Use of in situ generated ketene in the wynberg β-lactone synthesis: New transformations of the dichlorinated β-lactone products

Full text of DOI:10.1021/jo001010l

7248
J . Org. Chem. 2000, 65, 7248-7252
Sch em e 1
Use of In Situ Gen er a ted Keten e in th e
Wyn ber g â-La cton e Syn th esis: New
Tr a n sfor m a tion s of th e Dich lor in a ted
â-La cton e P r od u cts
Reginald Tennyson and Daniel Romo*
Department of Chemistry, Texas A&M University, P.O. Box
30012, College Station, Texas 77843-3255
romo@mail.chem.tamu.edu
Received J uly 6, 2000
cally active dichlorinated-â-lactones. We have also de-
veloped new transformations of the chlorinated â-lactones
leading to useful chiral synthons including chloro ep-
oxides, R-azido ketones, vinyl chlorides, and propargylic
benzyl ethers.
In tr od u ction
â-Lactones are useful synthetic intermediates since
they are in fact masked aldol products and thus are
important synthons in natural and unnatural product
synthesis.1 However, there are relatively few direct
methods for the synthesis of these heterocycles in opti-
cally pure form. Recent studies have begun to address
this lack of direct methods.2 In 1982, Wynberg and
Staring disclosed one of the first catalytic, asymmetric
reactions.3 They showed that various cinchona alkaloids,
such as quinidine and quinine, are excellent catalysts for
the net [2 + 2] cycloaddition of highly activated carbonyl
compounds, such as chloral, and ketene to form â-lactones
with excellent yields and enantioselectivity. Although
this method is efficient, there are serious limitations
including the use of activated aldehydes and a ketene
generator. To begin addressing these limitations, we first
sought to develop reaction conditions that would allow
the use of in situ generated ketene.4 The use of triethyl-
amine as both a base to effect dehydrochlorination and
a nucleophile to promote the reaction of ketene and
activated aldehydes has been previously demonstrated.5
Swiss chemists have also shown the compatibility of in
situ ketene generation in the Wynberg procedure with
chloral and trichloroacetone as carbonyl substrates.6 We
were interested in studying the scope of this process
further. Furthermore, while the utility of the chlorinated
â-lactones obtained via the Wynberg procedure has been
explored to some extent,7 a number of other useful
transformations can be envisioned. With these consider-
ations in mind, we have developed a modified and
simplified Wynberg procedure for the synthesis of opti-
The use of in situ generated ketene has been widely
employed in synthesis,8 and one of the simplest and most
practical methods involves the action of tertiary amines
on acid chlorides.4b There are at least two concerns in
using a tertiary amine base for dehydrochlorination
leading to in situ ketene generation in conjunction with
the Wynberg method (Scheme 1). The first concern is the
possibility that the tertiary amine used as a base may
also act as a nucleophilic catalyst 1 thus leading to
racemic product. The second concern is the possiblity of
the nucleophilic catalyst (i.e. (-)-quinidine (6), QUIN)
acting as a base leading to dehydrochlorination of the
acid chloride 7 and rendering it unavailable for catalysis.
The proposed catalytic cycle for the Wynberg procedure
is shown in Scheme 1. The sequence is proposed to
involve the ammonium enolate 2 that reacts with an
aldehyde in a tandem aldol-lactonization process to give
â-lactone 4.3c
Resu lts a n d Discu ssion
Control experiments indicated that use of Hunig’s base
alone with acetyl chloride and R,R-dichlorooctanal did not
lead to â-lactone formation as has previously been noted
in related reactions.2b,6 Furthermore, we determined that
use of toluene as solvent led to immediate formation of a
precipitate when acetyl chloride was added to Hunig’s
base at -25 °C. The precipitate was identified as the
hydrochloride salt of Hunig’s base (8). Pleasingly when
the reaction was repeated in the presence of 2 mol %
quinidine (6), â-lactone was produced with enantioselec-
tivities similar to those reported by Wynberg (vide infra).
In contrast to previous studies,6 diethyl ether and tet-
rahydrofuran were found to be inferior solvents relative
to toluene. After extensive experimentation, we found
(1) For a review describing transformations of â-lactones, see: (a)
Pommier, A.; Pons, J .-M. Synthesis 1993, 441-449. For a lead reference
to more recent transformations, see: (b) Yang, H. W.; Romo, D. J . Org.
Chem. 1999, 64, 7657-7660.
