Organocatalytic and enantioselective synthesis of β-(hydroxyalkyl)- γ-butyrolactones

Article abstract of DOI:10.1021/jo8005733

(Chemical Equation Presented) Organocatalytic cross-aldol reaction of methyl 4-oxobutyrate (2) and a variety of aldehydes 3 followed by reduction with NaBH₄ has provided a one-pot, general and efficient method for the synthesis of 4-(hydroxyalk

Full text of DOI:10.1021/jo8005733

SCHEME 1. Organocatalytic One-Pot Synthesis of Lactone 1
Organocatalytic and Enantioselective Synthesis of
ꢀ-(Hydroxyalkyl)-γ-Butyrolactones
Saumen Hajra* and Aswini Kumar Giri
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721 302, India
glutamic acid,7 and (v) enzymatic resolution.8 Catalytic asym-
metric hydrogenation of itaconic acid derivatives followed by
chemoselective reduction-lactonization9 and chiral Rh(II)-
catalyzed enantioselective intramolecular C-H insertion of alkyl
diazoacetates10 are the catalytic asymmetric synthesis of 1 (Z
) H). On the contrary, that of ꢀ-(hydroxyalkyl)-γ-butyrolactone
1 (Z ) OH) is achieved only by enzymatic resolution11 and
from L-glutamic acid via a number of steps.12 Herein, we report
one-pot synthesis of ꢀ-(hydroxyalkyl)-γ-butyrolactones 1 (Z )
OH) with high enantioselectivity (ee: 81 to >99%) and moderate
to good diastereoselectivity (dr: 4.5:1 to >24:1) via an orga-
nocatalytic cross-aldol reaction of methyl 4-oxobutyrate (2) with
acceptor aldehydes 3 followed by NaBH4 reduction (Sche-
me 1).
shajra@chem.iitkgp.ernet.in
ReceiVed March 17, 2008
Organocatalytic cross-aldol reaction of methyl 4-oxobutyrate
(2) and a variety of aldehydes 3 followed by reduction with
NaBH4 has provided a one-pot, general and efficient method
for the synthesis of 4-(hydroxyalkyl)-γ-butyrolactones 1 with
high diastereo- (dr > 24:1) and enantioselectivity (ee >
99%).
Asymmetric organocatalysis13,14 and organocatalytic aldol
reactions15,16 are a vigorously active area. Among the organo-
catalysts, proline and its derivatives have become very attractive
because of their efficiency, simplicity and wide applicability.14
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ꢀ-Substituted-γ-butyrolactones are important structural motifs
of a wide range of natural products and pharmaceuticals.1
Consequently, the asymmetric synthesis of the lactones with
general structure 1 constitutes an active area in organic synthesis.
A number of strategies have been developed for the asymmetric
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acid via chiral N-alkyl-unsaturated-γ-lactams6 and from L-
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10.1021/jo8005733 CCC: $40.75
Published on Web 04/09/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3935–3937 3935

