A cyclopropanol approach to the synthesis of both enantiomers of the C13-C21 fragment of epothilones

Article abstract of DOI:10.1016/j.tet.2009.02.003

Efficient syntheses of both enantiomers of the C13-C21 fragment of epothilone molecules have been performed by use of enantiomeric oxiranyl-substituted cyclopropylsulfonates as key intermediates. The latter were obtained by the cyclopropanation of easily

Full text of DOI:10.1016/j.tet.2009.02.003

Tetrahedron 65 (2009) 3518–3524
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A cyclopropanol approach to the synthesis of both enantiomers
of the C13–C21 fragment of epothilones
*
Alaksiej L. Hurski, Nikolai A. Sokolov, Oleg G. Kulinkovich
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 3 October 2008
Received in revised form 16 January 2009
Accepted 5 February 2009
Available online 11 February 2009
Efficient syntheses of both enantiomers of the C13–C21 fragment of epothilone molecules have been
performed by use of enantiomeric oxiranyl-substituted cyclopropylsulfonates as key intermediates. The
latter were obtained by the cyclopropanation of easily available (R)-methyl 2,3-O-isopropyl-
ideneglycerate and subsequent manipulation of the functional groups. Asymmetric allylation of 1-for-
mylcyclopropyl pivalate led to an alternative precursor of the target compounds with moderate
enantioselectivity.
Dedicated to Professor Jacques Salau¨n on
the occasion of his 70th birthday
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Epothilones
Cyclopropanols
Allyl halides
Homoallyl alcohols
1. Introduction
our knowledge, there are no published details on the preparation of
compound (S)-3 or (R)-3 from natural chiral precursors (Scheme 1).
Epothilones are bioactive macrocyclic natural products with
potent antitumour properties. These compounds were isolated
from extracts of the cellulose-degrading myxobacterium Sorangium
cellulosum1,2 and in the last decade they have served as lead
structures for the development of anticancer agents.3 Several
epothilones, including epothilone B 1, are currently in clinical trials
and the 15-aza analogue of epothilone B 2 (brand name: Ixempra)
has recently obtained FDA approval as an anticancer drug.4 Since
epothilone analogues possessing improved therapeutic properties
have been obtained efficiently by total synthesis, elaboration of
convenient procedures for their preparation has practical interest.
Among the synthetic approaches to the epothilones, macro-
lactonization and ring-closing olefin metathesis strategies have
been applied most frequently and both of these strategies allow the
efficient use of the thiazole-containing fragment (S)-3 as an ad-
vanced intermediate.5 The latter has been prepared by asymmetric
In continuation of our efforts on the development of cyclo-
propanol methodology for the synthesis of natural products, we
have recently reported the preparation of the C13–C21 epothilone
fragment 6 by the appropriate transformation of the ester groups in
O
O
12
13
15
S
S
21
8
7
15
HO
HO
N
N
6
3
O
NH
O
O
OH
O
O
OH
15-aza-epothilone B (Ixempra ) (2)
Epothilone B (1)
allylation of the thiazole-containing a,b-unsaturated aldehyde 4, in
accordance with Brown and Keck procedures,5a–d olefination of
TBS-protected hydroxyaldehyde precursor 55e and enantioselective
enzymatic resolution of allylic alcohol 35f or other precursors.5g,h To
OH
O
OTBS
O
13
N
21
N
S
N
S
15
or
S
(S)-3
4
5
* Corresponding author. Tel.: þ375 17 2095459; fax: þ375 17 2265609.
E-mail address: kulinkovich@bsu.by (O.G. Kulinkovich).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.003

A.L. Hurski et al. / Tetrahedron 65 (2009) 3518–3524
3519
1. EtMgBr, Ti(Oi-Pr)4
(10 mol-%)
OTHP
CO2Et
O
O
OTHP
15
O
t-BuOK, t-BuOH
ref. 6a
ref. 6b
2. PivCl, Py, CH2Cl2
reflux
Br
O
Br
1.
EtO2C
N
S
21
13
60%
70%
OH
OEt
OPiv
12
11
7
8
6
Scheme 2.
MLn
O3, CH2Cl2, -78 °C,
then Zn, AcOH
OPiv
O
2.Silica gel
85%
THP-protected (S)-diethyl malate 7 via the key bis-cyclopropanol
derivative 8 (Scheme 2).6 The homoallylic alcohol (S)-3 can be
prepared by Wittig olefination of aldehyde 65e and subsequent
deprotection of the hydroxyl group. However, the preparation of
enantiomeric alcohol (R)-3 by this pathway requires the use of the
corresponding derivatives of the rather expensive (R)-malic acid.
Since homoallylic alcohol (R)-3 could be employed for the prepa-
ration of (S)-15-aza-epothilones via inversion at the C15 center
with nitrogen-based nucleophiles,7 we were interested in elabo-
ration of the cyclopropanol approach to the syntheses of both en-
antiomers of the C13–C21 epothilone fragments (S)-3 and (R)-3.
OPiv
10
OH
OPiv
13, 0-79% ee
9
Yields
ee, %
MLn
13, %
a
b
SnBu3
0
-
CO2i-Pr
O
B
51
50
CO2i-Pr
O
14
(+)-B(Ipc)2
52
79
2. Results and discussion
15
a(S)-BINOL-titanium complex
At first, asymmetric allylation of 1-formylcyclopropyl pivalate 9
as a possible key step for the preparation of homoallylic alcohols
(S)-3 and (R)-3 was studied. Aldehyde 9 was obtained by reductive
ozonolysis of 1-vinylcyclopropanol 10, prepared in turn using
the approach to vinylcyclopropanols elaborated earlier by Salau¨n
et al.8 The titanium(IV)-catalyzed cyclopropanation of ethyl-3-
bromopropionate9 11 with ethylmagnesium bromide, followed by
esterification and dehydrobromination of 12 with potassium tert-
butoxide, gave vinylcyclopropanol derivative 10 in 42% overall
yield. Aldehyde 9 was prepared by reductive ozonolysis of vinyl-
cyclopropanol derivative 10 and subjected to asymmetric allylation
with Keck, Roush and Brown reagents.10–12 The allylation of 9 with
allyltri-n-butylstannane in the presence of the (S)-BINOL enantio-
directing ligand,10 proceeded slowly to give racemic homoallylic
alcohol derivative 13. Better results were obtained with allylboron
reagents. Aldehyde 9 reacted with diisopropyl (R,R)-tartrate-mod-
ified allylboronate 1411 and (þ)-diisopinocamphenyl-derived
allylborane 1512 to form 13 with 50% and 79% ee, respectively
(Scheme 3).
was used as the chiral catalyst.
bhomoallylic alcohol derivative 13 (45%)
along with starting compound 9 (55%)
were detected in the reaction mixture
after a month by 1H NMR.
Scheme 3.
was performed in the presence of equimolar amounts of CuI,17 a 4:1
mixture of monomesylate (S)-21 and diol (S)-22 was obtained in
66% overall yield. The ring opening of (S)-16 in the presence of
catalytic amounts of CuCN18 (10 mol %) gave the same mixture of
products in excellent yield. Acetylation of mesylate (S)-21, as well as
sequential acetylation of the less hindered secondary hydroxyl
group of diol (S)-22, followed by mesylation of the tertiary hydroxyl
unit, led to mesylate (S)-23 in 82% combined yield.
