Highly diastereoselective alkylation of vicinal dianions of chiral succinic acid derivatives: A new general strategy to (R)-β-arylmethyl-γ- butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2004.04.008

The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4- dione react with arylmethyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral α-arylmethylated succinic acid derivatives; the (R)-products are converted into (R)-β-arylmethyl-γ- butyrolactones and (R)-α-arylmethyl-γ-butyrolactones.

Full text of DOI:10.1016/j.tetlet.2004.04.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4315–4318
Highly diastereoselective alkylation of vicinal dianions of chiral
succinic acid derivatives: a new general strategy to
(R)-b-arylmethyl-c-butyrolactones
Manat Pohmakotr,* Darunee Soorukram, Patoomratana Tuchinda, Samran Prabpai,
Palangpon Kongsaeree and Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 12 December 2003; revised 8 March 2004; accepted 2 April 2004
Abstract—The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimid-
azolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione react with aryl-
methyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral a-arylmethylated succinic acid
derivatives; the (R)-products are converted into (R)-b-arylmethyl-c-butyrolactones and (R)-a-arylmethyl-c-butyrolactones.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Succinic acid derivatives are of importance because they
can serve as four-carbon building blocks in organic
synthesis. Having considered the basic skeleton of many
classes of compounds such as lignans1 possessing a c-
butyrolactone or tetrahydrofuran nucleus, it was found
that such compounds consisting of a four-carbon unit
could be considered as a carbon backbone derived from
succinic acid derivatives. Therefore, considerable atten-
tion has been focused on the synthetic utilities of succinic
acid derivatives.2 In connection with our recent reports
on the synthetic utilities of vicinal dianions derived from
a-aroylsuccinic esters as useful reagents for the synthesis
of a-arylideneparaconic esters and furofurans,3 it is of
interest to extend our investigation on new synthetic
strategies to chiral c-butyrolactone frameworks, espe-
cially some bioactive naturally occurring c-butyrolac-
tone lignans. We therefore studied the generation and
diastereoselective alkylation of vicinal dianions derived
from chiral succinic acid derivatives.4 This study is
focused on a new general diastereoselective synthesis of
chiral b-arylmethylated c-butyrolactones, which are
versatile intermediates for the asymmetric syntheses of
lignans. Several synthetic approaches for the optically
active b-arylmethyl-c-butyrolactones have been pub-
lished.5 The vicinal dianion 2a was generated by reacting
chiral succinic acid derivative 1a with 2 equiv of LDA in
THF at )78 ꢁC for 1 h. Treatment of 2a with 1 equiv of
benzyl bromide at )78 ꢁC for 5 h afforded the benzylated
product 3a in 50% yield as a single diastereomer, together
with the recovered starting material 1a in 41% yield. A
better yield of 3a (75%) was obtained, when 2.2 equiv of
benzyl bromide were employed under the same condi-
tions. It is noteworthy that the reaction using 1 or 2 equiv
of benzyl bromide gave only the monobenzylated prod-
uct 3a.6;7 The (S)-configuration at the new stereocenter of
compound 3a was confirmed by converting into the
corresponding known (S)-a-benzylsuccinic acid.8 When
the reaction was carried out in the presence of DMPU
and slowly warmed up from )78 ꢁC to room temperature
overnight, a complex mixture of products was obtained
as revealed by TLC and 1H NMR data. Having the
standard conditions, we next investigated the reactions
of the vicinal dianion 2a with methyl iodide and allyl
bromide. The products 3b and 3c were also obtained as a
single diastereomer in moderate yields as indicated in
Table 1 (entries 2 and 3, Scheme 1).
Similarly, the vicinal dianion 2b could be generated from
1b and reacted with arylmethyl bromides (2.2 equiv) at
)78 ꢁC for 5 h to give arylmethylated products 4a–c in
moderate yields (Table 1, entries 4–6). The reaction
proceeded with high diastereo- and regio-selectivities; all
compounds 4a–c were obtained as a single diastereomer.
