Asymmetric carbolithiation of 2-phenylselenofumarate derivatives: A short synthesis of (-)-roccellaric acid

Article abstract of DOI:10.1016/S0040-4039(99)02119-X

(-)-Roccellaric acid and variously substituted succinates are obtained through direct asymmetric carbolithiation of 2-phenylselenofumarate derivatives, followed by reaction with suitable electrophiles.

Full text of DOI:10.1016/S0040-4039(99)02119-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 561–565
Asymmetric carbolithiation of 2-phenylselenofumarate
derivatives: a short synthesis of (−)-roccellaric acid
Marco Bella,a,b Roberto Margarita,a,b Claudia Orlando,a Monica Orsini,a Luca Parlanti a,b,∗ and
Giovanni Piancatelli a,∗
aDipartimento di Chimica, Università ‘La Sapienza’, Piazzale Aldo Moro 5, Box No. 34-Roma 62, 00185 Rome, Italy
bCentro CNR di Studio per la Chimica delle Sostanze Organiche Naturali, Università ‘La Sapienza’, Piazzale Aldo Moro 5,
Box No. 34-Roma 62, 00185 Rome, Italy
Received 1 October 1999; accepted 10 November 1999
Abstract
(−)-Roccellaric acid and variously substituted succinates are obtained through direct asymmetric carbolithiation
of 2-phenylselenofumarate derivatives, followed by reaction with suitable electrophiles. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: lactones; asymmetric synthesis; selenium; selenium compounds.
Roccellaric and dihydroprotolichesterinic acids 1 and 2 are natural substances belonging to the class
of paraconic acids, a kind of compound in which the β-position of the lactone moiety is occupied by a
carboxy group. They exhibit a wide range of bioactivities and their stereoselective synthesis is of great
interest as shown by a growing literature attention.1
In this paper we describe an enantioselective approach both to roccellaric acid and also to chiral
2,3-disubstituted succinates, useful as potential peptidomimetic metalloproteinase inhibitors,2 using the
particular reactivity of 2-phenylselenofumaric diester, as shown in our previous work,3 affords only
conjugate addition products with no detectable traces of 1,2 adducts in the reaction with organolithium
compounds.
We developed an asymmetric carbolithiation protocol in which the presence of cyclohexyl based chiral
auxiliaries4 in the ester moieties of 2-phenylselenofumarate provides an excellent stereocontrol in the
formation of the two new stereogenic centers. (1R,2S)-(−)-trans-2-Phenyl-1-cyclohexanol proved to be
∗
Corresponding authors. E-mail: piancatelli@axrma.uniroma1.it (G. Piancatelli)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02119-X
tetl 16047

562
the auxiliary of choice and the corresponding fumaric diester was prepared according to the sequence
outlined in Scheme 1.
Scheme 1.
Dimethyl acetylenedicarboxylate 3 was thus transesterified to the corresponding chiral diester 4
via titanium catalyzed methodology;5 then, nucleophilic addition of in situ generated benzeneselenol6
proceeded with good yield and stereoselectivity to afford compound 5. Intermediate 5 was then tested in
carbolithiation reactions in the presence of 1 equivalent of organolithium reagent in dichloromethane at
−78°C7 (Scheme 2).
Scheme 2.
Results show that with methyllithium the reaction proceeds with high yield and excellent dia-
stereoselectivity (>15:1)8 to give succinate 6. The absolute configuration of C-2 in compound 6 was
determined by chemical correlation with the commercially available 2-(R)-methyl succinic acid. The
relative stereochemistry of C-2 and C-3 was deduced after stereospecific selenoxide syn-elimination
from the compound 6 that afforded only the 2-methyl maleate derivative, in agreement with an (S) C-3
configuration.
To explore the possibility of preparing trisubstituted succinates, we studied the reactivity of the ester
enolate resulting from methyllithium addition towards electrophiles (Scheme 3).9 Interestingly, our data
shows that ester enolate reactivity is clearly enhanced by using a commercially available cumene:THF
(9:1) methyllithium 1 M solution (Table 1, entries 7 and 8) instead of the usual 1.5 M ethereal solution
utilized in our previous reactions (Table 1, entries 1–6).
Scheme 3.

