Practical, One-Step Synthesis of Optically Active β-Lactones via the Tandeni Mukaiyama Aldol-Lactonization (TMAL) Reaction

Full text of DOI:10.1021/jo971837o

1344
J . Org. Chem. 1998, 63, 1344-1347
Sch em e 1
P r a ctica l, On e-Step Syn th esis of Op tica lly
Active â-La cton es via th e Ta n d em
Mu k a iya m a Ald ol-La cton iza tion (TMAL)
Rea ction
Hong Woon Yang and Daniel Romo*
Department of Chemistry, Texas A&M University,
College Station, Texas 77843-3255
Received October 6, 1997
Resu lts a n d Discu ssion
In tr od u ction
Our initial studies with optically active â-lactones
began with the chiral aldehyde 1a 6 bearing a â-stereo-
center (Table 1). This aldehyde served as a model for
our synthesis of (-)-panclicin D.4a Most of the TMAL
reactions were performed using the triethylsilyl (TES)
ketene acetal 2a which we recently found provides higher
yields of â-lactones as compared to the tert-butyldimeth-
ylsilyl (TBS) ketene acetals by minimizing formation of
â-chlorosilyl ester side products.4b However, in some
cases higher selectivities were observed using the TBS-
ketene acetals (see entry 1, Table 1). Reaction of â-siloxy
aldehyde 1a under typical aldol-lactonization conditions
with TBS-ketene acetal 2b gave the â-lactone 3a in 62%
yield as a 1:9.1 ratio of syn/anti diastereomers. As in
previous cases, the trans â-lactone is formed almost
exclusively (J 3,4 ) 4.0 Hz) while the minor diastereomer
arises from incomplete relative stereoselection. The
relative stereoselection observed is consistent with the
model recently proposed by Evans.7 Although slightly
higher yields resulted when the TES-ketene acetal was
employed, the relative stereoselectivity was diminished,
leading to a 1:5.3 ratio of syn/anti diastereomers (entry
1). In a similar manner aldehyde 1b8 gave a 1:4.8
mixture of diastereomers using the TES ketene acetal
2a along with ∼10-15% of diastereomeric tetrahydro-
furans (entry 2).9 The stereochemistry of the major
diastereomer 3b is based on analogy to â-lactone 3a and
The utility of â-lactones (2-oxetanones) continues to
grow as additional novel transformations of these strained
heterocycles are discovered.1 The development of concise
methods for the asymmetric synthesis of â-lactones will
therefore further enhance their utility as intermediates
in organic synthesis. Although several direct routes have
been developed for the synthesis of â-lactones in racemic
form,2 relatively few general approaches for the concise
synthesis of optically active â-lactones have been re-
ported.3 We recently described the development of a
highly diastereoselective route to racemic trans-3,4-
disubstituted â-lactones based on a tandem Mukaiyama
aldol-lactonization (TMAL) reaction that builds on the
work of Hirai.4 Herein we describe the application of the
TMAL reaction to a variety of optically active aldehydes
including aldehydes bearing R-epimerizable centers
(Scheme 1). Less than 2% racemization is observed with
most epimerizable aldehydes studied. In most cases the
degree of relative and internal stereoselection correlates
with previously reported chelation-controlled Mukaiyama
aldols resulting from either chelation or stereoelectronic
control.5 The derived â-lactones bear functionality which
enables further functionalization of these useful inter-
mediates.
* To whom correpondence should be addressed. Tel: 409-845-9571.
Fax: 409-845-4719. E-mail: romo@chemvx.tamu.edu.
1
comparison by H NMR.
(1) (a) Obitsu, K.; Maki, S.; Niwa, H.; Hirano, T.; Ohashi, M.
