A cyclopropanol-based approach to synthesis of Unit A of the cryptophycins

Article abstract of DOI:10.1016/j.tetasy.2014.03.011

A new asymmetric synthesis of Unit A of the cryptophycins has been carried out yielding 13% of the target product over 14 steps. The key steps of the synthesis were diastereoselective hydroboration-oxidation reactions performed on the alkenyl moiety of a

Full text of DOI:10.1016/j.tetasy.2014.03.011

Tetrahedron: Asymmetry 25 (2014) 644–649
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A cyclopropanol-based approach to synthesis of Unit A of the
cryptophycins
⇑
Denis G. Shklyaruck
Department of Organic Chemistry, Belarusian State University, Nezavisimosty Av., 4, 220030 Minsk, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 February 2014
Accepted 10 March 2014
A new asymmetric synthesis of Unit A of the cryptophycins has been carried out yielding 13% of the target
product over 14 steps. The key steps of the synthesis were diastereoselective hydroboration–oxidation
reactions performed on the alkenyl moiety of a 1,3-dioxane derivative 8, which can be easily prepared
via the Kulinkovich cyclopropanation of protected diethyl (S)-(ꢀ)-malate followed by transformation
of the resulting small rings of the product 6 into the functional groups necessary for the synthesis of
the target compound.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
caused by the action of paclitaxel, cisplatin, or etoposide.
Unfortunately, over the course of phase II clinical trials, depsipep-
Cryptophycins are macrocyclic compounds of natural origin,
which are representatives of the depsipeptide compound class
(see Table 1). The first of these compounds, cryptophycin-1 1
was isolated in 1990 by Schwartz et al.1a,b and later by Moore
et al.1c–g along with several other cryptophycins, from lipophilic
extracts of cyanobacteria Nostoc sp. (ATCC 53789) and Nostoc sp.
(GSV 224), respectively. In 1994, Kobayashi and Kitagawa2 ex-
tracted arenastatin A, a depsipeptide that is structurally equivalent
to cryptophycin-24 2, from the marine sponge Dysidea arenaria. A
total of approximately 30 cryptophycins have been isolated from
Nostoc sp., and original approaches to the overall synthesis, includ-
ing the synthesis of the key building blocks3,4 and their use in the
preparation of hybrid macrolides,5 have been developed.
tide 3 displayed pronounced neuromuscular toxicity (myasthenia,
myalgia, paresthesia).7 In 2004, preclinical trials8 of hydrolytically-
stable glycinate analogues of cryptophycin-1, cryptophycin-249 4,
and -309 5, which display lower neurotoxicity and higher anti-
tumor activity than other cryptophycins, were performed on
murine and human cancer cell lines. These compounds have been
proposed as 2nd generation candidates for clinical trials.8b
Most cryptophycin molecules consist of four structural units. In
the case of cryptophycin-1 these are (2E,5S,6S,7R,8R)-7,8-epoxy-5-
hydroxy-6-methyl-8-phenyloct-2-enoic acid (Unit A),
D-tyrosine
derivative (Unit B), (R)- -methyl-b-alanine (Unit C), and (S)-leucic
a
acid (Unit D) (Table 1). Units B and C are readily available amino
acid derivatives.
Cryptophycin-1 displays antifungal activity against Cryptococcus
Herein our aim was to find a new synthetic pathway to prepare
Unit A of the cryptophycins based on the Kulinkovich cyclopropa-
nation reaction.
