A general method for the enantioselective synthesis of pantolactone derivatives

Article abstract of DOI:10.1021/ol026489d

(matrix presented) An efficient enantioselective synthesis of β,β-dialkyl-γ-substituted pantolactones has been achieved utilizing the cationic [Sc((S,S)-R-pybox)]-(Cl)₂⁺, R = Ph (9), t-Bu (10), complex in a catalyzed aldol reaction as the key step. The pantolactone derivatives are isolated in enantiomeric excesses.

Full text of DOI:10.1021/ol026489d

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3379-3382
A General Method for the
Enantioselective Synthesis of
Pantolactone Derivatives
David A. Evans,* Jimmy Wu, Craig E. Masse, and David W. C. MacMillan
Department of Chemistry & Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received July 9, 2002
ABSTRACT
An efficient enantioselective synthesis of â,â-dialkyl-γ-substituted pantolactones has been achieved utilizing the cationic [Sc((S,S)-R-pybox)]-
(Cl)2+, R) Ph (9), t-Bu (10), complex in a catalyzed aldol reaction as the key step. The pantolactone derivatives are isolated in high enantiomeric
excesses.
The asymmetric synthesis of pantolactone (1a), pantothenic
acid (2a), and their derivatives (Figure 1) continue to be of
inhibitory properties toward lactic acid bacteria and malaria.3
The purpose of this Letter is to describe a catalytic enantio-
selective approach to the synthesis of this family of lactone
targets and their γ-substituted analogues.
Since racemic, unsubstituted pantolactone (1a) is readily
prepared in a “one-pot” reaction from hydroxypivalaldehyde,
sodium cyanide, hydrochloric acid, and calcium chloride,4
various methods for its chemical5 and enzymatic6 resolution
have been developed.
Direct access to enantiopure pantolactone may also be
achieved by enantioselective hydrogenation of 3,3-dimethyl-
2-oxobutyrolactone with a variety of different metal catalyst
systems.7 Recently, Upadhya has also reported that Sharp-
less’s asymmetric dihydroxylation of the corresponding
cyclic silylketene acetal pantolactone precursor affords the
desired pantolactone in high enantiomeric excess.8
Figure 1. Biologically active pantolactone and pantothenic acid
derivatives.
interest to organic chemists as a consequence of their
biological activity and utility as a secondary alcohol derived
chiral auxiliary. The taurine derivative of panthothenic acid
(pantoyltaurine, 2b) has been shown to inhibit the growth
of streptococci, pneumococci, plasmodium relictum,1 and
certain strains of diphtheria bacilli.2 γ-Methylpantolactone
and its open-chain derivative, as well as a variety of related
γ-substituted pantolactone analogues (1a-c), all possess
(3) (a) Drell, W.; Dunn, M. S. J. Am. Chem. Soc. 1948, 70, 2057-2063.
Drell, W.; Dunn, M. S. J. Am. Chem. Soc. 1954, 76, 2804-2808.
(4) Ford, J. H. J. Am. Chem. Soc. 1944, 66, 20-21.
(5) (a) Stiller, E. T.; Harris, S. A.; Finkelstein, J.; Keresztesy, J. C.;
Folkers, K. J. Am. Chem. Soc. 1940, 62, 1785-1790. (b) Fuji, K.; Node,
M.; Murata, M. Tetrahedron Lett. 1986, 27, 5381-5382. (c) Bevinakatti,
H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem. 1989, 54, 2453-
2455. (d) Kagan, F.; Heinzelman, R. V.; Weisblat, D. I.; Greiner, W. J.
Am. Chem. Soc. 1957, 79, 3545-3549.
(1) Winterbottom, R.; Clapp, J. W.; Miller, W. H.; English, J. P.; Roblin,
R. O., Jr. J. Am. Chem. Soc. 1947, 69, 1393-1401.
(2) Roblin, R. O., Jr. Chem. Rev. 1946, 38, 255-367.
(6) (a) Baumann, M.; Hauer, B. H.; Bornscheuer, U. T. Tetrahedron:
Asymmetry 2000, 11, 4781-4790.
10.1021/ol026489d CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/07/2002