563
Table 1
Dialkylation of fumarate 5
The stereoselectivities are excellent even when low yields are obtained. The stereochemistry of the
dialkylation products 7a–c has not yet been determined.
Having established the feasibility of a ‘one pot’ procedure in which an electrophile was used to quench
the carbolithiation product, we turned our attention to the synthesis of paraconic acids through reaction
of our enolate with a suitable aldehyde, such as myristyl aldehyde. The success of this transformation
would have led us to the corresponding 4-carboxy-butano-4-lactones, potential precursors of the naturally
occurring roccellaric and dihydroprotolichesterinic acids 1 and 2.10
Again, the use of methyllithium in cumene:THF (9:1) greatly enhanced the reactivity of the ester
enolate (Table 2, entry 3) allowing the formation of 8a in good yield and diastereoselectivity;11 no
formation of 8a was detected using the ethereal methyllithium solution (Scheme 4, Table 2, entries
1–2). Aromatic aldehydes were unreactive under these conditions (Scheme 4, Table 2, entries 4 and
5). Moreover, recovery of the chiral auxiliary with unaffected optical activity was possible through
chromatographic separation.
Table 2
Synthesis of lactone 8
Compound 8a was then treated under the usual radical hydrogenolysis conditions (Bu3SnH, AIBN),
but no reaction was observed; however, using another deselenylation protocol based upon the use of in
situ generated nickel boride12 we were able to obtain, in quantitative yield, a diastereomeric mixture of
compounds 9a and 9b in a 3.5:1 ratio (Scheme 5). The possibility of quantitatively transforming 9b into

564
Scheme 4.
9a via subsequent epimerization13 and separation overcomes the drawback of the limited selectivity of
this reaction.
Scheme 5.
Finally, 9a can be easily transformed into (−)-roccellaric acid, the enantiomer of the natural substance
1, [mp 107°C, [α]D=−25.4° (c=1.93), lit.1b mp 108°C, [α]D=−26° (c=1.93)] by treatment with basic
methanol, that allows also the complete recovery of the chiral auxiliary (Scheme 5).
In conclusion, we describe a novel stereoselective protocol to achieve direct asymmetric carbolithiation
of 2-phenylseleno fumarate derivatives; the procedure provides a new entry to chiral tri- and disubstituted
succinates and proved to be a valuable and straightforward synthetic tool. In fact, (−)-roccellaric acid 1
was easily obtained in three steps from the chiral synthon 5 (overall yield 42%); the sequence allows the
recovery of the chiral auxiliary that can be recycled. Studies are in progress to broaden the versatility of
the procedure, in order to develop a general method to obtain a wide range of differently 2,3-disubstituted
succinates in optically pure form.
Acknowledgements
We thank MURST COFIN 98 (Roma) for financial support.
References
1. (a) Mahato, S. B.; Siddiqui, K. A. I.; Bhattacharya, G.; Ghosal, T. J. Nat. Prod. 1987, 50, 245. (b) Mulzer, J.; Salimi, N.;
Harlt, H. Tetrahedron: Asymmetry 1993, 4, 457. (c) Zhu, G.; Lu, X. J. Org. Chem. 1995, 60, 1087. (d) Saicic, R. N.; Zard, S.
Z. Chem. Commun. 1996, 1631. (e) Jacobi, P. A.; Herradura, P. Tetrahedron Lett. 1996, 37, 8297. (f) Martin, T.; Rodriguez,
C. M.; Martin, V. S. J. Org. Chem. 1996, 61, 6450. (g) Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 274. (h)
Masaki, Y.; Arasaki, H.; Itoh, A. Tetrahedron Lett. 1999, 40, 4829. (i) Mandal, P. K.; Roy, S. C. Tetrahedron 1999, 55,
11395.

