A highly stereoselective route to medium-ring-sized trans-alkenolides via oxidative fragmentation of bicyclic oxycyclopropane precursors: Application to the synthesis of (+)-recifeiolide

Article abstract of DOI:10.1016/j.tet.2014.03.032

A new approach to the synthesis of medium-ring-sized trans-alkenolides, based on the oxidative fragmentation of a three-carbon ring in hydroxyalkyl substituted bicyclo[n.1.0]alkan-1-ols readily available from 2-alkylidenecycloalkanones, is described. This methodology was applied to the six-step transformation of cyclooctanone to the natural 12-membered trans-alkenolide antibiotic (+)-recifeiolide.

Full text of DOI:10.1016/j.tet.2014.03.032

Tetrahedron xxx (2014) 1e7
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Tetrahedron
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A highly stereoselective route to medium-ring-sized trans-
alkenolides via oxidative fragmentation of bicyclic oxycyclopropane
precursors: application to the synthesis of (þ)-recifeiolide
*
Dzmitry M. Zubrytski, Dzmitry G. Kananovich , Oleg G. Kulinkovich
Department of Organic Chemistry, Belarusian State University, Nezalezhnasci 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:
A new approach to the synthesis of medium-ring-sized trans-alkenolides, based on the oxidative frag-
mentation of a three-carbon ring in hydroxyalkyl substituted bicyclo[n.1.0]alkan-1-ols readily available
from 2-alkylidenecycloalkanones, is described. This methodology was applied to the six-step trans-
formation of cyclooctanone to the natural 12-membered trans-alkenolide antibiotic (þ)-recifeiolide.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 1 December 2013
Received in revised form 23 February 2014
Accepted 11 March 2014
Available online xxx
Keywords:
Alkenolides
Cyclopropanols
Hypervalent iodine compounds
Stereoselective synthesis
(þ)-Recifeiolide
1. Introduction
Oxycyclopropanes are reactive, easily available compounds that
are used as intermediates in the synthesis of other organic com-
pounds owing to their ability to undergo synthetically useful
transformations based upon the cleavage of the strained cyclo-
propane ring. Cleavage of either of the two adjacent to alcohol
group bonds of the cyclopropane usually results in the formation of
corresponding carbonyl compounds, whereas cleavage of the op-
posite carbonecarbon bond of the ring leads to allylic alcohols or
related compounds.1 Oxidative fragmentation of the substituted
cyclopropanols with Pb(OAc)4 or PhI(OAc)2, occurring via the
splitting of both carbonecarbon bonds adjacent to oxygen and
leading to the corresponding carboxylic acids and alkenes, is also
known.2,3 An essential feature of the latter transformations is its
high diastereoselectivity. This occurs, particularly, in the transfer of
the relative configuration of substituents at the cyclopropane ring
in bicyclic cyclopropanols 1 to the stereochemistry of the di-
substituted carbonecarbon double bond in the products of their
fragmentation, for example, exo-1 is exclusively converted
into trans-alkene 2, whereas endo-1 converts to cis-alkene 2
(Scheme 1).2e4 This sort of substrate diastereocontrol has made it
Scheme 1.
possible to efficiently use this oxidative fragmentation of the cy-
clopropane ring in appropriate bicyclic precursors to perform the
stereoselective generation of carbonecarbon double bonds in the
syntheses of the alkaloid (ꢀ)-pinidine,3b capsaicin4 and some
monoene insect pheromones.5
Since hydroxylic solvents are involved in the formation of
a carboneoxygen bond in this reaction (Scheme 1), we assumed
that the oxidation of bicyclo[n.1.0]alkan-1-ols 1, bearing a hydroxyl
* Corresponding author. E-mail address: kananovich82@tut.by (D.G.
Kananovich).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.032
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2
D.M. Zubrytski et al. / Tetrahedron xxx (2014) 1e7
group in alkyl substituent R, in aprotic solvents would afford the
corresponding lactones. In this case, the less sterically hindered
transformations of 2-alkylidenecycloalkanones without functional
groups in the side chain,4 the reductive cyclization of compounds
7a,b led to exo-bicyclo[n.1.0]alkan-1-ols 6a,b exclusively.14 In the
case of ketone 7c, which contains a remote benzyloxy substituent,
a chromatographically readily separable mixture of exo/endo-iso-
mers 6c in the ratio of 82:18 was obtained. We suggest that the
exclusive formation of exo-isomers 6a,b was favored due to the
intramolecular chelation of a metal atom with oxygen of the ben-
exo-diastereomers of bicyclo[n.1.0]alkan-1-ols
3 might form
the corresponding fused bicyclic intermediates 4, and the frag-
mentation of the bridge carbonecarbon bond in the latter should
provide alkenolides 5 with trans-configuration of the double bond
(Scheme 2).