sp., with both MIC50 and MIC90 values of 47 l
M,1a,b cytotoxic activ-
ity against tumor cells of mice: (KB, IC50 78 pM), (LoVo, IC50 4.6 pM),
as well as against human: nasopharynx (KB, IC50 9.2 pM) and colon
(LoVo, IC50 10 pM) carcinoma cell lines.1c
2. Results and discussion
Cryptophycin 52 3 is a synthetic analogue of cryptophycin-1. Its
pharmacological activity against tumor cells is twice as high as that
of cryptophycin-1 under comparable conditions. Due to its stability
toward hydrolysis in vivo; cryptophycin 52 (LY355703) was pro-
posed by the Eli Lilly Co. as a prospective candidate for clinical tri-
als.6 Treatment of cancer cells by cryptophycins causes apoptosis
with typical morphological changes that occur faster than those
Cyclopropanation of hydroxycarboxylic esters, readily available
in enantiomerically pure form, by using Grignard reagents in the
presence of catalytic amounts of titanium isopropoxide(IV), is a
convenient method for the preparation of 1-substituted cycloprop-
anols.9 Further cleavage of the C1–C2, C1–C3, or C2–C3 bonds of
the activated three-membered ring opens up wide possibilities10
for converting the ester groups into various functionalities, includ-
ing allyl halides,11 vinyl ketones,12 ethyl ketones,13 b-functional-
ized ketones,14
a
,b-epoxyketones,15 carboxylic acids,16 and their
⇑
Tel.: +375 17 209 51 88; fax: +375 17 209 57 20.
E-mail address: denis.shklyaruck@gmail.com
esters.16c In this way, tertiary cyclopropanols can be used as
http://dx.doi.org/10.1016/j.tetasy.2014.03.011
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

D. G. Shklyaruck / Tetrahedron: Asymmetry 25 (2014) 644–649
645
Table 1
Some natural and semisynthetic cryptophycins
Depsipeptides
R1
R2
R3
X
Structures
First-generation cryptophycins and their analogues
Unit A
Cryptophycin-1 1
Cryptophycin-24 (Arenastatin A) 2
Cryptophycin-52 3
Me
H
Me
H
H
Me
i-Bu
i-Bu
i-Bu
Cl
H
Cl
13
O
3'
16
O
Ph
1'
2'
O
O
1
HN
10
X
O
6
3
R3
O
N
H
O
OMe
R1 R2
Unit C
Unit B
Unit D
Second-generation cryptophycins (glycinate esters)
Cl
Cryptophycin-249 4
Cryptophycin-309 5
Me
Me
H
H
i-Bu
CH2CMe3
Cl
Cl
O
Ph
O
O
O
O
O
HN
X
O
H3N
Cl
R3
N
H
O
OMe
R1 R2
HO
a
c
b
O
O
Br
O
O
O
O
OH
OH
OTHP
anti:syn 7:1
6
8
7
9
Scheme 1. Reagents and conditions: (a) See Ref. 18b; (b) LiAlH4, Hünig’s base, Et2O, rt, 1 h, 91%; (c) 9-BBN, THF, 0 °C, 4 h, then H2O2, NaOH, rt, 2 h, 88%.
intermediates for the protection of the ester group in organic
molecules.
one-pot procedures (a,b) (Scheme 2). The values of spin–spin
coupling constants and the magnitude of the Overhauser effect
(experiment 1D-gNOESY) between the atoms, marked by the
arrows in Scheme 2, clearly indicate that the stereocenters in the
major diastereomer of 9 are in an anti-configuration.
The cyclopropanol approach was previously used to prepare a
series of natural compounds,17 as well as building blocks required
for the synthesis of laulimalide18a and epothilones,18b–d macrocy-
clic drugs with taxol-like activity. The complete synthesis of
epothilone D has also been achieved.19
Herein the conversion of THP-protected diethyl malate into the
key allyl bromide 7 was performed in 6 stages according to the
scheme developed by Kulinkovich et al.18b (Scheme 1), yielding
38% of the target compound. Bromide 7 was then subjected to
H
O
a, b
Me
MeO2C
MeO2C
O
Me
9
O
O
H
H
Me
20
hydrogenolysis of the CABr bond under the action of LiAlH4 in
the presence of Hünig’s base, to give the unsaturated acetal 8 in
J=10.2 Hz
10
a yield of 91%.21
nOe
spin-spin coupling
In order to perform the hydroboration–oxidation reaction of the
double bond in 8, we tested several hydroborating agents22
(see Table 2). The best stereoselectivity was achieved when using
a solution of 9-BBN in THF at 0 °C.23 Alcohol 9 was isolated in
88% yield as a mixture of diastereomers (anti:syn = 7:1).