Because allylation of aldehyde 9 proceeded with disappointing
enantioselectivity, we tried to prepare enantiomerically pure
homoallylic alcohols (S)-3 and (R)-3 by the use of ring opening of
the appropriate oxiranes (S)-16 and (R)-16 with vinylmagnesium
bromide as the key step. Both oxiranes were synthesized by
cyclopropanation of (R)-glycerate derivative 17, which is easily
EtMgBr,
Ti(Oi-Pr)4 (100 mol-%),
O
O
O
THF
60% 18, 25% 18'
O
O
O
OMe
+
OH
O
OH
available from relatively cheap
D
-mannitol,13 and subsequent
17
18
18'
functional group manipulations. The cyclopropanation of ester 17
with ethylmagnesium bromide in the presence of equimolar
amounts of titanium(IV) isopropoxide gave cyclopropanol 18 in 60%
isolated yield (Scheme 4) along with the corresponding tertiary
alcohol 180 as the main side product.14 Mesylation of 18, followed by
acetonide deprotection afforded cleanly the diol 19, which was
used as common intermediate for the preparation of oxiranes (S)-
16 and (R)-16.
OH
t-BuOSiMe2Cl, Et3N,
1. MsCl, Et3N, CH2Cl2;
2. PPTS, EtOH, reflux
HO
CH2Cl2 then MsCl
18
82%
87%
OMs
19
To prepare oxirane (S)-16 the primary hydroxyl group of diol 19
was protected as its tert-butoxydimethylsilyl ether15 and sub-
sequent mesylation of the secondary hydroxyl led to dimesylate 20.
Treatment of the latter with aqueous KOH in the presence of TEBA16
caused desilylation and subsequent formation of oxirane (S)-16.
Treatment of oxirane (S)-16 with vinylmagnesium bromide in
the presence of CuI or CuCN furnished homoallylic alcohol (S)-21
and its demesylation product (S)-22 (Scheme 4). When the reaction
aq. KOH,
TEBA,
THF
OMs
O
OMs
O
t-BuO
Si
93%
OMs
20
(S)-16
Scheme 4.

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A.L. Hurski et al. / Tetrahedron 65 (2009) 3518–3524
Ac2O, Et3N, DMAP, CH2Cl2
86%
CH2=CHMgBr,
CuCN (10 mol-%),
THF
OH
OH
AcCl, DMAP, Py,
then MsCl
OAc
(S)-16
+
75% 21, 22% 22
70%
OMs
OH
OMs
(S)-21
(S)-22
(S)-23
MgBr2, Et2O,
CHCl3, reflux
78%
BrMg
N
S
25, CuI,
Et2O, THF, 0 °C
OAc
t-BuOK, t-BuOH,
OAc
reflux
N
S
(S)-3
Br
68% over 2 steps
(S)-24
(S)-26
Scheme 5.
Cyclopropylsulfonate (S)-23 was subjected to cationic cyclopropyl–
allyl rearrangement by treatment with magnesium bromide in
ether/chloroform mixture19 to afford 2-substituted allyl bromide
(S)-24 in high yield.
The coupling of allyl bromide (S)-24 with 2-methylthiazol-4-yl-
magnesium bromide 25 in ether in the presence of CuI6b led to
acetate (S)-26 in low yield. The reaction proceeded more smoothly
when ether/THF mixture (1:2) was used as solvent and allyl acetate
(S)-26 was obtained in this case in 85% yield. Base-catalyzed allylic
shift of the disubstituted carbon–carbon double bond in compound
(S)-26 to the conjugated position6b proceeded simultaneously with
acetate deprotection to give target homoallylic alcohol (S)-3 with
>99% ee.
Tosylation of the primary hydroxyl group of diol 19 in the
presence of n-Bu2SnO20 furnished disulfonate 27 in excellent yield
and regioselectivity, which under treatment with aqueous KOH in
the presence of TEBA was smoothly converted to oxirane (R)-16.
The transformation of the latter into homoallylic alcohol (R)-3 was
performed via the corresponding intermediates (R)-21–(R)-26
(Scheme 6), in the same way as described for compound (S)-3, with
>99% ee (Scheme 5).
corresponding aldehydes with an allylboron reagent5a or with
allyltri-n-butylstannane in the presence of a chiral catalyst.5b,c
Nevertheless, the cyclopropanol approach is based on simple re-
action procedures and leads to the target products 3 with higher
enantiomeric purity. In addition, a convenient way to both key
oxiranes (S)-16 and (R)-16 described in this work has positive im-
plications for these new bifunctional C-5 building blocks within
other synthetically useful preparative approaches.
3. Conclusions
In conclusion, the reaction of 1-formylcyclopropyl pivalate 9
with chiral allylboron reagents gave the corresponding homoallylic
alcohol 13 with moderate enantioselectivity, whereas asymmetric
allylation of 9 under Keck conditions proceeded with lack of
enantioselectivity. Homoallylic alcohol derivatives (S)-23 and (R)-
23 in stereochemically pure form were effectively prepared starting
from easily available (R)-methyl 2,3-O-isopropylideneglycerate 17
via the cyclopropanation of the ester group, followed by conversion
of the cyclopropanol 18 into enantiomeric oxyranyl-substituted
cyclopropylsulfonates (S)-16 and (R)-16 and copper-catalyzed ep-
oxide ring opening with vinylmagnesium bromide. Compounds (S)-
23 and (R)-23 were successfully converted into C13–C21 epothilone
fragments (S)-3 and (R)-3 by use of earlier developed methods for
stereoselective transformation of the cyclopropylsulfonate group
into the alkenylthiazole fragment.
The synthesis of homoallylic alcohols (S)-3 and (R)-3 described
in this work required a longer reaction sequence than earlier
published syntheses of (S)-3 by asymmetric allylation of the
aq. KOH,
4. Experimental
4.1. General
TsCl, Bu2SnO,
Et3N, CH2Cl2
TEBA,
THF
OH
OH
TsO
HO
94%
93%
OMs
27
OMs
Melting points were determined with a capillary apparatus.
Optical rotations were measured at 20ꢀ2 ꢁC with a CM-3 polar-
imeter (scale factor: 0.05ꢁ). Column chromatography was per-
formed on Merck 60 silica gel (70–230 mesh). IR spectra were
recorded with a Vertex 70 spectrometer. 1H and 13C NMR spectra
were obtained with a Bruker AC 400 instrument at 400 and
19
O
See Scheme 5
(R)-3
OMs
(R)-16
100 MHz, respectively, in CDCl3 (CHCl3 at
d
¼7.26 ppm for 1H NMR
¼77.0 ppm for 13C NMR as internal standard).
Scheme 6.
and CHCl3 at
d

A.L. Hurski et al. / Tetrahedron 65 (2009) 3518–3524
3521
4.2. 1-(2-Bromoethyl)cyclopropyl pivalate (12)
dropwise. The reaction mixture was warmed to ambient temper-
ature, stored for a month and quenched with aqueous NaHCO3
(5 mL). The aqueous phase was separated and extracted with
CH2Cl2 (3ꢂ5 mL). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. Homoallylic al-
cohol 13 (45%) as well as starting aldehyde 9 (55%) was detected in
the residue by 1H NMR spectroscopy.