565
2. (a) Schwartz, M. A.; Van Wart, H. E. Progress Med. Chem. 1992, 29, 271. (b) Decicco, C. P.; Nelson, D. J.; Corbett, R. L.;
Dreabit, J. C. J. Org. Chem. 1995, 60, 4782. (c) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 1931 and references cited therein.
3. D’Onofrio, F.; Parlanti, L.; Piancatelli, G. Synlett 1996, 63.
4. For a review on cyclohexyl based chiral auxiliaries, see: Whitesell, J. K. Chem. Rev. 1992, 92, 953.
5. Krasik, P. Tetrahedron Lett. 1998, 39, 4223.
6. Barton, D. H. R.; Lalic, J.; Smith, G. A. Tetrahedron 1998, 54, 1725.
7. Typical carbolithiation procedure: diester 5 (587 mg, 1.00 mmol) was dissolved in dry dichloromethane (5 ml, 0.2 M) and the
solution cooled to −78°C under an inert atmosphere; methyllithium (0.8 ml of a 1.5 M solution in diethyl ether, 1.2 equiv.)
was then added dropwise and the resulting mixture stirred for 10 min. After that, the reaction was quenched by adding
methanol, warmed to room temperature and diluted with ethyl acetate; usual work-up (washing with brine, extraction and
drying) and chromatography (silica gel column, eluent hexane:ethyl acetate 95:5) afforded pure compound 6 as viscous oil
(561 mg, 93%). Selected data for 6: 1H NMR δ (CDCl3): 0.79 (d, 3H, J=7.0 Hz), 0.9–2.44 (m, 18H), 2.59 (dt, 1H, J1=12.0
Hz, J2=4.2 Hz), 3.26 (d, 1H, J=10.0 Hz), 4.70–4.87 (m, 2H), 7.08–7.49 (m, 15H). 13C NMR δ (CDCl3): 16.41, 25.07, 26.02,
26.25, 32.00, 34.00, 34.10, 41.77, 47.36, 49.59, 49.66, 77.21, 78.03, 126.87, 126.95, 128.07, 128.23, 128.66, 128.72, 128.86,
129.51, 135.37, 143.57, 143.85, 171.85, 179.18. [α]D=8.0° (c=1.5 in CHCl3). Anal. calcd for C35H40O4Se: C 69.64, H 6.68.
Found C 69.34, H 6.61.
8. All diasteroisomeric ratio were determined via 1H NMR (200 MHz) signals integration.
9. Typical dialkylation procedure: the methodology outlined in Ref. 7 was followed until the addition of methyllithium (in
the appropriate solvent, Table 1); the suitable electrophile (3 equiv.) and HMPA (0.1 ml) were then added and the mixture
warmed to room temperature. The reaction was then quenched with methanol and diluted with ethyl acetate; usual work-up
(washing with brine, extraction and drying) and silica gel chromatography afforded products 7a–c (Table 1).
10. D’Onofrio, F.; Margarita, R.; Parlanti, L.; Piancatelli, G.; Sbraga, M. Chem. Commun. 1998, 185.
11. Typical procedure for the synthesis of lactone 8a: the methodology outlined in Ref. 7 was followed until the addition of
methyllithium (cumene:THF, 9:1 solution); myristyl aldehyde (650 mg, 3 equiv.) dissolved in 1 ml of dichloromethane
was then added and the temperature raised to −40°C. After 30 min the reaction was quenched with methanol, diluted with
ethyl acetate and warmed to room temperature; the mixture was then neutralized with saturated NaHCO3 solution, washed
with brine and the organic layer dried over Na2SO4. Silica gel column chromatography (eluent hexane:ethyl acetate, 25:1)
1
afforded pure 8a as viscous oil (413 mg, 62%). Selected data for 8a: H NMR δ (CDCl3): 0.85–2.27 (m, 38H), 2.70 (dt,
1H, J1=4.2 Hz, J2=11.0 Hz), 3.85 (dd, 1H, J1=1.8 Hz, J2=10.2 Hz), 5.05 (dt, 1H, J1=4.2 Hz, J2=10.4 Hz), 7.13–7.48 (m,
10H). 13C NMR δ (CDCl3): 23.20, 25.13, 25.97, 27.45, 27.80, 29.32, 29.87, 29.99, 30.16, 32.42, 32.79, 34.39, 43.35, 49.67,
61.69, 80.63, 83.54, 125.95, 127.93, 128.36, 128.95, 129.12, 130.15, 130.72, 139.33, 142.99, 168.63, 176.26. [α]D=−27.3°
(c=1.3 in CHCl3). Anal. calcd for C37H52O4Se: C 69.46, H 8.19. Found C 69.44, H 8.18.
12. Back, T. G.; Birss, V. I.; Edwards, M.; Krishna, M. V. J. Org. Chem. 1988, 53, 3815.
13. Shimada, S.; Hashimoto, J.; Saigo, K. J. Org. Chem. 1993, 58, 5226.