Chemoenzymatic preparation of (6R)-5,6-dihydro-2H-pyran-2-one: A ubiquitous structural motif of biologically active lactones

Article abstract of DOI:10.1016/j.tetasy.2013.10.005

A chemoenzymatic synthesis of an enantiopure 6-substituted 5,6-dihydro-2H-pyran-2-one using bromobenzene as a starting material is presented. This important structural motif is found in a large number of chiral lactones that present a wide range of biological activities. The key features of the preparation include enzymatic dioxygenation of bromobenzene using Escherichia coli JM109 (pDTG601), microwave-assisted acyloin cleavage, and tin mediated lactonization. The stereochemical assignment for the alcohol was confirmed by NMR analysis of Moshers derivatives.

Full text of DOI:10.1016/j.tetasy.2013.10.005

Tetrahedron: Asymmetry 24 (2013) 1467–1472
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic preparation of (6R)-5,6-dihydro-2H-pyran-2-one:
a ubiquitous structural motif of biologically active lactones
⇑
Ignacio Carrera , Margarita Brovetto, Gustavo A. Seoane
Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de la República, General Flores 2124, 11800 Montevideo, Uruguay
a r t i c l e i n f o
a b s t r a c t
Article history:
A chemoenzymatic synthesis of an enantiopure 6-substituted 5,6-dihydro-2H-pyran-2-one using bromo-
benzene as a starting material is presented. This important structural motif is found in a large number of
chiral lactones that present a wide range of biological activities. The key features of the preparation
include enzymatic dioxygenation of bromobenzene using Escherichia coli JM109 (pDTG601), micro-
wave-assisted acyloin cleavage, and tin mediated lactonization. The stereochemical assignment for the
Received 14 August 2013
Accepted 4 October 2013
Available online 4 November 2013
´
alcohol was confirmed by NMR analysis of Moshers derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
have shown important antimicrobial, antifungal, and cytotoxic
properties, leading to several synthetic efforts.1 Umuravumbolide,2
synrotolide,3 spicegerolide,4 hyptolide,5 anamarine,6 synargento-
lide A,7 goniothalamin,1b,8 callystatin A,9 and argentilactone10 are
some examples of this conjugated d-lactone family (Scheme 1). It
is believed that the presence of a Michael acceptor moiety in their
a,b-Unsaturated-d-lactones are a ubiquitous structural unit
found in a large number of natural products that have a wide range
of biological activities. In particular, those containing a 5,6-dihydro-
2H-pyran-2-one with an (R)-configuration at the stereogenic center
O
O
O
O
O
OAc OAc
O
OAc OAc
OAc
synargentolide A
(-)-argentilactone
OAc OAc
spicegerolide
O
O
O
O
O
O
OAc OAc
R
1
OAc
hyptolide
(R)-goniotalamin
(R)-5,6-dihydro-2H-pyran-2-one
core
O
O
O
OAc OAc
O
OAc OAc
OAc OAc
anamarine
OAc OAc
synrotolide
Scheme 1. The (R)-5,6-dihydro-2H-pyran-2-one core is a ubiquitous structural unit found in a high number of cytotoxic natural products.
⇑
Corresponding author. Tel.: +59 829247881.
E-mail address: icarrera@fq.edu.uy (I. Carrera).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.005

1468
I. Carrera et al. / Tetrahedron: Asymmetry 24 (2013) 1467–1472
structure is responsible for their biological properties. From a syn-
thetic point of view, the (R) stereogenic center has been generated
in a number of ways, including the use of carbohydrates as building
blocks,11 enzyme-mediated asymmetric reductions,12 and asym-
metric hetero Diels–Alder methodology.13 Herein we report an
enantioselective synthesis of a (6R)-6-substituted-5,6-dihydro-
2H-pyran-2-one that can be used for the preparation of all members
of this d-lactone family. For this approach, the chirality is intro-
duced via enzyme-mediated dioxygenation of bromobenzene using
Escherichia coli JM109 (pDTG601) as a whole cell biocatalyst.14 In
this way, achiral bromobenzene is transformed into an important
optically active structural moiety. This methodology has been used
extensively for the preparation of other biologically active natural
products such as sugars, cyclitols, alkaloids, and terpenes.15
was submitted to acidic conditions using CuCl2ꢀ2H2O for the
removal of the isopropylidene group to afford 8 in 72% yield. This
reaction needed to be monitored carefully since prolonged reaction
times cause the undesired deprotection of the dimethylthexylsilyl
group. Selective oxidation of diol 8 to afford the enone 9 was
achieved using IBX in DMF at room temperature (other oxidants
such as PCC, MnO2 or oxalyl chloride/DMSO produced mainly
aromatization of 8 with only trace amounts of the desired enone).
Oxidative cleavage of the
a-hydroxyketone was achieved using
previously reported conditions,19 with silica-supported sodium
periodate under microwave irradiation. In this way, compound
10 was produced in excellent yield.
Oxoacid 10 proved to be very labile under silyl group deprotec-
tion trials using TBAF, HF, HF/Py, and CuCl2ꢀ2H2O resulting in the
total decomposition of the starting material. Similar behavior
was also found when trying to protect the carboxylic acid using
diazomethane, or lactonize it using DCC or Mitsunobu conditions.