Tetrahedron Lett. 1997, 38, 4111-4112. (b) Shao, H.; Wang, S. H. H.;
Lee, C.-W.; Osapay, G.; Goodman, M. J . Org. Chem. 1995, 60, 2956-
2957. (c) Dollinger, L. M.; Howell, A. R. J . Org. Chem. 1996, 61, 7248-
7249. (d) Zemribo, R.; Champ, M. S.; Romo, D. Synlett 1996, 278-
280. (e) Mead, K. T.; Zemribo, R. Synlett 1996, 1065-1066. (f) Fujisawa,
T.; Ito, T.; Fujimoto, K.; Shimuzu, M. Tetrahedron Lett. 1997, 38, 1593-
1596. (g) Danheiser, R. L.; Lee, T. W.; Menichincheri, M.; Brunelli, S.;
Nishiuchi, M. Synlett 1997, 469-470. (h) Zhao, C.; Romo, D. Tetrahe-
dron Lett. 1997, 38, 6537-6540.
We then turned our attention to aldehydes that were
capable of chelation-controlled additions and bearing
R-epimerizable stereocenters. The latter feature would
allow us to gauge the mildness of the TMAL reaction.
The benzyloxy aldehyde 1c10 derived from ethyl (S)-
lactate was studied first since it provided a model
reaction for our synthesis of okinonellin B.11 TMAL
reaction with aldehyde 1c provided the â-lactone 3c in
69% yield with nearly complete relative and internal
stereochemical control.5b Importantly, the enantiomeric
purity of the derived â-lactone was determined to be 96%
(chiral GC12), indicating that only slight epimerization
(2) For a recent review, see: Pommier, A.; Pons, J .-M. Synthesis
1993, 441-449.
(3) For some recent asymmetric methods, see: (a) Dymock, B. W.;
Kocienski, P. J .; Pons, J .-M. J . Chem. Soc., Chem. Commun. 1996,
1053-1054. (b) Arrastia, I.; Lecea, B.; Cossio, F. P. Tetrahedron Lett.
1996, 37, 245-248. (c) Zemribo, R.; Romo, D. Tetrahedron Lett. 1995,
36, 4159-4162. (d) Dirat, O.; Berranger, T.; Langlois, Y. Synlett 1995,
935-937. (e) Tamai, Y.; Someya, M.; Fukumoto, J .; Miyano, S. J . Chem.
Soc., Chem. Commun. 1994, 1549-1550. (f) Tamai, Y.; Yoshiwara, H.;
Someya, M.; Fukumoto, J .; Miyano, S. J . Chem. Soc., Chem. Commun.
1994, 2281-2282. (g) Capozzi, G.; Roelens, S.; Talami, S. J . Org. Chem.
1993, 58, 7932-7936. (h) Case-Green, S. C.; Davies, S. G.; Hedgecock,
C. J . R. Synlett 1991, 779-780. (i) Bates, R. W.; Fernandez-Moro, R.;
Ley, S. V. Tetrahedron Lett. 1991, 32, 2651.
(6) Aldehyde 1a was obtained from ethyl acetoacetate by yeast
reduction (85% ee) (a) Seebach, D.; Sutter, M. A.; Weber, R. H.; Zuger,
M. F. Org. Synth. VII, 215-220. (b) Ireland, R. E.; Wardle, R. B. J .
Org. Chem. 1987, 52, 1780-178] or by Noyori reduction (94% ee) (c)
Taber, D. F.; Silverberg, L. J . Tetrahedron Lett. 1991, 32, 4227-4230.
(d) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J . Am. Chem. Soc. 1987, 109, 5856-
5858].
(7) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem.
Soc. 1996, 118, 4322-4343. See also ref 4b.
(8) Available in three steps from dimethyl (S)-malate (Aldrich),
see: Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu,
S.; Moriwake, T. Chem. Lett. 1984, 1389-1392.
(4) (a) Yang, H. W.; Romo, D. J . Org. Chem. 1997, 62, 4-5. (b) Yang,
H. W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471-16488. (c)
Hirai, K.; Homma, H.; Mikoshiba, I. Heterocycles 1994, 38, 281-282.