(2) (a) For a recent review of methods for the synthesis of optically
active â-lactones, see: Yang, H. W.; Romo, D. Tetrahedron 1999, 55,
6403-6434. (b) For a recently described elegant method, see: Nelson,
S. G.; Peelen, T. J .; Wan, Z. J . Am. Chem. Soc. 1999, 121, 9742-9743.
(3) (a) Wynberg, H.; Staring, E. G. J . J . Am. Chem. Soc. 1982, 104,
166-168. (b) Wynberg, H.; Staring, E. G. J . J . Org. Chem. 1985, 50,
1977-1979. (c) Wynberg, H. Topics in Stereochemistry 1986, 16, 87-
130.
(4) (a) Tidwell, T. T. Ketenes; J ohn Wiley&Sons: New York, 1995.
For the first report of ketene synthesis from an R-chloro acid choride
using Zn dust, see: (b) Staudinger, H. Chem. Ber. 1905, 38, 1735-
1739. For the first report of a tertiary amine induced dehydrochlori-
nation to give ketene, see: Wedekind, E. Ann. Chim. 1902, 323, 246-
257.
(7) (a) Fujisawa, T.; Ito, T.; Fujimoto, K.; Shimuzu, M., Wynberg,
H.; Staring, E. G. J . Tetrahedron Lett. 1997, 38, 1593-1596. (b)
Fujisawa, T.; Ito, T.; Nishiura, S.; Shimuzu, M. Tetrahedron Lett. 1998,
39, 9735-9738 and references cited. (c) Song, C. E.; Lee, J . K.; Kim, I.
O.; Choi, J . H. Synth. Commun. 1997, 27, 1009-1014. (d) Song, C. E.;
Lee, J . K.; Lee, S. H.; Lee, S. G. Tetrahedron: Asymmetry 1995, 6,
1063-1066.
(8) (a) Brady, W. T.; Giang, Y. F.; Marchand, A. P.; Wu, A. J . Org.
Chem. 1987, 52, 3457-3461 and references cited. For some recent
examples, see: (b) Boivin, J .; Kaim, L. E.; Zard, S. Z. Tetrahedron 1995,
51, 2573-2584. (c) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J .
Am. Chem. Soc. 1999, 121, 9726-9727. (d) ref 2b.
(5) Borrman, D.; Wegler, R. German Patent DE-PS 1 214 211, 1966.
(6) J ackson, B. Swiss Patent CH681 302 A5, 1993.
10.1021/jo001010l CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/15/2000

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7249
Ta ble 1. â-La cton es Obta in ed via Nu cleop h ilic Ca ta lytic, Net [2 + 2] Cycloa d d ition s Usin g In Situ
Gen er a ted Keten e (Sch em e 2)
a
Absolute configuration of â-lactone 4b was determined by comparison of optical rotations to published data (ref 13). â-Lactones 4a ,
4c, and 4d are assumed to be of the same configuration. Yields refer to isolated, purified products. c Optical purity was determined by
chiral phase GC (TBS-â-cyclodextrin column). The enantiomeric purity was not determined however comparison of optical rotations
with known values indicated the (R)-configured â-lactone was obtained.
b
d
Sch em e 2
possibly due to the greater solubility of QUIN‚HCl
relative to EtNi-Pr2‚HCl in toluene, the QUIN‚HCl
remains in solution and is free-based by excess Hunig’s
base. This implies that the requirement for an effective
catalyst in this type of reaction is not an appropriate pKa
differential but rather an appropriate solubility dif-
ferential of the respective hydrochloride salts of the base
and catalyst used.
Using the optimized conditions described above, sev-
eral â-lactones were prepared using in situ ketene
generation with acetyl chloride (Table 1). The enantio-
meric purity was determined by chiral GC (â-cyclodex-
trin) on comparison with racemic â-lactones obtained
using the same procedure but with quinuclidine (1.0
equiv) as the nucleophilic reagent. The enantiomeric
â-lactones should also be available using quinine as
demonstrated previously.3b Current limitations of this
modified Wynberg procedure remain to be the need for
activated (i.e., dichlorinated) aldehydes which, however,
are available in one step from the corresponding alcohols
10 by the oxidation of De Buyck.10 Side chain functional-
ity must be compatible with this oxidation and, for
example, this mandated the use of a pivalate in aldehyde
3c.11 â-Substitution on the aldehyde led to a decrease in
yield of â-lactone (Table 1, entry 4). The use of trichlo-
roacetone gave comparable yields of â-lactone using our
developed conditions compared to those obtained previ-
ously (entry 5).12,13 Studies with other acid chlorides
that optimal yields were obtained by addition of 1.0 equiv
of acetyl chloride to a mixture of the aldehyde, Hunig’s
base, and 2 mol % quinidine in toluene at -25 °C
(Scheme 2). This contrasts to previous related studies in
which simultaneous addition of acid chloride and alde-
hyde was required for optimal yields.6 Precipitation of
the amine hydrochloride was instantaneous, and after
15 min, an additional 0.5 equiv acetyl chloride was added
to ensure near complete consumption of aldehyde.9
Performing the reaction at 0 °C or 25 °C led to similar
enantioselectivities (92-93% ee); however, lower yields
of â-lactone 4b (39-42%) were obtained suggestive of the
instability of ketene at these temperatures. Thus, in this
reaction sequence, Hunig’s base does not catalyze forma-
tion of the â-lactone nor does quinidine become ineffective
as a nucleophilic catalyst due to protonation. It is likely
that quinidine also leads to dehydrochlorination of the
acid chloride or is protonated to give salt 9. However,
(10) (a) De Buyck, L.; Veske, R.; Cantheyn, D.; Schamp, N. Bull.