Scheme 2. Reagents and conditions: (a) MeOH, cat. PPTS, reflux, 20 min, then
PhI(OAc)2, rt, 20 min, solvent removal by rotatory evaporation; (b) (MeO)2CMe2,
acetone, rt, 1 h, 71% (two steps).
The two diastereomers of alcohol 9 could not be separated at
this stage because of their equal chromatographic mobility. An at-
tempt to perform the oxidation of 9 by the action of PCC in CH2Cl2
Table 2
Results of the diastereoselective hydroboration reaction of 8
led to partial epimerization of aldehyde 11 at the a-stereocenter.
9, anti:syna
% Yieldb
Therefore, compound 9 was subjected to a Swern oxidation
reaction24 (Scheme 3), and the aldehyde 11 thus obtained was then
introduced in the next synthetic step as a crude product.
Entry
Hydroborating agent
1
2
3
4
BMS
1.1:1
—
3:1
7:1
94
0c
82
88
(+)-Ipc2BH
Cy2BH
9-BBN
The olefination of aldehyde 11 according to a Wittig reaction
(stage b) using benzaltriphenylphosphorane resulted in a mixture
of geometric isomers of compound 12 with an E:Z ratio of 5.9:1 in
an overall yield of 54% over 2 steps. Since the E:Z ratio achieved in
this reaction was not sufficiently high, olefination of the aldehyde
11 according to Horner–Wadsworth–Emmons was performed using
diethyl benzylphosphonate as the reagent and BuLi as the base.25
This reaction proved to be highly stereoselective, giving an E:Z ratio
a
b
c
Determined by 1H NMR spectroscopy on the crude reaction mixture.
The values represent the combined yields of the diastereomers.
The starting acetal was isolated instead of the target products.
In order to confirm the relative configuration of the stereocen-
ters in alcohol 9, it was converted into ester 10 by performing

646
D. G. Shklyaruck / Tetrahedron: Asymmetry 25 (2014) 644–649
a
b
c
O
O
O
O
O
O
O
OH
11
12
9
O
O
O
d
e
OMe OH
OMe OTBS
H
OTBS
15
13
14
g
f
EtO2C
EtO2C
OTBS
OH
16
17
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1 h; (b) BnP(O)(OEt)2, BuLi, THF, ꢀ78 °C, 3 h, 72% (two steps); (c) MeOH, cat. PPTS, reflux,
20 min, then PhI(OAc)2, rt, 0.5 h, 88%; (d) TBSCl, imidazole, DMF, rt, 2 h, 93%; (e) DIBAL-H, toluene, ꢀ78 °C, 1 h; (f) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C, 0.5 h, 74% (two steps);
(g) TBAFꢃ3H2O, THF, rt, 4 h, 74%.
of 23:1 in an acceptable yield (72% over 2 steps). The major diaste-
reomer anti-12 could be almost completely separated from the
syn-diastereomer 12 using column chromatography on silica gel
(the ratio of anti:syn = 26:1). The acetonide protecting group was re-
moved from compound 12 by acid-catalyzed methanolysis, and the
cyclopropanol moiety thus formed was subjected to oxidative
cleavage (stage c) by the action of phenyliodine(III) diacetate16b,c
to give 13. Silyl ether 14 was prepared from the b-hydroxyester
13 using a standard procedure.26 Further transformations of methyl
ester 14 included reducing the ester group to an aldehyde by the ac-
tion of DIBAL-H27 to yield 15, followed by the Horner–Wadsworth–
Emmons reaction of 15 with triethyl phosphonoacetate and sodium
hydride as a base (stage f), which gave known28 compound 16, the
TBS-protected target compound. The protecting group could then
be easily removed (stage g) to determine the enantiomeric excess.