zyloxy group in intermediate b
-metaloketones.15
Debenzylation of compounds 6aec by hydrogenolysis was per-
formed in the presence of 5 mol % of PdeC following a silyl pro-
tection of the tertiary hydroxyl group. The benzyl group in
TMS-protected cyclopropanols 9aec was smoothly removed in
aq tetrahyfrofuran with the retention of a three-carbon ring, and
was accompanied by the removal of the TMS-protecting group to
give hydroxyalkyl substituted cyclopropanols 3aec. It is notewor-
thy that unprotected cyclopropanols 6 were involved in Pd-
catalyzed three-carbon ring opening reactions16 and yields of the
target products 3 did not exceed 50%.
Scheme 2.
Similar diastereocontrol in the formation of trans-alkenolides
was observed during the oxidation of fused oxabicycloalkenes,6e9
as well as trialkylstannyl-substituted bicyclic lactols.10 However,
the formation of the double bond in these transformations was not
highly regioselective or the required substrates for the oxidation
were not readily available. At the same time, macrolactonization or
ring-closing methathesis, which are both frequently employed in
the synthesis of natural bioactive trans-alkenolides, quite often
gave products in low yields or with low stereoselectivity, which
required optimization of the reaction conditions.11,12 In this work,
we report a convenient method for the preparation of oxy-
substituted exo-bicyclo[n.1.0]alkan-1-ols 3 and their application to
the synthesis of medium-ring trans-alkenolides 5.
The oxidative fragmentation of exo-bicyclo[n.1.0]alkan-1-ol 3b
with phenyliodine(III) diacetate in anhydrous dichloromethane or
deuterochloroform was completed in 1 h to give trans-alkenolide
5b9 in 70% yield (Scheme 3). The signals of the olefinic protons in
the homodecoupled 1H NMR spectrum of trans-5b displayed mu-
tual splitting with a coupling constant of 15.4 Hz,17 which corre-
sponded to the trans-configuration of the double bond. The
presence of an absorption band at 975 cmꢀ1 in the IR spectrum of
trans-5b provided further support for the stereochemistry assign-
ment. The more reactive phenyliodine(III) bis(trifluoroacetate), as
was shown by 1H NMR inspection, reacted with diol exo-3b sig-
nificantly faster to complete the reaction within 12 min. However,
only a minor increase in the yield of lactone trans-5b (to 74%) was
observed.18 Under the same conditions, exo-bicyclo[n.1.0]alkan-1-
ol 3a gave the corresponding trans-alkenolide 5a in 60% isolated
2. Results and discussion
1
yield.19 At the same time, according to H NMR spectroscopy, exo-
bicyclo[n.1.0]alkan-1-ol 3c in reaction with PhI(OCOCF3)2 in CDCl3
was converted to the target macrolactone trans-5c in 23% yield (16%
isolated yield).
Bicyclic cyclopropanols 6aec, bearing benzyl-protected
hydroxyalkyl substituents, were obtained from unsaturated ke-
tones 7aec, which are readily available via aldol condensation
(Scheme 3). The treatment of unsaturated ketones 7aec with hy-
drogen iodide in dry benzene, followed by the reaction of in-
1H NMR analysis of the reaction mixtures also indicated the
formation of mixed anhydrides 10aec20 of the corresponding trans-
u
-hydroxyalkenoic acids as initial side products, which were
termediate b-iodoketones 8aec with zinc dust in the presence of
TiCl(Oi-Pr)3, under the previously described conditions,4 led to the
formation of the corresponding bicyclic cyclopropanols 6aec in
high (74e91%) overall yields.13 It is noteworthy that, unlike the
transformed gradually to acyclic trans- -acyloxyalkenoic acids as
a result of the cross-acylation reactions. As an example, in the re-
action exo-3c with PhI(OCOCF3)2 in CDCl3, the primary reaction
u
Scheme 3.
