Stereoselective synthesis of cis- or trans-2,4-disubstituted butyrolactones from Wynberg lactone

Article abstract of DOI:10.1016/j.tet.2012.04.107

(R)-Wynberg lactone was used to prepare various asymmetric 2,4-disubstituted butyrolactones in three to four steps. Attainment of any possible stereoisomer, based upon commencement from (R)- or (S)-4- trichloromethyl-2-oxetanone, and the capacity to insta

Full text of DOI:10.1016/j.tet.2012.04.107

Tetrahedron 68 (2012) 5396e5405
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journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of cis- or trans-2,4-disubstituted butyrolactones from
Wynberg lactone
*
Ashok Ganta, Julia L. Shamshina, Lauren R. Cafiero, Timothy S. Snowden
Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, AL 35487-0336, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
(R)-Wynberg lactone was used to prepare various asymmetric 2,4-disubstituted butyrolactones in three
to four steps. Attainment of any possible stereoisomer, based upon commencement from (R)- or (S)-4-
trichloromethyl-2-oxetanone, and the capacity to install disparate substituents at C2 make this ap-
proach particularly versatile.
Received 22 December 2011
Received in revised form 26 April 2012
Accepted 27 April 2012
Available online 4 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Butyrolactone
gem-Dichloroepoxide
Trichloromethyl carbinol
Wynberg lactone
b-Lactone
1. Introduction
nucleophilic acyl substitution by the tethered alkoxide (2) to afford
the decorated butyrolactone in a one-pot operation. We envisioned
Heteroatom-substituted butyrolactones serve as multipurpose
intermediates in organic synthesis, providing direct access to
highly functionalized carbonyl compounds or alcohols through
standard transformations. Substituted butyrolactones also find
application in the preparation of liquid crystals,1 and several exhibit
biological activity including cytotoxicity2 and hunger modulation.3
It has been estimated that asymmetric butyrolactones exist as
components of about 10% of all natural products.4 Considering the
importance of these structures in chemistry, biology, and materials
science, we intended to devise an expedient approach to variably
2,4-disubstituted butyrolactones taking advantage of our experi-
ence with reactions involving gem-dichloroepoxide intermediates.5
We also planned to offer a method where any one of the four
possible stereoisomers is equally and predictably attainable.
We reasoned that asymmetric 2,4-disubstituted lactones (1)
would be accessible in a single operation from a chiral 1-
trichloromethyl-1,3-diol (4) (Scheme 1). Treatment of 4 with base
in protic media would initiate a reaction cascade where asymmetric
gem-dichloroepoxide 3 would form after deprotonation of a tri-
chloromethyl carbinol. Inclusion of the desired nucleophile for in-
stallation at C2 would promote regioselective substitution with
stereospecific inversion of configuration followed by acid chloride
generation. The acyl chloride would be subject to intramolecular
the requisite syn- or anti-1,3-diols could arise from substrate-
directed borohydride reductions, whereby a newly formed R- or
S-stereocenter would be furnished based upon the absolute ste-
reochemistry of the carbinol substrate. Hence, we required con-
Scheme 1. Conceptualized route to asymmetric 2,4-disubstituted butyrolactones and
* Corresponding author. E-mail address: snowden@bama.ua.edu (T.S. Snowden).
related examples.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.107

A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
5397
OH
OH
CCl3
venient and affordable access to asymmetric 3-ketotrichloromethyl
O
OH
CCl3
, Solvent, Temp.
nM
+
R
carbinols 5, bearing disparate ‘R-groups’, to initiate the approach.
The research groups of Fujisawa and Romo took advantage of the
chirality resident in (S)- or (R)-4-trichloromethyl-2-oxetanone6
(Wynberg lactone 7)7 to synthesize select 3-hydroxytrichloromethyl
carbinols (8 and 10, Scheme 1).8 Each group also described a single
example of substituted butyrolactone preparation by an approach
involving gem-dichloroepoxides. Fujisawa briefly noted the formation
of C4 epimeric 9 in 75% yield after treatment of 1-trichloromethyl-1,3-
diol (8) in basic media. However, no reaction details or other examples
were disclosed. Romo prepared monosubstituted (S)-2-azidolactone
11 starting from Wynberg lactone. Notably, 11 was formed with only
2.5% racemization under the reaction conditions employed. Inspired
by these successes, we elected to exploit 7 for entry to 5 with the in-
tention of preparing stereodefined lactones (1). We expected the
proposed route to be particularly powerful given the variety of sub-
stituents amenable to incorporation at C2 and C4 of 1.
(R)-7
+ (R)-7
~25-40%
R
n = 1, M = MgX, Li, ZnX, CuLi
n = 2, M = Zn, CuLi, CuCN(Li)2
R
12
13
26-33%
13-38%
Scheme 2. Additions to Wynberg lactone (R)-7.
The Weinreb amide was reliably converted to asymmetric
-hydroxyketones by treatment with excess of any of several
b
freshly prepared organolithium or commercial Grignard reagents
(Table 1). We found that preliminary hydroxyl deprotonation by
introduction of i-PrMgCl, followed by addition of the desired nu-
cleophile offered superior yields in most cases (entries 2e5).13
Maintaining reaction temperatures below ꢀ10 ꢁC was critical, be-
cause higher temperatures permitted some double addition. It was
necessary to quench cold reaction mixtures of 12d and 12e by
rapid transfer through a chilled solution of 1 N HCl(aqueous) to cir-
cumvent N-methoxymethanamide conjugate addition to the
newly formed enone in 12e and to the crotonyl ketone resulting
from N-methoxymethanamide-promoted alkene isomerization in
12d.14
2. Results and discussion
2.1. Preparation of chiral trichloromethyl b-hydroxyketones
2.2. Directed reductions to syn- or anti-1,3-diols
We began by investigating formation of the requisite ketones (5)
by addition of common organometallic reagents to (R)-7.9 Although
7 smoothly undergoes Lewis acid-mediated FriedeleCrafts acyla-
tion with aromatic substrates (entry 1, Table 1),10 we discovered
that treatment with 1.0 equiv of an allyl lithium, magnesium, zinc,
or copper reagent afforded roughly equal mixtures of 12 and 13 and
(R)-7 (Scheme 2). Attempted Sakurai allylation using allyl-
trimethylsilane and BF3$Et2O also proved unsatisfactory. These re-
sults suggest that the carbonyl reforms after addition to 7 with
Next we explored directed syn- and anti-1,3-reductions of ke-
tones 12 to establish the
g-stereocenter in the prospective
substituted butyrolactones. After surveying several methods, we
found that diethylmethoxyborane and NaBH4 in cold methanol/THF
furnished syn-diols (15) in 79e97% yields and with good to ex-
ceptional diastereoselectivities (Table 2).15 anti-Diols (16) were
rendered with comparable results using Evans’ triacetoxyborohy-
dride/anhydrous acetic acid protocol (Table 3).16 In both reactions,
the minor diastereomers were easily separated by column chro-
matography affording diols of high enantiopurity.
concomitant b-lactone ring opening. The resultant b-alkoxy ketone,
presumably activated by metal-chelation, shows comparable re-
activity to 7 thereby precluding selective addition to the oxetanone.
We resorted to Weinreb amidation of 7 to deter regeneration of
the carbonyl following the initial addition to 14, thereby inhibiting
the formation of 13.11 We found that amidations conducted under
Lewis acidic conditions afforded 14 in excellent yields, even on
multigram scales (Table 1).12 This preparation proved superior in
reaction time, yields, and scalability to amidations using DIEA.
Table 2
Directed syn-reductions of 12
Entry
R
syn-Diol
Yielda (%)
drb
Table 1
1
2
3
4
5
6
Ph
2-Furyl
2-Thienyl
H2C]CHCH2e
H2C]CHe
n-C6H13
15a
15b
15c
15d
15e
15f
97
88
94
79
79
85
>98:2
91:9
>98:2
93:7
92:8
87:13
Preparations of
b-hydroxyketones 12
a
Yield of purified major diastereomer.
b
Established from 1H NMR spectra of crude reaction mixtures.
Table 3
Directed anti-reductions of 12
Entry
1
R
Conditions
Product Yield (%)
Ph
PhH, AlCl3, rt, 12 h directly
12a
89
from (R)-7
2
2-Furyl
1.0 equiv i-PrMgCl, then
1.25 equiv furyl
12b
85
Entry
R
anti-Diol
Yielda (%)
drb
lithium, THF, ꢀ15 ꢁC, 4 h;
3
4
5
6
2-Thienyl 1.0 equiv i-PrMgCl, then 1.25 equiv 12c
thienyl lithium, THF, ꢀ15 ꢁC, 4 h;
87
88
73
68
1
2
3
4
5
6
Ph
2-Furyl
2-Thienyl
H2C]CHCH2e
H2C]CHe
n-C6H13
16a
16b
16c
16d
16e
16f
85
89
80
79
77
92
94:6
91:9
> 98:2
90:10
90:10
94:6
Allyl
1.0 equiv i-PrMgCl, then 1.25 equiv 12d
allylMgCl, THF, ꢀ15 ꢁC, 4 h;
Vinyl
1.0 equiv i-PrMgCl, then 1.25 equiv 12e
vinylMgBr, THF, ꢀ15 ꢁC, 4 h;
n-C6H13
2.25 equiv hexylMgBr, PhMe,
12f
a
Yield of purified major diastereomer.
ꢀ15 ꢁC, 4 h
b
Established from 1H NMR spectra of crude reaction mixtures.

5398
A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
Table 5
2.3. Preparation of cis-2,4-disubstituted butyrolactones
Preparation of trans-disubstituted butyrolactones 18
Targeted cis-2,4-disubstituted lactones were prepared by dis-
solving the corresponding diols in DME/H2O, adding 4.0 equiv of
NaOH followed by 2.0 equiv of the desired nucleophile for in-
corporation at C2, and mixing at ambient temperature for 12 h
(Table 4). Notably, the relatively high nucleophilicity of azide in
protic media allows for its, rather than the solvated hydroxide’s,
selective substitution with 3.17 The workup procedure has a critical
impact on yield, because the products exist as a mixture of di-
substituted lactones and carboxylates prior to acidification. Hence,
the reaction mixture was quenched by addition of HCl to afford an
aqueous solution of pH¼2e3. This was mixed vigorously for 1e4 h
to promote lactonization (readily monitored by TLC analysis), then
the products were extracted to furnish 17 in uniformly high yields,
independent of the selected nucleophile.18 As expected, the
dichloroepoxide substitution occurred with stereospecific in-
version of configuration. Gratifyingly, little or no epimerization
occurred after cyclization, with 17f exhibiting only 5e7% epimeri-
zation in the worst case.
