Stereocontrolled synthesis of contignasterol's side chain

Article abstract of DOI:10.1016/S0040-4039(01)01964-5

The four models of the contignasterol's side chains (2-5) have been stereospecifically prepared. The key reaction in the synthesis is a dimethylaluminum chloride-mediated 'ene' reaction between the steroid derivative 6 and the pseudo-enantiomeric aldehydes 7 and 8.

Full text of DOI:10.1016/S0040-4039(01)01964-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8977–8980
Stereocontrolled synthesis of contignasterol’s side chain
Irene Izzo,* Vincenza Pironti, Carmela Della Monica, Guido Sodano and Francesco De Riccardis
Dipartimento di Chimica, Universita` di Salerno, Via S. Allende, Baronissi, I-84081 Salerno, Italy
Received 18 September 2001; revised 18 October 2001; accepted 19 October 2001
Abstract—The four models of the contignasterol’s side chains (2–5) have been stereospecifically prepared. The key reaction in the
synthesis is a dimethylaluminum chloride-mediated ‘ene’ reaction between the steroid derivative 6 and the pseudo-enantiomeric
aldehydes 7 and 8. © 2001 Elsevier Science Ltd. All rights reserved.
The recent isolation of potent anti-inflammatory com-
pounds, such as contignasterol1 (1), a highly oxy-
genated steroid isolated from the sponge Petrosia
contignata Thiele, and xestobergsterol,2 has been fol-
lowed by extensive biological studies3 but few synthetic
works.4
Our approach, an extension of the method developed
by Koreeda and co-workers,5 relies on a stereospecific
pericyclic coupling between the protected (Z)-17(20)-
ethylidene steroid 6 and the partner pseudo-enan-
tiomeric aldehydes 7 and 8.
As a part of our studies on the synthesis of steroids we
focused our attention on contignasterol (1), a polyhy-
droxysteroid presenting in its structure a 15-keto func-
tionality,
a
rare CD-cis ring junction and an
unprecedented side chain hemiacetal tetrahydropyranyl.
Accurate NMR studies by Andersen et al.1 allowed the
partial structural assignment of 1. The relative stereo-
chemistries at C-22 and C-24 side chain’s stereogenic
centers were established to be (22S,24S) or (22R,24R).
Attempts to determine the absolute configuration on a
derivative of 1, gave ambiguous results.1
The chosen strategy allows the stereocontrolled simulta-
neous introduction of all the side chain’s stereogenic
centers (C-20, C-22 and C-24).
In order to assign the absolute configurations at the
stereogenic centers of the contignasterol’s side chain
and with the idea to settle the basis for future investiga-
tions toward its total synthesis, here we report the
stereospecific synthesis of the four side-chain models
2–5, the formation of the related acetates, and the
assignment of the target side chain’s stereochemistries.
Our first goal was the preparation of the (Z)-3b-[(tert-
butyldiphenylsilyl)oxy]-5a-pregn-17-(20)-ene (6). This
was obtained in a two-step sequence6 (98% overall
yield) starting from the commercially available epi-
androsterone (9), as reported in Scheme 1.
Keywords: contignasterol; anti-inflammatory compounds; steroids;
marine metabolites.
* Corresponding author. Tel.: +39-089965230; fax: +39-089965296;
e-mail: izzire@mbox.chem.unisa.it
The synthesis of the aldehydes 7 and 8 was achieved
from (R)-limonene (11) in seven and nine steps (22 and
10% overall yield, respectively; Schemes 2 and 3).7
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01964-5