The ee value for 5-hydroxyester 17 was determined using
Mosher’s method.29 Derivatization of (5S,6R)-17 with (S)-MTPA
gave two diastereomers with distinct 6-methyl group doublets at
1.07 and 1.15 ppm in the 1H NMR spectra. Comparing the integral
intensity ratios of these doublets with those of the (S)-MTPA deriv-
ative of racemic 17 allowed us to determine that the enantiomeric
excess of the target compound was 98%.
chromatography (TLC) was performed on aluminum-backed plates
coated with silica gel 60; chromatograms were visualized with a
Ce/Mo reagent followed by heating. Column chromatography was
performed using Merck 60 silica gel (70–230 mesh). Flash column
chromatography was carried out on silica gel 60 (230–240 mesh).
1H, 13C NMR and spectra were recorded at 400 and 100 MHz,
respectively, in CDCl3 (CHCl3 at d = 7.26 ppm for 1H NMR and CHCl3
at d = 77.0 ppm for 13C NMR as internal standard) using a Bruker AC
400 spectrometer. The 1D gNOESY experiments were performed on
the same spectrometer. Peaks’ multiplicities are indicated as fol-
lows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of
doublets of doublets), dddd (doublet of doublets of doublets of
doublets), br s (broad signal). The FT-IR spectra were recorded
using a Vertex 70 spectrometer. Optical rotations were measured
at 20 2 °C using a CM-3 polarimeter (scale factor: 0.05°).
4.2. (S)-5,5-Dimethyl-7-(prop-1-en-2-yl)-4,6-dioxaspiro[2.5]
octane 8
Hünig’s base (0.6 mL, 3.44 mmol, in one portion) and a solution
of allyl bromide 7 (0.90 g, 3.45 mmol, dropwise) in anhydrous
diethyl ether (5 mL) were added consecutively to a stirred suspen-
sion of LiAlH4 (0.09 g, 2.37 mmol) in anhydrous diethyl ether
(10 mL) at room temperature. The reaction mixture was stirred
for 1 h at same temperature, and then cooled to ꢀ20 °C. Water
(5 mL) was then added dropwise, and the reaction mixture was
slowly warmed to room temperature. The organic layer was sepa-
rated, and the aqueous layer was extracted with diethyl ether
(3 ꢁ 5 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and filtered. The solvent was slowly
distilled off at atmospheric pressure through a small Vigreux col-
umn. The residue was purified by flash column chromatography
on silica gel (pentane/diethyl ether 35:1). Compound 8 (0.57 g,
3. Conclusion
A new scheme for the linear synthesis of Unit A of the crypto-
phycin structure starting from natural (S)-(ꢀ)-malic acid has been
developed, yielding 13% of the target compound over 14 steps. A
characteristic feature of the proposed scheme is using inexpensive
starting materials, reagents, and solvents. The approach used here-
in demonstrates new possibilities for the synthetic application of
readily available cyclopropane-containing compounds for both
the protection of alkoxycarbonyl functional groups and their con-
version into highly reactive 2-alkyl allyl bromide.
91%) was isolated as a light yellow oil; ½a D20
¼ þ44:2 (c 8.30,
ꢂ
Et2O); 1H NMR (CDCl3) d 0.38 (ddd, J = 10.2, 6.4, 5.4 Hz, 1H), 0.62
(ddd, J = 10.2, 6.4, 4.8 Hz, 1H), 0.74 (ddd, J = 10.7, 6.4, 5.4 Hz, 1H),
0.86 (dddd, J = 10.7, 6.4, 4.8, 1.8 Hz, 1H), 1.00 (dd, J = 13.2, 2.8 Hz,
1H), 1.40 (s, 3H), 1.55 (s, 3H), 1.75 (s, 3H), 2.19 (ddd, J = 13.2,
11.8, 1.8 Hz, 1H), 4.45 (dd, J = 11.8, 2.8 Hz, 1H), 4.85–4.87 (m,
1H), 5.01–5.03 (m, 1H); 13C NMR (CDCl3) d 9.9, 14.5, 18.3, 29.8,
4. Experimental
4.1. General
All reagents were purchased and used without further purifica-
tion unless otherwise stated. Solvents were dried according to
standard methods and distilled before use. Analytical thin layer
36.3, 53.6, 71.7, 100.2, 111.0, 115.8, 145.1; IR (CCl4) mmax: 3087,

D. G. Shklyaruck / Tetrahedron: Asymmetry 25 (2014) 644–649
647
1652 cmꢀ1. Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C,
72.54; H, 9.93.