Entry
R
Phd
Nu
trans-Lactonea
Yieldb (%)
drc
1
2
3
4
5
6
7
8
N3 (0.2 M)
N3 (0.125 M)
18a
18a
18a
18b
18c
18d
18e
18f
18g
18h
18i
d
70:30
78:22
86:14
85:15
84:16
75:25
84:16
80:20
90:10
88:12
82:18
80:20
84:16
80:20
d
N3 (0.05 M)
70
69
60
52
83
71
88
78e
55
df
74
69
OH
N3
OH
N3
OH
N3
OH
N3
2-Furyl
2-Thienyl
Allyl
9
10
11
12
13
14
Vinyl
OH
N3
OH
18j
18k
18l
d
n-C6H13
a
Reactions conducted by dissolving 1 mmol of 16 in 20 mL DME/H2O (1:4 v/v)
then adding 4 mmol of NaOH followed by 2 mmol of desired nucleophile (NaOH or
NaN3) with rapid mixing at rt for 12 h. Workup by extraction at pH 2e3.
Table 4
Preparation of cis-disubstituted butyrolactones 17
b
Yield of purified major diastereomer.
c
Established from 1H spectra of crude reaction mixtures.
d
Reactions required24 h to reachcompletion dueto limitedsolubilityinDME/H2O.
The yield is reported for the mixture of inseparable diastereomers.
e
f
Product could not be purified to homogeneity.
Entry
R
Phd
Nu
cis-Lactonea
Yieldb (%)
drc
converted to the corresponding a-amino derivatives by Staudinger
reduction in excellent reported yields.19
1
2
3
4
5
6
7
8
N3
OH
N3
OH
N3
OH
N3
OH
N3
OH
N3
17a
17b
17c
17d
17e
17f
17g
17h
17i
98
93
72
66
98
90
93
95
69
69
90
95
>98:2
95:5
94:6
94:6
>98:2
93:7
>98:2
>98:2
94:6
94:6
>98:2
96:4
Portions of both the cis- and trans-disubstituted lactones are
deprotonated to form enolates under the basic reaction con-
2-Furyl
2-Thienyl
Allyl
ditionsdalthough once the lactones are hydrolyzed to the
hydroxycarboylates, enolization is precluded based upon the re-
duced acidity of the carboxylate -methyne position. The different
b-
a
extents of epimerization between the cis- and trans-disubstituted
lactones may be rationalized by considering the relative stabilities
of the configurational isomers,20 and not the relative susceptibili-
9
Vinyl
10
11
12
17j
17k
17l
d
n-C6H13
OH
ties of each to
presumably more acidic than the trans because of the favorable
alignment of the -CeH -bond and the carbonyl orbital in 17.
a-deprotonation, since the cis diastereomers are
a
Reactions conducted by dissolving 1 mmol of 15 in 5 mL DME/H2O (1:4 v/v) then
adding 4 mmol of NaOH followed by 2 mmol of desired nucleophile (NaOH or NaN3)
with rapid mixing at rt for 12 h. Workup by extraction at pH 2e3.
a
s
p
*
The cis-2,4-disubstituted lactones 17 assume an envelope confor-
mation where the cis-substituents preferentially reside in pseu-
doequatorial positions (Fig. 1). Conversely, the trans-epimers (18)
have one substituent in a pseudoaxial position, thereby experi-
encing some interaction with the alternate pseudoaxial hydrogen.
Hence, 18 are more susceptible to isomerization, because the eno-
late from the trans-diastereomer is funneled toward the lower
energy cis-isomer during reprotonation, although only partial
equilibration of the trans-lactones is attained during the reaction.
This rationale also explains, at least in part, the greater epimeri-
b
Yield of purified major diastereomer.
c
Established from 1H spectra of crude reaction mixtures.
d
Reactions required 24 h to reachcompletion dueto limited solubility inDME/H2O.
2.4. Preparation of trans-2,4-disubstituted butyrolactones
The trans-2,4-disubstituted lactones (18) were generated in an
analogous manner with one important exception. When cyclization
of the anti-diols (16) was conducted at a 0.2 M substrate concen-
tration, significant quantities of epimerized products were
obtained. We found that decreasing the anti-diol concentration to
0.05 M in DME/H2O offered meaningful decreases in epimerization
(Table 5, entries 1e3). We anticipated that reactions involving
higher concentrations of diol and base (Table 5, entries 1 and 2)
would feature a higher rate of enolization, thereby partially equil-
ibrating more of the trans-disubstituted lactone to the lower energy
cis-diastereomer 17, vide infra, during the course of the reaction. At
the 0.05 M substrate concentration, lactones 18 were prepared in
good yields and with acceptable diastereoselectivities (Table 5,
entries 3e14).18 As with the diastereomeric diols, the major cis- and
trans-lactone stereoisomers were readily separated by chroma-
tography, with the exception of 18h and 18j, which could not be
zation of the a-hydroxy-substituted lactones compared to the a-
azido products, since hydroxyl groups are highly solvated in protic
media exacerbating the interaction with the pseudoaxial hydrogen
relative to the trans-products bearing an azide.21 Intramolecular
hydrogen bond stabilization of 2-hydroxylactones in 17 relative to
18 may also play a role, although such an interaction may be
mitigated by the polar protic media. Another possible explanation
O
H
O
N3,HO
-OH
O
O
R
R
OH,N3
18
H
H
H
17
purified to homogeneity. Importantly, the
a
-azido lactones may be
Fig. 1. Configurational partial equilibration in 18.

A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
5399
for the greater extent of epimerization of 18 relative to 17 is the
higher susceptibility of 17 to nucleophilic acyl substitution with
hydroxide on steric grounds. If such a rate difference is significant,
lactones 18 will have a longer lifetime in the reaction milieu, and
aqueous 1 N HCl (3ꢂ25 mL) and then dried with MgSO4 and con-
centrated. The crude product was purified by bulb-to-bulb distilla-
tion at 82 ꢁC and 0.2 mmHg to obtain 4-trichloromethyl-2-
oxetanone (7) as a white solid, which was a mixture of enantio-
20
a greater opportunity for
a
-deprotonationereprotonation leading
mers. [
a
]
ꢀ10.7 (c 1.0, cyclohexane). The major enantiomer was
578
to more extensive epimerization than 17.
isolated by recrystallization from methylcyclohexane to obtainwhite
20
solid (R)-7 (29.4 g, 62% yield), mp 51e52 ꢁC, [
clohexane), equal to 98% ee.7a 1H NMR (360 MHz, CDCl3)
(dd, J¼5.7, 3.6 Hz, 1H), 3.72 (dd, J¼5.7, 11.4 Hz, 1H), 3.60 (dd, J¼3.6,
11.4 Hz, 1H); 13C NMR (90 MHz, CDCl3)
ppm: 163.8, 96.7, 76.1, 42.5.
a]
578 ꢀ15.6 (c 1.0, cy-
3. Conclusions
d
ppm: 5.00
We devised a versatile route to any of the four possible stereo-
isomers of 2,4-disubstituted butyrolactones from (R)- or (S)-Wyn-
berg lactone in just three or four steps.9 The approach is amenable
to installation of varied carbon substituents at C4 and heteroatom
functionalities at C2 and should be attractive for diversity-oriented
or target-directed synthesis applications.
d
4.2.2. (R)-4,4,4-Trichloro-3-hydroxy-N-methoxy-N-methylbutanamide
(14). (R)-4,4,4-Trichloro-3-hydroxy-N-methoxy-N-methylbutana-
mide was prepared by a modified Shimizu and Nakata method.12 A
two-neck flask was charged with a solution of Me2AlCl (1.0 M in
hexane, 150 mmol, 150 mL) (CAUTION: pyrophoric!) and diluted
with CH2Cl2 (150 mL). Then N,O-dimethylhydroxylamine hydro-
chloride (150 mmol, 14.5 g) was added portionwise over a 15 min
period under argon at 0 ꢁC. The mixture was warmed to room
temperature and stirred for 1 h. Then, a solution of (R)-7 (75 mmol,
4.2 g) in DCM (750 mL) was added portionwise over a period of
10 min via syringe. After mixing at room temperature for 12 h, the
reaction mixture was added to a saturated aqueous solution of
NH4Cl (3 mL per 1 mmol of Me2AlCl) at 0 ꢁC, and stirring was
continued for 10 min. The reaction mixture was diluted with DCM,
filtered through a pad of Celite, and then the Celite was washed
thoroughly with DCM. The aqueous layer was extracted with DCM
(3ꢂ5 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated. The residue was purified by
silica gel flash column chromatography using 6:4 hexanes/EtOAc as
the eluent to give (R)-4,4,4-trichloro-3-hydroxy-N-methoxy-N-
4. Experimental section
4.1. General information
The 1H and 13C NMR spectra were recorded at 360 or 500 MHz
and 90 or 125 MHz, respectively, and were referenced to acetone-d6
(2.05 and 30.83 ppm) or CDCl3 (7.26 and 77.0 ppm). High-
resolution mass spectra were recorded on an AutoSpec-UltimaÔ
NT mass spectrometer using electron ionization (EI) at 70 eV. All
melting points are uncorrected. TLC visualization was achieved by
UV light (254 nm) or KMnO4 staining. Commercial alkyl, allyl, and
vinyl Grignard reagents were purchased as 1.0 or 2.0 M solutions in
THF or diethyl ether from Aldrich and were used without titration.
Thienyl lithium was used directly from a Sure-seal bottle that was
purchased as a 1 M solution in hexanes from Aldrich. Alkyl lithium
reagents (e.g., butyllithium) were titrated using the procedure of
Kofron and Baclawski.22
methylbutanamide (14) as a white solid (18.5 g, 98% yield), mp
20
47e48 ꢁC, [
d
a]
þ39.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
D
ꢀ
Acetonitrile and benzene were dried over 4 A molecular sieves
ppm: 5.12 (d, J¼4.3 Hz,1H), 4.64e4.61 (m,1H), 3.69 (s, 3H), 3.17 (s,
prior to use. Diisopropylethyl amine was used directly from a Sure-
seal bottle that was purchased from Aldrich. THF and Et2O were
distilled from sodium benzophenone ketyl radical. Dichloro-
methane was distilled from calcium hydride. Chloral was pur-
3H), 3.04 (d, J¼16.1 Hz, 1H), 2.92 (dd, J¼16.1, 9.4 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d ppm: 170.9, 102.7, 79.0, 61.3, 34.3, 32.0; FTIR:
3373 (s), 2978 (m), 2943 (s), 1635 (s), 1462 (s) cmꢀ1; HRMS m/z
calcd for C7H9Cl3O2 248.9726; found 248.9721.