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D.M. Zubrytski et al. / Tetrahedron xxx (2014) 1e7
3
product trans-10c demonstrated in 1H NMR an easily visible triplet
at 3.75 ppm, typical of the protons of the CH2OH group. The in-
tensity of this signal gradually decreased in conjunction with an
increase in a triplet at 4.34 ppm attributed to methylene protons
alkenolides 5 were obtained in good yields from exo-bicyclo[n.1.0]
alkan-1-ols 3a,b,d bearing -hydroxyalkyl substituents at the cy-
clopropane ring, which favored the formation of bicyclic hemiketal
intermediate 4. The methodology was successfully applied to the
six-step synthesis of the enantiomerically enriched antibiotic (R)-
(þ)-recifeiolide (trans-5d) from cyclooctanone in 33% overall yield.
d
b
d
of the CH2OCOCF3 group.21 It should be noted that mixed tri-
fluoroacetic acid anhydride trans-10c could also be employed as
a potential precursor for the macrolactonization reactions.22
Using the methodology described above, we implemented the
synthesis of a natural antibiotic (R)-(þ)-recifeiolide (trans-5d),
isolated from the fungus Cephalosporium recifei,23 starting from
cyclooctanone and enantiomerically enriched (R)-3-benzyloxy
butanal (11) (Scheme 4).6,24 The latter was prepared in three
steps in 43% yield and with 65% ee from ethyl acetoacetate by
4. Experimental section
4.1. General
All solvents were purified and dried by conventional methods
prior to use. Titanium(IV) chlorotriisopropoxide was prepared from
distilled titanium(IV) chloride and titanium(IV) isopropoxide.29
Zinc dust was activated by successive washings with dilute
hydrochloric acid, water, ethanol, acetone, and anhydrous diethyl
ether and dried under reduced pressure at 100 ꢁC for 1e2 h. Phe-
nyliodine(III) bis(trifluoroacetate) was synthesized according to the
literature procedure.30 Other reagents were used as purchased
from commercial suppliers. All the reactions with organometallics
were carried out under dry argon. Silica gel Sorbfil plates were used
for TLC. Chromatographic separations were performed on Merck 60
silica gel (70e230 mesh). In the case of isolation of acidophobic
compounds (3, 6, 9) silica gel was pretreated with triethylamine (ca.
0.2 mL per 2 g of SiO2). The mixture of petroleum ether and ethyl
acetate in various ratios was used as an eluent. 1H NMR (400 MHz)
and 13C NMR (100.6 MHz) spectra were taken on a Bruker AC 400
spectrometer in CDCl3 as a solvent. Chemical shifts were given in
successive asymmetric reduction of the
borohydride/(
b-keto group with a sodium
L
)-tartaric acid system,25 benzylation of the hydroxyl
group26 and DIBAL reduction of the obtained ester. Aldol coupling
of (R)-3-benzyloxybutanal and cyclooctanone, followed by de-
hydration, resulted in the formation of (R)-2-(3-(benzyloxy)buty-
lidene)cyclooctan-1-one (7d) in 70% yield over two steps.
d
value with CHCl3
(
d
¼7.26 ppm) and CDCl3
(
d
¼77.16 ppm) as in-
ternal standards for 1H NMR and 13C NMR spectra, respectively. The
multiplicity of signals in 13C NMR spectra was determined by DEPT-
135 experiment. IR spectra were taken on a Bruker Vertex 70
spectrometer. Optical rotation was measured on a PerkinElmer 141
polarimeter.
4.2. General procedure for the preparation of ketones 7
To the cooled ꢀ78 ꢁC stirred solution of lithium diisopropyla-
mide (39.8 mmol) in THF (40 mL), a solution of corresponding
cycloalkanone (38.3 mmol) in THF (7 mL) was added dropwise over
15 min via syringe. After 20 min, a solution of benzyloxyaldehyde
(38.3 mmol) in THF (15 mL) was added dropwise over 30 min. After
1.5 h, the reaction mixture was quenched by the addition of
NaHCO3 solution (35 mL, satd aq) and was allowed to warm to room
temperature. The aqueous layer was separated and extracted with
ether (4ꢂ40 mL). The combined organic phases were washed with
cold HCl solution (1% aq), NaHCO3 solution (satd aq), brine
(2ꢂ30 mL) and dried (Na2SO4). Solvents were removed in vacuo
and the obtained crude aldols were used in the next step without
further purification.