CH2Cl2 (15 mL) was added. The reaction mixture was stirred for
0.5 h at ꢀ78 °C, and triethylamine (15.1 mL, 108 mmol) was added
in one portion. After 0.5 h at ꢀ78 °C, the mixture was allowed to
warm to room temperature for approximately 1.5 h and diluted
with water (25 mL). The organic layer was separated, and the aque-
ous layer was extracted with CH2Cl2 (3 ꢁ 20 mL). The combined or-
ganic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Crude aldehyde 11 was used
in the next reaction without further purification.
4.3. (R)-2-((S)-5,5-Dimethyl-4,6-dioxaspiro[2.5]octan-7-yl)
propan-1-ol 9
A solution of unsaturated acetal 8 (1.10 g, 6.04 mmol) in anhy-
drous THF (10 mL) was added dropwise under an argon atmo-
sphere and stirring at ꢀ5 °C to a solution of 9-BBN, prepared30
from BMS complex (95%, 1.81 mL, 18.2 mmol) and cis,cis-1,5-cyclo-
octadiene (1.97 g, 18.2 mmol) in anhydrous THF (20 mL). After
completion of the addition, the reaction mixture was warmed to
0 °C and stirred for 4 h at the same temperature. The reaction mix-
ture was then cooled to ꢀ15 °C (ice/salt bath), and sequentially
added ethyl alcohol (15 mL), an aqueous solution of sodium
hydroxide (3.0 M, 12.5 mL, 37.5 mmol) and H2O2 (30 wt % aqueous
solution, 12.5 mL, 122 mmol). Stirring was continued for 2 h at
room temperature, after which the reaction mixture was diluted
with diethyl ether (10 mL) and saturated with K2CO3. The organic
layer was separated, and the aqueous layer extracted with diethyl
ether (4 ꢁ 15 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate 5:1). Compound 9 as a mixture of
syn- and anti-isomers (1.06 g, 88%), was isolated by column chro-
matography on silica gel (petroleum ether/ethyl acetate) as a col-
4.5.1. (S)-5,5-Dimethyl-7-((R,E)-4-phenylbut-3-en-2-yl)-4,6-di-
oxaspiro[2.5]octane 12
A solution of diethyl benzylphosphonate (4.15 g, 18.2 mmol) in
anhydrous THF (30 mL) was cooled to ꢀ78 °C under an argon
atmosphere, after which
a 1.2 M solution of n-BuLi/hexane
(9.0 mL, 10.8 mmol) was added. The reaction mixture was stirred
for 1 h at same temperature, and aldehyde 11 was added dropwise.