Pivaloyl chloride (9.5 mL, 67.6 mmol) was added to a solution of
1-(2-bromoethyl)cyclopropanol (7.67 g, 46.5 mmol), prepared in
accordance with described procedure9c from ester 11 (10.0 g,
55.2 mmol) and ethylmagnesium bromide (120.8 mmol) in the
presence of Ti(Oi-Pr)4 (1.64 mL, 5.5 mmol) in Et2O, and pyridine
(12.0 mL, 148 mmol) in CH2Cl2 (85 mL). The reaction mixture was
left overnight at room temperature and quenched with water
(20 mL). The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (2ꢂ10 mL). The combined organic extracts
were washed with aqueous NaHCO3, dried over MgSO4 and con-
centrated under reduced pressure. The residue was chromato-
graphed on silica gel (petroleum ether/ethyl acetate) to give
4.5.2. Procedure B11
A solution of aldehyde 9 (0.17 g, 1 mmol) in toluene (1 mL) was
added dropwise at ꢃ78 ꢁC to a stirred solution of (R,R)-diisopro-
pyltartrate-modified allylboronate 14 (0.28 g, 1 mmol) in toluene
(4 mL). The reaction mixture was stirred over 1 h, quenched with
water (5 mL) and extracted with ether (3ꢂ5 mL). The combined
organic extracts were washed with brine, dried over MgSO4 and
concentrated under reduced pressure. Silica gel (0.5 g) was added to
a solution of the residue in petrol ether (3 mL) and the mixture was
stirred overnight, filtered and concentrated in vacuo. The residue
was chromatographed on silica gel (petroleum ether/ethyl acetate)
to give homoallylic alcohol 13 (0.11 g, 51%) as a colourless oil.
pivalate 12 (9.62 g, 83%) as a colourless oil. 1H NMR (CDCl3)
d 0.73–
0.76 (m, 2H, 2-H, 3-H), 0.82–0.85 (m, 2H, 2-H, 3-H), 1.19 (s, 9H,
C(CH3)3), 2.30 (t, J¼7.4 Hz, 2H, 10-H), 3.44 (t, J¼7.4 Hz, 2H, 20-H). 13C
NMR (CDCl3)
d
11.8 (ꢂ2), 26.9 (ꢂ3), 28.7, 38.1, 38.6, 58.2, 178.3. IR
(CCl4) nmax: 1745 cmꢃ1. Anal. Calcd for C10H17BrO2: C, 48.21; H, 6.88.
Found: C, 47.96; H, 6.95.
4.3. 1-Vinylcyclopropyl pivalate (10)
4.5.3. Procedure C12
A
solution of aldehyde 9 (0.11 g, 0.65 mmol) in ether
To a solution of t-BuOK prepared from potassium (1.46 g,
37.4 mmol) in t-BuOH (45 mL) was added pivalate 12 (6.21 g,
24.9 mmol). The mixture was refluxed for 45 min and concentrated
in vacuo. The residue was quenched with aqueous NH4Cl (50 mL)
and extracted with ether (3ꢂ20 mL). The organic layer was washed
with brine, dried over MgSO4 and concentrated under reduced
pressure. The residue was distilled to give 10 (2.51 g, 60%) as
(0.3 mL) was added dropwise at ꢃ78 ꢁC to a stirred solution of (þ)-
diisopinocamphenyl-derived allylborane 15 (0.33 M in ether, 2 mL,
0.65 mmol). The reaction mixture was stirred for 1 h, warmed to
ambient temperature, concentrated in vacuo and the residue was
dissolved in THF (3 mL). Sodium perborate (0.30 g, 2 mmol) and
water (2 mL) were added and the mixture was stirred overnight.
The aqueous phase was separated and extracted with ether
(3ꢂ5 mL). The combined organic extracts were washed with brine,
dried over MgSO4 and concentrated under reduced pressure. Silica
gel (0.5 g) was added to a solution of residue in petrol ether (3 mL)
and the mixture was stirred overnight, filtered and concentrated in
vacuo. The residue was chromatographed on silica gel (petroleum
ether/ethyl acetate) to give homoallylic alcohol 13 (72 mg, 52%) as
a colourless oil. bp 55–65 ꢁC/10 Torr. 1H NMR (CDCl3)
d 0.95–1.00
(m, 2H, 2-H, 3-H), 1.03–1.08 (m, 2H, 2-H, 3-H), 1.19 (s, 9H, C(CH3)3),
4.96 (dd, J¼17.2, 0.5 Hz, 1H, CHH]CH), 5.02 (dd, J¼11.0, 0.5 Hz, 1H,
CHH]CH), 5.67 (dd, J¼17.2, 11.0 Hz, 1H, CH2]CH). 13C NMR (CDCl3)
d
14.6 (ꢂ2), 27.0 (ꢂ3), 38.6, 58.4, 111.4, 137.6, 177.8. IR (CCl4) nmax
:
1749 cmꢃ1. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59. Found: C,
71.53; H, 9.64.
a colourless oil. 1H NMR (CDCl3) 0.56–0.66 (m, 2H, 20-H, 30-H), 0.74
d
(m, 1H, 20-H), 0.83 (m, 1H, 30-H), 1.19 (s, 9H, C(CH3)3), 2.48–2.61 (m,
2H, 2-H), 2.63 (br s, 1H, OH), 4.50 (dd, J¼8.1, 5.8 Hz, 1H, 1-H), 5.03
(dd, J¼10.2, 1.5 Hz, 1H, 4-H), 5.10 (dd, J¼17.2, 1.5 Hz, 1H, 4-H), 5.77
4.4. 1-Formylcyclopropyl pivalate (9)
Ozone was bubbled at ꢃ78 ꢁC through a solution of vinyl-
cyclopropane derivative 10 (4.00 g, 23.8 mmol) in CH2Cl2 (120 mL)
until a persistent blue solution was obtained. After elimination of
excess ozone by oxygen bubbling, zinc dust (3.10 g, 47.6 mmol) and
50% acetic acid (64 mL) were added and the mixture was allowed to
reach room temperature with vigorous stirring. The mixture was
diluted with CH2Cl2 (100 mL), the organic layer was separated,
washed with water, aqueous NaHCO3 and brine, dried over MgSO4
and concentrated under reduced pressure. The residue was passed
through a short column of silica gel (petroleum ether/ethyl acetate)
to give aldehyde 9 (3.44 g, 85%) as a colourless oil. 1H NMR (CDCl3)
(ddt, J¼17.2, 10.2, 7.2 Hz, 1H, 3-H). 13C NMR (CDCl3)
d 12.3, 12.5, 27.2
(ꢂ3), 35.6, 38.9, 57.1, 77.7, 117.5, 133.9, 178.1. IR (CCl4) nmax: 3600,
3486, 1729 cmꢃ1. Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found:
C, 68.16; H, 9.39.