As a result of this high reactivity it was decided to reduce the alde-
hyde in order to increase the stability of this compound. Thus,
reduction with NaBH4 and further esterification with diazometh-
ane (produced by basic decomposition of N-nitrosomethylurea)
afforded alcohol 11 in 70% overall yield for both steps. Finally,
protective group manipulation (introduction of a p-nitrobenzoyl
group on the primary alcohol and dimethylthexylsilyl ether
removal) gave alcohol 12, which was ready for intramolecular
transesterification.
2. Results and discussion
The retroanalysis for the preparation of the lactone core is
14
described in Scheme 2. As recently reported
enzymatic dihydr-
oxylation of bromobenzene using a biphasic fermentation with
E. coli JM109 (pDTG601) affords the enantiomerically pure
cis-3-bromocyclohexadienediol 2 in excellent yields. This diol can
be used as a starting material to obtain the desired lactone. As key
steps for this transformation, selective oxidation of 2 would produce
enone 3, which after oxidative cleavage affords the oxoacid 4. This
compound can be reduced selectively and protected to promote
the corresponding lactonization to give the target product.
Protection of the diol functionality in 2 with the isopropylidene
group was carried out using standard conditions,16 followed by
epoxidation using m-chloroperbenzoic acid (Scheme 3). The epox-
idation in this system had been studied before to produce com-
pound 5 in 75% yield in a regio- and stereoselective fashion.17
Treatment of 5 with LAH for the reductive cleavage of the epoxide,
followed by tin radical-mediated dehalogenation conditions,
afforded compound 6 in 70% overall yield for both steps. The
regioselectivity observed for the hydride-mediated epoxide
cleavage in the allylic position was expected according to previous
studies.15b,18 Quantitative protection of the resulting alcohol with
dimethylthexylsilyl chloride (TDSCl) produced compound 7, which
At this point we wanted to check the stereochemical integrity of
12, since the stereogenic center supporting the hydroxyl group in
oxoacid 10 is adjacent to a carbonyl function, which may produce
some racemization during the oxidative cleavage process. With
´
this in mind, Moshers derivatives were prepared and analyzed
using 1H and 13C NMR. The preparation of both derivatives was
clean, producing only one product each, which confirmed the
enantiomeric purity of 12. In addition, the absolute configuration
could also be confirmed, as shown in Scheme 4, where conforma-
´
tional structures for both Moshers derivatives are represented
assuming that the absolute configuration in 12 was (R). According
to the literature, the most representative conformation is that in
which the HC–O bond, the carbonyl and the CF3 groups are situated
Br
Br
O
CO2H
O
OH
OH
E.coli JM109 (pDTG601)
O
OH
35 g/L
CHO
H
OR
HO
O
2, >99% ee
3
4
Scheme 2. Retrosynthetic analysis for the preparation of the target (R)-5,6-dihydro-2H-pyran-2-one using cis-3-bromo-1,2-dihydrocatechol 2 as a starting material.
Br
Br
OH
OH
O
O
OH
OH
O
O
O
O
(f)
(g)
(a,b)
(h)
(c,d)
(i, j)
(e)
O
5
6
OH
7
8 OTDS
OTDS
2
O
O
COOH
CHO
COOMe
OPNBz
COOMe
OH
(m)
(k, l)
O
OH
9
OTDS
10 OTDS
OTDS
11
12
13
OH
OPNBz
Scheme 3. Reagents and conditions: (a) dimethoxypropane, acetone, rt, 90%; (b) MCPBA, DCM, 0 °C to rt, 75%; (c) LiAlH4 THF, reflux; (d) HSnBu3, AIBN, THF, reflux; 70% two
steps; (e) TDSCl, imidazole, DMF, rt, 98%; (f) CuCl2ꢀ2H2O (1.5 equiv), MeCN, 72%; (g) IBX, DMF, rt, 72%; (h) NaIO4/SiO2, microwave 200 W, 50 °C, 90%; (i) NaBH4, MeOH, rt; (j)
CH2N2, Et2O, 70% overall for 2 steps; (k) PNBzCl, TEA, DMAP, DCM, 94%; (l) CuCl2ꢀ2H2O (4.0 equiv), MeCN, 97%; (m) Bu2SnO, toluene, reflux, 80%.

I. Carrera et al. / Tetrahedron: Asymmetry 24 (2013) 1467–1472
1469
(S)-Mosher derivative 14
15
(R)-Mosher derivative
CF3
CF3
O
O
(R) alcohol
MeO
c
Ph
Ph
OMe
c
a
a
OPNB
OPNB
d
e
d
CO2Me
CO2Me
e
Ph shields protons and carbon in "c", "d" and "e"
Ph shields protons and carbon in "a"
+0.14
-0.14
+0.11
-0.11
O
+0.06
+0.05
O
-0.06
-0.05
O
COOMe
COOMe
OPNBz
+0.03
O
+0.06
+0.10
-0.10
COOMe
COOMe
OPNBz
-0.03
-0.06
+0.26
O
OPNBz
-0.43
-0.26
O
OPNBz
+0.43
O
O
Ph
OMe
Ph
OMe
OMe
Ph
OMe
Ph
(R)-Mosher
(S)-Mosher
15
14
F3C
Δδ 1H-NMR
F3C
1H-NMR
F3C
Δδ 13C-NMR
F3C
13C-NMR
Δδ = δ in (S)-Mosher 14 - δ in (R)-Mosher 15
Δδ = δ in (R)-Mosher 15 - δ in (S)-Mosher 14
Scheme 4. Assignment of the absolute configuration in 12 using Mosher’s esters.