ꢀ
€
chased from Riedel-de Haen and distilled neat onto 4 A molecular
sieves. Acetyl chloride was distilled from one-tenth the volume of
N,N-dimethylaniline. Anhydrous acetic acid was prepared by stir-
ring a 1:1 mixture of acetic acid with acetic anhydride for 1 h, and
4.3. Synthesis of (R)-b-ketotrichloromethyl carbinols (12)
4.3.1. (R)-4,4,4-Trichloro-3-hydroxy-1-phenylbutan-1-one (12a). Com-
pound 12a was prepared by a modification of Fujisawa’s reported
procedure.8a To a solution of powdered AlCl3 (3.75 mmol, 500 mg)
in benzene (20.0 mL) was added a solution of (R)-7 (1 mmol,
189 mg) in benzene (10 mL) at 0 ꢁC. The mixture was warmed to
room temperature and stirred. After 12 h, the reaction mixture was
cooled to 0 ꢁC and quenched with aqueous saturated NH4Cl
(w20 mL). The aqueous layer was extracted with benzene
(3ꢂ5 mL). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated. The residue was purified by
silica gel flash column chromatography using 8:2 hexanes/Et2O as
ꢀ
then the acetic acid was distilled onto 4 A molecular sieves.
4.2. Synthesis of (R)-7 and 14
4.2.1. (R)-4-Trichloromethyl-2-oxetanone
((R)-7). (R)-4-
Trichloromethyl-2-oxetanone ((R)-7) is occasionally commercially
available from Aldrich, or it can be prepared on a 250 mmol scale
using the following protocol.7,23 A dry 1 L three-neck round-bottom
flask was fitted with two dry addition funnels under a blanket of
argon. The three-neck round-bottom flask was charged with quini-
dine (1.25 mmol, 406 mg) and freshly distilled diethyl ether
(165 mL). Anhydrous diisopropylethyl amine (287.5 mmol, 47.5 mL)
was added and the solution was cooled to ꢀ15 ꢁC. A solution of
freshly distilled chloral (250 mmol, 24.4 mL) in 115 mL of anhydrous
diethyl ether was added to one of the addition funnels. A solution of
freshly distilled acetyl chloride (250 mmol, 17.8 mL) in 115 mL of
anhydrous diethyl ether was added to the other addition funnel. The
chloral and the acetyl chloride solutions were added to the reaction
mixture simultaneously over 1 h at approximately equal rates. After
the addition was complete, the reaction mixture was stirred for an
additional 2 h. Aqueous 1 N HCl(125 mL) was added and the reaction
mixture was warmed to room temperature. The phases were sepa-
rated, and the aqueous phase was extracted with diethyl ether
(3ꢂ30 mL). The combined organic phases were washed with
the eluent to give (R)-4,4,4-trichloro-3-hydroxy-1-phenylbutan-1-
20
one (12a) as a white solid (239 mg, 89% yield), mp 62e63 ꢁC, [
a]
D
þ35.2 (c 1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm: 7.98e7.96
(m, 2H), 7.61e7.57 (m, 1H), 7.46 (t, J¼7.6 Hz, 2H), 4.91 (ddd, J¼8.7,
5.0, 2.1 Hz, 1H), 4.39 (d, J¼5.0 Hz, 1H), 3.62 (dd, J¼17.4, 2.1 Hz, 1H),
3.52 (dd, J¼17.4, 8.7 Hz,1H); 13C NMR (90 MHz, CDCl3)
d ppm: 197.1,
136.3,133.9,128.8,128.3,102.5, 79.0, 40.7; FTIR: 3464 (m), 3055 (m),
2927 (w), 1686 (s), 1446 (w) cmꢀ1; HRMS m/z calcd for C10H9Cl3O2
265.9668; found 247.9562, which corresponds to [MꢀH2O]þ.
4.3.2. (R)-4,4,4-Trichloro-1-(furan-2-yl)-3-hydroxybutan-1-one
(12b). n-Butyllithium (500 mL of a 2.5 M solution in hexanes,
1.25 mmol) was added slowly to a stirred solution of furan (100 mL,
1.38 mmol) in dry THF (0.55 mL) at ꢀ78 ꢁC under a blanket of argon.

5400
A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
The solution was allowed to warm to 0 ꢁC, stirred for an additional
30 min, and then cooled to ꢀ40 ꢁC. To a solution of Weinreb amide
14 (251 mg, 1 mmol) in anhydrous THF (2 mL) in a separate round-
bottom flask at ꢀ15 ꢁC, was added isopropylmagnesium chloride
(2 M in THF, 0.96 mmol, 0.48 mL). After 1 h, the ꢀ40 ꢁC furyl lith-
ium solution (2.5 M in THF, 1.25 mmol) was added dropwise via
cannula and the reaction mixture was stirred for an additional 4 h
at ꢀ15 ꢁC. The cold reaction was quenched by transferring it
through a 0 ꢁC 1 M aqueous HCl solution via cannula. The tem-
perature was allowed to rise to room temperature, the mixture was
diluted with EtOAc, and the layers were separated. The aqueous
layer was extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated. The residue was purified by silica gel flash column chro-
matography using 8:2 hexanes/Et2O as the eluent to give the (R)-
4,4,4-trichloro-1-(furan-2-yl)-3-hydroxybutan-1-one (12b) as
4.45 (br s, 1H), 3.24 (d, J¼6.9 Hz, 2H), 3.07 (dd, J¼17.4, 2.1 Hz, 1H),
2.93 (dd, J¼17.4, 9.0 Hz, 1H); 13C NMR (90 MHz, CDCl3)
d ppm:
205.7, 129.4, 119.6, 102.5, 78.3, 48.3, 44.1; FTIR: 3421 (s), 3055 (w),
2962 (w), 1716 (m), 1417 (m) cmꢀ1; HRMS m/z calcd for C7H9Cl3O2
229.9668; found 113.0599, which corresponds to [MꢀCCl3].
4.3.5. (R)-6,6,6-Trichloro-5-hydroxyhex-1-en-3-one (12e). To a solu-
tion of Weinreb amide 14 (251 mg,1 mmol) in anhydrous THF (2 mL)
at ꢀ15 ꢁC was added isopropylmagnesium chloride (2 M in THF,
0.96 mmol, 0.48 mL). The reaction mixture was stirred for 1 h, then
vinylmagnesium chloride (1 M in THF, 1.25 mmol, 1.25 mL) was
added, and the reaction mixture was stirred for an additional 4 h.
The ꢀ15 ꢁC reaction was quenched by transferring it through a 0 ꢁC
1 M aqueous HCl solution via cannula. The temperature was allowed
to rise to room temperature, the mixture was diluted with EtOAc,
and the layers were separated. The aqueous layer was extracted with
EtOAc (3ꢂ5 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated. The residue was purified
by silica gel flash column chromatography using 8:2 hexanes/Et2O to
give (R)-6,6,6-trichloro-5-hydroxyhex-1-en-3-one (12e) as a white
a white solid (219 mg, 85% yield), mp 66e67 ꢁC, [
a
]
20 þ30.8 (c 1.0,
D
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
ppm: 7.64 (dd, J¼0.5, 1.5 Hz,
1H), 7.29 (dd, J¼0.5, 3.5 Hz, 1H), 6.58 (dd, J¼3.5, 1.5 Hz, 1H), 4.83
(ddd, J¼2.0, 4.0, 9.0 Hz, 1H), 3.67 (d, J¼4.0 Hz, 1H), 3.50 (dd, J¼2.0,
17.0 Hz, 1H), 3.37 (dd, J¼9.0, 17.0 Hz, 1H); 13C NMR (125 MHz,
solid (159 mg, 73% yield), mp 36e37 ꢁC, [
a]
D
20 þ29.0 (c 1.0, CH2Cl2).
CDCl3)
d
ppm: 185.6, 152.2, 147.1, 118.3, 112.6, 102.5, 78.7, 40.6; FTIR:
1H NMR (360 MHz, CDCl3)
d
ppm: 6.42 (dd, J¼17.7, 10.1 Hz, 1H), 6.32
3400 (m), 3054 (m), 2986 (m), 1670 (m), 1421 (m) cmꢀ1; HRMS m/z
(dd, J¼17.7, 1.2 Hz, 1H), 5.96 (dd, J¼10.1, 1.2 Hz, 1H), 4.73 (ddd, J¼8.9,
4.6, 2.1 Hz, 1H), 3.73 (dd, J¼4.6, 1.0 Hz, 1H), 3.26 (ddd, J¼17.3, 2.1,
1.0 Hz, 1H), 3.12 (dd, J¼17.3, 8.9 Hz, 1H); 13C NMR (90 MHz, CDCl3)
calcd for C8H7Cl3O3 255.9461; found 255.9461.
4.3.3. (R)-4,4,4-Trichloro-3-hydroxy-1-(thiophen-2-yl)butan-1-one
(12c). To a solution of Weinreb amide 14 (251 mg, 1 mmol) in an-
hydrous THF (2 mL) at ꢀ15 ꢁC, was added isopropylmagnesium
chloride (2 M in THF, 0.96 mmol, 0.48 mL) and the reaction mixture
was stirred for 1 h. Thienyl lithium (1 M in hexanes, 1.25 mmol,
1.25 mL) was added and reaction mixture was stirred for an addi-
tional 4 h. The ꢀ15 ꢁC reaction was quenched by transferring it
through a 0 ꢁC 1 M aqueous HCl solution via cannula. The tem-
perature was allowed to rise to room temperature, the mixture was
diluted with EtOAc, and the layers were separated. The aqueous
layer was extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated. The residue was purified by silica gel flash column chro-
matography using 8:2 hexanes/Et2O as the eluent to give (R)-4,4,4-
d ppm: 197.4, 136.1, 130.2, 102.5, 78.5, 41.4; FTIR: 3460 (s), 3055 (s),
2987 (m), 2306 (m), 1709 (s), 1421 (s) cmꢀ1; HRMS m/z calcd for
C6H7Cl3O2 215.9512, found 99.0520, which corresponds to [MꢀCCl3].