4.5.4. Determination of the enantiomeric purity of (S)-13
The ee value of (S)-13 was determined by Mosher’s method21
from the integral intensities of the signals of the protons at
d
¼4.81
and 4.87 ppm (CHOMTPA) in the 1H NMR spectra of the (S)-MTPA
esters. In this way the enantiomeric purity of compound (S)-13
obtained in accordance with procedures A, B and C was determined
to be 0%, 50% and 79%, ee, respectively.
d
1.23 (s, 9H, C(CH3)3), 1.26–1.30 (m, 2H, 2-H, 3-H), 1.51–1.55 (m, 2H,
2-H, 3-H), 9.21 (s, 1H, CHO). 13C NMR (CDCl3)
d
15.4 (ꢂ2), 26.9 (ꢂ3),
38.5, 63.3, 178.4, 196.5. IR (CCl4) nmax: 1748, 1731 cmꢃ1. Anal. Calcd
4.6. (R)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)cyclopropanol (18)
and (R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)pentan-3-ol (180)
for C9H14O3: C, 63.51; H, 8.29. Found: C 63.29, H 8.38.
4.5. (S)-1-(1-Hydroxycyclopropyl)but-3-enyl pivalate (13)
A solution of ethylmagnesium bromide prepared from magne-
sium (7.50 g, 313 mmol) and ethyl bromide (23.4 mL, 313 mmol) in
a mixture of THF (210 mL) and benzene (20 mL) was added over 2 h
to a stirred solution of ester 17 (10.00 g, 62.5 mmol) and Ti(Oi-Pr)4
(19.0 mL, 62.5 mmol) in THF (65 mL). The mixture was concen-
trated in vacuo, diluted with CH2Cl2 (150 mL), quenched with
aqueous NH4Cl (40 mL), filtered and the filter cake was washed
thoroughly with CH2Cl2 (3ꢂ100 mL). The filtrate was washed with
aqueous NaHCO3, dried over MgSO4 and concentrated under re-
duced pressure. The residue was chromatographed on silica gel
4.5.1. Procedure A10
A mixture of (S)-BINOL (50 mg, 0.18 mmol), Ti(Oi-Pr)4 (1 M in
CH2Cl2, 0.18 mL, 0.18 mmol) and oven-dried powdered 4 Å mole-
cular sieves (0.70 g) in CH2Cl2 (1.8 mL) was heated under reflux for
1 h and cooled to ambient temperature. A solution of aldehyde 9
(0.30 g, 1.75 mmol) in CH2Cl2 (0.3 mL) was added and the reaction
mixture was stirred for 10 min. The contents were cooled to ꢃ78 ꢁC
and allyltri-n-butylstannane (0.87 g, 2.6 mmol) was added

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A.L. Hurski et al. / Tetrahedron 65 (2009) 3518–3524
(petroleum ether/ethyl acetate) to give cyclopropanol derivative 18
(5.93 g, 60%) as a colourless oil and tertiary alcohol 180 (2.90 g, 25%).
0 ꢁC. The mixture was allowed to reach room temperature, stirred
for 30 min, quenched with aqueous NaHCO3 (100 mL) and extrac-
ted with CH2Cl2 (3ꢂ30 mL). The combined organic extracts were
washed with brine, dried over MgSO4 and concentrated under re-
duced pressure. The residue was chromatographed on silica gel
(petroleum ether/ethyl acetate) to give protected diol 20 (16.7 g,
4.6.1. Cyclopropanol 18
[
a
]
D þ12 (c 3.4, CHCl3). 1H NMR (CDCl3)
d 0.51 (m, 1H, 2-H), 0.64
(m, 1H, 3-H), 0.83–0.89 (m, 2H, 2-H, 3-H), 1.38 (s, 3H, 20-Me), 1.47 (s,
3H, 20-Me), 2.42 (br s, 1H, OH), 3.72 (t, J¼6.9 Hz, 1H, 40-H), 4.01 (dd,
82%) as a colourless oil. [
a
]
þ28 (c 6.2, CHCl3). 1H NMR (CDCl3)
D
J¼6.9, 0.8 Hz, 2H, 50-H). 13C NMR (CDCl3)
d
9.5, 12.4, 25.3, 26.4, 53.8,
d
0.14 (s, 6H, SiMe2),1.04 (m, 1H, 20-H),1.25 (m,1H, 30-H),1.28 (s, 9H,
65.7, 80.9, 109.2. IR (CCl4) nmax: 3585, 3479 cmꢃ1. Anal. Calcd for
C(CH3)3), 1.37 (m, 1H, 20-H), 1.74 (dt, J¼11.4, 7.3 Hz, 1H, 30-H), 3.11 (s,
3H, Ms), 3.13 (s, 3H, Ms), 3.92 (dd, J¼11.8, 7.8 Hz, 1H, 2-H), 4.03 (dd,
J¼11.8, 3.7 Hz, 1H, 2-H), 4.70 (dd, J¼7.8, 3.7 Hz, 1H, 1-H). 13C NMR
C8H14O3: C, 60.74; H 8.92. Found: C, 60.61; H, 8.98.
4.6.2. Tertiary alcohol 180
(CDCl3)
d
ꢃ0.4 (ꢂ2), 11.2, 11.6, 31.9 (ꢂ3), 38.9, 39.5, 61.4, 64.6, 72.8,
[
a
]
D þ21 (c 5.2, CHCl3). 1H NMR (CDCl3)
d
0.87 (t, J¼7.7 Hz, 3H, 1-
85.4. IR (CCl4) nmax: 1366, 1178 cmꢃ1. Anal. Calcd for C13H28O8S2Si:
H), 0.88 (t, J¼7.7 Hz, 3H, 5-H), 1.28–1.48 (m, 2H, 2-H, 4-H), 1.36 (s,
3H, 20-Me),1.41 (s, 3H, 20-Me),1.55–1.66 (m, 2H,1-H, 5-H),1.86 (br s,
1H, OH), 3.87 (dd, J¼8.2, 7.7 Hz, 1H, 40-H), 3.93 (dd, J¼7.7, 6.1 Hz, 1H,
C, 38.59; H, 6.98. Found: C, 38.26; H, 6.85.
4.10. (S)-1-(Oxiran-2-yl)cyclopropyl methanesulfonate
((S)-16)
40-H), 4.04 (dd, J¼8.2, 6.1 Hz, 1H, 40-H). 13C NMR (CDCl3)
d 7.4, 7.7,
25.6, 26.1, 26.4, 28.7, 64.5, 73.3, 79.4, 108.7. IR (CCl4) nmax
:
3580 cmꢃ1. Anal. Calcd for C10H20O3: C, 63.80; H, 10.71. Found: C,
63.91; H, 10.73.
TEBA (90 mg) and 25% aqueous KOH (6 mL) were added to
a solution of protected diol 20 (0.92 g, 2.3 mmol) in THF (9 mL). The
mixture was vigorously stirred for 1 h and diluted with ether
(9 mL). The aqueous phase was separated and extracted with ether
(3ꢂ5 mL). The combined organic extracts were washed with brine,
dried over MgSO4 and concentrated under reduced pressure. The
residue was chromatographed on silica gel (petroleum ether/ethyl
acetate) to give oxirane (S)-16 (0.38 g, 93%) as a colourless oil.