The configuration of the new chiral center of 4b was
proved to be (R) by single crystal X-ray diffraction
Keywords: Vicinal dianion; Chiral succinic acid; c-butyrolactone.
* Corresponding author. Tel.: +66-02-2015158; fax: +66-02-6445126;
e-mail: scmpk@mahidol.ac.th
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.008

4316
M. Pohmakotr et al. / Tetrahedron Letters 45 (2004) 4315–4318
Table 1. Alkylation of vicinal dianions 2a and 2b
Entry
1
RX
3b or 4b, R ¼
3a, PhCH2
3b, Me
Yield (%)a
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
PhCH2Br
MeI
75
48
49
53
67
67
CH2@CHCH2Br
3,4-MeOPhCH2Br
3-MeOPhCH2Br
3,4-CH2(O)2PhCH2Br
3c, CH2@CHCH2
4a, 3,4-MeOPhCH2
4b, 3-MeOPhCH2
4c, 3,4-CH2(O)2PhCH2
a Isolated yields. All compounds were fully characterized by 1H NMR, 13C NMR, MS, and CHN analyses or HRMS.
28
D
b The specific rotation values, ½aŠ of 3a–c and 4a–c are as follows: 3a; +127.84 (c 0.51, MeOH); 3b, +117.45 (c 0.55, CHCl3); 3c, +107.50 (c 0.64,
CHCl3); 4a, )45.02 (c 0.31, CHCl3); 4b, )64.57 (c 0.70, CHCl3); 4c, +46.85 (c 0.29, CHCl3).
Re-face
Ar CH Br
2
O
O
Li
Li
O
N
X
X
O
c
c
Me
Ph
N
Z
X
X
LDA (2 eq.)
THF, -78 o
Me
Me
c
c
N
2b-A
N
Z
Li
O
C
O
O
O
Li
Me
Ph
1a, 1b
2a, 2b
RX, -78 oC , 5 h
O
O
O
N
Me
O
Ph
Me
(S)
(R)
X
X
c
N
c
X
N
O
Li
X
4
c
2b-B
2a-A
c
O
N
R
O
Me
R
O
H
Me
Ph
Ar
4
3
O
Me
NR SN
1a, 2a and 3: X =
c
Li
O
N
Ph
Ph
O
Ph
Me
Me
Me
Z
Me
N
O
3
N
Z
O
N
Me
Ph
O
Li
N
N
R
Me
1b, 2b and 4: X =
S
c
Me
CH
Ar
Br
2
Si-face
Scheme 1.
Figure 2. Proposed models for the stereochemical course of the
alkylation of the vicinal dianions 2a and 2b.
Based on the evidence that Li-chelated (Z)-enolates were
formed upon treatment of 1-acyl-2-imidazolidinones
with LDA,10 the vicinal dianion intermediate 2b is pro-
posed to exist in the (Z,Z)-configuration possessing the
defined six-membered ring chelate structure 2b–A. In the
formation of 4a–c, the arylmethyl bromides would
approach from the Re-face of the vicinal dianion 2b–A to
avoid the steric repulsion with phenyl and methyl groups
leading to an intermediate 2b–B. The second aryl-
methylation of 2b–B does not occur due to the steric
hindrance between the a-arylmethyl and the chiral aux-
iliary phenyl groups. As similar model 2a–A may also be
applied to the alkylation of the vicinal dianion 2a, in
which the alkylating agent approaches from the Si-face
(Fig. 2).
Having established that highly diastereoselective alkyl-
ation of the vicinal dianion 2b furnishes the single
diastereomer of compounds 4a–c possessing the (R)-
configuration at the a-carbon, we turn our attention to
the preparation of (+)-b-arylmethyl-c-butyrolactones.
This could be accomplished by a hydrolysis–anhydride
Figure 1. Crystal structure of compound 4b.
analysis9 (Fig. 1), which suggested the simple model for
the stereochemical course of the benzylation of the vic-
inal dianion 2b shown in Figure 2.