4.3.6. (R)-1,1,1-Trichloro-2-hydroxydecan-4-one (12f). To a solution
of Weinreb amide 14 (251 mg, 1 mmol) in anhydrous toluene
(5 mL) at ꢀ15 ꢁC, was added hexylmagnesium bromide (2 M in
diethyl ether, 2.26 mmol, 1.13 mL), and the reaction mixture was
stirred for an additional 12 h. The ꢀ15 ꢁC reaction was quenched by
transferring it through a 0 ꢁC 1 M aqueous HCl solution via cannula.
The temperature was allowed to rise to room temperature, the
mixture was diluted with EtOAc, and the layers were separated. The
aqueous layer was extracted with EtOAc (3ꢂ5 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The residue was purified by silica gel flash column
chromatography using 8:2 hexanes/Et2O as the eluent to give (R)-
trichloro-3-hydroxy-1-(thiophen-2-yl)butan-1-one (12c) as a yel-
20
low oil (238 mg, 87% yield), [
(360 MHz, CDCl3)
a
]
D
þ30.0 (c 0.50, CH2Cl2). 1H NMR
d
ppm: 7.81 (dd, J¼3.9, 1.1 Hz, 1H), 7.72 (dd, J¼5.0,
1,1,1-trichloro-2-hydroxydecan-4-one (12f) as a yellow oil (186 mg,
20
1.1 Hz, 1H), 7.17 (dd, J¼5.0, 3.9 Hz, 1H), 4.84 (ddd, J¼9.0, 4.4, 2.1 Hz,
68% yield), [
d
a
]
D
þ25.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
1H), 3.69 (dd, J¼4.4, 0.7 Hz, 1H), 3.58 (ddd, J¼16.8, 2.1, 0.7 Hz, 1H),
ppm: 4.65 (ddd, J¼9.1, 4.4, 2.0 Hz, 1H), 3.74 (d, J¼4.4 Hz, 1H), 3.07
3.43 (dd, J¼16.8, 9.0 Hz, 1H); 13C NMR (90 MHz, CDCl3)
d
ppm:
(dd, J¼17.3, 2.0 Hz, 1H), 2.90 (dd, J¼17.3, 9.1 Hz, 1H), 2.50 (t,
J¼7.5 Hz, 2H), 1.69 (br s, 1H), 1.62e1.59 (m, 1H), 1.32e1.29 (m, 6H),
189.7, 143.3, 134.9, 133.1, 128.3, 102.5, 78.9, 41.3; FTIR: 3437(s), 3053
(w), 2981 (w), 1660 (s), 1421(m) cmꢀ1; HRMS m/z calcd for
C8H7Cl3O2S 271.9232; found 271.9231.
0.88 (t, J¼6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d ppm: 208.2,
102.5, 78.8, 44.3, 43.9, 31.5, 28.7, 23.5, 22.4, 14.0; FTIR: 3423 (m),
3055 (m), 2986 (m), 2859 (m), 1716 (m) cmꢀ1; HRMS m/z calcd for
C10H17Cl3O2 274.0294, found 274.0302.
4.3.4. (R)-7,7,7-Trichloro-6-hydroxyhept-1-en-4-one (12d). To a so-
lution of Weinreb amide 14 (251 mg, 1 mmol) in anhydrous THF
(2 mL) at ꢀ15 ꢁC, was added isopropylmagnesium chloride (2 M in
THF, 0.96 mmol, 0.48 mL) and the reaction mixture was stirred for
1 h. Allylmagnesium chloride (2 M in THF, 1.25 mmol, 0.625 mL)
was added, and the reaction mixture was stirred for an additional
4 h. The ꢀ15 ꢁC reaction was quenched by transferring it through
a 0 ꢁC 1 M aqueous HCl solution via cannula. The temperature was
allowed to rise to room temperature, the mixture was diluted with
EtOAc, and the layers were separated. The aqueous layer was
extracted with EtOAc (3ꢂ5 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated. The res-
idue was purified by silica gel flash column chromatography using
8:2 hexanes/Et2O as the eluent to give (R)-7,7,7-trichloro-6-
hydroxyhept-1-en-4-one (12d) as a yellow oil (204 mg, 88%
4.4. General procedure for the synthesis of syn-diols (15)
The syn-diols (15) were prepared by a modification of the pro-
cedure reported by Prasad et al.15 To a solution of a
b-ketotri-
chloromethyl carbinol 12 (1 mmol) in freshly distilled THF (10 mL)
and anhydrous methanol (2 mL) at room temperature under argon
was added diethylmethoxyborane (0.14 mL, 1.2 mmol) via syringe.
The reaction mixture was stirred at room temperature for 30 min
and then cooled to ꢀ70 ꢁC. Sodium borohydride (53 mg, 1.4 mmol)
was added under positive pressure of argon. The mixture was
stirred for 12 h at ꢀ70 ꢁC then quenched at ꢀ70 ꢁC by addition of
0.5 mL of 30% aqueous H2O2. The mixture was allowed to warm
slowly to ambient temperature then concentrated. The residue was
dissolved in water (2 mL) and extracted with EtOAc (3ꢂ5 mL). The
combined organic layers were dried over MgSO4 and concentrated.
yield), [
a
]
20 þ33.6 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
D
5.92e5.81 (m, 1H), 5.20e5.11 (m, 2H), 4.63 (dd, J¼9.0, 2.1 Hz, 1H),

A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
5401
The mixture was purified by flash chromatography on silica gel to
afford the corresponding syn-diol (15) as outlined below.
NMR (500 MHz, CDCl3)
d
ppm: 4.94 (s, 1H), 4.26 (d, J¼9.7 Hz, 1H),
3.93e3.89 (m, 1H), 3.35 (s, 1H), 2.21 (dt, J¼14.5, 2.2 Hz, 1H), 1.77 (dt,
J¼14.5, 9.8 Hz, 1H), 1.57e1.46 (m, 2H), 1.35e1.21 (m, 8H), 0.87 (t,
4.4.1. (1S,3R)-4,4,4-Trichloro-1-phenylbutane-1,3-diol
(15a). The
J¼6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d ppm: 103.0, 82.8, 71.4,
crude material was purified by silica gel flash chromatography using
37.8, 37.5, 31.7, 29.2, 25.1, 22.5, 14.0; FTIR: 3403 (m), 3054 (m), 2986
(m), 2868 (m), 1421 (m) cmꢀ1; m/z calcd for C10H19Cl3O2 258.0345;
found 258.0344, which corresponds to [MꢀH2O]þ.
6:4 hexane/Et2O asthe eluent. The indicated compoundwasobtained
as a yellow oil (261 mg, 97% yield), mp 120e121 ꢁC, [
a]
D
20 þ41.2 (c 1.0,
CH2Cl2). 1H NMR (360 MHz, acetone-d6)
d ppm: 7.45e7.26 (m, 5H),
5.88 (d, J¼5.3 Hz, 1H), 5.04e4.99 (m, 1H), 4.73 (d, J¼3.5 Hz, 1H),
4.5. General procedure for the synthesis of anti-diols (16)
4.02e3.97 (m, 1H), 2.44e2.38 (m, 1H), 2.25e2.17 (m, 1H); 13C NMR
(90 MHz, acetone-d6)
d
ppm: 146.2, 130.1, 129.3, 128.0, 106.0, 82.8,
The anti-diols (16) were prepared by a modification of the
method reported by Evans et al.16 To a solution of tetramethy-
lammonium triacetoxyborohydride (2.148 g, 8 mmol) in anhydrous
acetonitrile (4.5 mL) was added anhydrous acetic acid (4.5 mL). The
mixture was stirred at room temperature for 1 h. The mixture then
was cooled to less than ꢀ45 ꢁC (we found that diastereoselectivity
was severely compromised when the bath temperature exceeded
73.6, 42.8; FTIR: 3415 (s), 3055 (w), 2987 (w),1641 (s),1421 (w) cmꢀ1
;
HRMS m/z calcd for C10H11Cl3O2 267.9825; found 267.9818.
4.4.2. (1S,3R)-4,4,4-Trichloro-1-(furan-2-yl)butane-1,3-diol
(15b). The crude material was purified by silica gel flash chroma-
tography using 6:4 hexane/Et2O as the eluent. The indicated com-
pound was obtained as a white solid (228 mg, 88% yield), mp
ꢀ4 ꢁC), and
a solution of b-ketotrichloromethyl carbinol 12
20
102e103 ꢁC, [
d
a
]
D
þ9.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
(1 mmol) in anhydrous acetonitrile (1.5 mL) was added slowly via
syringe. The mixture was stirred at ꢀ45 to ꢀ50 ꢁC for 18e36 h. The
reaction was quenched with 15 mL of 0.5 N aqueous sodium po-
tassium tartrate and warmed slowly to room temperature. After
diluting with dichloromethane, the layers were separated. The or-
ganic phase was then washed with a saturated solution of aqueous
sodium bicarbonate. The aqueous phase was back extracted with
dichloromethane (4ꢂ5 mL), and the combined organic layers were
washed with a saturated solution of aqueous sodium bicarbonate
until pH >7. The resultant organics were dried over MgSO4 and
concentrated. The crude product was purified by flash chromatog-
raphy on silica gel to afford the corresponding anti-diol (16) as
outlined below.
ppm: 7.41 (dd, J¼1.8, 0.8 Hz, 1H), 6.37 (dd, J¼3.2, 1.8 Hz, 1H), 6.34
(d, J¼3.2 Hz, 1H), 5.06e5.02 (m, 1H), 4.22 (ddd, J¼10.0, 3.8, 2.0 Hz,
1H), 3.85 (dd, J¼3.8, 0.8 Hz, 1H), 2.83 (d, J¼3.8 Hz, 1H), 2.64e2.60
(m, 1H), 2.31e2.25 (m, 1H); 13C NMR (125 MHz, CDCl3)
d ppm:
154.7,142.5, 110.3,106.7,102.7, 81.7, 66.4, 36.7; FTIR: 3428 (m), 3054
(m), 2986 (m), 1421 (m) cmꢀ1; HRMS m/z calcd for C8H9Cl3O3
257.9671; found 257.9626.