CAUTION: neat oxiranes 16 were disposed to vigorous de-
composition. A THF solution of the latter was stable upon storage in
4.7. (R)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)cyclopropyl
methanesulfonate
Methanesulfonyl chloride (5.8 mL, 74.5 mmol) was added
dropwise at 0 ꢁC to a stirred solution of cyclopropanol derivative 18
(9.05 g, 57.3 mmol) and triethylamine (12.0 mL, 86.3 mmol) in
CH2Cl2 (120 mL). The reaction mixture was stirred at room tem-
perature for 30 min, quenched with aqueous NaHCO3 (60 mL) and
extracted with CH2Cl2 (2ꢂ20 mL). The combined organic extracts
were washed with brine, dried over MgSO4 and concentrated under
reduced pressure to give crude (R)-1-(2,2-dimethyl-1,3-dioxolan-4-
yl)cyclopropyl methanesulfonate (13.01 g, 96%), which was
a fridge over a few months. [
a
]
D ꢃ11 (c 2.1, CHCl3). 1H NMR (CDCl3)
d
0.82–0.95 (m, 2H, 2-H, 3-H), 1.26–1.28 (m, 2H, 2-H, 3-H), 2.68 (dd,
J¼4.9, 2.4 Hz,1H, 30-H), 2.88 (dd, J¼4.9, 3.8 Hz,1H, 30-H), 3.07 (s, 3H,
Ms), 3.53 (dd, J¼3.8, 2.4 Hz, 1H, 20-H). 13C NMR (CDCl3)
d 8.6, 9.7,
39.5, 46.2, 51.1, 64.5. IR (CCl4) nmax: 1357, 1171 cmꢃ1. Anal. Calcd for
employed in the next step without further purification. [
a
]
þ4 (c
C6H10O4S: C, 40.44; H, 5.66. Found: C, 40.70; H, 5.77.
D
1.8, CHCl3). 1H NMR (CDCl3):
d 94 (m, 1H, 2-H), 1.01 (m, 1H, 3-H),
1.23–1.36 (m, 2H, 2-H, 3-H), 1.32 (s, 3H, 20-Me), 1.39 (s, 3H, 20-Me),
4.11. (S)-1-(1-Hydroxybut-3-enyl)cyclopropyl
methanesulfonate ((S)-21) and (S)-1-(1-hydroxybut-3-
enyl)cyclopropanol ((S)-22)
3.03 (s, 3H, Ms), 3.9 (dd, J¼8.6, 6.0 Hz, 1H, 50-H), 4.13 (dd, J¼8.6,
6.6 Hz, 1H, 50-H), 4.47 (t, J¼6.4 Hz, 1H, 40-H). 13C NMR (CDCl3):
d 8.5,
9.2, 25.0, 26.1, 39.6, 65.6, 66.8, 75.6, 109.7. IR (CCl4) nmax: 1355,
1168 cmꢃ1. Anal. Calcd for C9H16O5S: C, 45.75; H, 6.83. Found: C,
45.98; H, 6.97.
Vinylmagnesium bromide (1 M in THF, 58 mL, 58.0 mmol) was
added dropwise at ꢃ15 ꢁC under argon to a stirred suspension of
CuCN (0.13 g, 1.4 mmol) in THF (70 mL). The mixture was stirred for
5 min and a solution of oxirane (S)-16 (2.71 g, 14.5 mmol) in THF
(10 mL) was added dropwise. After stirring for 45 min at ꢃ10 ꢁC the
reaction mixture was quenched with a mixture of saturated aque-
ous solutions of NH4Cl (50 mL) and NH4OH (50 mL), and extracted
with diethyl ether (3ꢂ30 mL). The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure. The
residue was chromatographed on silica gel (petroleum ether/ethyl
acetate) to give monomesylate (S)-21 (2.36 g, 75%) as a colourless
oil and diol (S)-22 (0.41 g, 22%) as white crystals.
4.8. (R)-1-(1,2-Dihydroxyethyl)cyclopropyl methane-
sulfonate (19)
A solution of unpurified (R)-1-(2,2-dimethyl-1,3-dioxolan-4-
yl)cyclopropyl methanesulfonate (13.01 g, 55.1 mmol) and PPTS
(1.4 g) in ethanol (120 mL) was heated under reflux for 2 h. The
reaction mixture was concentrated in vacuo and the residue was
chromatographed on silica gel (petroleum ether/ethyl acetate) to
give mesylate 19 (9.88 g, 91%) as a viscous oil. [
a
]
þ10 (c 1.54,
D
CHCl3). 1H NMR (CDCl3)
d
0.94 (m, 1H, 2-H), 1.05 (m, 1H, 3-H), 1.28
(m, 1H, 2-H), 1.48 (m, 1H, 3-H), 2.31 (br s, 1H, OH), 3.09 (s, 3H, Ms),
4.11.1. Monomesylate (S)-21
3.21 (br s,1H, OH), 3.60 (m,1H,10-H), 3.75 (dd, J¼11.3, 6.9 Hz,1H, 20-
[
a
]
D ꢃ21 (c 3.0, CHCl3). 1H NMR (CDCl3)
d 0.83 (m, 1H, 2-H), 1.03
H), 3.84 (dd, J¼11.3, 4.1 Hz, 1H, 20-H). 13C NMR (CDCl3)
d
9.9, 10.2,
(m, 1H, 3-H), 1.18 (m, 1H, 2-H), 1.52 (m, 1H, 3-H), 2.39 (m, 1H, 20-H),
2.49 (m, 1H, 20-H), 2.78 (m, 1H, OH), 3.11 (s, 3H, Ms), 3.44 (dt, J¼8.4,
5.4 Hz, 1H, 10-H), 5.13 (dd, J¼10.2, 1.5 Hz, 1H, 40-H), 5.17 (dd, J¼17.2,
1.5 Hz, 1H, 40-H), 5.88 (ddt, J¼17.2, 10.2, 6.9 Hz, 1H, 30-H). 13C NMR
39.6, 63.5, 66.8, 74.4. IR (film) nmax: 3391, 1345, 1165 cmꢃ1. Anal.
Calcd for C6H12O5S: C, 36.73; H, 6.16. Found: C, 36.87; H, 6.22.
4.9. (R)-2-(tert-Butoxydimethylsiloxy)-1-(1-(methylsulfony-
loxy)cyclopropyl)ethyl methanesulfonate (20)
(CDCl3) d 10.6, 10.8, 38.1, 39.5, 68.8, 74.5, 117.9, 134.0. IR (CCl4) nmax:
3537, 1351, 1169 cmꢃ1. Anal. Calcd for C8H14O4S: C, 46.59; H, 6.84.