(5) (a) Gennari, C.; Bernardi, A.; Scolastico, C.; Potenza, D. Tetra-
hedron Lett. 1985, 26, 4129-4132. (b) Gennari, C.; Beretta, M. G.;
Bernardi, A.; Moro, G.; Scolastico, C.; Todeschini, R. Tetrahedron 1986,
42, 893-909. (c) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishino,
H.; Ke, Y. Y.; Tamura, Y. J . Org. Chem. 1988, 53, 554-561.
S0022-3263(97)01837-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

Notes
J . Org. Chem., Vol. 63, No. 4, 1998 1345
Ta ble 1. Op tica lly Active â-La cton es Obta in ed via th e Ta n d em Mu k a iya m a Ald ol-La cton iza tion Rea ction
had occurred under the reaction conditions. Aldehydes
1d 13 and 1e10 also led to high diastereoselectivity to
deliver the â-lactones 3d and 3e, respectively. However
partial racemization of aldehyde 1e was observed and is
presumably the result of the increased acidity of the
R-protons due to the R-phenyl group. The stereochemistry
of â-lactone 3c was determined by conversion to the
known, all-syn-butyrolactone 414 via tandem transacyl-
ation-debenzylation with ferric chloride1d and is consis-
tent with a chelation-controlled aldol reaction (Scheme
2). Conversion of â-lactone 3c to hydroxy â-lactone 6
allowed more precise measurement of the diastereose-
lectivity due to interference at the â-lactone stage of a
benzylation side product.15
(9) The stereochemistry of the major diastereomeric tetrahydrofuran
i isolated after treatment with diazomethane has not been rigorously
determined but is based on the â-lactone 3b undergoing inversion
during cyclization of the pendant silyl ether.
In analogy to â-lactone 3c, the stereochemistries of
â-lactones 3d and 3e are assigned as that derived from
chelation-controlled additions. Further evidence for the
(10) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767-5790.
(11) Schmitz, W. D.; Messerschmidt, B.; Romo, D. Manuscript in
preparation.
(12) Shitangkoon, A.; Vigh, G. J . Chromatogr. A 1996, 31-42.
(13) Available in four steps from (R)-phenylalanine, see: Degerbeck,
F.; Fransson, B.; Grehn, L.; Ragnarsson, U. J . Chem. Soc., Perkin
Trans. 1 1993, 11-14.

1346 J . Org. Chem., Vol. 63, No. 4, 1998
Notes
Sch em e 2
prolonged reaction times which is consistent with our
previous observations with R-alkyl-substituted aldehydes
such as pivaldehyde.4a,b Interestingly, again no epimer-
ization is observed even with this aldehyde which is
known to be quite susceptible to epimerization.19b As
expected, use of the acetic acid derived ketene acetal 2c
gave good yields but poor diastereoselectivity (entries 8
and 9).
In summary, the TMAL reaction provides a concise and
direct route to optically active â-lactones from various
chiral aldehydes under mild conditions. In most cases,
less than 2% racemization of the R-chiral aldehyde
substrates and high internal stereoselection is observed.
In light of recently discovered, novel transformations of
â-lactones, the optically active â-lactones described herein
should prove to be useful synthetic intermediates. Ongo-
ing mechanistic studies of this intriguing reaction have
led to some interesting observations that will be the
subject of future reports.