Table 1. Catalyst Survey for Silylketene Acetals and Ketone Enolsilane Additions to Ethyl Glyoxylate (eqs 2, 3)a
catalyst
% eeb
configc
conv%
catalyst
% eeb
configc
conv %
[Cu((S,S)-t-Bu-box)](OTf)2 (6)
[Sn((S,S)-Bn-box)](OTf)2 (7)
[Sc((S,S)-Ph-pybox)](OTf)3 (8)
[Sc((S,S)-Ph-pybox)](Cl2)(SbF6) (9)
[Sc((S,S)-t-Bu-pybox)](Cl2)(SbF6) (10)
98
95
6
95
62
(S)
(S)
(R)
(R)
(S)
61
89
87
90
45
[Cu((S,S)-t-Bu-box)](OTf)2 (6)
[Sn((S,S)-Bn-box)](OTf)2 (7)
[Sc((S,S)-Ph-pybox)](OTf)3 (8)
[Sc((S,S)-Ph-pybox)](Cl2)(SbF6) (9)
[Sc((S,S)-t-Bu-pybox)](Cl2)SbF6) (10)
95
76
4
32
95
(S)
(S)
(R)
(R)
(S)
<5
<5
90
70
85d
a All reactions were carried out in CH2Cl2 for 16 h at -78 °C. b Enantiomeric excess determined by HPLC using Chiracel AD or OD-H columns. c See
Supporting Information for absolute configuration assignments. d Reaction was run at -35 °C with 2 equiv of TMS-Cl.
While there have been numerous reports on the asymmetric
synthesis of pantolactone 1a, to the best of our knowledge,
only one paper has been published concerning the stereo-
selective synthesis of γ-substituted pantolactones. This
synthesis employed a diastereoselective enzymatic reduction
of the corresponding ketone precursor.9 Herein, we report
an efficient method for the asymmetric synthesis of differ-
entially substituted â,â-dialkyl pantolactones and a general
method for the diastereo- and enantioselective preparation
of â,â-dialkyl-γ-aryl-substituted pantolactone derivatives.
The key step in the preparation of these analogues is an
enantioselective scandium-catalyzed aldol reaction of either
thiosilylketene acetal 3a or enolsilane 3b nucleophiles with
ethyl glyoxylate to give 4a,b (Scheme 1). Raney nickel
selective aldol reactions between thiosilylketene acetals and
enolsilanes with ethyl glyoxylate.12 In complementary studies,
we have shown that [Cu((S,S)-t-Bu-box)](OTf)2 (6) also
catalyzes enolsilane aldol additions to pyruvate esters,13 while
[Sn((S,S)-Bn-box](OTf)2 catalyzes the addition of thio-
silylketene acetals to both glyoxylate and pyruvate esters.14
A survey of ligand-metal complexes 6-10 revealed that
[Cu((S,S)-t-Bu-box)](OTf)2 (6), [Cu((S,S)-(Bn-box)](OTf)2
(7), and [Sc((S,S)-Ph-pybox)](Cl2)(SbF6) (9) mediated the
aldol reaction between thiosilylketene acetal 11 and ethyl
glyoxolate to give the malate derivative 12 in high enantio-
meric excesses and conversions (Table 1, eq 2).14b A catalyst
survey was also conducted to determine the best complex
for the additions of enolsilanes to ethyl glyoxylate (Table 2,
eq 3). Initially, complex 10 afforded the desired product in
excellent enantioselectivity (92%), albeit in low conversion
(27%). When the temperature was elevated from -78 °C to
-25 °C, increased conversion (69%) was observed with an
attendant decrease in enantiomeric excess (86% ee). When
a stoichiometric amount of complex 10 was employed,
complete conversion was achieved in less than 0.5 h with
increased enantiomeric excess (>99% ee). These experiments
Scheme 1
(7) (a) Ojima, I.; Kogure, T.; Terasaki, T. J. Org. Chem. 1978, 43, 3444-
3446. (b) Kagan, H. B.; Tahar, M.; Fiaud, J.-C. Tetrahedron Lett. 1991,
32, 5959-5962. (c) Genet, J.-P.; Pinel, C.; Mallart, S.; Juge, S.; Cailhol,
H.; Laffitte, J. A. Tetrahedron Lett. 1992, 33, 5343-5346. (d) Takahashi,
H.; Hattori, M.; Chiba, M.; Morimoto, T.; Achiwa, K. Tetrahedron Lett.
1986, 37, 4477-4480. (e) Roucoux, A.; Agbossou, F.; Mortreux, A.; Petit,
F. Tetrahedron: Asymmetry 1993, 4, 2279-2282. (f) Chiba, M.; Takahashi,
H.; Morimoto, T. Achiwa, K. Tetrahedron Lett. 1987, 28, 3675-3678.
(8) Upadhya, T. T.; Gurunath, S.; Sudalai, A. Tetrahedron: Asymmetry
1999, 10, 2899-2904.
(9) Hata, H.; Shimizu, S.; Hattori, S.; Yamada, H. J. Org. Chem. 1990,
55, 4377-4380.
(10) (a) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158. (b) Evans, D. A.; Chapman,
K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560-3578.
(11) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095-12096.
reduction of thioester 4a or directed reduction10 of hydroxy
ketone 4b affords pantolactones 5a,b, respectively.
Table 1 documents the relative effectiveness of these metal
complexes in promoting the additions of silylketene acetal
and ketone enolsilane nucleophiles to ethyl glyoxylate.
In several recent studies, we have reported that [Sc((S,S)-
Ph-pybox)](OTf)3 (8), catalyzes the enantioselective addition
of allenylsilanes to ethyl glyoxylate,11 while [Sc((S,S)-Ph-
pybox)](Cl2)(SbF6) (9) is an effective catalyst for syn-
(12) (a) See preceding paper in this issue. (b) For assignment of absolute
stereochemistry, also see preceding paper in this issue.
(13) (a) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.;
Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936-7943. (b) Evans, D.
A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 1997, 119, 7893-7894.
(14) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem.
Soc. 1997, 119, 10859-10860.
3380
Org. Lett., Vol. 4, No. 20, 2002