Compound 7a was obtained according to the following de-
hydration procedure: methanesulfonyl chloride (5.92 mL,
76.5 mmol) was added in one portion to the cooled (0ꢁC) and
stirred solution of crude aldol (30.6 mmol) and DMAP (14.9 g,
122 mmol) in dichloromethane (240 mL). After the completion of
the reaction (TLC-monitoring), NaHCO3 (150 mL, satd aq) and H2O
(150 mL) were added to the reaction mixture. The aqueous layer
was separated and extracted with dichloromethane (3ꢂ40 mL). The
combined organic phases were washed with brine (20 mL) and
dried (Na2SO4). Evaporation and chromatography of the residue
(from 1:13 to 1:7 ethyl acetate/petroleum ether) gave compound 7a
as a light yellow liquid.
Scheme 4.
A reductive cyclization of unsaturated ketone 7d via its pre-
liminary conversion to the corresponding
b-iodoketone gave
a mixture of diastereomeric cyclopropanols 6d in 87% combined
yield and with exo/endo diastereoselectivity of 85:15. The forma-
tion of minor endo-6d isomers27 in this case can be explained by the
greater steric bulk at the benzylic oxygen bonded to the secondary
carbon, which may have hindered the chelation of the metal atom
in the
b-metaloketone intermediate. After debenzylation of di-
astereomeric exo-bicyclo[6.1.0]alkan-1-ol 6d, in a manner analo-
gous to that described above, and subsequent oxidation of the
obtained diols exo-3d with PhI(OCOCF3)2, the target (R)-(þ)-reci-
feiolide 5d was obtained in 33% total yield, based on the starting
cyclooctanone. The enantiomeric purity of the obtained product
trans-5d (ee 64%) was virtually identical to that of aldehyde 11 (ee
65%), which indicated that no significant racemization of the chiral
center occurred during the synthesis.28
3. Conclusion
In conclusion, we present a new methodology for the synthesis
of trans-alkenolides based on the stereoselective preparation of
exo-hydroxyalkyl-substituted bicyclo[n.1.0]alkan-1-ols, followed by
the stereoselective oxidative fragmentation of the three-carbon
ring in these compounds with phenyliodine dicarboxylates in dry
dichloromethane. Under these conditions, medium-sized trans-
Compounds 7bed were obtained according to the following
dehydration procedure: the solution of a crude aldol (30.6 mmol) in
benzene (150 mL) was refluxed in the presence of a catalytic
amount of p-toluenesulfonic acid monohydrate using a DeaneStark
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4
D.M. Zubrytski et al. / Tetrahedron xxx (2014) 1e7
trap. After the completion of the reaction (TLC-monitoring), the
reaction mixture was cooled to room temperature, washed with
NaHCO3 solution (2ꢂ20 mL, satd aq), and dried (Na2SO4). Evapo-
ration and chromatography of the residue (from 1:13 to 1:7 ethyl
acetate/petroleum ether) gave compounds 7bed as light yellow
liquids.
warmed up and turned dark brown. When the reaction was com-
pleted (TLC monitoring), a solution of NH4Cl (10 mL, satd aq) was
added, precipitate was filtered off and washed thoroughly with
Et2O (5ꢂ15 mL). The filtrate was washed with brine (15 mL), dried
(Na2SO4), the solvent was evaporated and chromatography of the
residue (from 1:10 to 1:6 ethyl acetate/petroleum ether) gave
compounds 6aed as colorless or pale-yellow liquids.
4.2.1. (E)-2-(3-(Benzyloxy)propylidene)cyclopentanone (7a). Yield
73%. Found: C, 78.18; H, 7.90. C15H18O2 requires C, 78.23; H, 7.88%; Rf
(25% EtOAc/petroleum ether) 0.53; nmax (liquid film) 3092, 3063,
4.3.1. exo-6-(2-(Benzyloxy)ethyl)bicyclo[3.1.0]hexan-1-ol
(exo-
6a). Yield 74%. Found: C, 77.49; H, 8.70. C15H20O2 requires C, 77.55;
H, 8.68%; Rf (25% EtOAc/petroleum ether) 0.52; nmax (liquid film)
3030, 1717, 1652 cmꢀ1
; dH (400 MHz, CDCl3) 7.55e7.18 (5H, m, Ph),
6.62e6.52 (1H, m, H-olef.), 4.52 (2H, s, CH2Ph), 3.58 (2H, t, J¼6.7 Hz,
CH2OBn), 2.65e2.55 (2H, m), 2.54e2.41 (2H, m), 2.33 (2H, t,
J¼7.7 Hz), 1.98e1.88 (2H, m); dC (100 MHz, CDCl3) 207.0 (C]O),
139.0 (Cquart.), 138.3 (Cquart.), 132.4 (CH-olef.), 128.5 (CH-arom.),
127.8 (2CH-arom.), 127.8 (2CH-arom.), 73.3 (CH2), 68.7 (CH2), 38.7
(CH2), 30.6 (CH2), 27.0 (CH2), 19.9 (CH2).