in the same plane,20 so it can be appreciated that for the
(S)-Mosher derivative 14 the anisotropic effect of the phenyl group
would shield the protons and carbons in position ‘a’, while for the
(R)-Mosher derivative 15 the same effect would shield positions ‘c,
internal reference, and carbon chemical shifts are reported in ppm
relative to the center line of the CDCl3 triplet (77.0 ppm). Elemental
analyses (EA) were determined on a Fisions EA 1108 CHNS–O mic-
roanalyzer. Optical rotations were measured on a Zuzi 412 polar-
d, and e’. This fact can be confirmed by analysis of the NMR
values for both derivatives, which confirmed the initial stereo-
chemical assignment of the alcohol in 12 as (R).
In order to promote the lactonization of 12, dibutyltin oxide
was used for nucleophilic enhancement of the hydroxyl group to
give 13 in 80% yield.21 This methodology has been used extensively
for promoting nucleophilic alkylation and acylation in oxygenated
compounds.22,23 In this way, the target lactone was produced in 13
steps from diol 2 with an overall yield of 11%.
D
d
imeter using a 0.5 dm cell. [
a
]
values are given in units of
D
deg cm2 gꢁ1 and concentration values are expressed in g/100 mL.
Production of cis-cyclohexadienediols using the recombinant
organism E. coli JM109 (pDTG601) was performed in a Biostat A
plus fermentor (5 L) according to a biphasic protocol previously
described by us.14 Analytical TLC was performed on silica gel
60F-254 plates and visualized with UV light (254 nm) and/or
p-anisaldehyde in acidic ethanolic solution. Flash column chroma-
tography was performed using silica gel (Kieselgel 60, EM reagent,
230–400 mesh).
3. Conclusion
4.2. (1S,2S,5R,6R)-3-Bromo-5,6-oxy-1,2-O-isopropylidencyclo-
hex-3-en-1,2-diol 517
In conclusion, bromobenzene was transformed into an enantio-
merically pure (6R)-5,6-dihydro-2H-pyran-2-one, a common struc-
tural unit found in the conjugated d-lactone family of biologically
active natural products. The synthetic procedure consists of 14
steps with an overall yield of 11%. The key features of the synthesis
include enzymatic dioxygenation of bromobenzene, microwave-
assisted acyloin cleavage, and tin-mediated lactonization. In addi-
tion the stereochemical assignment for the alcohol was confirmed
To a stirred solution of cis-3-bromocyclohexadienediol pro-
tected with an isopropylidene group16 in CH2Cl2 (15 mL/g),
m-chloroperbenzoic acid (MCPBA, 2.1 equiv) was added in portions
at 0 °C and the reaction was left to stand overnight at room
temperature. Upon complete conversion of the starting material,
the mixture is diluted with CH2Cl2 and washed sequentially with
saturated solutions of NaHSO3, NaHCO3, and brine. The organic
layer was dried over Na2SO4 and evaporated in vacuo. The residue
was then chromatographed on silica gel (EtOAc:Hex, 5:95) to
afford the pure epoxide 5 as a white solid in 75% yield. 1H NMR
(400 MHz, CDCl3): d 1.45 (s, 3H); 1.48 (s, 3H); 3.34 (ddd, 1H, J 4.5
3.7 1.0 Hz); 3.60 (dd, 1H, J 3.6, 1.8 Hz); 4.43 (dd, 1H J 6.7, 1.0);
4.86 (ddd, 1H, J 6.8, 1.8, 1.1 Hz), 6.50 (dd, 1H, J 4.4, 4.2 Hz) 13C
NMR (100 MHz, CDCl3): d 26.4 (CH3), 27.9 (CH3), 48.7 (C–O), 49.9
(C–O), 73.0 (HC–O), 74.5 (HC–O), 111.7 (C), 126.9 (HC@), 130.2 (C).
´
by NMR analysis of Moshers derivatives.
4. Experimental
4.1. General
All non-hydrolytic reactions were carried out in a nitrogen
atmosphere with standard techniques for the exclusion of air. All
solvents were distilled prior to use. Mass spectra (MS) were
recorded on a Shimadzu GC–MS QP 1100 EX instrument using
the electron impact mode (70 or 20 eV). Infrared spectra (IR) were
recorded either on neat samples (KBr disks) or in solution on a
Shimadzu FT-IR 8101A spectrophotometer. NMR spectra were
obtained in CDCl3 on a Bruker Avance DPX-400 instrument. Proton
chemical shifts (d) are reported in ppm downfield from TMS as an
4.3. (1R,2S,3R)-2,3-O-Isopropylidenecyclohex-4-ene-1,2,3-triol 6
A flame dried two neck round bottomed flask under nitrogen
atmosphere was charged with LAH (2.0 equiv), followed by the
addition of dry THF (0.14 mmol of LAH/mL). The suspension was
then stirred in an ice bath and a solution of the epoxide 5 in THF

1470
I. Carrera et al. / Tetrahedron: Asymmetry 24 (2013) 1467–1472
(0.4 M based on epoxide) was added slowly. The mixture was
heated at reflux and monitored by TLC. After complete reduction
of the starting material, the reaction was cooled down to 0 °C. Ethyl
acetate (0.5 mL/mL of THF in the reaction suspension) was added
slowly to the mixture and after stirring for 10 min NaOH 10%
(0.5 mL/mL of THF in the reaction suspension) was added carefully.