M. Pohmakotr et al. / Tetrahedron Letters 45 (2004) 4315–4318
4317
References and notes
1. LiOH (5eq)
THF / H2O
reflux, 42 h
O
OH
0
Ar
HO
Ar
Ac2O
oC , 10 min
1. Ayres, D. C.; Loike, J. D. Lignans: Chemical, Biological
and Clinical Properties; Cambridge University Press:
Cambridge, 1990; Ward, R. S. Nat. Prod. Rep. 1999, 16,
75–96.
2. For examples, see: (a) Csa’ky, A. G.; Plumet, J. Chem.
Soc. Rev. 2001, 30, 313–320; (b) Sibi, M. P.; Liu, P.; Ji, J.;
Hajra, S.; Chen, J. J. Org. Chem. 2002, 67, 1738–1745; (c)
Sibi, M. P.; Hasegawa, H. Org. Lett. 2002, 4, 3347–3349;
(d) Langer, T.; Illich, M.; Helmchen, G. Synlett 1996,
1137–1139; (e) Beckett, R. P.; Crimmin, M. J.; Davis, M.
H.; Spavold, Z. Synlett 1993, 137–138.
4a-c
O
O
O
O
2. 2 M HCl
6
5a (89%)
5b (90%)
5c (87%)
1. NaBH4 / THF
0-5 oC , 1 h
2. 1 M, HCl
3. (a) Pohmakotr, M.; Sampaongoen, L.; Issaree, A.; Tuc-
hinda, P.; Reutrakul, V. Tetrahedron Lett. 2003, 44, 6717–
6720;; (b) Pohmakotr, M.; Issaree, A.; Sampaongoen, L.;
Tuchinda, P.; Reutrakul, V. Tetrahedron Lett. 2003, 44,
7937–7940.
4. Syntheses based on vicinal anion of ())-dimenthyl succi-
nate, see: (a) Lee, E.; Choi, S.-J.; Kim, H.; Han, H.-O.;
Kim, Y.-K.; Min, S.-I.; Son, S.-H.; Lim, S.-M.; Jang,
W.-S. Angew. Chem., Int. Ed. 2002, 41, 176–179; (b)
Kende, A. S.; Fujii, Y.; Mendoza, J. S. J. Am. Chem. Soc.
1990, 112, 9645–9646; (c) Misumi, A.; Iwanaga, K.;
Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1985,
107, 3343–3345.
Ar
Ar
O
O
O
O
7a (43%)
7b (44%)
7c (44%)
8a (26%)
8b (25%)
8c (27%)
Scheme 2.
5. (a) Bolm, C.; Palazzi, C.; Francio, G.; Leitner, W. Chem.
Commun. 2002, 1588–1589; (b) Doyle, M. P.; Hu, W.;
Valenzuela, M. V. J. Org. Chem. 2002, 67, 2954–2959, and
references cited therein; (c) Caro, Y.; Masaguer, C. F.;
Ravina, E. Tetrahedron: Asymmetry 2001, 12, 1723–1726;
(d) Takekawa, Y.; Shishido, K. J. Org. Chem. 2001, 66,
8490–8503; (e) Kamlage, S.; Sefkow, M.; Zimmermann, N.;
Peter, M. G. Synlett 2002, 77–80; (f) Kamlage, S.; Sefkow,
M.; Pool-Zobel, B. L.; Peter, M. G. Chem. Commun. 2001,
331–332; (g) Sibi, M. P.; Liu, P.; Johnson, M. D. Can. J.
Chem. 2000, 78, 133–138; (h) Chenevert, R.; Mohammadi-
Ziarani, G.; Caron, D.; Dasser, M. Can. J. Chem. 1999, 77,
223–226; (i) Brinksma, J.; Deen, H. V. D.; Oeveren, A. V.;
Feringa, B. L. J. Chem. Soc., Perkin Trans. 1 1998, 4159–
4163; (j) Charlton, J. L.; Chee, G. Can. J. Chem. 1997, 75,
1076–1083; (k) Gagnon, R.; Gagnon, G.; Groussain, E.;
Pedragosa-Moreau, S.; Richardson, P. F.; Roberts, S. M.;
Willetts, A. J.; Alphand, V.; Letreton, J.; Furstoss, R. J.
