. Udagawa and K. Kawai, J. Chem.
Soc., Perkin Trans. 1, 1987, 1735.
2 M. A. Rizzacasa and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1,
1988, 2425.
3 K. Kawai, M. Shiro and K. Nozawa, J. Chem. Res., 1995, 701.
4 G. I. Feutrill and R. N. Mirrington, Aust. J. Chem., 1972, 25, 1719.
5 E. A. Mash, K. A. Nelson, E. V. Densen and S. B. Hemperly, Org.
Synth., 1993, Coll. Vol. VIII, 155.
6 J. R. Cannon, T. M. Cresp, B. W. Metcalf, M. V. Sargent, G.
Vinciguerra and J. A. Elix, J. Chem. Soc. (C), 1971, 3495.
7 B. H. Lipschutz, F. Kayser and Z.-P. Lui, Angew. Chem., Int. Ed. Engl.,
1994, 33, 1842.
1
chiral columns8 nor did the H and 19F NMR spectra of the
derived Mosher diester show the presence of the other
enantiomer even in the presence of a lanthanide shift reagent.
The CD spectrum (MeCN) of the derived dibenzoate 21 showed
exciton splitting centred at l 226 nm with a positive first Cotton
effect (l 237 nm, De 24.3) and a negative second effect (l 215
nm, De 29.0) in keeping with the R configuration of the diol
19.9
Since O-methylorcinol 6 undergoes C-monoacetylation at
both positions ortho to the hydroxy group, the diol 19 was
isopropylated and the resultant ether 20 was acetylated with
AcOH and TFAA, which supplied an inseparable mixture of the
8 Pirkle type 1A and Chiralpak OT (+).
9 N. Harada and K. Nakanishi, Circular Dichroic Spectroscopy: Exciton
Coupling in Organic Spectrochemistry, University Science Books, Mill
Valley, 1983.
H
10 CD spectra: Degradation product l(MeOH)/nm 227 and 270 (De 7.7
and 26.5). Synthetic product l(MeCN)/nm 196, 216, 231, 275, 296 and
340 (De 10.4, 231.8, 18.3, 29.0, 3.8 and 1.9). The racemic diketone
was not resolved on HPLC nor was its 1H NMR spectrum resolved in the
presence of (S)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol.
11 CD spectrum: l(MeCN)/nm 196, 216, 230, 276, 295 and 335 (De
219.8, 52.7, 233.5, 14.7, 27.5 and 25.2).
Me
O
O
CH2OBn
CH2OBn
MeO
H
Fig. 1 Newman projection along the 2,3-bond of the
conformation for the coupling reaction leading to 15.
D-threitol 14 in the
Communication 8/08146H
2714
Chem. Commun., 1998, 2713–2714