Sch em e 3
Exp er im en ta l Section
Gen er a l. Aldehydes were prepared according to literature
procedures by DIBAl-H reduction of the corresponding ester
(1a -e), by NaIO4 cleavage of the corresponding diol (1f), or by
Swern oxidation of the corresponding alcohol (1g) and were
typically used directly in the TMAL reaction (especially R-epimer-
izable aldehydes) without purification to prevent potential
racemization on silica gel.19b Solvent purification/drying, flash
chromatography, thin-layer chromatography, and optical purity
determination were performed as previously described.4b
Gen er a l P r oced u r e for TMAL Rea ction a s Descr ibed for
â-La cton e 3a . Anhydrous ZnCl2 (482 mg, 3.46 mmol, 1.4 equiv)
was freshly fused at ∼0.5 mmHg, and after cooling to ambient
temperature, CH2Cl2 (appropriate volume to make the final
concentration of aldehyde in CH2Cl2 ∼0.15 M) was added. The
aldehyde (527 mg, 2.47, 1.0 equiv) was then added neat or as a
CH2Cl2 solution at room temperature, resulting in a cloudy,
colorless solution. After 15 min of stirring, the thiopyridylketene
acetal (847 mg, 2.86 mmol, 1.2 equiv) was added neat and the
resulting yellow suspension was stirred vigorously for the time
indicated in the table. As the reaction proceeded, the reaction
solution typically went from a yellow suspension to a homoge-
neous yellow solution, and finally, an off-white precipitate
formed.
Sch em e 4
assigned stereochemistry of â-lactone 3d is based on
coupling constant analysis16 of the all-syn-butyrolactone
7 obtained using our recently improved conditions for the
tandem debenzylation-transacylation reaction (Scheme
3).11 Once again the diastereoselectivity was determined
after hydrogenolysis which delivered the hydroxy â-lac-
tone 9.15
As previously reported, high trans selectivity (internal
stereoselection) was observed with most aldehydes stud-
ied. An exception is â-lactone 3f derived from glyceral-
dehyde 1f17 which gave a 3.6:1 ratio of trans/cis â-lactone
diastereomers but gave excellent relative stereocontrol
favoring the Felkin-Ahn product (entry 6).5c Impor-
tantly, the diastereomers could be readily separated by
flash chromatography to give the major diastereomeric
â-lactone 3f with >99% ee in 63% isolated yield. The
stereochemistry of â-lactone 3f was determined by reduc-
tion to the known diol 10 (Scheme 4).18
After addition of pH 7 buffer, the mixture was stirred
vigorously for 10 min and filtered through Celite with CH2Cl2.
The organic layer was separated, dried over MgSO4, filtered,
taken up in CH2Cl2 (appropriate volume to make the final
concentration ∼0.15 M), and directly treated with CuBr2 (1.3
equiv relative to ketene acetal) to remove excess thiopy-
ridylketene acetal and any thioester formed. The resulting
suspension was stirred for 1.5 h, filtered through Celite, and
washed with 10% aqueous K2CO3 and brine. The organic layer
was dried over MgSO4, filtered, concentrated in vacuo to afford
the crude product, and purified by flash chromatography (silica
gel) to give 444 mg (69%) of â-lactone 3a as a colorless oil with
the following physical and spectral characteristics. The following
data were obtained for â-lactone 3a using aldehyde 1a derived
from yeast reduction of ethyl acetoacetate: Rf 0.44 (10:90 EtOAc:
hexanes); [R]26D 72.8 (c 1.05, CHCl3);1H NMR (200 MHz, CDCl3)
δ 4.36 (ddd, J ) 4.2, 4.2, 8.7 Hz, 1H), 3.92-4.07 (m, 1H), 3.23
(dq, J ) 4.0, 7.5 Hz, 1H), 1.73-1.96 (m, 2H), 1.39 (d, J ) 7.5
TMAL reaction with R-methyl-â-benzyloxy aldehyde
1g19 (Table 1, entry 7) gave low yields even after
(14) Chiarello, J .; J oullie, M. M. Synth. Commun. 1989, 19, 3379-
3383.
(15) After hydrogenolysis, p-tolyltoluene was isolated indicating that
the benzylation leading to aldehyde 1c and 1d led to Friedel-Crafts
alkylation of the benzyl ether. This byproduct was obtained regardless
of the source of benzyltricholoracetimidate (Lancaster, Aldrich, or
freshly prepared). The presence of ∼10% of this p-tolylbenzyl-protected
material was readily apparent by 1H NMR in the starting aldehydes
1c and 1d and in the â-lactones 3c and 3d . See spectral data in
Supporting Information.