Ethyl acetate was then added to dilute and the whole mixture was
washed sequentially with H2O and brine. The organic phase was
dried over Na2SO4 and evaporated in vacuo to afford a colorless
oil that corresponded to the hydride cleaved epoxide at the allylic
position. This oil was taken without any further purification to the
next de-bromination step to afford 6. For this purpose, it was dis-
solved in dry THF (20 mL/0.7 mmol) under a nitrogen atmosphere
with vigorous stirring at room temperature. Next, HSnBu3
(2.0 equiv) was added and then the whole system was heated at
reflux. Catalytic amounts of AIBN (0.2 equiv) were added in
portions. Upon complete conversion of the starting material, the
solvent was evaporated in vacuo to afford a crude residue that is
chromatographed on silica gel (AcOEt:Hex, 5:95) to obtain a
colorless oil which corresponded to triol 6 (75% overall yield in
was transferred to a decantation funnel by the addition of ethyl ace-
tate and brine. The aqueous phase was extracted with EtOAc. The
combined organic layers were dried over Na2SO4, and evaporated
to obtain a crude oil that was chromatographed on silica gel
(EtOAc:Hex 3:7) to obtain diol 8 in 72% yield. ½a D25
¼ ꢁ93:0 (c 0.69,
ꢂ
CH2Cl2); IR m
max (KBr)/cmꢁ1:3800 (broad), 2959, 2868, 1466, 1379,
1252, 1091 (broad); 1H NMR (400 MHz, CDCl3): d 0.16 (s, 3H), 0.18
(s, 3H), 0.90 (m, 12H), 1.66 (septet, 1H, J 6.9 Hz), 2.10 (m, 1 Hz),
2.46 (ddd, 1H, J 17.9, 4.6, 4.6 Hz), 3.60 (dd, 1H, J 9.3, 4.8 Hz), 4.02
(ddd, 1H, J 8.9 5.5 5.5 Hz), 4.38 (dd, 1H, J 4.0, 4.0 Hz); 5.79 (m, 2H);
13C NMR (100 MHz, CDCl3): d ꢁ2.4 (CH3–Si), ꢁ1.7 (CH3–Si), 19.0
(CH3), 34.6 (CH), 34.7 (CH2), 66.9 (HC–O), 68.6 (HC–O), 84.5
(HC–O), 126.7 (HC@), 129.2 (HC@); MS (IE, 70 eV) m/z(%): 235
(169, M+⁄–C8H18Si), 75 (34,Me2SiOH); EA Calcd for C14H28O3Si C
61.72, H 10.36. Found: C 61.42, H 10.42.
4.6. (5R,6S)-5-[Dimethyl(1,1,2-trimethylpropyl)silyloxy]-6-hy-
droxycyclohex-2-ene-1-one 9
To a solution of alcohol 8 in dry CH2Cl2, IBX (3.0 equiv) was
added and the suspension was stirred for 5 h after which additional
IBX was added (3.0 equiv) to promote complete conversion. The
solvent was evaporated in vacuo and the residue was suspended
in water. Next, Na2S2O3 (7.0 equiv) was added to obtain a clear
solution. The aqueous phase was extracted with diethylether. The
combined organic layers were washed sequentially with NaHCO3
saturated solution and brine, then dried over Na2SO4. The suspen-
sion was filtered and the filtrate was concentrated in vacuo. The
residue was then chromatographed in silica gel (EtOAc:Hex 1:9)
to afford a pure yellow oil that corresponded to 9 in 72% yield.
the two steps). ½a D25
ꢂ
¼ ꢁ158 (c 1.03, CH2Cl2); IR mmax (KBr)/cmꢁ1
:
3440, 2900, 1215, 1055; 1H NMR (400 MHz, CDCl3): d 1.41 (s,
3H), 1.55 (s, 3H), 3.34 (dd, 1H, J 3.8, 3.8 Hz), 3.55 (dd, 1H, J 3.7,
1.9 Hz), 4.46 (ddd, 1H, J 7.0, 2.0, 2.0 Hz), 4.78 (dd, 1H, J 7.0,
1.7 Hz), 5.81 (ddd, 1H, J 10.2, 1.4, 1.4 Hz); 6.06 (ddd, 1H, J 10.2,
3.9, 1.5 Hz). 13C NMR (100 MHz, CDCl3): d 23.8 (CH3), 28.2 (CH3),
46.9 (C–O), 49.6 (C–O), 77.1 (C–O), 71.3 (HC–O), 110.9 (C), 123.9
(HC@), 132.4 (HC@); MS (EI, 70 eV) m/z (%): 170 (2, M+⁄), 155
(50), 95(100); EA Calcd for C9H14O3 C 63.51, H 8.29. Found: C
63.40, H 8.35.