4.4.3. (1S,3R)-4,4,4-Trichloro-1-(thiophen-2-yl)butane-1,3-diol
(15c). The crude material was purified by silica gel flash chroma-
tography using 6:4 hexane/Et2O as the eluent. The indicated com-
pound was obtained as a yellow oil (259 mg, 94% yield), [
a
]
20 þ10.0
D
(c 0.6, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d
ppm: 7.31 (d, J¼5.0 Hz,
1H), 7.06 (d, J¼3.0 Hz, 1H), 7.00 (dd, J¼5.0, 3.6 Hz, 1H), 5.32e5.27
(m, 1H), 4.25e4.21 (m, 1H), 3.78 (d, J¼3.7 Hz, 1H), 2.89 (d, J¼2.7 Hz,
1H), 2.57 (dd, J¼14.2, 3.7 Hz, 1H), 2.36e2.29 (m, 1H); 13C NMR
4.5.1. (1R,3R)-4,4,4-Trichloro-1-phenylbutane-1,3-diol
(16a). The
crude material was purified by silica gel flash chromatography using
6:4 hexane/Et2O as the eluent. The indicated compound was
20
(90 MHz, CDCl3)
d
ppm: 146.6, 126.8, 125.3, 124.3, 102.7, 81.9, 69.0,
obtained as a white solid (228 mg, 85% yield), mp 105e10 ꢁC, [
a]
D
40.3; FTIR: 3417 (s), 3055 (s), 2987 (m), 2306 (m), 1423 (m) cmꢀ1
;
þ65.7 (c 2.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm: 7.42e7.30
HRMS m/z calcd for C8H9Cl3O2S 273.9389; found 273.9372.
(m, 5H), 5.11 (d, J¼9.5 Hz, 1H), 4.43 (dd, J¼9.5, 2.7 Hz, 1H), 3.34 (d,
J¼3.7 Hz, 1H), 2.45 (dd, J¼14.3, 9.5 Hz, 1H), 2.35 (d, J¼3.5 Hz, 1H),
4.4.4. (2R,4R)-1,1,1-Trichlorohept-6-en-2,4-diol (15d). The crude
material was purified by silica gel flash chromatography using 6:4
hexane/Et2O as the eluent. The indicated compound was obtained as
2.09e2.04 (m, 1H); 13C NMR (125 MHz, CDCl3)
d ppm: 143.7, 128.7,
127.9, 125.5, 103.8, 79.9, 70.9, 40.2; FTIR: 3410 (m), 3055 (m), 2986
(m), 1643 (m), 1423 (m) cmꢀ1; HRMS m/z calcd for C10H11Cl3O2
267.9825; found 267.9828.
a colorless oil (184 mg, 79% yield), [a D20
]
þ41.0 (c 1.0, CH2Cl2). 1H NMR
(360 MHz, CDCl3)d ppm: 5.88e5.77 (m,1H), 5.22e5.16 (m, 2H), 4.31 (dt,
J¼10.0, 2.1 Hz), 4.23 (d, J¼2.1 Hz, 1H), 4.05e3.97 (m, 1H), 2.59 (d, J¼2.1
4.5.2. (1R,3R)-4,4,4-Trichloro-1-(furan-2-yl)butane-1,3-diol
(16b). The crude material was purified by silica gel flash chromatog-
1H), 2.42e2.25 (m, 3H), 1.88e1.79 (m, 1H); 13C NMR (125 MHz, CDCl3)
d
ppm: 133.4, 119.2,102.8, 82.7, 70.1, 42.2, 37.3; FTIR: 3581 (m), 3055 (s),
raphy using 6:4 hexane/Et2O as the eluent. The indicated compound
20
2985(s), 2306 (m), 1423 (s) cmꢀ1; HRMS m/z calcd for C7H11Cl3O2
231.9825; found 115.0757, which corresponds to [MꢀCCl3]þ.
was obtained as a white solid (231 mg, 89% yield), mp 81e82 ꢁC, [
a
]
D
þ25.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm: 7.40 (d,
J¼2.0 Hz, 1H), 6.36 (dd, J¼2.0, 3.0 Hz, 1H), 6.32 (d, J¼3.0 Hz, 1H),
5.11e5.07 (m,1H), 4.49e4.46 (m,1H), 3.13 (dd, J¼1.5, 5.0 Hz,1H), 2.63e
2.57 (m, 1H), 2.28 (d, J¼6.0 Hz, 1H), 2.17e2.12 (m, 1H); 13C NMR
4.4.5. (2R,4S)-1,1,1-Trichlorohex-5-en-2,4-diol (15e). The crude ma-
terial was purified by silica gel flash chromatography using 6:4
hexane/Et2O as the eluent. The indicated compound was obtained
(90 MHz, CDCl3)
d ppm: 155.6, 142.3, 110.3, 106.2, 103.6, 79.6, 64.6,
as a white solid (173 mg, 79% yield), mp 40e41 ꢁC, [
a
]
20 þ5.9 (c 1.0,
36.7; FTIR: 3421 (m), 3054 (m), 2987 (m), 1647 (m), 1421 (m) cmꢀ1
;
D
CH2Cl2). 1H NMR (360 MHz, CDCl3)
d
6.05e5.88 (m, 1H), 5.35 (m,
HRMS m/z calcd for C8H9Cl3O3 257.9671; found 257.9619.
1H), 5.25e5.17 (m, 1H), 4.52e4.41 (m, 1H), 4.29 (d, J¼9.9 Hz, 1H),
3.93 (s, 1H), 2.41 (s, 1H), 2.30 (ddd, J¼14.4, 4.0, 2.0 Hz, 1H),
4.5.3. (1R,3R)-4,4,4-Trichloro-1-(thiophen-2-yl)butane-1,3-diol
(16c). The crude material was purified by silica gel flash chroma-
tography using 6:4 hexane/Et2O as the eluent. The indicated com-
1.99e1.90 (m, 1H). 13C NMR (125 MHz, CDCl3)
d ppm: 139.3, 116.1,
102.8, 82.0, 71.9, 37.7; FTIR: 3584 (m), 3055 (s), 2987 (s), 2306 (m),
1425 (m) cmꢀ1; HRMS m/z calcd for C6H9Cl3O2 217.9668; found
101.0603, which corresponds to [MꢀCCl3]þ.
pound was obtained as a white solid (220 mg, 80% yield), mp
20
119e12 ꢁC, [
d
a]
þ41.3 (c 2.2, CH2Cl2). 1H NMR (360 MHz, CDCl3)
D
ppm: 7.28 (dd, J¼5.0, 1.3 Hz, 1H), 7.06e7.03 (m, 1H), 7.00 (dd,
4.4.6. (2R,4R)-1,1,1-Trichlorodecane-2,4-diol (15f). The crude mate-
rial was purified by silica gel flash chromatography using 6:4
hexane/Et2O as the eluent. The indicated compound was obtained
J¼5.0, 3.5 Hz, 1H), 5.40e5.32 (m, 1H), 4.49 (ddd, J¼10.0, 4.7, 1.8 Hz,
1H), 3.17 (dd, J¼4.7, 1.8 Hz, 1H), 2.56 (ddt, J¼14.0, 9.5, 1.8 Hz, 1H),
2.48 (dd, J¼5.2, 0.9 Hz, 1H), 2.24e2.16 (m, 1H); 13C NMR (90 MHz,
as a colorless oil (236 mg, 85% yield), [
a]
20 þ20.0 (c 5.0, CH2Cl2), 1H
CDCl3) d ppm: 147.5, 126.9, 124.8, 123.7, 103.5, 79.6, 66.9, 40.1; FTIR:
D

5402
A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
3417 (s), 3055 (s), 2987 (s), 1423 (m) cmꢀ1; HRMS m/z calcd for
C8H9Cl3O2S 273.9389; found 273.9387.
stirred at room temperature until judged complete by TLC analysis
(12e24 h), then it was cooled to 0 ꢁC and the pH was adjusted to
pH¼2 with 0.5 N HCl (or an aqueous solution of KH2PO4 with 17d).
This mixture was stirred vigorously for 1e4 h to promote lactoni-
zation. The aqueous phase was extracted with EtOAc (5ꢂ5 mL),
dried with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel flash chro-
matography using hexane/EtOAc as eluent as outlined below.
4.5.4. (2R,4S)-1,1,1-Trichlorohept-6-ene-2,4-diol (16d). The crude
material was purified by silica gel flash chromatography using 6:4
hexane/Et2O as the eluent. The indicated compound was obtained
20
as a white solid (184 mg, 79% yield), mp 102e10 ꢁC, [
a
]
ꢀ40.0 (c
D
1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm: 5.89e5.78 (m, 1H),
5.22e5.16 (m, 2H), 4.43 (d, J¼10.0 Hz, 1H), 4.08e4.02 (m, 1H), 3.34
(br s, 1H), 2.42e2.23 (m, 2H), 2.15e2.08 (m, 1H), 1.95 (s, 1H),
4.7.1. (3S,5S)-3-Azidodihydro-5-phenylfuran-2(3H)-one (17a). The
crude material was purified by silica gel flash chromatography
1.90e1.83 (m, 1H); 13C NMR (90 MHz, CDCl3)
d ppm: 133.8, 119.1,
103.9, 79.6, 67.3, 42.0, 37.8; FTIR: 3581 (m), 3055 (s), 2985 (s), 1423
(s) cmꢀ1; HRMS m/z calcd for C7H11Cl3O2 231.9825; found 115.0757,
which corresponds to [MꢀCCl3]þ.
using 8:2 hexane/EtOAc as the eluent. The indicated compound was
20
obtained as yellow oil (50 mg, 98% yield), [
a
]
ꢀ207.7 (c 1.0,
D
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
ppm: 7.42e7.34 (m, 5H), 5.40
(dd, J¼10.4, 5.6 Hz, 1H), 4.50 (dd, J¼11.1, 8.6 Hz, 1H), 2.98e2.92 (m,
4.5.5. (2R,4R)-1,1,1-Trichlorohex-5-ene-2,4-diol (16e). The crude
material was purified by silica gel flash chromatography using 6:4
hexane/Et2O as the eluent. The indicated compound was obtained
1H), 2.14 (dt, J¼12.9,11.0 Hz,1H); 13C NMR (125 MHz, CDCl3)
d ppm:
172.9, 137.2, 129.1, 128.9, 125.7, 78.4, 58.1, 37.3; FTIR: 2927 (w), 2848
(w), 1780 (s), 1456 (w) cmꢀ1; HRMS m/z calcd for C10H9N3O2
203.0695; found 175.0628, which corresponds to [MꢀN2]þ.
as a white solid (169 mg, 77% yield), mp 103e104 ꢁC, [
a
]
20 þ22.0 (c
D
1.0, CH2Cl2).. 1H NMR (360 MHz, CDCl3)
d
ppm: 5.96 (ddd, J¼17.2,
10.5, 5.4 Hz, 1H), 5.36 (dt, J¼17.2, 1.4 Hz, 1H), 5.21 (dt, 10.51, 1.4 Hz,
1H), 4.54 (s, 1H), 4.43e4.39 (m, 1H), 3.48 (d, J¼4.2 Hz, 1H),
2.23e2.16 (m, 2H), 2.01e1.93 (m, 1H); 13C NMR (90 MHz, CDCl3)
4.7.2. (3S,5S)-Dihydro-3-hydroxy-5-phenylfuran-2(3H)-one
(17b). The crude material was purified by silica gel flash chroma-
tography using 59:40:1 hexane/EtOAc/triethylamine as the eluent.