Soc. Chim. Belg. 1980, 89, 441-458. (b) De Buyck, L.; Casaert, F.; De
Lepeleire, C. Schamp, N. Bull. Soc. Chim. Belg. 1988, 97, 525-533.
(11) For example, a primary triisopropylsilyl ether was found to be
incompatible with these oxidation conditions.
(9) Small quantities of unreacted aldehyde (<10%) were commonly
detected on analysis of the crude reaction mixture.

7250 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
Sch em e 3
Sch em e 4
In summary, Wynberg’s procedure for the asymmetric
synthesis of â-lactones has been extended to the use of
in situ generated ketene with dichlorinated aldehydes.
The use of toluene as solvent to precipitate the hydro-
chloride salt of Hunig’s base and in this way free-base
the nucleophilic catalyst, quinidine, was crucial for the
success of this reaction. Several transformations of the
resulting optically active dichlorinated â-lactones are
described that extend the utility of these products.
including R-acetoxy, R-methoxy, propionyl, and R-azido
acetyl chloride gave only trace quantities (e5%) of
â-lactone.
Although we have not yet identified conditions to
dechlorinate the â-lactone products while maintaining
the integrity of the lactone ring,14 we were able to convert
â-lactone 4b15 to the corresponding â-hydroxy ester 10
in a single step. Wynberg and co-workers had previously
accomplished this transformation in two steps in similar
overall yield.13 We were also interested in identifying
transformations of the dichlorinated â-lactones that
would make use of the resident chlorine atoms. Toward
this goal, we reduced â-lactone 4b to the diol 117b and
selectively protected the primary alcohol as the triiso-
propylsilyl ether 12 (Scheme 3). Treatment of this alcohol
with NaH led to formation of chloroepoxide 13 in good
yield as a 38:1 ratio of diastereomers.16 Transformation
of epoxide 13 to the R-azido ketone 14 was accomplished
by treatment with NaN3 in aqueous DME17 with no loss
in optical purity as determined by chiral phase HPLC.18
Exp er im en ta l Section
Gen er a l. Solvent purification/drying, flash chromatography,
spectroscopy, and thin-layer chromatography were performed
as previously described.19 All reactions were carried out under
N2 in oven-dried glassware unless noted otherwise. Diisopropyl-
ethylamine was distilled from potassium hydroxide, and acetyl
chloride was distilled from PCl5. (-)-Quinidine and anhydrous
dimethylformamide were purchased from Aldrich Chemical Co.
and used as received. All other commercially available materials
were purchased from Aldrich Chemical Co. or Fluka and used
as received. GC analyses were performed using a 20 m 30% tert-
butyldimethylsilyl-â-cyclodextrin in a OV1701 column (kindly
provided by Prof. Gyula Vigh, Texas A&M) at an oven temper-
ature of 140 °C and H2 carrier pressure of 5 psi. HPLC analyses
were performed using a Chiracel OD column. Known aldehydes
3a , 3b, and 3d were prepared by the method of De Buyck10 from
commercially available alcohols.
Ald eh yd e 3c. 4-Pivaloyloxy-1-butanol20 (2.30 g, 13.2 mmol)
and DMF (6.66 mL) were added to a three-neck flask equipped
with a vent outlet leading to a mineral oil bubbler, glass stopper,
Unsaturation could also be introduced by controlled
eliminations of the dichlorinated products. To prevent
competing epoxide formation, the secondary alcohol of
diol 11 was first protected as the benzyl ether in a two-
step process proceeding through benzylidene acetal 15
to give alcohol 16 (Scheme 4). Treatment of this alcohol
with 1.9 equiv of KOt-Bu gave the vinyl chloride 18 as a
7.2:1 ratio of geometrical isomers contaminated with
trace amounts of alkyne 17. Conversion to the alkyne 17
was accomplished using 4.0 equiv of KOt-Bu.