½
a 2D5
ꢂ
¼ þ7:3 (c 0.41, CH2Cl2); IR mmax (KBr)/cmꢁ1: 3450 (broad),
4.4. (1R,2S,3R)-1-O-[Dimethyl(1,1,2-trimethylpropyl)silyl]-2,3-
O-isopropylidenecyclohex-4-ene-1,2,3-triol 7
2959, 2868, 1686, 1252, 1115; 1H NMR (400 MHz, CDCl3): d 0.15
(s, 3H), 0.20 (s, 3H), 0.92 (m, 12H), 1.66 (septet, 1H, J 6.9 Hz),
2.54 (dddd, 1H, J 9.5, 5.4, 2.4, 2.4 Hz), 2.70 (ddd, 1H, J 11.6, 5.8,
5.8 Hz), 3.90 (dd, 1H, J 9.6, 5.4 Hz), 4.08 (dd, 1H, J 10.6, 2.16 Hz),
6.15 (dd, 1H, J 10.1, 3.1 Hz); 6.94 (ddd, 1H, J 6.2, 2.2, 2.2 Hz); 13C
NMR (100 MHz, CDCl3): d ꢁ2.5 (CH3–Si), ꢁ2.1 (CH3–Si), 18.9
(CH3), 19.1 (CH3), 20.5 (CH3), 20.7 (CH3), 25.3 (C), 34.6 (HC), 36.1
(CH2), 73.8 (HC–O), 79.9 (HC–O), 127.9 (HC@), 148.9 (HC@),
199.7 (C@O), MS m/z (%): 271 (1, M+⁄ꢁ1), 185 (23, M+⁄ꢁ1–
C6H11), 157 (9, M+⁄–C6H13Si); 103 (86), 111 (4, M+⁄–C8H19OSi), 75
(100); EA Calcd for C14H26O3Si C 62.18, H 9.69. Found: C 62.20, H
9.86.
Compound 6 was dissolved in dry DMF (1 mL/mmol) with vig-
orous stirring at room temperature. Imidazole (4.0 equiv) was then
added in portions followed by TDSCl (1.5 equiv). The reaction mix-
ture was monitored by TLC until the starting material was con-
sumed. The mixture was diluted by the addition of water and
diethyl ether and transferred to a decantation funnel. The aqueous
layer was extracted with Et2O. The combined organic layers were
washed sequentially with a CuSO4 saturated solution and brine,
then dried over Na2SO4. The suspension was filtered and the fil-
trate was concentrated in vacuo. The residue was then chromato-
graphed in silica gel (EtOAc:Hex 2:98) to afford a colorless oil
4.7. (5R,2Z)-5-[Dimethyl(1,1,2-trimethylpropyl)sililoxy]-6-oxo-
that corresponded to 7 in 98% yield. ½a D25
ꢂ
¼ ꢁ73:7 (c 1.03, CH2Cl2);
2-hexenoic acid 1019
IR mmax (KBr)/cmꢁ1: 2950, 2868, 1466, 1379, 1252, 1163, 1118,
1064; 1H NMR (400 MHz, CDCl3): d 0.13 (s, 3H), 0.16 (s, 3H), 0.90
(m, 12H), 1.40 (s, 3H), 1.48 (s, 3H), 1.66 (septet, 1H, J 6.9 Hz),
2.02 (dd, 1H, J 16.7, 7.6 Hz), 2.32 (ddd, 1H, J 16.2, 4.4, 4.4 Hz),
3.89 (ddd, 1H, J 7.3, 4.7, 4.7 Hz), 4.01 (dd, 1H, J 6.7 6.7 Hz), 4.60
(d, 1H, J 6.1 Hz); 5.8 (m, 2H); 13C NMR (100 MHz, CDCl3): d ꢁ2.4
(CH3–Si), ꢁ2.1 (CH3–Si), 18.9 (CH3), 18.9 (CH3), 20.5 (CH3), 20.6
(CH3), 25.6 (C), 26.6 (CH3), 28.6 (CH3), 31.9 (CH2), 34.6 (CH), 69.7
(HC–O), 73.2 (HC–O), 78.9 (HC–O), 109.1 (C), 125.2 (HC@), 128.5
(HC@); MS (EI, 70 eV) m/z (%): 169 (100, M+⁄–C6H13–H2O), 75
(48, Me2SiOH); EA Calcd for C17H32O3Si C 65.33, H 10.32. Found:
C 65.55, H 6.07.