The indicated compound was obtained as a yellow oil (41 mg, 93%
d
ppm: 139.8, 115.3, 103.6, 79.7, 69.6, 37.7; FTIR: 3415 (m), 3054 (m),
2987 (m), 1421 (m) cmꢀ1; HRMS m/z calcd for C6H9Cl3O2 217.9668;
yield), [
a
]
20 ꢀ32.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
D
found 217.9666.
7.43e7.36 (m, 5H), 5.43 (dd, J¼10.2, 5.7 Hz, 1H), 4.70 (dd, J¼11.0,
8.3 Hz, 1H), 3.74 (t, J¼3 Hz, 1H), 3.25e3.18 (m, 1H), 2.53e2.46 (m,
4.5.6. (2R,4S)-1,1,1-Trichlorodecane-2,4-diol (16f). The crude mate-
rial was purified by silica gel flash chromatography using 6:4
hexane/Et2O as the eluent. The indicated compound was
obtained as a white solid (255 mg, 92% yield), mp 107e108 ꢁC,
1H); 13C NMR (125 MHz, CDCl3)
d ppm: 176.9, 137.7, 129.0, 128.8,
125.8, 77.7, 69.0, 39.6; FTIR: 3435 (s), 3086 (m), 2933 (m), 2852 (m),
1776 (s), 1637 (m), 1442 (w) cmꢀ1; HRMS m/z calcd for C10H10O3
178.0630; found 178.0628.
[
a
]
20 þ26.0 (c 1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm: 4.39
D
(dd, J¼8.3, 1.8 Hz, 1H), 4.02e3.95 (m, 2H), 2.25 (br s, 1H),
2.10e2.05 (m, 1H), 1.89e1.83 (m, 1H), 1.58e1.53 (m, 2H),
1.33e1.30 (m, 8H), 0.88 (t, J¼6.6 Hz, 3H); 13C NMR (90 MHz,
4.7.3. (3S,5S)-3-Azidodihydro-5-(furan-2-yl)dihydrofuran-2(3H)-
one (17c). The crude material was purified by silica gel flash
chromatography using 6:4 hexane/EtOAc as the eluent. The in-
dicated compound was obtained as a yellow oil (35 mg, 72% yield),
CDCl3)
d ppm: 104.0, 79.7, 68.8, 38.2, 37.7, 31.7, 29.2, 25.6, 22.6,
14.0; FTIR: 3421 (m), 3055 (m), 2987 (m), 1421 (m) cmꢀ1; HRMS
m/z calcd for C10H19Cl3O2 276.0451; found 258.0338, which cor-
responds to [MꢀH2O]þ.
[
a
]
20 ꢀ109.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm: 7.47
D
(d, J¼1.1 Hz, 1H), 6.51 (d, J¼3.3 Hz, 1H), 6.40 (dd, J¼3.3, 1.8 Hz, 1H),
5.40 (dd, J¼10.5, 5.9 Hz, 1H), 4.45 (dd, J¼11.1, 8.7 Hz, 1H), 2.82 (ddd,
J¼13.1, 8.7, 5.9 Hz, 1H), 2.50 (dt, J¼13.1, 10.8 Hz, 1H); 13C NMR
4.6. General procedure for the synthesis of cis-3-azidodihydro-
5-alkylfuran-2(3H)-ones and 3-azidodihydro-5-arylfuran-
2(3H)-ones (17)
(125 MHz, CDCl3) d ppm: 172.1, 148.7, 144.2, 110.9, 110.7, 71.4, 57.5,
32.8; FTIR: 3057 (m), 2989 (m), 1644 (m) cmꢀ1; HRMS m/z calcd for
C8H7N3O3 193.0487; found 193.0490.
The trichloromethyl carbinol 15 (0.25 mmol) in DME/water
(0.5:2.0 mL/mL) was placed in a 4-dram vial, and then sodium
azide (32 mg, 0.5 mmol) (CAUTION: may explode if ground or
contacted by some metal surfaces) and powdered NaOH (40 mg,
1.0 mmol) were added at once. The reaction mixture was vigor-
ously stirred at room temperature until judged complete by TLC
analysis (12e24 h), then it was cooled to 0 ꢁC and the pH was
adjusted to pH¼2 with 0.5 N HCl (or an aqueous solution of
KH2PO4 with 17c). This mixture was stirred vigorously for 1e4 h
to promote lactonization. The aqueous phase was extracted with
EtOAc (5ꢂ5 mL), dried with anhydrous Na2SO4, and concentrated
under reduced pressure. The crude product was purified by silica
gel flash chromatography using hexane/EtOAc as eluent as out-
lined below.
4.7.4. (3S,5S)-5-(Furan-2-yl)dihydro-3-hydroxyfuran-2(3H)-one
(17d). The crude material was purified by silica gel flash chro-
matography using 59:40:1 hexane/EtOAc/triethylamine as the el-
uent. The indicated compound was obtained as a yellow oil
20
(28 mg, 66% yield), [
CDCl3)
a
]
ꢀ42.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz,
D
d
ppm: 7.43 (d, J¼1.1 Hz, 1H), 6.42 (d, J¼3.2 Hz, 1H), 6.37
(dd, J¼3.2, 1.8 Hz, 1H), 5.60 (dd, J¼8.6, 2.8 Hz, 1H), 4.85 (t, J¼8.6 Hz,
1H), 3.05 (br s, 1H), 2.83 (ddd, J¼13.1, 8.2, 2.8 Hz, 1H), 2.59 (dt,
J¼13.1, 8.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d ppm: 177.0, 150.6,
143.7, 110.6, 109.8, 71.7, 67.3, 34.7; FTIR: 3429 (m), 3055 (m), 2987
(m), 1639 (m), 1421 (m) cmꢀ1; HRMS m/z calcd for C8H8O4
168.0423; found 168.0423.
4.7.5. (3S,5S)-3-Azidodihydro-5-(thiophen-2-yl)furan-2(3H)-one
(17e). The crude material was purified by silica gel flash chroma-
4.7. General procedure for the synthesis of cis-3-hydroxydihydro-
5-alkylfuran-2(3H)-ones and 3-hydroxydihydro-5-arylfuran-
2(3H)-ones (17)
tography using 8:2 hexane/EtOAc as the eluent. The indicated
20
compound was obtained as a yellow oil (50 mg, 98% yield), [a]
D
ꢀ109.0 (c 1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm: 7.40 (dd,
J¼5.1, 1.1 Hz, 1H), 7.14 (d, J¼3.6 Hz, 1H), 7.03 (dd, J¼5.1, 3.6 Hz, 1H),
5.63 (dd, J¼10.5, 5.6 Hz, 1H), 4.48 (dd, J¼11.2, 8.5 Hz, 1H), 2.99 (ddd,
J¼13.0, 8.5, 5.6 Hz, 1H), 2.31 (ddd, J¼13.0, 11.2, 10.5 Hz, 1H); 13C
The trichloromethyl carbinol (0.25 mmol) in DME/water
(0.5:2 mL/mL) was placed in a 4-dram vial, and then powdered
NaOH (40 mg, 1.0 mmol) was added. The reaction mixture was
NMR (125 MHz, CDCl3) d ppm: 172.0, 139.4, 127.3, 127.2, 127.1, 74.2,

A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
5403
20
57.9, 37.2; FTIR: 2925 (s), 2858 (m), 1780 (s), 1437 (m) cmꢀ1; HRMS
m/z calcd for C8H7N3O2S 209.0259; found 209.0260.
as a yellow oil (48 mg, 90% yield), [
NMR (360 MHz, CDCl3)
a]
ꢀ117.0 (c 1.0, CH2Cl2). 1H
D
d
ppm: 4.42e4.37 (m, 1H), 4.32 (dd, J¼11.0,
8.7 Hz, 1H), 2.63 (ddd, J¼12.9, 8.7, 5.4 Hz, 1H), 1.80e1.73 (m, 1H),
1.68e1.58 (m, 1H), 1.51e1.41 (m, 1H), 1.29e1.27 (m, 8H), 0.88 (t,
4.7.6. (3S,5S)-Dihydro-3-hydroxy-5-(thiophen-2-yl)furan-2(3H)-one
(17f). The crude material was purified by silica gel flash chroma-
tography using 59:40:1 hexane/EtOAc/triethylamine as the eluent.
The indicated compound was obtained as yellow oil (43 mg, 94%
J¼6.8 Hz, 3H); 13C NMR (90 MHz, CDCl3)
d ppm: 173.0, 77.9, 57.8,
35.2, 34.9, 31.5, 28.8, 24.8, 22.4,13.9; FTIR: 3055 (m), 2986 (m), 1641
(m), 1421 (m) cmꢀ1; HRMS m/z calcd for C10H17N3O2 211.1321;
found 211.1314.
yield), [
a
]
20 þ23.0 (c 0.5, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm:
D
7.40 (dd, J¼5.0, 1.2 Hz, 1H), 7.21e7.11 (m, 1H), 7.04 (dd, J¼5.0, 3.6 Hz,
1H), 5.60 (dd, J¼11.0, 5.2 Hz, 1H), 4.67 (dd, J¼11.2, 8.2 Hz, 1H), 3.05
(ddd, J¼12.7, 8.2, 5.2 Hz, 1H), 2.88 (br s, 1H), 2.44 (dt, J¼12.7, 11.1 Hz,
4.7.12. (3S,5R)-3-Hydroxy-5-hexyldihydrofuran-2-one
crude material was purified by silica gel flash chromatography using
59:40:1 hexane/EtOAc/triethylamine as the eluent. The indicated
(17l). The
1H);13C NMR (125 MHz, CDCl3)
d
ppm:176.2,139.9,127.2,127.1,127.0,
20
73.5, 68.8, 39.3; FTIR: 3695 (m), 3055 (m), 2987 (m), 1778 (m), 1423
compound was obtained as a yellow oil (44 mg, 95% yield), [a]
D
(m) cmꢀ1; HRMS m/z calcd for C8H8O3S 184.0194; found 184.0199.