Chem. Soc., Perkin Trans. 1 1995, 2527–2528; (l) Lemoult, S.
C.; Richardson, P. F.; Roberts, S. M. J. Chem. Soc., Perkin
Trans. 1 1995, 89–91; (m) Itoh, T.; Chika, J.; Takagi, Y.;
Nishiyama, S. J. Org. Chem. 1993, 58, 5717–5723; (n)
Morimoto, T.; Chiba, M.; Achiwa, K. Tetrahedron 1993, 49,
1793–1806; (o) Koch, S. S. C.; Chamberlin, A. R. J. Org.
Chem. 1993, 58, 2725–2737; (p) Filho, H. C. A.; Filho, U. F.
L.; Pinheiro, S.; Vasconcellos, M. L. A. A.; Costa, P. R. R.
Tetrahedron: Asymmetry 1994, 5, 1219–1220; (q) Takano,
S.; Ohashi, K.; Sugihara, T.; Ogasawara, K. Chem. Lett.
1991, 203–206; (r) Morimoto, T.; Chiba, M.; Achiwa, K.
Tetrahedron Lett. 1990, 31, 261–264; (s) Morimoto, T.;
Chiba, M.; Achiwa, K. Heterocycles 1990, 30, 363–366; (t)
Shao, L.; Miyata, S.; Muramatsu, H.; Kawano, H.; Ishii, Y.;
Saburi, M.; Uchida, Y. J. Chem. Soc., Perkin Trans. 1 1990,
1441–1445; (u) Yoda, H.; Kitayama, H.; Katagiri, T.;
Takabe, K. Tetrahedron 1990, 48, 3313–3322.
formation–reduction sequence, starting from chiral
succinic acid derivatives 4 (Scheme 2).
Thus, hydrolyses of 4a–c employing LiOH (5 equiv) in
aqueous THF under reflux for 40–42 h provided the
corresponding succinic acid derivatives 5a–c in good
yields after acidic work-up.11 Treatment of these acids
with excess Ac2O at 0 ꢁC afforded the corresponding acid
anhydrides 6 in quantitative yields. Reduction of 6 with
NaBH4 in THF at 0–5 ꢁC for 1 h afforded the mixtures of
the expected (R)-b-arylmethyl-c-butyrolactones 712 and
(R)-a-arylmethyl-c-butyrolactones 8,12 which could be
separated by chromatography on silica gel.
In conclusion, we have described a general entry to an
enantioselective synthesis of (R)-b-arylmethyl-c-butyrolac-
tones. The method involves highly regio- and diastereo-
selective arylmethylations of the vicinal dianions derived
from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-
dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-di-
one and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenyl-
imi-dazolidin-1-yl]butane-1,4-dione. It is anticipated
that the methodology described herein will find a number
of useful applications in asymmetric synthesis of lignans.
Acknowledgements
We thank the Thailand Research Fund for financial
support (BRG/22/2544) to M.P. and the award of a
Senior Research Scholar to V.R. D.S. thanks the
Development and Promotion of Science and Technology
Talent Project (DPST) for a scholarship. Thanks are also
made to the Higher Education Development Project:
Postgraduate Education and Research Program in
Chemistry (PERCH) for support. We are grateful to
Professor Paul Knochel, LMU, Munich, Germany, for
the HRMS and CHN determination of some com-
pounds.
6. Treatment of 1a with 1 equiv of LDA, followed by
reacting with 1 or 2 equiv of benzyl bromide under the
standard conditions provided a low yield of the expected
product 3a.