Hydroxyketone 9 was dissolved in a round-bottomed flask after
which silica-supported sodium metaperiodate (3.0 equiv in NaIO4)
was added. The solvent was evaporated and the free-flowing silica
was placed in a proper microwave test tube (sure sealed 10 mL test
tubes with magnetic stirring). After the indicated time of irradia-
tion at 200 W, and 50 °C, in a monomode microwave reactor from
CEM corporation, model Discover, ethyl acetate was added and the
silica was filtered off. The solvent was evaporated and the reaction
crude was purified by column chromatography (EtOAc:Hex 4:6) to
afford a yellow oil which corresponded to compound 10 in 90%
yield. ½a 2D5
ꢂ
¼ þ7:8 (c 0.61, CH2Cl2); IR mmax (KBr)/cmꢁ1: 3055,
2959, 1736, 1697, 1252, 1113; 1H NMR (400 MHz, CDCl3): d 0.15
(s, 3H), 0.16 (s, 3H), 0.91 (m, 12H), 1.66 (septet, 1H, J 6.9 Hz),
3.09 (m, 2H), 4.17 (ddd, 1H, J 11.5, 1.6, 1.6 Hz), 5.96 (ddd, 1H, J
11.5, 1.6, 1.6 Hz), 6.41 (ddd, 1H, J 14.8, 7.4, 4.1 Hz), 9.65 (d, 1H, J
1.35 1 Hz); 13C NMR (100 MHz, CDCl3): d ꢁ2.6 (CH3–Si), ꢁ2.2
(CH3–Si), 18.9 (CH3), 19.0 (CH3), 20.5 (CH3), 20.6 (CH3), 29.7 (C),
32.8 (CH2), 34.5 (C), 77.1 (HC–O), 121.8 (HC@), 146.6 (HC@),
170.6 (COOH), 203.0 (C@O); MS m/z (%): 201 (18, M+⁄–C6H13),
4.5. (1R,2S,3R)-1-[Dimethyl(1,1,2-trimethylpropyl)silyl]cyclohex-
4-ene-1,2,3-triol 8
Compound 7 was dissolved with vigorous stirring in MeCN
(2 mL/0.06 mmol), followed by the addition of CuCl2ꢀ2H2O (1.5
equiv.). Upon consumption of the starting material (monitored by
TLC) the solvent was evaporated in vacuo to obtain a residue that

I. Carrera et al. / Tetrahedron: Asymmetry 24 (2013) 1467–1472
1471
183 (65, M+⁄+1–2CH3,CHO,COOH), 155 (75, M+⁄ꢁC6H13ꢁCOOH),
101 (20), 81(32, M+⁄ꢁC8H19SiO–COOH), 75 (100); EA Calcd for
The p-nitrobenzoyl protected alcohol was dissolved with vigor-
ous stirring in MeCN (2 mL/0.06 mmol), followed by addition of
CuCl2ꢀ2H2O (4.0 equiv). When no further conversion was detected
by TLC, the solvent was evaporated in vacuo to obtain a residue
that was transferred to a decantation funnel by the addition of
ethyl acetate and brine. The aqueous phase was extracted with
ethyl acetate. The combined organic layers were dried over Na2SO4,
and evaporated to obtain a crude oil that was chromatographed on
silica gel (EtOAc:Hex 3:7) to obtain alcohol 12 in a 97% yield based
C14H26O4Si: C, 58.7; H, 9.1. Found: C, 59.0; H, 8.9.
4.8. (2Z,5R)-5-[Dimethyl(1,1,2-trimethylpropyl)silyloxy]-6-oxo-
2-hexenoic acid 11
Compound 10 was dissolved with vigorous stirring in MeOH
(10 mg/mL) at 0 °C in an ice bath. Next NaBH4 (1.2 equiv) was added,
and reaction was monitored by TLC. After the starting material was
consumed, the solvent was evaporated, and the residue suspended
with ethyl acetate, transferred to a decantation funnel and then
washed with a 1 M HCl aqueous solutionand brine. The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo to obtain
a crude material which was used in the next reaction withoutfurther
purification. The reaction crude was dissolved in diethyl ether con-
taining diazomethane which was prepared according the following
procedure. N-Nitrosomethylurea (2.0 equiv referred to compound
10) was dissolved in a bi-phasic system formed by NaOH (5 M)
and diethyl ether. The organic layer turned yellow while gas evolu-
tion was observed. The diethyl ether phase was taken and used to
dissolve the residue of the first reaction. After the reaction was com-
plete, the solvent was evaporated and the crude material was chro-
matographed in silica gel (EtOAc:Hex 2:8) to afford a colorless oil
which corresponded to compound 11 in an overall yield of 70% over
on the recovered starting material. ½a D22
¼ þ41 (c 0.1, CH2Cl2); IR
ꢂ
mmax (KBr)/cmꢁ1: 3500, 3113, 2953, 1726, 1647, 1607, 1528,
1441, 1350, 1280, 1175, 1127, 1103; 1H NMR (400 MHz, CDCl3):
d 2.92 (m, 1H), 3.01 (m, 1H), 3.09 (d, 1H, J, 4.6 Hz), 3.74 (s, 3H),
4.18 (m, 1H), 4.38 (dd, 1H, J, 11.3, 6.2 Hz), 4.45 (dd, 1H, J, 11.3,
3.9 Hz), 6.02 (ddd, 1 H, J 11.5, 1.4, 1.4, 1H), 6.43 (ddd, 1H. J, 11.5,
8.0, 7.9 Hz); 13C NMR (100 MHz, CDCl3): d 33.0 (CH2), 51.5 (C–O),
69.2 (C–O), 69.3 (C–O), 122.5 (C@), 123.6 (2CPh@), 130.9 (2CPh@),
135.2 (C), 144.6 (C@), 150.6 (C), 164.7 (C@O), 167.3 (C@O); HRMS
Calcd for C14H15NNaO7 (M++Na+) 332.0746. Found: 332.0749.