Found: C, 46.54; H, 6.91.
tert-Butoxychlorodimethylsilane15 (8.97 g, 54.0 mmol) was
added dropwise at 0 ꢁC to a stirred solution of diol 19 (9.60 g,
48.9 mmol) and triethylamine (20.5 mL, 147 mmol) in CH2Cl2
(200 mL). The reaction mixture was stirred for 10 min and meth-
anesulfonyl chloride (5.7 mL, 74 mmol) was added dropwise at
4.11.2. Diol (S)-22
Mp 58–59 ꢁC. [
a
]
D
þ1 (c 2.7, CHCl3). 1H NMR (CDCl3)
d 0.53–
0.63 (m, 2H, 2-H, 3-H), 0.79–0.90 (m, 2H, 2-H, 3-H), 1.97 (br s, 1H,
OH), 0.40–2.52 (m, 3H, OH, 20-H), 3.19 (dd, J¼8.4, 4.6 Hz, 1H, 10-H),

A.L. Hurski et al. / Tetrahedron 65 (2009) 3518–3524
3523
5.09 (d, J¼9.9 Hz, 1H, 40-H), 5.14 (d, J¼17.2 Hz, 1H, 40-H), 5.92 (ddt,
warmed to ꢃ60 ꢁC and a solution of MgBr2 prepared from mag-
nesium (0.23 g, 9.4 mmol) and dibromoethane (0.81 mL, 9.4 mmol)
in diethyl ether (9 mL) was added. The contents were warmed to
0 ꢁC and diluted with THF (35 mL) followed by the subsequent
addition of CuI (93 mg, 0.49 mmol) and a solution of (S)-24 (0.857 g,
3.68 mmol) in THF (5 mL). After stirring for 5 min the reaction
mixture was quenched with saturated aqueous NH4Cl (15 mL). The
aqueous phase was separated and extracted with ether (3ꢂ10 mL).
The combined organic extracts were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The residue was
chromatographed on silica gel (petroleum ether/ethyl acetate) to
J¼17.2, 9.9, 7.2 Hz, 1H, 30-H). 13C NMR (CDCl3)
d 11.1, 12.7, 37.9, 57.8,
76.2, 117.6, 135.0. IR (CCl4) nmax: 3587, 3481 cmꢃ1. Anal. Calcd for
C7H12O2: C, 65.60; H, 9.44. Found: C, 65.93; H, 9.52.
4.12. (S)-1-(1-(Methylsulfonyloxy)cyclopropyl)but-3-enyl
acetate ((S)-23)
4.12.1. Conversion of monomesylate (S)-21 into homoallyl acetate
(S)-23
Acetic anhydride (0.74 mL, 7.8 mmol) was added at 0 ꢁC to
a stirred solution of monomesylate (S)-21 (1.40 g, 6.5 mmol), DMAP
(0.16 g, 1.31 mmol) and triethylamine (1.8 mL, 13.0 mmol) in CH2Cl2
(35 mL). The reaction mixture was stirred for 1 h, warmed to am-
bient temperature and quenched with water (20 mL). The aqueous
phase was separated and extracted with CH2Cl2 (2ꢂ10 mL). The
combined organic extracts were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The residue was
chromatographed on silica gel (petroleum ether/ethyl acetate) to
give thiazole (S)-26 (0.785 g, 85%) as a yellow oil. [
a
]
ꢃ19 (c 1.3,
D
CHCl3). 1H NMR (CDCl3):
d
2.00 (s, 3H, COCH3), 2.40 (t, J¼7.0 Hz, 2H,
4-H), 2.68 (s, 3H, 200-Me), 3.48 (d, J¼16.6 Hz, 1H, 10-H), 3.53 (d,
J¼16.6 Hz, 1H, 10-H), 4.94 (s, 1H, 1-H), 5.03 (dd, J¼10.0, 1.5 Hz, 1H, 6-
H), 5.06 (dd, J¼17.3, 1.5 Hz, 1H, 6-H), 5.16 (s, 1H, 1-H), 5.30 (t,
J¼6.5 Hz, 1H, 3-H), 5.69 (ddt, J¼17.3, 10.0, 7.0 Hz, 1H, 5-H), 6.81 (s,
1H, 500-H). 13C NMR (CDCl3)
d 19.1, 21.0, 34.7, 37.6, 74.9, 114.2, 114.3,
117.6,133.4,144.4,153.5,165.5,170.1. IR (CCl4) nmax: 1741 cmꢃ1. Anal.
give homoallyl acetate (S)-23 (1.45 g, 86%) as a colourless oil. [
a
]
Calcd for C13H17NO2S: C, 62.12; H, 6.82. Found: C, 61.77; H, 6.75.
D
ꢃ41 (c 2.7, CHCl3). 1H NMR (CDCl3)
d
0.83 (m, 1H, 20-H), 1.12–1.20
(m, 2H, 20-H, 30-H),1.54 (m,1H, 30-H), 2.09 (s, 3H, COCH3), 2.42–2.58
(m, 2H, 2-H), 3.07 (s, 3H, Ms), 4.75 (dd, J¼8.8, 5.3 Hz, 1H, 1-H), 5.07
(dd, J¼10.2, 1.3 Hz, 1H, 4-H), 5.12 (dd, J¼17.2, 1.3 Hz, 1H, 4-H), 5.74
4.14.1. Preparation of (S,E)-2-methyl-1-(2-methylthiazol-4-yl)hexa-
1,5-dien-3-ol ((S)-3)
A
solution of t-BuOK prepared from potassium (0.20 g,
(ddt, J¼17.2, 10.2, 7.0 Hz,1H, 3-H). 13C NMR (CDCl3)
d
10.5,12.4, 20.9,
5.0 mmol) and t-BuOH (20 mL) was added to (S)-26 (0.519 mg,
2.07 mmol). The mixture was refluxed for 45 min and concen-
trated in vacuo. The residue was quenched with water (10 mL)
and extracted with ether (3ꢂ5 mL). The combined organic ex-
tracts were washed with brine, dried over MgSO4 and concen-
trated under reduced pressure. The residue was chromatographed
on silica gel (petroleum ether/ethyl acetate) to give (S)-3 (344 mg,
35.3, 39.7, 66.6, 75.2, 118.1, 132.8, 170.4. IR (CCl4) nmax: 1742, 1369,
1175 cmꢃ1. Anal. Calcd for C10H16O5S: C, 48.37; H, 6.50. Found: C,
48.38; H, 6.43.
4.12.2. Conversion of diol (S)-22 into homoallyl acetate (S)-23
Acetyl chloride (0.21 mL, 2.9 mmol) was added at 0 ꢁC to
a
solution of (S)-22 (0.33 g, 2.6 mmol) and DMAP (63 mg,
80%) as a yellow oil. [
a
]
D ꢃ22 (c 1.9, CHCl3). 1H NMR (CDCl3)
d 2.02
0.52 mmol) in pyridine (5.2 mL). The reaction mixture was left in
a fridge at 5 ꢁC for 3 h. After that methanesulfonyl chloride
(0.4 mL, 5.2 mmol) was added to the reaction mixture. The latter
was left in a fridge at 5 ꢁC overnight and quenched in the same
manner as described above. Column chromatography on silica gel
(petroleum ether/ethyl acetate) gave (S)-23 (0.75 g, 70%) as
a colourless oil.