and
a plastic tube with attached needle for chlorine gas
introduction. Chlorine gas was bubbled through the solution for
15 min. The flask was cooled with an ice/water bath to maintain
a reaction temperature of 50-60 °C. The green reaction mixture
was stirred at room temperature for 8 h. The reaction was then
extracted with ether (3 × 10 mL), and the combined organic
layers were washed with concentrated HCl (30 mL) and 50%
H2SO4 (30 mL). The organic layer was then neutralized with
solid CaCO3 and concentrated in vacuo. Purication of the residue
by distillation gave the aldehyde 3c (0.85 g, 21% yield) which
distilled at 110 °C (5 mmHg) as a clear liquid: Rf 0.20 (EtOAc/
hexanes ) 1:3); IR (thin film) 1731 cm-1 1H NMR (300 MHz,
;
(12) In this case, reaction in diethyl ether gave a comparable yield
(ref 6).
(13) Ketelaar, P. E. F.; Staring, E. G. J .; Wynberg, H. Tetrahedron
Lett. 1985, 26, 4665-4668.
(14) For a report describing selective radical dehalogenation of one
or two chlorine atoms from (R)-4-(trichloromethyl)oxetan-2-one fol-
lowing lactone cleavage, see ref 7d.
(15) We utilized â-lactone 4b in further transformations because the
derived products were nonvolatile.
(16) The stereochemistry of the major diastereomer has not been
determined.
CDCl3) δ 9.23 (s, 1H), 4.37 (t, J ) 6.3 Hz, 2H), 2.71 (t, J ) 6.3
Hz, 2H), 1.20 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 184.2, 178.3,
86.0, 60.1, 40.1, 38.9, 27.3; FAB HRMS calcd for [M + H]
241.0394, found 241.0398.
Gen er a l P r oced u r e for th e Mod ified Wyn ber g P r oce-
d u r e As Descr ibed for â-La cton e 4b. Aldehyde 3b (0.50 g,
2.54 mmol, 1.00 equiv) was added to a 25 mL round-bottomed
flask followed by quinidine (0.02 g, 0.05 mmol, 0.02 equiv),
toluene (3.60 mL), and Hunig’s base (0.64 mL, 3.68 mmol, 1.45
equiv). The flask was cooled to -25 °C, and then acetyl chloride
(0.18 mL, 2.54 mmol, 1.00 equiv) was added dropwise over a
(17) Corey, E. J .; Link, J . O. J . Am. Chem. Soc. 1992, 114, 1906-
1908.
(18) The %ee of the corresponding, chromophore-containing TBDPS-
protected azido ketone was determined by chiral HPLC analysis after
reduction and in situ Boc protection by the literature procedure: Saito,
S.; Nakajma, H.; Inabe, M.; Moriwake, T. Tetrahedron Lett. 1989, 30,
837-838.
(19) Yang, H. W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471-
16488.
(20) Wu, Y.; Ahlberg, P. Acta Chem. Scand. 1995, 49, 364-374.

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7251
1-2 min period. A precipitate formed immediately, the hetero-
geneous mixture was stirred for 15 min, and then more acetyl
chloride (0.09 mL, 1.27 mmol, 0.50 equiv) was added slowly. The
resulting heterogeneous, light-yellow mixture was stirred an
additional 45 min at -25 °C and then warmed to 25 °C. After
dilution with 10 mL of Et2O, the mixture was transferred to a
separatory funnel, and additional Et2O was used to transfer all
the solids. The organics were washed with 4 N HCl (3 × 10 mL)
and brine (10 mL). The organic layers were dried over MgSO4
and concentrated in vacuo. The product was purified by flash
chromatography (EtOAc/hexanes ) 1:20 to 1:3) to afford â-lac-
tone 4b (0.45 g, 73% yield) as a light-yellow oil in 93% ee: GC,
tR (R) ) 17.9 ( 0.1 min, tR (S) ) 19.7 ( 0.1 min; Rf 0.58 (EtOAc/
hexanes ) 1:3); [R]25D +1.40° (c 4.37, CHCl3); IR (thin film) 1844
quenched with acetone (5 mL), 1 M sodium/potassium tartrate
solution (30 mL), and EtOAc (20 mL). The mixture was warmed
to 25 °C and stirred for 1 h. The layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 40 mL). The
combined organic layers were washed with brine (100 mL), dried
over Na2SO4, and concentrated in vacuo to give the diol 12 (0.96
g, 95% yield) as a light-yellow oil which was of sufficient purity
to carry on directly to the next step: Rf 0.18 (EtOAc/ hexanes )
-1
1:3); IR (thin film) 3375 cm
;
1H NMR (300 MHz, CDCl3) δ
4.10 (dd, J ) 2.1, 10.2 Hz, 1H), 3.85-4.00 (m, 2H), 3.18 (s, 1H),
2.50 (s, 1H), 2.10-2.27 (m, 3H), 1.80-1.95 (m, 1H), 1.62-1.79
(m, 2H), 1.29-1.41 (m, 6H), 0.94 (t, J ) 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 98.8, 78.6, 61.0, 43.5, 33.8, 31.8, 29.1, 25.0,
22.8, 14.3; FAB HRMS calcd for [M + H] 243.0919, found
243.0929.