4.10. (R)-6-[p-Nitrobenzoyloxymethyl]-5,6-dihydro-2H-pyran-
2-one 13
In a two neck round bottomed flask equipped with a Dean–Stark
apparatus, alcohol 12 was dissolved in dry toluene and Bu2SnO
(0.6 equiv) was added. The whole system was heated at reflux, and
the starting material was consumed after 30 min. Toluene was evap-
orated in vacuo to obtain a residue that was chromatographed on sil-
ica gel (EtOAc:Hex, 3:7) to afford a white solid, which corresponded
the two steps. ½a D25
ꢂ
¼ þ5:5 (c 0.34, CH2Cl2); IR mmax (KBr)/cmꢁ1
:
3400, 2957, 2868, 1725, 1711, 1252, 1174, 1107, 1055; 1H NMR
(400 MHz, CDCl3): d 0.15 (s, 3H), 0.16 (s, 3H), 0.91 (m, 12H), 1.66
(septet, 1H, J 6.9 Hz), 2.55 (t, 1H, 7.2 Hz), 2.73 (m, 1H), 3.08 (m,
1H), 3.50 (m, 2H), 3.75 (s, 3H), 3.97 (m, 1H), 5.93 (ddd, 1H, J 11.6,
1.4, 1.4 Hz), 6.37 (m, 1H), 13C NMR (100 MHz, CDCl3): d ꢁ2.3 (CH3–
Si), ꢁ2.2 (CH3–Si), 18.9 (CH3), 19.0 (CH3), 20.7 (CH3), 20.71 (CH3),
30.1 (C), 33.6 (CH2), 34.6 (HC), 51.6, (CH3–O) 65.9 (CH2O), 72.3
(HC–O), 121.7 (HC@), 146.2 (HC@), 167.6 (COOR); MS (IE, 70 eV)
m/z (%): 271 (4, M+⁄ꢁC2H7), 217 (5, M+⁄ꢁC6H13), 185 (28, M+⁄ꢁC7
H17O), 157 (23, M+⁄ꢁC8H16O2), 75 (100); HRMS Calcd for C15H30
NaO4Si (M+⁄+Na+), 325.1811. Found: 325.1791.
to compound 13 in 80% yield. ½a D22
¼ þ62:9 (c 3.2, CH2Cl2); IR mmax
ꢂ
(KBr)/cmꢁ1: 3107, 3023, 2853, 2912 1728, 1606, 1523, 1279, 1014;
1H NMR (400 MHz, CDCl3): d 2.55 (m, 2H), 4.60 (dd, 2H, J 3.8, 1.4,
1.0 Hz), 4.86 (ddd, 1H, J 9.5, 9.5, 4.7 Hz), 6.10 (ddd, 1H, J 9.8, 2.6,
1.3 Hz), 6.97 (ddd, 1H, J 9.8, 5.8, 2.8), 8.23 (d, 2H, J 8.9 Hz), 8.31
(d, 2H, J 8.9 Hz) 13C NMR (100 MHz, CDCl3): d 25.8 (CH2), 65.9
(CH2-O), 75.1 (HC–O), 121.4 (HC@), 123.6 (2CPh@), 131.0 (2CPh@),
134.7 (C), 144.4 (HC@), 150.7 (C), 163.1 (C@O), 164.3 (C@O); HRMS,
Calcd for C13H11NNaO6 (M++Na+), 300.04841. Found: 300.04786.
4.9. Methyl (2Z,5R)-5-hydroxy-6-p-nitrobenzoyloxy-2-hexenoate
12
4.11. Methyl (2Z,5S)-5-[(S)-3,3,3-trifluoro-2-methoxy-2-pheny-
lpropanoyloxy]-6-p-nitrobenzoyloxy-2-hexenoate 14 and methyl
(2Z,5R)-5-[(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl-
oxy]-6-p-nitrobenzoyloxy-2-hexenoate 15
A solution of alcohol 11 in dry CH2Cl2 (0.15 M) was stirred at
0 °C followed by the addition of triethylamine (2.5 equiv), p-nitro-
benzoyl chloride (PNBzCl) (1.5 equiv), and 4-N,N-dimethylamino-
pyridine (catalytic). The reaction was monitored by TLC and
when no further starting material was detected, the solvent was
evaporated in vacuo to obtain a residue, which was suspended in
ethyl acetate and transferred into a decantation funnel. The organic
phase was sequentially washed with water; CuSO4 saturated solu-
tion and brine, then dried over Na2SO4 and evaporated. The ob-
tained crude material was chromatographed in silica gel to afford
A solution of alcohol 12 in dry CH2Cl2 (0.15 M) was stirred at
0 °C followed by the addition of triethylamine (2.5 equiv), the
corresponding MTPACl (1.5 equiv), and 4-N,N-dimethylaminopyri-
dine (catalytic). The reaction was monitored by TLC and when no