3409, 3088, 3064, 3029 cmꢀ1
; dH (400 MHz, CDCl3) 7.43e7.23 (5H,
m, Ph), 4.59 (1H, d, J¼12.2 Hz, CH2Ph), 4.54 (1H, d, J¼12.2 Hz,
CH2Ph), 4.05 (1H, br s, OH), 3.61 (1H, dt, J¼8.7, 3.6 Hz, CH2OBn), 3.46
(1H, ddd, J¼11.3, 8.7, 2.5 Hz, CH2OBn), 2.09e1.95 (2H, m), 1.95e1.81
(2H, m), 1.71e1.57 (2H, m), 1.57e1.48 (1H, m), 1.18e1.00 (1H, m),
0.95 (1H, t, J¼4.0 Hz, H-cycloprop.), 0.76 (1H, dt, J¼10.6, 4.0 Hz, H-
cycloprop.); dC (100 MHz, CDCl3) 138.0 (Cquart. arom.), 128.6 (2CH-
arom.), 127.9 (CH-arom.), 127.8 (2CH-arom.), 73.5 (CH2), 70.7 (CH2),
66.6 (Cquart. cycloprop.), 34.4 (CH2), 30.0 (CH cycloprop.), 28.6 (CH2),
26.9 (CH2), 23.9 (CH cycloprop.), 21.6 (CH2).
4.2.2. (E)-2-(3-(Benzyloxy)propylidene)cyclohexanone (7b). Yield
81%. Found: C, 78.57; H, 8.27. C16H20O2 requires C, 78.65; H, 8.25%;
Rf (25% EtOAc/petroleum ether) 0.63; nmax (CCl4) 3090, 3067, 3032,
1691, 1620 cmꢀ1
; dH (400 MHz, CDCl3) 7.38e7.27 (5H, m, Ph),
6.66e6.59 (1H, m, H-olef.), 4.52 (2H, s, CH2Ph), 3.57 (2H, t, J¼6.7 Hz,
CH2OBn), 2.53e2.37 (6H, m), 1.89e1.79 (2H, m), 1.79e1.68 (2H, m);
dC (100 MHz, CDCl3) 201.0 (C]O), 138.3 (Cquart.), 137.9 (Cquart.), 135.6
(CH-olef.), 128.5 (CH-arom.), 127.8 (2CH-arom.), 127.8 (2CH-arom.),
73.2 (CH2), 68.8 (CH2), 40.3 (CH2), 28.7 (CH2), 27.0 (CH2), 23.6 (CH2),
23.4 (CH2).
4.3.2. exo-7-(2-(Benzyloxy)ethyl)bicyclo[4.1.0]heptan-1-ol
(exo-
6b). Yield 80%. Found: C, 77.95; H, 9.02. C16H22O2 requires C, 78.01;
H, 9.00%; Rf (25% EtOAc/petroleum ether) 0.52; nmax (CCl4) 3478,
3090, 3068, 3033, 3006, 2978 cmꢀ1
; dH (400 MHz, CDCl3) 7.39e7.27
(5H, m, Ph), 4.57 (1H, d, J¼12.0 Hz, CH2Ph), 4.54 (1H, d, J¼12.0 Hz,
CH2Ph), 3.77 (1H, br s, OH), 3.58 (1H, dt, J¼8.7, 3.7 Hz, CH2OBn), 3.46
(1H, ddd, J¼11.3, 8.7, 2.6 Hz, CH2OBn), 2.08e1.86 (4H, m), 1.66e1.54
(1H, m), 1.53e1.44 (1H, m), 1.43e1.33 (1H, m), 1.32e1.15 (2H, m),
1.12e0.98 (1H, m), 0.79 (1H, ddd, J¼7.5, 5.7, 1.3 Hz, H-cycloprop.),
0.51 (1H, ddd, J¼10.0, 5.7, 4.5 Hz, H-cycloprop.); dC (100 MHz,
CDCl3) 138.1 (Cquart. arom.), 128.6 (2CH-arom.), 127.9 (3CH-arom.),
73.6 (CH2), 70.8 (CH2), 56.5 (Cquart. cycloprop.), 33.1 (CH2), 29.3
(CH2), 27.9 (CH cycloprop.), 25.8 (CH cycloprop.), 24.5 (CH2), 21.9
(CH2), 21.8 (CH2).