Hz, 3H), 1.18 (d, J ) 6.1 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13
C
NMR (50 MHz, CDCl3) δ 172.1, 76.8, 64.9, 50.7, 44.2, 25.7, 24.3,
17.9, 12.3, -4.3, -4.9; IR (thin film) 1832 cm-1; FAB HRMS calcd
for [M + H] 259.1729, found 259.1719. Anal. Calcd for
C13H26O3Si: C, 60.42; H, 10.14. Found: C, 60.27; H, 10.16.
(16) J aime, C.; Segura, C.; Dinares, I.; Font, J . J . Org. Chem. 1993,
58, 154-158.
(17) Niu, C.; Pettersson, T.; Miller, M. J . J . Org. Chem. 1996, 61,
1014-1022.
(19) (a) Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki,
A.; Sunagawa, M. Tetrahedron 1988, 44, 2149-2165. (b) Roush, W.
R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990, 112, 6348-
6359.
(18) Heathcock, C. H.; Young, S. D.; Hagen, J . P.; Pirrung, M. C.;
White, C. T.; VanDerveer, D. J . Org. Chem. 1980, 45, 3846-3856.

Notes
Using the general procedure described above, â-lactones 3a -g
J . Org. Chem., Vol. 63, No. 4, 1998 1347
f 1:2 EtOAc:hexanes) to give 7.1 mg (81%) of hydroxy â-lactone
9: [R]26D-67.8 (c 2.05, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.23-7.37 (m, 5H), 4.11 (dd, J ) 3.9, 4.2 Hz, 1H), 3.97-4.04 (m,
1H), 3.51 (dq, J ) 3.9, 7.8 Hz, 1H), 2.96 (dd, J ) 7.5, 13.5 Hz,
1H), 2.84 (dd, J ) 6.3, 13.5 Hz, 1H), 2.15 (br s, 1H), 1.30 (d, J )
7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.4, 136.3, 129.3,
128.8, 127.0, 80.0, 72.0, 46.9, 39.5, 12.0; IR (thin film) 3120-
3710, 1814 cm-1; EI HRMS calcd for [M+] 206.0943, found
206.0945.
were prepared in the reaction times and diastereo- and enan-
tioselectivities indicated in the table. Characterization data for
â-lactones 3b-g can be found in the Supporting Information.
γ-La cton e 4 was prepared according to the method described
previously. Data not previously reported or different from that
previously reported follow: Rf 0.07 (10:90 EtOAc:hexanes); mp
57-58 °C, lit.14 mp 51-53 °C; [R]26 -45.6 (c 0.92, CHCl3), lit.14
D
[R]25 -48.0 (c 1.13, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.49
D
(dq, J ) 3.0, 6.6 Hz, 1H), 4.28 (br s, 1H), 2.75 (dq, J ) 5.1, 7.5
Hz, 1H), 2.10 (br s, 1H), 1.44 (d, J ) 6.6 Hz, 3H), 1.28 (d, J )
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 78.9, 72.4, 42.4,
Tetr a h yd r ofu r a n i: Rf 0.43 (10:90 EtOAc:hexanes); [R]26
D
+13.2 (c 0.68, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.42 (dddd,
J ) 2.4, 2.4, 4.8, 5.7 Hz, 1H), 4.23 (ddd, J ) 6.3, 6.9, 9.3 Hz,
1H), 3.93 (dd, J ) 4.8, 9.3 Hz, 1H), 3.69 (s, 3H), 3.62 (ddd, J )
0.6, 2.4, 9.3 Hz, 1H), 2.58 (dq, J ) 6.9, 6.9 Hz, 1H), 1.90 (dddd,
J ) 0.6, 2.4, 6.3, 12.9 Hz, 1H), 1.80 (ddd, J ) 5.7, 9.3, 12.9 Hz,
1H), 1.23 (d, J ) 6.9 Hz, 3H), 0.88 (s, 9H), 0.058 (s, 3H), 0.050
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.9, 79.2, 76.0, 72.6, 51.7,
44.2, 39.5, 25.8, 18.0, 13.7, -4.76, -4.83; IR (thin film) 1741
cm-1; FAB HRMS calcd for [M + H] 289.1835, found 289.1850.