cm-1 1H NMR (300 MHz, CDCl3) δ 4.69 (dd, J ) 4.2, 5.7 Hz,
;
1H), 3.70 (dd, J ) 3.9, 16.8 Hz, 1H), 3.62 (dd, J ) 5.7, 16.8 Hz,
1H), 2.11-2.32 (m, 2H), 1.59-1.79 (m, 2H), 1.29-1.40 (m, 6H),
0.90 (t, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6,
91.7, 723.3, 43.9, 41.6, 31.3, 28.4, 24.3, 22.3, 13.8; FAB HRMS
calcd for [M + Na] 239.06056, found 239.06061.
Mon o-TIP S P r otected Alcoh ol 12. The diol 11 (0.75 g, 3.08
mmol) was added to a flask, followed by imidazole (0.25 g, 3.70
mmol), DMF (6.17 mL), and TIPS-Cl (0.79 mL, 3.70 mmol). The
mixture was stirred at 25 °C for 9 h and then quenched with
saturated NaHCO3 (1 mL). The mixture was then extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with water (30 mL) and brine (30 mL), dried, and concentrated
in vacuo. Purification by flash chromatography (EtOAc/hexanes
) 1:20 to 1:5) gave mono-TIPS protected alcohol 12 (1.19 g, 97%
yield) as a light-yellow oil: Rf 0.80 (EtOAc/hexanes ) 1:3); IR
â-La cton e 4a . This â-lactone was prepared from aldehyde
3a (0.50 g, 2.46 mmol). Purification by flash chromatography
(EtOAc/ hexanes ) 1:20 to 1:3) gave â-lactone 4a (0.52 g, 85%)
as a light-yellow oil in 93% ee: GC, tR (R) ) 31.0 ( 0.1 min, tR
(S) ) 33.6 ( 0.1 min;: Rf 0.56 (EtOAc/hexanes ) 1:3); [R]25
D
-111° (c 5.49, CHCl3); IR (thin film) 1839 cm-1; H NMR (300
(thin film) 3457 cm-1; H NMR (300 MHz, CDCl3) δ 3.80-4.10
1
1
MHz, CDCl3) δ 7.36 (s, 5H), 4.58 (dd, J ) 3.9 Hz, 5.7 Hz, 1H),
3.62 (app d, J ) 0.9 Hz, 2H), 3.66 (dd, J ) 3.9, 16.8 Hz, 1H),
3.50 (dd, J ) 5.7, 16.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
165.4, 132.7, 131.2, 128.4, 128.2, 90.2, 71.4, 49.8, 41.4; FAB
HRMS calcd for [M + Na] 266.9955, found 266.9951
(m, 4H), 2.12-2.35 (m, 3H), 1.82-2.00 (m, 1H), 1.61-1.80 (m,
2H), 1.21-1.40 (m, 6H), 0.99-1.15 (m, 21H), 0.88 (t, J ) 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 98.3, 78.8, 62.4, 44.0, 34.1,
31.9, 29.1, 24.9, 22.8, 18.2, 17.9, 14.3, 12.1; FAB HRMS calcd
for [M + H] 399.2253, found 399.2266.
â-La cton e 4c. This â-lactone was prepared from aldehyde
3c (0.50 g, 2.07 mmol). Purification by flash chromatography
(EtOAc/ hexanes ) 1:20 to 1:3) gave â-lactone 4c (0.47 g, 80%
yield) as a white solid in 94% ee: GC, tR (R) ) 39.0 ( 0.1 min,
Ch lor o Ep oxid e 13. A THF (2.50 mL) solution of the alcohol
12 (100 mg, 0.25 mmol) was added to NaH (60% dispersion in
mineral oil, 9.0 mg, 0.38 mmol) which had been washed with
hexane (3 × 1 mL), and the mixture was stirred at 25 °C for 7
h. The reaction was washed with water (5 mL), brine (5 mL),
dried over MgSO4, and concentrated to afford the chloroepoxide
13 (83.0 mg, 92% yield) as a light-yellow oil and as a 38:1 ratio
of diastereomers. This epoxide was not stable to silica gel
chromatography: Rf 0.73 (EtOAc/ hexanes ) 1:10); 1H NMR (300
MHz, CDCl3) δ 3.91 (t, J ) 5.9 Hz, 2H), 3.13 (dd, J ) 5.3, 6.5
Hz, 1H), 1.92-2.05 (m,4H), 1.50-1.61 (m, 2H), 1.20-1.39 (m,
6H), 0.99-1.15 (m, 21H), 0.88 (t, J ) 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 84.6, 61.3, 60.5, 40.7, 32.9, 31.9, 28.9, 25.0, 22.7,
18.2, 14.3, 12.2; FAB HRMS calcd for [M + H] 363.2486, found
363.2485.