TABLE 1. Synthesis of Lactone 1a by Sequential Cross-Aldol
Reaction and Reduction
TABLE 2. L-Proline Catalyzed Enantioselective One-Pot Synthesis
of Butyrolactones 1
entry R (equiv. of aldehyde) product
dra
eeb
yieldc (%)
1
2
3
4
5
6
7
8
C6H5 (5.0)
1a
1b
1c
1d
1e
1f
1g
1h
1i
10:1
10:1
9:1
4.5:1
12:1
5.5:1
-
16:1
>24:1 >99
12.5:1 >99
90
47
59
63
41
47
4-NO2C6H4 (2.5)
3-NO2C6H4 (2.5)
3-BrC6H4 (2.5)
4-FC6H4 (2.5)
2-naphthyl (2.5)
4-MeOC6H4 (5.0)
4-BzOC6H4 (2.5)
i-Pr (5.0)
92d
92d
81
94
94
-
50d
<5
55e
50
entry cat. temp. (°C)
solvent
DMF
DMF
DCM/THF
DMF
dra
eeb
90
yieldc (%)
1
2
3
4
5
6
5
5
5
6
7
8
4
12
4
4
4
10:1
>24:1 58
-
15:1
6:1
-
47
55
-
50
25
<5
88
9
10
11
-
c-C6H11 (5.0)
1j
1k
55
84
26d
-
f
n-C5H11
Mixture of products
DMF
DMF
a The dr’s were determined by the analysis of 1H NMR spectra. b The
ee’s were measured by HPLC (Chiralpak AD-H column) using 2-
propanol and n-hexane as solvents. Enantiomers were confirmed by
HPLC analysis of all corresponding lactones obtained by both L-proline
and D-proline catalyzed reactions. c Combined isolated yield of all
4
a The dr’s were determined by the analysis of 1H NMR spectra. b The
ee’s were measured by HPLC (Chiralpak AD-H column) using 2-propanol
and n-hexane as solvents. Enantiomers of lactone 1a were identified by
HPLC analysis of the reactions with L-proline and D-proline. c Combined
isolated yield of all isomers of lactone 1a after flash chromatography.
d Reverse enantioselectivity, i.e., opposite enantiomer as a major one.
isomers of lactone
1
after flash chromatography. d The ee’s were
measured after benzoyl protection of OH. e Complete lactonization was
obtained on treatment with PPTS. f Using 1-5 equiv under different
conditions.19
The present investigation began with the reaction of methyl
4-oxobutyrate (2)17 and benzaldehyde (3a) in the presence of
L-proline as a catalyst (Table 1). It was carried out with
4-oxobutyrate 2 (1.0 equiv) and benzaldehyde 3a (5.0 equiv)
in dry DMF containing of L-proline (20 mol %) at 4 °C under
an argon atmosphere. Addition of 4-oxobutyrate 2 to the reaction
mixture was performed through a microsyringe pump during
22 h to avoid its self-aldol reaction.
After an additional 4 h of stirring, the resulting mixture was
diluted with methanol at 4 °C. NaBH4 (0.5 equiv) was then
added portionwise. This was followed by stirring at 35-40 °C
for 1 h. Work up of the reaction mixture afforded ꢀ-hydroxy-
phenylmethyl-γ-butyrolactone 1a with high diastereo-(dr
10:1) and enantioselectivity (ee 90%) in 47% yield (Table 1,
entry 1). When conducted at higher temperature (12 °C), a slight
increase in yield (55%) and diastereoselectivity at the cost of
ee (Table 1, entry 2) was observed. The change of reaction
medium gave inferior results with respect to the yields (Table
1, entry 3). We also studied aldol reactions with few L-proline
derived catalysts 6-8, which are relatively more soluble in a
range of organic solvents.18 Tetrazole catalyst 6 furnished
comparable results with that of L-proline (Table 1, entry 4).
Interestingly, catalyst 7 showed inverse enantioselectivity, but
with low selectivity and yield (Table 1, entry 5). N-Tosyl amide
catalyst 8 did not bring about the aldol reaction (Table 1, entry
6), even with more reactive 4-nitrobenzaldehyde under different
reaction conditions. Since the intermediate aldol adduct 4a could
not be isolated in pure form, the crude aldol adduct was
submitted to reduction with NaBH4 (0.5 equiv) in MeOH to
provide 1a in 22% yield. Thus, proline was found to be the
best among all the catalysts studied for the synthesis of lactones
1. The synthesis was generalized with several substituted
aromatic and aliphatic aldehydes (Table 2). Proline-catalyzed
reaction of 4-oxobutyrate 2 with aromatic aldehydes 3b-e and
2-naphthaldehyde 3f followed by in situ reduction provided the
lactones 1b-f with 81-94% of ee and moderate-to-good
diastereoselectivity (dr: 4.5:1 to 12:1) and yields (entries 2-6).
4-Methoxybenzaldehyde 3g did not provide the desired
butyrolactone under the similar reaction conditions (entry 7),
whereas 4-benzoyloxybenzaldehyde 3h did undergo the reaction
and provided the lactone 1h with 88% of ee in moderate yield
(entry 9). Aliphatic aldehydes, i.e., iso-butyraldehyde 3i and
cychlohexanecarboxaldehyde 3j, yielded the lactone 1i and 1j
with excellent enantioselectivity (>99% ee) and good diaste-
reoselectivity (entries 9 and 10). However, enolizable aldehyde,
such as n-hexanal, provided an inseparable mixture of products
even under different reaction conditions.19
(15) Selected reference on organo-catalytic aldehyde-aldehyde cross-aldol
reactions: (a) Storer, R. I.; Macmillan, D. W. C. Tetrahedron 2004, 60, 7705–
7714. (b) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2006, 45, 5527–5529. (c) Cr´dova, A. Tetrahedron
Lett. 2004, 45, 3949–3952. (d) Zhang, S.; Duan, W.; Wang, W. AdV. Synth.
Catal. 2006, 348, 1228–1234. (e) Northrup, A. B.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798–6799. (f) Zhao, G.-L.; Liao, W.-W.; Co´rdova, A.
Tetrahedron Lett. 2004, 45, 3949–3952. (g) Alcaide, B.; Almendros, P. Angew.
Chem., Int. Ed. 2003, 42, 858–860.
(16) Selected reference on organo-catalytic ketone-aldehyde cross-aldol
reactions: (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem.
Soc. 2003, 123, 5260–5267. (b) Co´rdova, A.; Notz, W.; Barbas, C. F., III. Chem.
Commun. 2002, 3024–3025. (c) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734–
735. (d) Dodda, R.; Zhao, C.-G. Synlett 2007, 1605–1609. (e) Chimni, S. S.;
Mahajan, D. Tetrahedron 2005, 61, 5019–5025. (f) Dodda, R.; Zhao, C.-G. Org.
Lett. 2006, 8, 4911–4914. (g) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup,
K.; Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077–1085.
(18) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley,
S. V. Org. Biomol. Chem. 2005, 3, 84–96.
(19) In addition to the general procedure, the reaction was carried out under
different conditions, e.g., (a) to a suspension of L-proline in dry DMF at 4 °C,
a solution of aldehydes 2 (1.0 equiv) and n-hexanal 3k (1.0 equiv) was added
over 22 h, (b) by changing the mole proportions such as using 2 (2.0 equiv) and
3k (1.0 equiv), and (c) a solution of 2 (2.0 equiv), 3k (1.0 equiv), and proline
(0.2 equiv) in dry DMF was stirred at 4 °C for overnight. All of the attempts led
to an inseparable mixture of products.
(17) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804–6805.
3936 J. Org. Chem. Vol. 73, No. 10, 2008