7. Attempts to prove the presence of the vicinal dianion 2a
by quenching with D2O were unsuccessful. No deuterium
1
incorporation was observed as revealed by H NMR and
MS. In spite of these results, it was still assumed that the

4318
M. Pohmakotr et al. / Tetrahedron Letters 45 (2004) 4315–4318
31
D
25
D
vicinal dianion 2a was generated under the conditions
described. This may be due to a strong H-bonded complex
between diisopropylamine and the dilithiated derivative.
Such interaction effecting incomplete deuteration of the
generated lithium derivative was reported by Seebach
(Laube, T.; Dunitz, J. D.; Seebach, D. Helv. Chim. Acta,
1985, 68, 1373–1393). The reaction of the vicinal dianion
2a with 2.2 equiv of benzyl bromide at )78 ꢁC to room
temperature overnight (12–16 h) afforded dibenzylated
product 9 in 20–30% yields together with 30–40% yields
of the chiral auxiliary, (4S,5R)-(+)-1,5-dimethyl-4-phenyl-
2-imidazolidinone and compound 11. The formation of 9
supported the presence of the vicinal dianion 2a. Com-
pound 9 was obtained as a single diastereomer and its
structure is proposed as shown below. The results also
indicated that the vicinal dianion 2a slowly decom-
posed during warming from )78 ꢁC to rt to provide 10
and 11.
8. ½aŠ (observed) )20.19 (c 2.08, EtOAc). Lit. ½aŠ )27 (c 2,
EtOAc); Cohen, S. G.; Milovanovic, A. J. Am. Chem. Soc.
1968, 90, 3495–3502.
9. Crystal data for 4b: C34H38N4O5, MW ¼ 582:70, ortho-
rhombic, space group
P21 2 21, a ¼ 8:1187ð5Þ,
3
ꢀ
ꢀ
b ¼ 10:1120ð5Þ,
c ¼ 38:5830ð5Þ A,
V ¼ 3167:5ð3Þ A ,
Z ¼ 4, Dcalcd ¼ 1:222 Mg/m3. A total of 2,115 unique
reflections (1,724 observed, jFoj > 4rjFoj) were measured
at room temperature from a 0.30 · 0.15 · 0.15 mm3 color-
less crystal using graphite monochromated Mo Ka radia-
ꢀ
tion (k ¼ 0:71073 A) on a Bruker–Nonius kappaCCD
diffractometer. The crystal structure was solved by direct
methods using SIR-97, and then all atoms except hydro-
gen atoms were refined anisotropically on F 2 using
SHELXL-97 to give a final R-factor of 0.0493 and
wR ¼ 0:1130(all data). Atomic coordinates, bond lengths,
bond angles, and thermal parameters have been deposited
with the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, ENGLAND (CCDC
216625).
Ph
Ph
Me
O
O
10. Kise, N.; Ueda, T.; Kumuda, K.; Terao, Y.; Ueda, N. J.
Org. Chem. 2000, 65, 464–468, and references cited
therein.
11. The chiral auxillary was recovered in 85–95%
yields and could be reused without loss of diastereoselec-
tivity.
(S)
(S)
N
N
Me
Me
N
N
O
O
Ph
Me
Ph
29
9, [α] = +146.3 (c 1.226, CHCl )
28
3
D
12. Specific rotation values for 7a–c and 8a–c. 7a: ½aŠ +8.75
D
24
D
31
D
(c 0.32, CHCl3); Lit.5j: ½aŠ +8.3 (c 1.33, CHCl3). 7b: ½aŠ
20
D
+7.31 (c 0.74, CHCl3); Lit.5k: ½aŠ +6.41 (c 2.08, CHCl3).
O
O
30
D
20
D
7c: ½aŠ
31
+5.12 (c 1.13, CHCl3); Lit.5j ½aŠ
28
+5.2
Me
Me
N
N
NH
Ph
N
Ph
28
D
(1.14, CHCl3). 8a: ½aŠ )58.00 (c 0.20, CHCl3). 8b:
½aŠ )53.78 (c 0.48, CHCl3). 8c: ½aŠ )51.34 (c 0.26,
D
CHCl3).
D
Me
Me
Ph
11
10