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I. Izzo et al. / Tetrahedron Letters 42 (2001) 8977–8980
The synthesis of 8 (Scheme 3) was achieved through
benzylation of the alcohol 17,10 K2CO3-induced
deacetylation of the ether 18 and Cr(VI)-mediated oxi-
dation of the free primary alcohol.
The continuation of the synthesis required the coupling
of the steroid 6 with the partner aldehydes 7 and 8
(Scheme 4). Both the ‘ene’ reactions were accomplished
uneventfully. As expected the (20S,22S) adducts 20 and
22 were prevalent and easily separated from their
(20S,22R) minor epimers 21 and 23.11
Scheme 1. Reagents and conditions: (a) 1.4 equiv. DBU, 1.2
equiv. TBDPSCl, CH2Cl2, overnight, quant.; (b) 2.7 equiv.
t-BuOK, 3.0 equiv. EtPPh3Br, THF, 3 h, reflux, 98%.
The indicated stereochemistries were assigned on the
strength of comparative analysis with the results of
Koreeda and co-workers.5 The (S)-C-22 absolute
configuration of the major adducts 20 and 22 was
confirmed according the modified Mosher’s esters
method12 (Scheme 5) through comparison of the 1H
NMR and COSY spectra of the a-methoxy-a-(trifl-
uoromethyl)phenylacetate (MTPA) derivatives 26–29.13
The stage was now set for the construction of the side
chain tetrahydropyran present in 1. Deprotection of the
adducts 20–23 (Scheme 6) and stereoselective D16-
hydrogenation, afforded the four stereoisomeric diols
30–33.
The b-orientation of the side chain was assigned
according literature data.14 It is known, in fact, that the
stereoselectivity of the hydrogenation depends on the
CD-ring junction: CD-trans junction induces the forma-
tion of b-oriented side chains (natural configuration);
CD-cis junction brings to unnatural C-17a side chains.
Scheme 2. Reagents and conditions: (a) 1 equiv. H2, PtO2,
MeOH; (b) (i) O3, CH2Cl2, MeOH, −60°C, 1 h, (ii) 2.8 equiv.
Me2S, 0.07 equiv. p-TsOH, MeOH, −60“0°C, 1 h, 60%,
overall; (c) (i) 3% HClO4 in H2O/THF (1:1). quant., (ii) 1.2
equiv. LiAl(OC(C2H5)3)3H, THF, −78°C, 1 h, 98%; (d) 1.4
equiv. DBU, 1.2 equiv. TPBDSCl, CH2Cl2, overnight, 96%;
(e) 3 equiv. MCPBA, CHCl3, reflux, 48 h, quant.; (f) 1.1
equiv. TBAF, THF, 0°C, 1 h, 60%; (g) 2 equiv. PDC, CH2Cl2,
,
MS 4 A, 2 h, 66%.
Scheme 3. Reagents and conditions: (a) 1.1 equiv. Ag2O, 1.3
equiv. BnBr, CH2Cl2, 57%; (b) K2CO3, MeOH, 40°C, 8 h,
Scheme 4. Reagents and conditions: (a) 3.1 equiv. 7, 6.2 equiv.
Me2AlCl, CH2Cl2, −78“−30°C, 6 h, 20: 80%, 21: 16%; (b) 3.1
equiv. 8, 6.2 equiv. Me2AlCl, CH2Cl2, −78“−30°C, 6 h, 22:
50%, 23: 10%.
,
81%; (c) 2 equiv. PDC, CH2Cl2, MS 4 A, 2 h, 66%.
The synthesis of 7 started with a selective hydrogena-
tion of 11 to give (R)-menthene (12). Oxidative cleav-
age of the double bond and subsequent in situ
protection of the unstable aldehyde (not isolated) gave
the keto-acetal 13. The keto-alcohol 14 was formed by
mild hydrolysis of the corresponding dimethyl acetal
(3% solution of HClO4 in THF/H2O), followed by
chemoselective reduction with lithium tris[(3-ethyl-3-
pentyl)oxy]aluminohydride.7a Protection of the hydroxy
group as t-butyldiphenylsilyl ether was necessary to
ensure a quantitative yield in the Baeyer–Villiger reac-
tion step.7a Fluoride induced desilylation8 and pyri-
dinium dichromate (PDC) oxidation9 gave the
enantiopure building block 7.
Scheme 5. Reagents and conditions: (a) 3 equiv. (S)-(+)-
MTPA-Cl, pyr., 0.5 h, quant.; (b) 3 equiv. (R)-(−)-MTPA-Cl,
pyr., 0.5 h, quant.