A solution of methyl 4-oxobutyrate (2) (0.15 g, 1.29 mmol, 1.0
equiv) in dry DMF (1.5 mL) was slowly added during 22 h through
a syringe pump. After an additional 4 h, dry methanol (1.5 mL)
was added to the reaction mixture followed by portionwise addition
of sodium borohydride (0.152 g, 4.01 mmol). The reaction mixture
was then allowed to stir at 35-40 °C for 1 h. It was quenched
with a saturated ammonium chloride solution (50 mL) and extracted
by dichloromethane (3 × 75 mL). The combined extracts were
washed with water and brine, dried (Na2SO4), and concentrated
under vacuum. The crude material was purified by flash column
chromatography using petroleum ether (60-80)/EtOAc as an eluent
to give 0.116 g of ꢀ-(hydroxyphenylmethyl)-γ-butyrolactone 1a
(47%; dr 10: 1)).
FIGURE 1. ORTEP diagram of lactone 1c.
The stereochemistry of γ-butyrolactones 1 was established
by the comparison with the literature reports15,20 and the single
crystal X-ray analysis of the lactone 1c (Figure 1).21
In summary, we have developed an efficient organocatalyst-
based asymmetric synthesis of ꢀ-(hydroxyalkyl)-γ-butyrolac-
tones, in particular ꢀ-{hydroxyl(arylmethyl)}-γ-butyrolactones
1 with high diastereo-(>24:1) and enantioselectivity (>99%).
Proline was found to be the best catalyst among all of the
catalysts examined.
(4R,4′R)-4-(4′-Hydroxyphenylmethyl)dihydrofuran-2-one (1a).
27
Gummy liquid, yield: 0.116 g (47%; dr 10:1); [R]D +42.97 (c
1.00, CHCl3); ee 90%. Enantioselectivity was determined by HPLC
analysis using Chiralpak AD-H column (n-Hexane/i-PrOH ) 90/
10, flow rate: 0.75 mL/min, 210 nm, 25 °C) tR 12.6 min and tR
16.2 min. 1H NMR (400 MHz, CDCl3): δ 7.45-7.3 (m, 5H); 4.66
(d, J ) 7.6 Hz, 1H); 4.5-4.35 (m, 2H); 3.0-2.82 (m, 1H); 2.40
(dd, J ) 18.0, 8.8 Hz, 1H); 2.31 (dd, J ) 18.0, 7.6 Hz, 1H); 2.236
(br s, 1H). 13C NMR (100 MHz, CDCl3): δ 176.9, 141.7, 128.8
(2C), 128.4, 126.0 (2C), 75.1, 70.3, 42.4, 31.3. HRMS Found: m/z
215.0679 [M + Na]+; Calc. for C11H12O3Na 215.0684. FTIR
Experimental Section
General Procedure for the Synthesis of ꢀ-(Hydroxyalkyl)-γ-
butyrolactones 1. To a solution of freshly distilled benzaldehyde
3a (0.685 g, 6.46 mmol, 5.0 equiv) in dry DMF (1.1 mL), cooled
to 4 °C, under an argon atmosphere L-proline (0.029 g, 0.26 mmol,
0.2 equiv) was added. The resulting mixture was stirred for 2 min.
(CHCl3) υmax 3439, 2920, 1770, 1182, 1023, 767, 704 cm-1
.
Acknowledgment. We thank CSIR, New Delhi (01(2007)/
05/EMR-II) for providing financial support, S. N. Khatua for
the X-ray analysis, and Prof. D. Mal for helpful suggestions.
A.K.G. thanks CSIR, New Delhi for his fellowship.
(20) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387. (b)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., Jr. J. Am. Chem. Soc. 2001,
123, 5260–5267. (c) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273–11283. (d) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 125, 16–17.
(21) Crystal data for 1c: C11H11NO5, MW ) 237.21, T ) 293(2) K,
Monoclinic, P21, a ) 6.0650(10) Å, b ) 5.9654(9) Å, c ) 14.695(2) Å, ꢀ )
Supporting Information Available: Spectral data, spectra
and chromatograph of lactones 1, and CIF of 1c. This material
is available free of charge via the Internet at http://pubs.acs.org.
91.142(5)°. V ) 531.55(15) Å3. Z ) 2, Fcalcd ) 1.482 Mg/m3, µ ) 0.119 mm-1
,
)
γ ) 0.71073 Å, 2θmax ) 56.64, reflection collected/unique ) 7909/2797, Rint
0.0264, R1 ) 0.0444, wR2 ) 0.1020 for 2150 reflections [I > 2σ (I)], Flack(×)
parameter ) 0.0(10).
JO8005733
J. Org. Chem. Vol. 73, No. 10, 2008 3937