tR (S) ) 45.2 ( 0.1 min; Rf 0.60 (EtOAc/ hexanes ) 1:3); [R]25
D
+7.99° (c 5.71, CHCl3); IR (thin film) 1844 cm-1 and 1726 cm-1
;
1H NMR (300 MHz, CDCl3) δ 4.75 (dd, J ) 3.9, 5.4 Hz, 2H),
4.38-4.52 (m, 2H), 3.72 (dd, J ) 3.9, 16.8 Hz, 1H), 3.64 (dd, J
) 5.4, 16.8 Hz, 1H), 2.59-2.78 (m, 2H), 1.21 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 178.1, 165.2, 88.6, 73.0, 59.9, 42.7, 41.7, 38.6,
27.0; FAB HRMS calcd for [M + Na] 305.0323, found 305.0337.
â-La cton e 4d . This â-lactone was prepared from aldehyde
3d (0.50 g, 3.22 mmol). Purification by flash chromatography
(EtOAc/ hexanes ) 1:20 to 1:3) gave â-lactone 4d (0.25 g, 40%)
as a light-yellow oil: GC, tR (R) ) 4.20 ( 0.1 min, tR (S) ) 4.45
( 0.1 min; Rf 0.54 (EtOAc/ hexanes ) 1:3); [R]25D +19.4° (c 9.65,
CHCl3); IR (thin film) 1849 cm-1; 1H NMR (300 MHz, CDCl3) δ
4.85 (dd, J ) 3.9, 5.7 Hz, 1H), 3.74 (dd, J ) 3.9, 16.8 Hz, 1H),
3.63 (dd, J ) 5.7, 16.8 Hz, 1H), 2.48 (sept, J ) 6.6 Hz, 1H), 1.24
(d, J ) 6.6, 3H), 1.18 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 161.5, 97.0, 71.7, 42.2, 40.7, 18.1, 17.9; FAB HRMS
calcd for [M + Na] 218.99555, found 218.99484. GC analysis
r-Azid o Keton e 14. The epoxide 13 (50.0 mg, 0.11 mmol)
was added to a flask, followed by NaN3 (36.0 mg, 0.55 mmol),
DME (0.69 mL), and H2O (0.34 mL) at 25 °C. The reaction was
stirred at 25 °C for 84 h. The mixture was then diluted with 5
mL EtOAc, washed with water (5 mL) and brine (5 mL), dried
over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (EtOAc/ hexanes ) 1:20 to 1:6) afforded the
R-azido ketone 14 (42.1 mg, 83% yield) as a light-yellow oil: Rf
indicated an enantiomeric purity of 99% (R enantiomer, tR
4.20 min, S enantiomer, tR ) 4.45 min.).
)
0.74 (EtOAc/ hexanes ) 1:3); [R]25 -2.57° (c 1.40, CHCl3); IR
D
â-La cton e 4e. This â-lactone was prepared in 25% yield (61.9
mg) as a yellow oil from trichloroacetone (200 mg, 1.24 mmol).
Purification by flash chromatography (EtOAc/hexanes ) 1:10
to 1:5) gave â-lactone 4e. Spectral data for this compound
matched that previously reported.3 [R]25D +5.64° (c 4.40, CHCl3);
(thin film) 2105 and 1705 cm-1
;
1H NMR (300 MHz, CDCl3) δ
4.10 (dd, J ) 4.2, 9.3 Hz, 1H), 3.83 (dd, J ) 4.4, 7.0 Hz, 2H),
2.54 (app dt, J ) 2.4, 7.5 Hz, 2H), 2.00-2.10 (m, 1H), 1.72-
1.83 (m, 1H), 1.49-1.61 (m, 2H), 1.20-1.39 (m, 6H), 0.99-1.15
(m, 21H), 0.88 (t, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 207.8, 64.7, 59.1, 39.8, 33.7, 31.6, 28.8, 23.4, 22.5, 18.0, 14.0,
11.8; FAB HRMS calcd for [M + H] 370.28898, found 370.28956.