(s, 3H, 2-Me), 2.29–2.46 (m, 3H, 4-H, OH), 2.69 (s, 3H, 20-Me), 4.20
(t, J¼6.3 Hz, 1H, 3-H), 5.11 (d, J¼10.2 Hz, 1H, 6-H), 5.15 (dd, J¼17.2,
1.3 Hz, 1H, 6-H), 5.81 (ddt, J¼17.2, 10.2, 7.2 Hz, 1H, 5-H), 6.55 (s,
1H, 1-H), 6.92 (s, 1H, 50-H). 13C NMR (CDCl3)
d 14.3, 19.1, 40.0, 76.4,
115.5, 117.8, 119.0, 134.5, 141.4, 152.7, 164.6. IR (CCl4) nmax: 3615,
3311 cmꢃ1. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22. Found: C,
63.29; H, 7.10. The spectral data are in agreement with the liter-
ature data.5a,b
4.13. (S)-2-(Bromomethyl)hexa-1,5-dien-3-yl acetate ((S)-24)
4.14.2. Determination of the enantiomeric purity of (S)-3 and (R)-3
The ee values of (S)-3 and (R)-3 were determined by Mosher’s
method21 from the integral intensities of the singlets of the protons
A solution of homoallyl acetate (S)-23 (1.43 g, 3.8 mmol) in
CHCl3 (70 mL) was added to a solution of MgBr2 prepared from
magnesium (0.55 g, 23.1 mmol) and dibromoethane (2.2 mL,
25.4 mmol) in diethyl ether (20 mL). The mixture was heated under
reflux for 5 h, quenched with water (50 mL) and extracted with
CHCl3 (2ꢂ20 mL). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. The residue was
chromatographed on silica gel (petroleum ether/ethyl acetate) to
at
d
¼6.57 and 6.45 ppm (1-H) in the 1H NMR spectra of the (R)-
MTPA esters. In this way the enantiomeric purity of compounds (S)-
3 and (R)-3 was determined to be >99% ee.
4.15. (R)-2-Hydroxy-2-(1-(methylsulfonyloxy)cyclopropyl)-
ethyl 4-methylbenzenesulfonate (27)
give (S)-24 (1.05 g, 78%) as a colourless oil. [
NMR (CDCl3)
a
]
D ꢃ6 (c 4.3, CHCl3). 1H
d
2.06 (s, 3H, COCH3), 2.44–2.58 (m, 2H, 4-H), 3.96 (d,
J¼10.8 Hz, 1H, 10-H), 4.15 (d, J¼10.8 Hz, 1H, 10-H), 5.08 (d, J¼6.9 Hz,
1H, 6-H), 5.11 (d, J¼17.2 Hz, 1H, 6-H), 5.29 (s, 1H, 1-H), 5.38 (s, 1H, 1-
H), 5.43 (dd, J¼7.4, 5.6 Hz, 1H, 3-H), 5.73 (ddt, J¼17.2, 10.2, 6.9 Hz,
To a solution of diol 19 (3.00 g, 15.3 mmol) and triethylamine
(2.34 mL, 16.8 mmol) in CH2Cl2 (50 mL) were added Bu2SnO
(76 mg, 0.31 mmol) and toluenesulfonyl chloride (3.06 g,
16.1 mmol). The reaction mixture was stirred for 5 h, filtered over
silica gel, washed with water (10 mL), dried over MgSO4 and con-
centrated under reduced pressure. The residue was chromato-
graphed on silica gel (petroleum ether/ethyl acetate) to give
1H, 5-H). 13C NMR (CDCl3)
d
21.0, 32.1, 37.9, 73.3, 118.1 (ꢂ2), 133.0,
143.2, 170.0. IR (CCl4) nmax: 1744 cmꢃ1. Anal. Calcd for C9H13BrO2: C,
46.37; H, 5.62. Found: C, 46.25; H, 5.79.
4.14. (S)-2-((2-Methylthiazol-4-yl)methyl)hexa-1,5-dien-3-yl
acetate ((S)-26)
tosylate 27 (5.00 g, 93%) as a viscous oil. [
NMR (CDCl3)
a
]
D þ10 (c 2.1, CHCl3). 1H
d
0.93 (m, 1H, 20-H), 1.03 (m, 1H, 30-H), 1.24 (m, 1H, 20-
H), 1.52 (m, 1H, 30-H), 2.45 (s, 3H, tosyl CH3), 3.04 (s, 3H, Ms), 3.67 (t,
J¼5.8 Hz, 1H, 2-H), 4.14 (dd, J¼10.5, 6.4 Hz, 1H, 1-H), 4.26 (dd,
J¼10.5, 5.4 Hz, 1H, 1-H), 7.36 (d, J¼8.1 Hz, 2H, tosyl CH), 7.80 (d,
A solution of n-BuLi in hexane (1.6 M, 4.6 mL, 7.3 mmol) was
added dropwise at ꢃ78 ꢁC to a stirred solution of 4-bromo-2-
methylthiazole 2522 (1.30 g, 7.3 mmol) in diethyl ether (4.6 mL).
The reaction mixture was stirred for 3 h at the same temperature,
J¼8.1 Hz, 2H, tosyl CH). 13C NMR (CDCl3)
d 9.9, 10.5, 21.6, 39.3, 65.8,
70.0, 72.2, 128.0 (ꢂ2), 129.9 (ꢂ2), 132.5, 145.2. IR (film) nmax: 3514,

3524
A.L. Hurski et al. / Tetrahedron 65 (2009) 3518–3524
1357, 1176 cmꢃ1. Anal. Calcd for C13H18O7S2: C, 44.56; H, 5.18.
Found: C, 44.69; H, 5.23.
identical with those of enantiomeric homoallylic alcohol (S)-3 (see
above).
Acknowledgements
4.16. (R)-1-(Oxiran-2-yl)cyclopropyl methanesulfonate
((R)-16)
This work was carried out with support of the Ministry of Ed-
ucation of the Republic of Belarus.
TEBA (0.47 g) and 25% aqueous KOH (24 mL) were added to
a solution of tosylate 27 (4.70 g, 13.4 mmol) in THF (24 mL). The
mixture was vigorously stirred over 1 h and diluted with ether
(25 mL). The aqueous phase was separated and extracted with
ether (3ꢂ10 mL). The combined organic extracts were washed with
brine, dried over MgSO4 and concentrated under reduced pressure
to give (R)-16 (2.40 g, 94%). This material was employed in the next
step without further purification. CAUTION: neat oxiranes 16 were
References and notes
1. Ho¨fle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. DE-4138042, 1993; Chem. Abstr.
1994, 120, 52841.
2. Washausen, G. P.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 560.
3. For reviews see: (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem.
1998, 110, 2120; Angew. Chem., Int. Ed. 1998, 37, 2014; (b) Harris, C. R.; Dani-
shefsky, S. J. J. Org. Chem. 1999, 64, 8434; (c) Mulzer, J.; Martin, H. J.; Berger, M.
J. Heterocycl. Chem. 1999, 36, 1421; (d) Nicolaou, K. C.; Ritzen, A.; Namoto, K.
Chem. Commun. 2001, 1523; (e) Altmann, K.-H. Org. Biomol. Chem. 2004, 2, 2137;
(f) Watkins, E. B.; Chittiboyina, A. G.; Jung, J. C.; Avery, M. A. Curr. Pharm. Des.
2005, 11, 1615; (g) Watkins, E. B.; Chittiboyina, A. G.; Avery, M. A. Eur. J. Org.
Chem. 2006, 4071; (h) Altmann, K.-H.; Pfeiffer, B.; Arseniyadis, S.; Pratt, B. A.;
Nicolaou, K. C. Chem. Med. Chem. 2007, 2, 396; (i) Feyen, F.; Cachoux, F.; Gertsch,
J.; Wartmann, M.; Altmann, K.-H. Acc. Chem. Res. 2008, 41, 21.
disposed to vigorous decomposition. [
NMR data were identical with those of enantiomeric oxirane (S)-16
a
]
D þ10 (c 2.0, CHCl3). IR and
(see above).