ꢀ120.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm: 4.52 (dd,
J¼11.1, 8.4 Hz, 1H), 4.40e4.34 (m, 1H), 2.72e2.67 (m, 1H), 1.88 (dt,
J¼12.4, 10.9 Hz, 1H), 1.84e1.76 (m, 1H), 1.70e1.62 (m, 1H), 1.57 (br s,
1H), 1.50e1.44 (m, 1H), 1.34e1.27 (m, 7H), 0.89 (t, J¼6.9 Hz, 3H); 13C
4.7.7. (3S,5R)-5-Allyl-3-azidodihydrofuran-2(3H)-one
(17g). The
crude material was purified by silica gel flash chromatography
using 6:4 hexane/EtOAc as the eluent. The indicated compound was
NMR (125 MHz, CDCl3) d ppm: 177.4, 77.4, 68.7, 37.1, 35.3, 31.6, 28.9,
20
obtained as a yellow oil (39 mg, 93% yield), [
a
]
ꢀ197.0 (c 1.0,
24.9, 22.5, 14.0; FTIR: 3425 (m), 3054 (m), 2986 (m), 1774 (m), 1642
(m), 1421 (s) cmꢀ1. HRMS m/z calcd for C10H18O3 186.1256; found
186.1250.
D
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
ppm: 5.78e5.71 (m, 1H),
5.20e5.16 (m, 2H), 4.50e4.44 (m, 1H), 4.35 (dd, J¼10.9, 8.8 Hz, 1H),
2.61 (ddd, J¼13.0, 8.8, 5.5 Hz, 1H), 2.56e2.51 (m, 1H), 2.47e2.41 (m,
1H), 1.86e1.80 (m, 1H); 13C NMR (125 MHz, CDCl3)
d ppm: 172.8,
131.1, 119.6, 76.8, 57.6, 39.0, 34.1; FTIR: 3032 (m), 2850 (w), 1780 (s),
1626 (m), 1450 (m) cmꢀ1; HRMS m/z calcd for C7H9N3O2 167.0695;
found 139.0630, which corresponds to [MꢀN2]þ.
4.8. General procedure for the synthesis of trans-3-azidodihydro-
5-alkylfuran-2(3H)-ones and 3-azidodihydro-5-arylfuran-2(3H)-
ones (18)
4.7.8. (3S,5R)-5-Allyl-3-hydroxydihydrofuran-2(3H)-one (17h). The
crude material was purified by silica gel flash chromatography
using 59:40:1 hexane/EtOAc/triethylamine as the eluent. The in-
The trichloromethyl carbinol (0.25 mmol) in DME/water
(1:4 mL/mL) was placed in a 4-dram vial, and then sodium azide
(32 mg, 0.5 mmol) (CAUTION: may explode if ground or contacted
by some metal surfaces) and powdered NaOH (40 mg, 1.0 mmol)
were added at once. The reaction mixture was vigorously stirred at
room temperature until judged complete by TLC analysis
(12e24 h), then it was cooled to 0 ꢁC and the pH was adjusted to
pH¼2 with 0.5 N HCl (or an aqueous solution of KH2PO4 with 18c).
This mixture was stirred vigorously for 1e4 h to promote lactoni-
zation. The aqueous phase was extracted with EtOAc (5ꢂ5 mL),
dried with anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was purified by silica gel flash chro-
matography using hexane/EtOAc as eluent as outlined below.
dicated compound was obtained as a yellow oil (34 mg, 95% yield),
20
[
a]
ꢀ72.0 (c 0.5, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
D
5.83e5.74 (m, 1H), 5.21e5.18 (m, 2H), 4.53 (dd, J¼11.0, 8.4 Hz, 1H),
4.44 (dt, J¼11.0, 6.1 Hz, 1H), 2.71e2.65 (m, 2H), 2.59e2.56 (m, 1H),
2.50e2.46 (m, 1H), 1.95 (dt, J¼12.5, 10.8 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d ppm: 177.2, 131.6, 119.6, 76.3, 68.8, 39.4, 36.6;
FTIR: 3464 (m), 3062 (m), 2989 (m), 1775 (m), 1426 (m) cmꢀ1
;
HRMS m/z calcd for C7H10O3 142.0630; found 142.0630.
4.7.9. (3S,5S)-3-Azidodihydro-5-vinylfuran-2(3H)-one
(17i). The
crude material was purified by silica gel flash chromatography
using 6:4 hexane/EtOAc as the eluent. The indicated compound was
20
obtained as a yellow oil (26 mg, 69% yield), [
a
]
D
ꢀ152.0 (c 1.0,
4.9. General procedure for the synthesis of trans-3-
hydroxydihydro-5-alkylfuran-2(3H)-ones and 3-hydroxydihydro-
5-arylfuran-2(3H)-ones (18)
CH2Cl2). 1H NMR (500 MHz, CDCl3)
d
ppm: 5.87 (ddd, J¼17.1, 10.4,
6.7 Hz, 1H), 5.42 (d, J¼17.1 Hz, 1H), 5.34 (d, J¼10.4 Hz, 1H),
4.86e4.81 (m, 1H), 4.36 (dd, J¼10.8, 8.6 Hz, 1H), 2.72 (ddd, J¼13.0,
8.5, 5.8 Hz, 1H), 1.92 (dt, J¼13.0, 10.6 Hz, 1H); 13C NMR (125 MHz,
The trichloromethyl carbinol (0.25 mmol) in DME/water
(1:4 mL/mL) was placed in a 4-dram vial, and then powdered NaOH
(40 mg, 1.0 mmol) was added. The reaction mixture was stirred at
room temperature until judged complete by TLC analysis
(12e24 h), then it was cooled to 0 ꢁC and the pH was adjusted to
pH¼2 with 0.5 N HCl (or an aqueous solution of KH2PO4 with 18d).
This mixture was stirred vigorously for 1e4 h to promote lactoni-
zation. The aqueous phase was extracted with EtOAc (5ꢂ5 mL),
dried with anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was purified by silica gel flash chro-
matography using hexane/EtOAc as eluent as outlined below.
CDCl3)
d ppm: 172.6, 134.2, 119.4, 77.8, 57.5, 35.1; FTIR 3057 (m),
2989 (m), 1791 (m), 1432 (m) cmꢀ1; HRMS m/z calcd for C6H7N3O2
153.0538; found 111.0445, which corresponds to [MꢀN3]þ.
4.7.10. (3S,5S)-Dihydro-3-hydroxy-5-vinylfuran-2(3H)-one
(17j). The crude material was purified by silica gel flash chroma-
tography using 59:40:1 hexane/EtOAc/triethylamine as the eluent.
The indicated compound was obtained as a yellow oil (22 mg, 69%
yield), [
a
]
D
20 ꢀ20.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
5.90 (ddd, J¼17.1, 10.4, 6.7 Hz, 1H), 5.43 (d, J¼17.1 Hz, 1H), 5.34 (d,
J¼10.4 Hz,1H), 4.83e4.78 (m,1H), 4.57e4.54 (m,1H), 2.81e2.75 (m,
2H), 2.07e2.00 (m, 1H); 13C NMR (125 MHz, CDCl3)
d
ppm: 176.6,
4.9.1. (3S,5R)-3-Azidodihydro-5-phenylfuran-2(3H)-one (18a). The
crude material was purified by silica gel flash chromatography
134.6, 119.1, 77.2, 68.5, 37.3; FTIR: 3454 (m), 3048 (m), 2983 (m),
1770 (m), 1423 (m) cmꢀ1; HRMS m/z calcd for C6H8O3 128.0473;
found 111.0447, which corresponds to [MꢀOH]þ.
using 6:4 hexane/EtOAc as the eluent. The indicated compound was
20
obtained as a yellow oil (36 mg, 70% yield), [
CH2Cl2). 1H NMR (500 MHz, CDCl3)
7.30e7.28 (m, 2H), 5.64 (t, J¼6.5 Hz, 1H), 4.36 (dd, J¼7.8, 6.1 Hz, 1H),
2.59e2.44 (m, 2H); 13C NMR (125 MHz, CDCl3)
ppm: 172.7, 138.1,
129.0, 128.8, 125.1, 79.2, 57.1, 36.8; FTIR: 2927 (s), 2854 (m),1776 (s),
a
]
ꢀ175.6 (c 1.0,
D
d
ppm: 7.42e7.36 (m, 3H),
4.7.11. (3S,5R)-3-Azido-5-hexyldihydrofuran-2-one (17k). The crude
material was purified by silica gel flash chromatography using 6:4
hexane/EtOAc as the eluent. The indicated compound was obtained
d

5404
A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
20
1452 (m) cmꢀ1; HRMS m/z calcd for C10H9N3O2 203.0695; found
161.0628, which corresponds to [MꢀN2]þ.
obtained as a yellow oil (39 mg, 93% yield), [
a
]
ꢀ197.0 (c 1.0, in
D
CH2Cl2). 1H NMR (360 MHz, CDCl3)
d
ppm: 5.77e5.72 (m, 1H), 5.22
(s,1H), 5.19e5.18 (m,1H), 4.70e4.65 (m,1H), 4.29 (dd, J¼8.5, 4.7 Hz,
4.9.2. (3S,5R)-Dihydro-3-hydroxy-5-phenylfuran-2(3H)-one
(18b). The crude material was purified by silica gel flash chroma-
tography using 59:40:1 hexane/EtOAc/triethylamine as the eluent.