After stirring for 2 h, the reaction mixture was quenched with a
saturated aqueous NH4Cl solution and warmed to rt. The organic
layer was separated, and the aqueous layer was extracted with
diethyl ether (3 ꢁ 20 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (petroleum ether/ethyl acetate 25:1) to give
compound 12 (1.75 g, 72%) as a colorless oil; ½a D20
¼ þ58:5 (c
ꢂ
4.70, CHCl3); 1H NMR (CDCl3) d 0.27 (ddd, J = 10.5, 6.4, 5.9 Hz,
1H), 0.48 (ddd, J = 10.5, 6.4, 4.8 Hz, 1H), 0.64 (ddd, J = 11.0, 6.4,
5.9 Hz, 1H), 0.73 (dddd, J = 11.0, 6.4, 4.8, 1.3 Hz, 1H), 0.81 (dd,
J = 13.1, 2.6 Hz, 1H), 1.05 (d, J = 6.9 Hz, 3H), 1.31 (s, 3H), 1.45 (s,
3H), 2.07 (ddd, J = 13.1, 11.8, 1.3 Hz, 1H), 2.29–2.41 (m, 1H), 3.92
(ddd, J = 11.8, 5.2, 2.6 Hz, 1H), 6.19 (dd, J = 16.1, 7.7 Hz, 1H), 6.32
(d, J = 16.1 Hz, 1H), 7.10–7.31 (m, 5H); 13C NMR (CDCl3) d 9.9,
14.6, 15.5, 21.3, 29.8, 34.3, 41.6, 53.5, 71.8, 100.0, 126.0 (ꢁ2),
orless viscous oil; ½a D20
ꢂ
¼ þ37:1 (c 6.22, CHCl3); 1H NMR (CDCl3) d
0.39 (ddd, J = 10.5, 6.4, 5.6 Hz, 1H), 0.58 (ddd, J = 10.5, 6.4, 4.9 Hz,
1H), 0.74 (ddd, J = 11.0, 6.4, 5.6 Hz, 1H), 0.80–0.86 (m, 1H), 0.83
(d, J = 6.9 Hz, 3H), 1.02 (dd, J = 13.1, 2.6 Hz, 1H), 1.37 (s, 3H), 1.54
(s, 3H), 1.74–1.83 (m, 1H), 2.10 (ddd, J = 13.1, 11.0, 1.5 Hz, 1H),
3.03 (br s, 1H), 3.60–3.65 (m, 2H), 3.96 (ddd, J = 11.0, 7.9, 2.6 Hz,
1H); 13C NMR (CDCl3) d 9.9, 12.8, 14.7, 21.2, 29.8, 35.9, 40.2,
53.5, 67.6, 74.4, 100.0; IR (CCl4)
m
max: 3542, 3087 cmꢀ1. Anal. Calcd
126.9, 128.4 (ꢁ2), 129.9, 132.3, 137.7; IR (CCl4)
m .
max: 3084 cmꢀ1
Anal. Calcd for C18H24O2: C, 79.37; H, 8.88. Found: C, 79.46; H, 8.86.
for C11H20O3: C, 65.97; H, 10.07. Found: C, 65.82; H, 10.05.
4.4. Methyl 2-((4S,5R)-2,2,5-trimethyl-1,3-dioxan-4-yl)acetate 10
4.6. (3S,4R,E)-Methyl 3-hydroxy-4-methyl-6-phenylhex-5-eno-
ate 13
A solution of alcohol 9 (0.10 g, 0.50 mmol) and PPTS (0.01 g,
0.04 mmol) in methanol (3 mL) was refluxed for 20 min. The reac-
tion mixture was then cooled to room temperature, and PhI(OAc)2
(0.18 g, 0.56 mmol) was added in one portion with stirring. After
0.5 h, the solvent was evaporated under reduced pressure. The res-
idue was dissolved in dry acetone (2 mL), cooled to 0 °C (ice/water
bath), and 2,2-dimethoxypropane (0.16 g, 1.50 mmol) was added
under stirring. The reaction course was monitored using TLC. After
0.5 h, the solvents were evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (petroleum ether/ethyl acetate 15:1) to yield ester 10 (0.07 g,
71%) as a colorless oil; 1H NMR (CDCl3) d 0.76 (d, J = 6.9 Hz, 3H),
1.36 (s, 3H), 1.45 (s, 3H), 1.59 (m, 1H) 2.39 (dd, J = 15.4, 8.8 Hz,
1H), 2.58 (dd, J = 15.4, 3.2 Hz, 1H), 3.53 (dd, J = 11.5, 11.5 Hz, 1H),
3.65 (dd, J = 11.5, 5,1 Hz, 1H), 3.70 (s, 3H) 3.98 (ddd, J = 10.2, 8.8,
3.2 Hz, 1H); 13C NMR (CDCl3) d 12.5, 18.9, 29.6, 33.9, 38.8, 51.6,
A
solution of PPTS (0.05 g, 0.20 mmol) and 12 (0.90 g
3.30 mmol) in dry methanol (20 mL) was refluxed for 20 min.