The enantiomeric purity of the TBDPS protected R-azido ketone
was determined to be 85% ee by HPLC analysis (5% 2-propanol/
hexane, 1 mL/min) after reduction and in situ protection (H2,
Pd/C, Boc2O, EtOAc).
Ben zylid en e Aceta l 15. The diol 11 (1.00 g, 4.11 mmol) was
added to a flask followed by TsOH (78.2 mg, 0.41 mmol), MgSO4
(0.99 g, 8.23 mmol), CH2Cl2 (11.4 mL), and benzaldehyde (0.50
mL, 4.94 mmol) at 25 °C. The mixture was stirred at 25 °C for
4 h and then filtered and extracted with satd NaHCO3 (3 × 10
mL). Drying the organics over MgSO4 and concentration in vacuo
was followed by purification by flash chromatography (EtOAc/
hexanes ) 1:20 to 1:5) gave the benzylidene acetal 15 (0.93 g,
68% yield) as a light-yellow oil: Rf 0.74 (EtOAc/hexanes ) 1:3);
1H NMR (300 MHz, CDCl3) δ 7.,47-7.51 (m, 2H), 7.30-7.41 (m,
3H), 5.55 (s, 2H), 4.38 (ddd, J ) 1.5, 5.1, 11.7 Hz, 1H), 4.10 (dd,
lit. [R]25 +6.20° (c 2, EtOH).3b
D
â-Hyd r oxy Ester 10. The â-lactone 4b (100 mg, 0. 42 mmol)
was added to a flask followed by Pd/C (40 mg, 0.04 mmol),
K2CO3 (0.14 g), MgSO4 (1.00 equiv), and methanol (1.40 mL). A
balloon of hydrogen gas was attached and the reaction was
stirred for 3.5 h at 25 °C. The mixture was then filtered and
concentrated in vacuo. The product was purified by flash
chromatography (EtOAc/ hexanes ) 1:20 to 1:3) to afford the
â-hydroxy ester 10 (53.7 mg, 64% yield) as a light-yellow oil.
Spectral data for this compound matched that previously
reported.3 [R]25 +11.4° (c 4.19, CHCl3); lit. [R]25 +25.8 o (c 1.0,
D
D
cyclohexane).13
Diol 11. DIBAl-H (1.86 mL, 10.45 mmol) was added to a flask
containing CH2Cl2 (10.5 mL). This mixture was added slowly
via cannula to a solution of â-lactone 4b (1.00 g, 4.18 mmol) in
CH2Cl2 (31.3 mL) at 0 °C. The mixture was then warmed to 25
°C and stirred for 3 h. After cooling to 0 °C, the reaction was

7252 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
J ) 2.4, 11.1 Hz, 1H), 4.00 (app dt, J ) 2.7, 12.0 Hz, 1H), 2.22-
2.35 (m, 3H), 2.05 (app dq, J ) 2.4, 13.2 Hz, 1H), 1.66-1.75 (m,
2H), 1.31-1.39 (m, 6H), 0.89 (t, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 138.2, 129.2, 128.5, 126.3, 101.5, 94.7, 83.0, 66.9,
43.9, 31.9, 29.0, 26.3, 24.9, 22.8, 14.3; FAB HRMS calcd for [M
+ H] 331.1232 found 331.1230.
Alk yn e 17. The alcohol 16 (46.0 mg, 0.14 mmol) was added
to a flask followed by KOtBu (61.9 mg, 0.5520 mmol). The flask
was then cooled to 0 °C, and then THF (1.4 mL) was added. The
mixture was stirred at 0 °C for 30 min and then raised to 25 °C
and stirred for an additional 21.5 h. The mixture was cooled to
0 °C and then quenched with 0.5 mL of 4 N HCl. The reaction
was diluted in 5 mL of EtOAc, washed with water (5 mL) and
brine (5 mL), dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (1:10 f 1:3 EtOAc/
hexanes) afforded alkyne 17 (24.6 mg, 69% yield) as a light-
brown oil which was contaminated with inseparable products
(∼95% pure). HPLC analysis of this alkyne indicated that it was
obtained with <5% racemization. Rf 0.47 (EtOAc/hexanes ) 1:3);
[R]25D +102° (c 1.00, CHCl3); IR (thin film) 3450, 2233 and 1644
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.21-7.37 (m, 5H), 4.82 (d,
12.0 Hz, 1H), 4.50 (d, J ) 12.0 Hz, 1H), 4.30-4.36 (m, 1H), 3.86-
3.95 (m, 1H),3.76-3.81 (m, 1H), 2.26 (dt, J ) 6.9, 7.2 Hz, 2H),
2.00 (dd, 2H, J ) 5.7, 11.1 Hz), 1.51-1.58 (m, 2H),1.26-1.42
(m, 4H), 0.91 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
138.0, 133.3, 128.7, 128.2, 87.9, 78.3, 70.8, 68.4, 60.6, 38.5, 31.3,
28.6, 22.4, 18.9, 14.3; FAB HRMS calcd for [M + H] 261.18546,
found 261.18565.