4.17. (R)-1-(1-Hydroxybut-3-enyl)cyclopropyl
methanesulfonate ((R)-21) and (R)-1-(1-hydroxybut-3-
enyl)cyclopropanol ((R)-22)
4. (a) Altmann, K. H. Curr. Pharm. Des. 2005, 11, 1595; (b) Larkin, J. M. G.; Kaye, S. B.
Expert Opin. Invest. Drugs 2006, 15, 691; (c) Conlin, A.; Fornier, M.; Hudis, C.; Kar,
S.; Kirkpatrick, P. Nat. Rev. Drug Discov. 2007, 6, 953.
5. (a) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.;
Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974; (b) Meng, D.; Berti-
nato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S. J.
J. Am. Chem. Soc. 1997, 119, 10073; (c) Taylor, R. E.; Haley, J. D. Tetrahedron Lett.
1997, 38, 2061; (d) Taylor, R. E.; Chen, Y. Org. Lett. 2001, 3, 2221; (e) Schinzer, D.;
Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M. Angew. Chem. 1997, 109, 543;
Angew. Chem., Int. Ed. 1997, 36, 523; (f) Zhu, B.; Panek, J. S. Tetrahedron Lett.
2000, 41, 1863; (g) Broadrup, R. L.; Sundara, H. M.; Swindell, C. S. Bioorg. Chem.
2005, 33, 116; (h) Sinha, S. C.; Sun, J.; Miller, G.; Barbas, C. F.; Lerner, R. A. Org.
Lett. 1999, 1, 1623; (i) Taylor, R. E.; Chen, Y.; Galvin, G. M.; Pabb, P. K. Org. Biomol.
Chem. 2004, 2, 127; (j) Matsuya, Y.; Kawaguchi, T.; Ishihara, K.; Ahmed, K.; Zhao,
Q.-L.; Kondo, T.; Nemoto, H. Org. Lett. 2006, 8, 4609.
Compoumds (R)-21 and (R)-22 were obtained in the same
manner as enantiomeric monomesilate (S)-21 and diol (S)-22 (see
above).
4.17.1. Monomesylate (R)-21
Yield: 75%. [
a
]
þ20 (c 2.5, CHCl3). IR and NMR data were
D
identical with those of enantiomeric sulfonate (S)-21.
4.17.2. Diol (R)-22
6. (a) Bekish, A. V.; Kulinkovich, O. G. Tetrahedron Lett. 2005, 46, 6975; (b) Bekish,
A. V.; Isakov, V. E.; Kulinkovich, O. G. Tetrahedron Lett. 2005, 46, 6979.
7. (a) Stachel, S. J.; Lee, C. B.; Spassova, M.; Chappell, M. D.; Bornmann, W. G.;
Danishefsky, S. J.; Chou, T.-C.; Guan, Y. J. Org. Chem. 2001, 66, 4369; (b) Stachel,
S. J.; Chappell, M. D.; Lee, C. B.; Danishefsky, S. J.; Chou, T.-C.; He, L.; Horwitz, S.
B. Org. Lett. 2000, 2, 1637.
8. (a) Sylvestre, I.; Ollivier, J.; Salau¨n, J. Tetrahedron Lett. 2001, 42, 4991;
(b) Racouchot, S.; Sylvestre, I.; Ollivier, J.; Kozyrkov, Y. Y.; Pukin, A.; Kulinkovich,
O. G.; Salau¨n, J. Eur. J. Org. Chem. 2002, 2160.
Yield 22%. [
with those of enantiomeric diol (S)-22.
a
]
D ꢃ1 (c 4.1, CHCl3). IR and NMR data were identical
4.18. (R)-1-(1-(Methylsulfonyloxy)cyclopropyl)but-3-enyl
acetate ((R)-23)
Acetate (R)-23 was obtained from monomesylate (R)-21 and diol
(R)-22 in the same manner as enantiomeric homoallyl acetate (S)-
23 in 85% combined yield (88% yield from monomesylate (R)-21
9. (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org.
Khim. 1989, 25, 2245; (b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. Synthesis 1991, 234; (c) Sviridov, S. V.; Vasilevskii, D. A.; Ku-
linkovich, O. G. Zh. Org. Khim 1991, 27, 1431; J. Org. Chem. USSR (Engl. Transl.)
1991, 27, 1251; for reviews, see: (d) Kulinkovich, O. G. Izv. Akad. Nauk, Ser. Khim.
2004, 1022; Russ. Chem. Bull., Int. Ed. (Engl. Transl.) 2004, 53, 1065;
(e) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
10. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.
11. Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186.
12. Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
and 73% yield from diol (R)-22). [
data were identical with those of enantiomeric acetate (S)-23 (see
a
]
D þ41 (c 2.2, CHCl3). IR and NMR
above).
13. (a) Lichtenthaler, F. W.; Jarglis, P.; Lorenz, K. Synthesis 1988, 790; (b) Schmid, C.
R.; Bradley, D. A. Synthesis 1992, 587.
14. Cyclopropanation of ester 17 in the presence of 25 mol % of titanium(IV) iso-
propoxide gave cyclopropanol 18 and tertiary alcohol 180 in 30:70 ratio.
15. Brandes, D.; Blaschette, A. Monatsh. f. Chem. 1975, 106, 1299.
4.19. (R)-2-(Bromomethyl)hexa-1,5-dien-3-yl acetate ((R)-24)
Bromide (R)-24 was obtained from sulfonate (R)-23 in the same
manner as enantiomeric bromide (S)-24 (see above). Yield 76%. [a]
D
16. In the absence of the phase transfer catalyst only trace amounts of oxirane (S)-
16 were formed.
þ6 (c 4.3, CHCl3). IR and NMR data were identical with those of
enantiomeric bromide (S)-24 (see above).
´
17. Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullez, M.; Colobert, F.; Solladie, G.
Tetrahedron Lett. 2003, 44, 2695.
18. Reddy, P. P.; Yen, K.-F.; Uang, B.-J. J. Org. Chem. 2002, 67, 1034.
19. (a) Kozyrkov, Y. Y.; Kulinkovich, O. G. Synlett 2002, 443; (b) Kulinkovich, O. G.;
Kozyrkov, Y. Y.; Bekish, A. V.; Matiushenkov, E. A.; Lysenko, I. L. Synthesis 2005,
1713.
4.20. (R,E)-2-Methyl-1-(2-methylthiazol-4-yl)hexa-1,5-dien-
3-ol ((R)-3)
20. For application of n-Bu2SnO for monotosylation of vicinal diols, see: Martinelli,
M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.; Vaidyanathan, R.
Org. Lett. 1999, 1, 447.
21. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
22. Karama, U.; Ho¨fle, G. Eur. J. Org. Chem. 2003, 1042.
Homoallylic alcohol (R)-3 was obtained from bromide (R)-24 in
the same manner as enantiomeric alcohol (S)-3 (see above). Yield
over two steps 70%. [
a
]D þ22 (c 1.4, CHCl3). IR and NMR data were