The indicated compound was obtained as a yellow oil (31 mg, 69%
1H), 2.50e2.39 (m, 2H), 2.26e2.16 (m, 2H); 13C NMR (125 MHz,
CDCl3)
d ppm: 172.9, 131.1, 119.9, 76.7, 57.1, 39.1, 33.0; FTIR: 3032
(m), 2927 (m), 2858 (w), 2116 (s), 1780 (s), 1628 (m), 1456 (m)
cmꢀ1; HRMS m/z calcd for C7H9N3O2 167.0695; found 139.0630,
which corresponds to [MꢀN2]þ.
yield), [
a
]
20 ꢀ19.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
D
7.41e7.35 (m, 3H), 7.30e7.28 (m, 2H), 5.72 (dd, J¼7.8, 4.2 Hz, 1H),
4.56 (t, J¼7.7 Hz, 1H), 3.01 (br s, 1H), 2.73e2.67 (m, 1H), 2.64e2.57
4.9.8. (3S,5S)-5-Allyl-3-hydroxydihydrofuran-2(3H)-one (18h). The
crude material was purified by silica gel flash chromatography
using 8:2 hexane/EtOAc as the eluent. The indicated compound was
obtained as a yellow oil (28 mg, 78% yield), 88:12 de. 1H NMR
(m, 1H); 13C NMR (125 MHz, CDCl3)
d ppm: 177.0, 138.8, 128.9,
128.5, 125.0, 78.5, 67.2, 38.2; FTIR: 3435 (s), 2933 (m), 2849 (w),
1776 (s), 1637 (m), 1439 (w) cmꢀ1; HRMS m/z calcd for C10H10O3
178.0630; found 178.0637.
(500 MHz, CDCl3)
d ppm: 5.81e5.72 (m, 1H), 5.24e5.16 (m, 1H),
4.58e4.47 (m, 2H), 2.88 (ddd, J¼13.5, 8.6, 5.8 Hz,1H), 2.64e2.58 (m,
4.9.3. (3S,5R)-3-Azidodihydro-5-(furan-2-yl)dihydrofuran-2(3H)-
one (18c). The crude material was purified by silica gel flash
chromatography using 6:4 hexane/EtOAc as the eluent. The in-
dicated compound was obtained as a yellow oil (29 mg, 60% yield),
1H), 2.52e2.46 (m, 1H), 2.22e2.16 (m, 1H); 13C NMR (125 MHz,
CDCl3)
d ppm: 171.8, 131.0, 119.6, 77.1, 51.0, 39.1, 38.0. Material
contained a minor impurity that could not be completely removed.
As such, compound was not characterized further.
[
a]
20 ꢀ177.0 (c 1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm: 7.44
D
(dd, J¼1.8, 0.7 Hz, 1H), 6.45e6.44 (m, 1H), 6.38 (dd, J¼3.3, 1.9 Hz,
1H), 5.57 (dd, J¼8.1, 4.0 Hz, 1H), 4.64 (t, J¼8.1 Hz, 1H), 2.77 (ddd,
J¼13.4, 8.1, 4.0 Hz, 1H), 2.44 (dt, J¼13.4, 8.1 Hz, 1H); 13C NMR
4.9.9. (3S,5R)-5-Vinyl-3-azidodihydrofuran-2(3H)-one
(18i). The
crude material was purified by silica gel flash chromatography using
6:4 hexane/EtOAc as the eluent. The indicated compound was
20
(125 MHz, CDCl3)
d
ppm: 172.6, 149.9, 143.8, 110.7, 110.2, 72.1, 56.9,
obtained as a yellow oil (21 mg, 55% yield), [
a]
ꢀ123.0 (c 1.0,
D
33.0; FTIR: 3055 (m), 2986 (m),1788 (m),1421 (m) cmꢀ1; HRMS m/z
CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm: 5.91e5.81 (m, 1H),
calcd for C8H7N3O3 193.0487; found 193.0490.
5.42e5.30 (m, 2H), 5.08e5.03 (m,1H), 4.29 (t, J¼7.6 Hz,1H), 2.31 (dd,
J¼7.6, 6.3 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d ppm: 172.7, 134.5,
4.9.4. (3S,5R)-Dihydro-3-hydroxy-5-(furan-2-yl)furan-2-(3H)-one
(18d). The crude material was purified by silica gel flash chroma-
tography using 59:40:1 hexane/EtOAc/triethylamine as the eluent.
The indicated compound was obtained as a yellow oil (29 mg, 52%
118.2, 78.2, 56.6, 34.3; FTIR: 3055 (m), 2987 (m),1780 (m),1423 (m)
cmꢀ1; HRMS m/z calcd for C6H7N3O2 153.0538; found 153.0532.
4.9.10. (3S,5S)-3-Azido-5-hexyldihydrofuran-2-one (18k). The crude
material was purified by silica gel flash chromatography using 6:4
yield), [
a
]
20 þ28.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
D
7.48 (d, J¼1.1 Hz, 1H), 6.52 (d, J¼3.3 Hz, 1H), 6.41 (dd, J¼3.3, 1.8 Hz,
1H), 5.37 (dd, J¼11.0, 5.5 Hz, 1H), 4.68e4.63 (m, 1H), 3.07 (d,
J¼2.5 Hz, 1H), 2.88 (ddd, J¼12.7, 8.3, 5.5 Hz, 1H), 2.61 (dt, J¼12.7,
hexane/EtOAc as the eluent. The indicated compound was obtained
20
as a yellow oil (44 mg, 84% yield), [
NMR (360 MHz, CDCl3)
a]
ꢀ190.0 (c 1.0, CH2Cl2). 1
H
D
d
ppm: 4.62e4.57 (m, 1H), 4.27 (dd, J¼8.1,
11.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
ppm: 176.3, 149.2, 144.0,
5.8 Hz, 1H), 2.24e2.19 (m, 1H), 2.16e2.11 (m, 1H), 1.72e1.68 (m, 1H),
1.60e1.57 (m, 1H), 1.43 (m, 1H), 1.31e1.28 (m, 7H), 0.88 (t, J¼6.8 Hz,
110.8,110.7, 70.7, 68.4, 34.9; FTIR: 3428 (m), 3055 (m), 2987 (m),1639
(m) cmꢀ1; HRMS m/z calcd for C8H8O4 168.0423; found 168.0422.
3H); 13C NMR (125 MHz, CDCl3)
d ppm: 173.0, 79.4, 57.3, 35.4, 34.2,
31.6, 28.9, 25.1, 22.5, 14.0; FTIR: 3055 (m), 2931 (m), 2859 (m), 1779
(m), 1641 (m), 1421 (m) cmꢀ1; HRMS m/z calcd for C10H17N3O2
211.1321; found 211.1324.
4.9.5. (3S,5R)-3-Azidodihydro-5-(thiophen-2-yl)furan-2(3H)-one
(18e). The crude material was purified by silica gel flash chroma-
tography using 6:4 hexane/EtOAc as the eluent. The indicated com-
pound was obtained as a yellow oil (43 mg, 83% yield), [
a
]
20 ꢀ215.0 (c
4.9.11. (3S,5S)-3-Hydroxy-5-hexyldihydrofuran-2-one
(18l). The
D
1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d
ppm: 7.37 (dd, J¼5.1,1.2 Hz,
crude material was purified by silica gel flash chromatography
using 59:40:1 hexane/EtOAc/triethylamine as the eluent. The in-
dicated compound was obtained as a yellow oil (36 mg, 78% yield),
1H), 7.10e7.09 (m,1H), 7.02 (dd, J¼5.1, 3.6 Hz,1H), 5.87e5.83 (m,1H),
4.45 (dd, J¼7.8, 6.7 Hz,1H), 2.71e2.64 (m,1H), 2.60e2.53 (m,1H); 13C
20
NMR (125 MHz, CDCl3)
d
ppm: 172.2, 140.4, 127.2, 126.8, 126.3, 75.5,
[a
]
ꢀ49.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3)
d ppm:
D
57.1, 36.6; FTIR: 3054 (m), 2986 (m), 1765 (s), 1421 (m) cmꢀ1. HRMS
4.66e4.62 (m, 1H), 4.50 (t, J¼7.8 Hz, 1H), 2.77 (br s, 1H), 2.37e2.31
(m, 1H), 2.28e2.23 (m, 1H), 1.73e1.65 (m, 1H), 1.61e1.54 (m, 1H),
1.37e1.24 (m, 8H), 0.88 (t, J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
m/z calcd for C8H7N3O2S 209.0259; found 209.0260.
4.9.6. (3S,5S)-3-Hydroxydihydro-5-(thiophen-2-yl)furan-2(3H)-one
(18f). The crude material was purified by silica gel flash chroma-
tography using 59:40:1 hexane/EtOAc/triethylamine as the eluent.
The indicated compound was obtained as a yellow oil (33 mg, 71%
d ppm: 177.2, 78.7, 67.5, 35.7, 35.5, 31.6, 28.9, 25.3, 22.5, 14.0; FTIR:
3403 (m), 3054 (m), 2986 (m), 1777 (m), 1421 (m) cmꢀ1; HRMS m/z
calcd for C10H18O3 187.1334; found 187.1338.
yield), [
a
]
20 ꢀ30.0 (c 1.0, CH2Cl2). 1H NMR (360 MHz, CDCl3)
d ppm:
D
Acknowledgements
7.40 (dd, J¼5.1, 1.2 Hz, 1H), 7.17e7.16 (m, 1H), 7.03 (dd, J¼5.1, 3.6 Hz,
1H), 5.60 (dd, J¼11.0, 5.2 Hz, 1H), 4.69 (dd, J¼11.2, 8.1 Hz, 1H), 3.16
(br s, 1H), 3.05 (ddd, J¼12.7, 8.1, 5.2 Hz, 1H), 2.45 (dt, J¼12.7, 11.2 Hz,
We gratefully acknowledge the American Chemical Society Pe-
troleum Research Fund (44401-G1) for financial support of this
research.
1H); 13C NMR (90 MHz, CDCl3)
d ppm: 176.3, 139.8, 127.2, 127.1,
127.0, 73.5, 68.8, 39.3; FTIR: 3665 (m), 3045 (m), 2982 (m),1765 (m),
1423 (m) cmꢀ1; HRMS m/z calcd for C8H8O3S 184.0194; found
184.0191.
Supplementary data
4.9.7. (3S,5S)-5-Allyl-3-azidodihydrofuran-2(3H)-one
crude material was purified by silica gel flash chromatography
using 8:2 hexane/EtOAc as the eluent. The indicated compound was
(18g). The
1H and 13C NMR spectra of all reported compounds. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2012.04.107.

A. Ganta et al. / Tetrahedron 68 (2012) 5396e5405
5405
conditions described to obtain the enantiomer of any compound reported with
comparable efficiency
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