further starting material was detected, the solvent was evaporated
in vacuo to obtain a residue, which was suspended in ethyl acetate
and transferred to a decantation funnel. The organic phase was
sequentially washed with water, CuSO4 saturated solution and
brine, then dried over Na2SO4, and evaporated. The residue
obtained was chromatographed in silica gel to afford the correspond-
the corresponding protected alcohol in 94% yield. ½a D22
¼ ꢁ12 (c
ꢂ
0.2, CH2Cl2); IR mmax (KBr)/cmꢁ1: 3115, 2957, 2868, 1726, 1647,
1608, 1531, 1466, 1441, 1408, 1275, 1174, 1101; 1H NMR
(400 MHz, CDCl3): d 0.12 (s, 3H), 0.15 (s, 3H), 0.84 (s, 3H), 0.85
(s, 3H), 0.87 (s, 3H), 0.89 (s, 3H), 1.62 (septet, 1H, J 6.9 Hz), 2.98
(m, 1H), 3.10 (m, 1H), 3.71 (s, 3H), 4.21 (ddddd, 1H, J, 5.4, 5.4,
5.4, 5.4, 5.4 Hz), 4.32 (m, 2H), 5.95 (ddd, 1H, J, 11.6, 1.5, 1.5 Hz),
6.42 (ddd, 1H, J 11.5, 7.0, 7.0 Hz), 8.25 (d, 1H, J, 8.9 Hz), 8.33
(d, 1H, J, 8.9 Hz) 13C NMR (100 MHz, CDCl3): d ꢁ2.6 (2 CH3–Si),
18.5 (CH3), 18.6 (CH3), 20.1 (CH3), 20.2 (CH3), 24.8 (C), 33.9
(CH2), 34.1 (HC), 51.1, (CH3–O), 68.7 (CH2O), 69.2 (HC–O), 121.5
(HC@), 123.5 (2 CPh@), 130.8 (CPh@), 130.9 (CPh@), 135.5 (C),
145.1 (C@), 150.6 (C), 164.5 (C@O), 166.6 (C@O); HRMS Calcd for
ing Mosher derivative 14 or 15. Compound 14, ½a D24
¼ ꢁ15:5 (c 0.8,
ꢂ
CH2Cl2); IR (cmꢁ1): 3112, 2954, 2918, 1751, 1727, 1494, 1272,
1174, 1103; 1H NMR (400 MHz, CDCl3): d 3.17 (ddd, 1H, J 6.9,
6.9, 1.5), 3.54 (s, 3H), 3.71 (s, 1H), 4.46 (dd, 3H, J 12.2, 8.1 Hz),
4.66 (m, 1H, J 12.2, 2.8 Hz), 5.68 (m, 1H), 5.91 (ddd, 1H, J, 11.3,
1.5, 1.5 Hz), 6.11 (ddd, 1 H, J 11.5, 7.4, 7.4, 1H), 7.33 (m, 3H),
7.54 (d, 1H, J 7.7 Hz), 8.14 (ddd, 2H J 8.8, 2.0, 2.0), 8.28 (ddd, 2H J
8.8, 2.0, 2.0); 13C NMR (100 MHz, CDCl3): d 29.8 (CH2), 51.4
(C–O), 55.4 (C–O), 65.9 (C–O), 73.0 (C–O), 84.5 (C), 123.0 (C@),
123.6 (2CPh@), 123.7 (CPh@) 124.7 (C) 127.2 (CPh@), 128.4
(3CPh@), 129.8 (CPh@), 130.8 (2CPh@), 131.9 (C), 134.7 (CPh@),
C
22H33NNaO7Si (M++Na+), 474.1924. Found: 474.1935.

1472
I. Carrera et al. / Tetrahedron: Asymmetry 24 (2013) 1467–1472
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142.0 (C@), 150.7 (C), 164.1 (C@O); 166.2 (C@O); compound 15;
½
a 2D4
ꢂ
¼ þ3:4 (c 0.8, CH2Cl2); IR (cmꢁ1): 3112, 2992, 2921, 2850,
1751, 1727, 1494, 1347, 116, 1103; 1H NMR (400 MHz, CDCl3): d
3.22 (ddd, 1H, J 6.9, 6.9, 1.5), 3.52 (s, 3H), 3.74 (s, 1H), 4.43 (dd,
3H, J 12.4, 7.1 Hz), 4.61 (dd, 1H, J 12.2, 7.1 Hz), 5.60 (m, 1H), 5.97
(m, 1H), 6.25 (m, 1H), 7.33 (m, 3H), 7.50 (d, 1H, J 7.7 Hz), 8.12
(ddd, 2H J 8.8, 2.0, 2.0), 8.30 (ddd, 2H J 8.8, 2.0, 2.0); 13C NMR
(100 MHz, CDCl3): d 30.1 (CH2), 51.4 (C–O), 55.4 (C–O), 65.5
(C–O), 73.1 (C–O), 84.5 (C), 123.1 (C@), 123.1 (2CPh@), 123.6 (C),
127.3 (CPh@), 128.5 (3CPh@), 129.7 (2CPh@), 130.8 (CPh@),
131.7 (C), 134.7 (CPh@), 142.1 (C@), 150.7 (C), 164.1 (C@O);
166.2 (C@O).
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Acknowledgment
Financial support from ANII (Agencia Nacional de Investigación
e Innovación) Project FCE344 is acknowledged.
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