The reaction mixture was then cooled to room temperature and
PhI(OAc)2 (1.07 g, 3.32 mmol) was added in one portion with stir-
ring. After 0.5 h, the solvent was evaporated under reduced pres-
sure. The residue was chromatographed on silica gel (petroleum
ether/ethyl acetate 6:1) to give hydroxy ester 13 (0.68 g, 88%) as
a colorless oil; ½a D20
ꢂ
¼ þ8:5 (c 11.8, CHCl3); 1H NMR (CDCl3) d
1.09 (d, J = 6.9 Hz, 3H), 2.32–2.40 (m, 1H), 2.41–2.43 (m, 2H),
3.24 (br s, 1H), 3.61 (s, 3H), 3.95 (dt, J = 8.7, 4.6 Hz, 1H), 6.12 (dd,
J = 16.1, 8.4 Hz, 1H), 6.33 (d, J = 16.1 Hz, 1H), 7.12–7.30 (m, 5H);
13C NMR (CDCl3) d 16.5, 38.8, 42.8, 51.8, 71.5, 126.1 (ꢁ2), 127.3,
128.5 (ꢁ2), 130.9, 131.3, 137.1, 173.5; IR (CCl4)
mmax: 3567,
1728 cmꢀ1. Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C,
71.85; H, 7.73.
65.8, 72.2, 98.4, 171.9; IR (CCl4) m .
max: 1743 cmꢀ1
4.7. (3S,4R,E)-Methyl 3-(tert-butyldimethylsilyloxy)-4-methyl-
4.5. (S)-2-((S)-5,5-Dimethyl-4,6-dioxaspiro[2.5]octan-7-yl) pro-
6-phenylhex-5-enoate 14
panal 11
A solution of the hydroxy ester 13 (0.57 g, 2.43 mmol) in DMF
(15 mL) was cooled to 0 °C, and imidazole (0.25 g, 3.67 mmol)
was added with stirring, followed by TBSCl (0.44 g, 2.92 mmol)
after 5 min. The stirring at 0 °C was continued for 15 min, then
the reaction mixture was warmed up to room temperature and
stirred for 2 h at the same temperature. A solution of diethyl ether
in hexane (5%, v/v, 10 mL) and water (25 mL) were added to this
mixture, the organic layer was separated, and the aqueous phase
A solution of DMSO (1.50 mL, 21.1 mmol) in dry CH2Cl2 (5 mL)
was added dropwise under an argon atmosphere and with stirring
at ꢀ78 °C to a solution of oxalyl chloride (0.86 mL, 10.0 mmol) in
dry CH2Cl2 (15 mL). The solution was warmed up to ꢀ50 °C, and
stirring was continued for 5 min at the same temperature. The
reaction mixture was then cooled to ꢀ78 °C, and a solution of 9
(1.65 g, 8.24 mmol) as a mixture of syn- and anti-isomers in dry

648
D. G. Shklyaruck / Tetrahedron: Asymmetry 25 (2014) 644–649
was extracted with (4 ꢁ 15 mL) portions of the 5% diethyl ether
solution in hexane. The combined organic layers were dried over
anhydrous Na2SO4 and then filtered. The solvents were evaporated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate 40:1)
to give the TBS-protected hydroxy ester 14 (0.79 g, 93%) as a vis-
4.10. (2E,5S,6R,7E)-Ethyl 5-hydroxy-6-methyl-8-phenylocta-2,7-
dienoate 17
At first, TBAFꢃ3H2O (0.61 g, 1.93 mmol) was added to a solution of
unsaturated ester 16 (0.25 g, 0.64 mmol) in THF (20 mL), and the
reaction mixture was stirred for 4 h at rt. The solvent was evaporated
under reduced pressure, and the residue was purified by flash col-
umn chromatography on silica gel (petroleum ether/ethyl acetate