Alcoh ol 16. To a solution of benzylidene acetal 15 (0.99 g,
2.99 mmol) in CH2Cl2 (25.0 mL) was added a solution of
DIBAL-H (1.60 mL, 8.96 mmol) in CH2Cl2 (4.80 mL) at 0 °C.
The mixture was warmed to 25 °C and stirred for 9 h. The
reaction was quenched with 1.5 mL acetone, 10 mL of 1 M
sodium/potassium tartrate solution, and 10 mL of EtOAc at 0
°C. After allowing the reaction to warm to 25 °C and stirring
for 45 min, the reaction was extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with brine (50 mL),
dried over MgSO4, and concentrated in vacuo. The product was
purified by flash chromatography (EtOAc/hexanes ) 1:20 to 1:3)
to give alcohol 16 (0.69 g, 69% yield) as a light-yellow oil: Rf
0.48 (EtOAc/hexanes ) 1:3); IR (thin film) 3450 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.36 (m, 5H), 4.96 (d, J ) 11.1 Hz, 1H) 4.75
(d, J ) 11.1, 1H), 4.04 (dd, J ) 2.4, 9.3 Hz, 1H), 3.65-3.83 (m,
2H), 2.17-2.35 (m, 3H), 1.85-1.98 (m, 1H), 1.63-1.79 (m, 2H),
1.41 (s, 1H), 1.25-1.39 (m, 6H), 0.90 (t, 3H, J ) 6.9 Hz); 13C
NMR (75 MHz, CDCl3) δ 138.0, 128.7, 128.3, 128.2, 98.0, 84.5,
75.8, 60.0, 43.4, 34.6, 31.8, 29.1, 25.0, 22.8, 14.2; FAB HRMS
calcd for [M + H] 333.1388, found 333.1387.
Ack n ow led gm en t. Support of this work by the NSF
(CAREER Award to D.R., CHE 9624532), the Robert A.
Welch Foundation (A-1280), and Zeneca Pharmaceuti-
cals is gratefully acknowledged. D.R. is an Alfred P.
Sloan Fellow and a Camille and Henry Dreyfus Teacher-
Scholar. Mass spectral analyses were obtained at the
Texas A&M Center for Characterization on instruments
acquired by generous funding from the NSF (CHE-
8705697) and the TAMU Board of Regents Research
Program.
Alk en e 18. To a THF solution (0.50 mL) of the alcohol 16
(62.0 mg, 0.19 mmol) was added a solution of KOtBu (39.6 mg,
0.35 mmol) in THF (1.36 mL) slowly over a period of 15 min at
25 °C. The reaction was stirred for 6 h and then quenched with
0.5 mL of 4 N HCl. The mixture was then diluted in 5 mL of
EtOAc and washed with water (5 mL) and brine (5 mL), dried
over MgSO4, and concentrated in vacuo. The product was then
purified by flash chromatography (EtOAc/hexanes ) 1:20 to 1:3)
to give alkene 18 (33.5 mg, 61% yield) as a yellow oil and a 7.2:1
ratio of stereoisomers: Rf 0.48 (EtOAc/ hexanes ) 1:3); [R]25
D
+66.9 (c 0.77, CHCl3); IR (thin film) 1650 and 3450 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.21-7.40 (m, 5H), 5.80 (t, J ) 6.9
Hz, 1H), 4.62 (d, J ) 11.7 Hz, 1H), 4.31 (d, J ) 11.7 Hz, 1H),
4.11 (dd, J ) 4.5, 8.4 Hz, 1H), 3.67-3.81 (m, 2H), 2.22-2.39 (m,
2H), 1.99-2.13 (m, 1H),1.81-1.90 (m, 1H), 1.26-1.46 (m, 6H),
0.91 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 137.7,
133.2, 129.6, 128.5, 128.0, 127.9, 80.7, 70.2, 60.2, 36.2, 31.4, 28.2,
28.0, 22.4, 14.0; FAB HRMS calcd for [M + Na] 319.1443, found
319.1442.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of â-lactones 4a -d , epoxide 13, azido ketone 14, vinyl
chloride 18, and acetylene 17. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O001010L