I. Izzo et al. / Tetrahedron Letters 42 (2001) 8977–8980
8979
Scheme 8. Reagents and conditions: (a) Ac2O, pyr., 24 h,
50–60%.
Scheme 6. Reagents and conditions: (a) K2CO3, MeOH; (b)
H2, Pt/C, EtOH, quant. (two steps); (c) H2, Pd/C, EtOH; (d)
H2, Pt/C, EtOH, quant. (two steps).
predominantly the supposed C-29 equatorial acetoxy
epimers 40 and 41 (1H NMR analysis).18
The side-chain cyclization was oxidatively achieved
using the ruthenium complex (PPh3)3RuCl2 (Scheme
7).15 The d lactones (34–37) were reduced with DIBAL-
H16 affording the desired lactols 2–5 in excellent yields.
1
Table 1 shows the similarity of the H NMR values
between compound 44,1 synthesized by Andersen,
through reduction and acetylation of contignasterol
and our models 38 and 42, thus confirming the
(22S,24S) or (22R,24R) Andersen’s relative stereo-
chemistry assignment. The (22S,24S) side chain’s abso-
lute configurations are suggested for contignasterol
considering:
The assignment of the side chain’s stereogenic centers
was possible only after acetylation of the free hydroxy
groups17 (Scheme 8). Surprisingly, lactols 3 and 4 gave
1. that the resonance value of H-29 in synthetic 38 is
almost coincident with the resonance value found in
the pentaacetate 44 (44: lH-29=5.75; 38: lH-29=5.76
while for 42: lH-29=5.93);
1
2. the almost identical H NMR values showed by the
minor epimers 45 and 39 found in mixture with 44
and 38, respectively (see Table 1).19
Scheme 7. Reagents and conditions: (a) 1 equiv. RuCl2(PPh3)3,
benzene, 6 h (34: 70%; 35: 70%; 36: 88%, 37: 87%); (b) 3
equiv. DIBAL-H, CH2Cl2, −78°C (2: 93%; 3: 98%; 4: 76%, 5:
83%).
In conclusion the synthesis and a tentative assignment
of the side chain’s absolute configurations of contignas-
terol have been reported. Future efforts in our labora-
tory will be directed to the total synthesis of 1.
1
Table 1. Comparison of selected H NMR data (C6D6, 400 MHz) among models 38–43 and the pentaacetate derivatives of
contignasterol 44 and 45 (multiplicities and coupling constants are reported in parenthesis)
1H at C
38
39
40
41
42
43
44
45
21
22
1.11 (d, 6.8)
3.50 (dd, 10.1, 3.96 (m)
2.0)
–
1.08 (d, 6.8)
1.10 (d, 6.7)
1.12 (d, 6.8)
–
1.03 (d, 6.8)
–
4.10 (dt, 10.8, 4.04 (bd, 10.3) 3.52 (bd, 11.1) 4.09 (bd, 11.7) 3.54 (dd, 9.4, 3.96 (m)
3.8)
5.9)
26
27
29
0.75 (d, 6.8)
0.76 (d, 6.8)
5.76 (dd, 9.5, 6.49 (d, 2.7)
2.2)
–
–
0.81 (d, 7.0)
0.83 (d, 7.0)
0.83 (d, 7.0)
0.83 (d, 7.0)
0.76 (d, 6.8)
0.78 (d, 6.8)
–
–
0.74 (d, 6.8)
0.76 (d, 6.8)
5.75 (dd, 9.7, 6.49 (d, 2.7)
2.2)
–
–
6.82 (dd, 5.0, 6.35 (dd, 5.0, 5.93 (dd, 9.8, 6.59 (bs)
4.9)
4.9)
1.9)
COCH3
1.76 (s)
1.75 (s)
1.73 (s)
1.73 (s)
1.73(s)
1.74 (s)
1.76 (s)
1.76 (s)

8980
I. Izzo et al. / Tetrahedron Letters 42 (2001) 8977–8980
9. Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Com-
Acknowledgements
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This work has been supported by the MURST (‘PRIN:
Chimica dei Composti Organici di Interesse Biologico’).
We are indebted to Professor Raymond Andersen for
11. When less than 2.0 equiv. of the Lewis acid were used, an
Oppenauer-like oxidation gives variable amounts of the
ketones 24 and 25 (10–15%). Interestingly, the reduction
of those ketones with NaBH4 in absolute ethanol/THF
(95:5) affords preferentially the alcohols 21 and 23 (24“
21: 56%, 20: 14%; 25“23: 58%, 22: 12%).
1
providing us the H NMR spectrum of 44 and 45.
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17. The acetylation ‘eliminates the effects of the hemiacetal
1
epimerization which complicates the H NMR’.1
18. The absence of the epimer with the axial acetoxy group
can be understood considering the unfavorable C-24/C-
29 1,3-diaxial interaction.
19. The 1H NMR data shown in Table 1 for the minor
epimer 45 were not reported by Andersen et al.1 even
though its resonances are evident in the spectrum of 44,
kindly provided to us by Professor R. Andersen.
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