7:1) to give the deprotected hydroxy ester 17 (0.13 g, 74%) as a
cous colorless oil; ½a D20
ꢂ
¼ þ18:7 (c 8.00, CHCl3); 1H NMR (CDCl3)
d ꢀ0.04 (s, 3H), 0.01 (s, 3H), 0.81 (s, 9H), 1.04 (d, J = 6.9 Hz, 3H),
2.35 (d, J = 6.4 Hz, 2H), 2.42–2.44 (m, 1H), 3.57 (s, 3H), 4.13 (dt,
J = 10.0, 6.4 Hz, 1H), 6.07 (dd, J = 16.1, 7.7 Hz, 1H), 6.31 (d,
J = 16.1 Hz, 1H), 7.11–7.28 (m, 5H); 13C NMR (CDCl3) d ꢀ4.8,
ꢀ4.7, 15.0, 25.8 (ꢁ3), 29.4, 39.3, 43.0, 51.5, 72.8, 126.1 (ꢁ2),
viscous oil; ½a 2D0
ꢂ
¼ þ62:8 (c 1.06, CHCl3); 1H NMR (CDCl3) d 1.15
(d, J = 6.9 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.87 (br s, 1H), 2.30–2.53
(m, 3H), 3.63–3.70 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 5.92 (d,
J = 15.6 Hz, 1H), 6.14 (dd, J = 15.9, 8.4 Hz, 1H), 6.48 (d, J = 15.9 Hz,
1H), 7.03 (dt, J = 15.6, 7.7 Hz, 1H), 7.20–7.41 (m, 5H); 13C NMR
(CDCl3) d 14.2, 16.8, 37.3, 43.3, 60.2, 73.8, 123.7, 126.2 (ꢁ2), 127.4,
127.1, 128.5 (ꢁ2), 130.5, 131.5, 137.5, 172.5; IR (CCl4) mmax
:
3027, 1741, 1091 cmꢀ1. Anal. Calcd for C20H32O3Si: C, 68.92; H,
9.25. Found: C, 69.01; H, 9.23.
128.5 (ꢁ2), 130.9, 132.0, 137.0, 145.3, 166.3; IR (film)
mmax: 3456,
4.8. (3S,4R,E)-3-(tert-Butyldimethylsilyloxy)-4-methyl-6-phenyl
hex-5-enal 15
3059, 1717, 1600 cmꢀ1. Anal. Calcd for C17H22O3: C, 74.42; H, 8.08.
Found: C, 74.52; H, 8.10.
To a solution of compound 14 (0.65 g, 1.86 mmol) in dry toluene
(12 mL) at ꢀ78 °C DIBAL-H (1.2 M solution in toluene, 2.1 mL,
2.52 mmol) was added slowly under an argon atmosphere and with
stirring. Stirring was continued at the same temperature for 1 h,
then the reaction mixture was quenched with dry methanol
(0.1 mL) and stirred for 0.5 h. at ꢀ78 °C. Next, a saturated aqueous
solution of Rochelle’s salt (3.5 mL) and NaHCO3 (3.5 mL) were
added. The resulting mixture was warmed up to room temperature
and stirred for another 0.5 h. The organic layer was separated and
the aqueous layer extracted with (3 ꢁ 10 mL) portions of diethyl
ether. The combined diethyl ether extracts were dried over Na2SO4
and concentrated under reduced pressure to give crude aldehyde 15
(0.58 g). This material was used in the next synthetic stage without
further purification; 1H NMR (CDCl3) d 0.07 (s, 3H), 0.08 (s, 3H), 0.91
(s, 9H), 1.14 (d, J = 6.9 Hz, 3H), 2.52–2.58 (m, 3H), 4.27 (dt, J = 9.5,
6.4 Hz, 1H), 6.14 (dd, J = 16.0, 7.9 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H),
Acknowledgements
This work was carried out with the support of the Ministry of
Education of the Republic of Belarus. The author is very grateful
to Professor Kulinkovich O. G. for the original idea and leadership
of the present work.
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ꢂ
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