Table 2. Reaction Scope of Pantolactone Synthesisa
a See Supporting Information for detailed procedures on aldol addition and reduction/cyclization sequence. b Enantiomeric excesses were determined
from the aldol product by HPLC using either Chiracel AD or OD-H column c Isolated yield over two and three steps for thiosilylketene acetal and enolsilane
nucleophiles, respectively). d Because complex 9 afforded aldol production poor selectivities, this reaction was run using (R,R)-7, which mediated the aldol
reaction 94% ee and 60% yield. e Relative stereochemistry was confirmed by single-crystal X-ray analysis of the pantolactone product. f Enantiomeric excess
was determined again after cyclization and found to be within experimental error of the initial measurement. Unless otherwise noted, relative stereochemistry
1
was determined by analogue via H NMR.
suggest that the addition step may be fast and that a relatively
slow silyl transfer and subsequent turnover of the metal-
aldolate adduct might be the cause of incomplete con-
cyclization promoted by catalytic p-TSA yielded 16 as a 20:1
mixture of diastereomers (eq 5).10a Diastereomer separation
15
version at lower temperatures. Indeed, when the reaction
was conducted at -35 °C, in the presence of 15 mol % of
[Sc((S,S)-t-Bu-pybox)](Cl2)(SbF6) (10) and 2 equiv of chloro-
trimethylsilane (TMS-Cl) to facilitate catalyst turnover,16
aldol adduct 14 was isolated in 85% yield and 95%
enantiomeric excess.
With the desired R-hydroxyesters in hand, attention was
directed to the reduction/cyclization sequence. Hydrogenation
of thioester 12 to the derived primary alcohol and spontane-
ous lactonization afforded the pantolactone derivative 15 in
95% enantioselectivity and 80% yield over two steps (eq
4). Hydroxyl-directed syn reduction of 14 with diethyl-
methoxyborane and sodium borohydride,10a followed by
(15) Other aldol processes that have utilized silylation as the turnover
event: (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392-393. (b) Chini. M.: Crotti, P.; Gardelli, C.;
Minutolo, F.; Pineschi, M. Gazz. Chim. Ital. 1993, 123, 673-676. (c)
Kiyooka, S.-I.; Tsutsui, T.; Maeda, H.; Kaneko, Y.; Isobe, K. Tetrahedron
Lett. 1995, 36, 6531-6534.
(16) The sense of asymmetric induction is opposite to that of thiosilyl-
ketene acetal addition to ethyl glyoxylate. See preceding paper in this issue
for assignment of absolute stereochemistry as well as stereochemical
rationale.
by column chromatography afforded the desired trans panto-
lactone 16 in 62% isolated yield over three steps (Table 2,
entry 9). Similarly, the cis pantolactone derivative 17 was
isolated as a single diastereomer in 60% yield after anti
reduction of hydroxyester 14 with Me4NHB(OAc)3 followed
by treatment with catalytic p-TSA (eq 6).10b Thus, with the
appropriate choice of scandium catalyst, it is possible to
Org. Lett., Vol. 4, No. 20, 2002
3381

acccess all four diastereomers of â,â,γ-substituted panto-
lactones.
substituted â,â-dialkyl pantolactones and the diastereo- and
enantioselective preparation of â,â-dialkyl-γ-aryl-substituted
pantolactones.
The scope of this methodology is summarized in Table 2.
This sequence afforded the pantolactones in high enantio-
selectivities and yields for a variety of cyclic and acylic
substitution patterns on the thiosilylketene acetal nucleophiles
(entries 1-4). When enolsilanes are used as the nucleophile,
a wide array of aromatic groups can be present, including
phenyl, 4-fluorophenyl, and naphthyl (entries 6-8). Fur-
thermore, both dimethyl and cyclopentyl substituents on the
enolsilanes are also well tolerated (entries 5, 8).
In conclusion, we have developed a highly efficient,
catalytic, asymmetric process for the synthesis of substituted
and unsubstituted pantolactones. This process represents a
general method for the efficient synthesis of differentially
Acknowledgment. We acknowledge the National Science
Foundation for generous financial support of this research.
J.W. gratefully thanks the American Society for Engineering
Education for a predoctoral NDSEG Fellowship.
Supporting Information Available: Representative ex-
perimental procedures and analytical data for all panto-
lactones prepared. Details of the X-ray diffraction data and
structure for Table 2, entry 5. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL026489D
3382
Org. Lett., Vol. 4, No. 20, 2002