13.7, 8.0; IR (KBr) 3130-3610, 1752 cm-1
.
Hyd r oxy â-la cton e 6 was prepared as described below for
hydroxy â-lactone 9: Rf 0.2 (1:2 EtOAc:hexanes); [R]26 67.6 (c
D
1.02, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.05 (dd, J ) 3.9,
5.4 Hz, 1H), 3.92-4.00 (m, 1H), 3.48 (dq, J ) 3.9, 7.5 Hz, 1H),
2.05 (br s, 1H), 1.41 (d, J ) 7.5 Hz, 3H), 1.29 (d, J ) 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 171.2, 81.9, 67.9, 47.1, 18.3,
12.1; IR (thin film) 3050-3720, 1822 cm-1; FAB HRMS calcd
for [M + Na] 153.0528, found 153.0525.
Ack n ow led gm en t. Support of this work by the NSF
in the form of a CAREER award (CHE 9624532) to D.R.
is gratefully acknowledged. We thank Dr. Kaapjoo Park
for providing aldehyde 1a . We also thank Dr. Lloyd
Sumner and Dr. Barbara Wolf of the Texas A&M Center
for Characterization for mass spectral analyses obtained
on instruments acquired by generous funding from the
NSF (CHE-8705697) and the TAMU Board of Regents
Research Program.
γ-La cton e 7. To a solution of â-lactone en t-3d (79.9 mg, 0.27
mmol) in 1.5 mL of CH2Cl2 was added 0.28 mL of BCl3 (1 M
solution in hexane, 0.28 mmol) at -78 °C. After 20 min, 1 mL
of pH 7 buffer was added. To the resulting mixture was added
3 mL of CH2Cl2. The organic phase was washed with brine,
dried over MgSO4, filtered, concentrated in vacuo, and purified
by flash chromatography (1:4 f 1:3 f 1:2 EtOAc:hexanes) to
give 41.4 mg (74%) of γ-lactone 7 as a white solid: Rf 0.09 (20:
80 EtOAc:hexanes); [R]26 -34.9 (c 1.06, CHCl3); mp 109-111
D
°C; 1H NMR (300 MHz, CDCl3-D2O) δ 7.12-7.31 (m, 5H), 4.79
(br s, 1H), 4.52 (ddd, J ) 3.0, 7.2, 7.5 Hz, 1H), 4.25 (dd, J ) 3.0,
4.8 Hz, 1H), 3.21 (dd, J ) 7.2, 13.8 Hz, 1H), 3.11 (dd, J ) 7.5,
13.8 Hz, 1H), 2.70 (dq, J ) 4.8, 7.0 Hz, 1H), 1.26 (d, J ) 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 136.4, 129.2, 128.6,
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for â-lactones 3b-g. 1H and 13C NMR spectra of
â-lactones 3a -d ,f γ-lactone 7, hydroxy â-lactones 6 and 9, and
tetrahydrofuran i. Representative GC traces (for â-lactone 3f)
for enantiomeric purity determination (21 pages). This mate-
rial is contained in libraries on microfiche, immediately follows
this article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
126.8, 83.3, 71.2, 42.1, 34.5, 8.0; IR (KBr) 3250-3610, 1756 cm-1
FAB HRMS calcd for [M + H] 207.1021, found 207.1021.
;
Hyd r oxy â-La cton e 9. To a solution of â-lactone 3d (12.7
mg, 0.043 mmol) in 3 mL of THF was added 15 mg of Pd/C. After
being stirred overnight under a H2 atmosphere at ambient
temperature, the reaction mixture was filtered through Celite,
concentrated, and purified by flash chromatography (1:6 f 1:4
J O971837O