4.2.3. (E)-2-(6-(Benzyloxy)hexylidene)cyclohexanone
(7c). Yield
82%. Found: C, 79.61; H, 9.17. C19H26O2 requires C, 79.68; H, 9.15%; Rf
(25% EtOAc/petroleum ether) 0.61; nmax (liquid film) 3087, 3063,
3030, 1686, 1613 cmꢀ1
; dH (400 MHz, CDCl3) 7.40e7.20 (5H, m, Ph),
6.65e6.55 (1H, m, H-olef.), 4.49 (2H, s, CH2Ph), 3.45 (2H, t, J¼6.5 Hz,
CH2OBn), 2.52e2.35 (4H, m), 2.17e2.03 (2H, m), 1.90e1.78 (2H, m),
1.78e1.68 (2H, m), 1.68e1.55 (2H, m), 1.53e1.32 (4H, m); dC
(100 MHz, CDCl3) 201.3 (C]O),139.6 (CH-olef.), 138.7 (Cquart.), 136.4
(Cquart.), 128.5 (2CH-arom.), 127.7 (2CH-arom.), 127.6 (CH-arom.),
73.0 (CH2), 70.4 (CH2), 40.3 (CH2), 29.7 (CH2), 28.4 (CH2), 27.8 (CH2),
26.8 (CH2), 26.2 (CH2), 23.7 (CH2), 23.5 (CH2).
4.3.3. exo-7-(5-(Benzyloxy)pentyl)bicyclo[4.1.0]heptan-1-ol
(exo-
6c). Yield 75%. Found: C, 79.07; H, 9.80. C19H28O2 requires C, 79.12;
H, 9.78%; Rf (25% EtOAc/petroleum ether) 0.63; nmax (liquid film)
3397, 3088, 3064, 3030, 2996 cmꢀ1
; dH (400 MHz, CDCl3) 7.40e7.22
4.2.4. (R,E)-2-(3-(Benzyloxy)butylidene)cyclooctanone (7d). Yield
(5H, m, Ph), 4.51 (2H, s, CH2Ph), 3.54e3.40 (2H, m, CH2OBn),
2.12e1.91 (3H, m), 1.90e1.78 (1H, m), 1.73e1.53 (2H, m), 1.53e1.31
(8H, m), 1.29e1.15 (2H, m), 1.13e0.99 (1H, m), 0.66 (1H, ddd, J¼7.6,
6.0, 1.3 Hz, H-cycloprop.), 0.39 (1H, dt, J¼6.3, 6.0 Hz, H-cycloprop.);
dC (100 MHz, CDCl3) 138.7 (Cquart. arom.), 128.5 (2CH-arom.), 127.8
(2CH-arom.), 127.6 (CH-arom.), 73.0 (CH2), 70.6 (CH2), 58.1 (Cquart.
cycloprop.), 32.9 (CH2), 29.8 (CH2), 29.7 (CH2), 29.4 (CH cycloprop.),
27.3 (CH2), 25.9 (CH2), 24.8 (CH cycloprop.), 24.5 (CH2), 21.9 (CH2),
21.6 (CH2).
70%. Found: C, 79.63; H, 9.17. C19H26O2 requires C, 79.68; H, 9.15%;
17
Rf (20% EtOAc/petroleum ether) 0.63; [
a
]
ꢀ2.6 (C 3.0, CHCl3);
D
nmax (CCl4) 3095, 3066, 3031, 1684, 1617 cmꢀ1
; dH (400 MHz,
CDCl3) 7.38e7.21 (5H, m, Ph), 6.64 (1H, t, J¼7.4 Hz, H-olef.), 4.57
(1H, d, J¼11.7 Hz, CH2Ph), 4.49 (1H, d, J¼11.7 Hz, CH2Ph),
3.72e3.55 (1H, m, CH(OBn)Me), 2.71e2.38 (5H, m), 2.36e2.26
(1H, m), 1.83e1.71 (2H, m), 1.61e1.49 (4H, m), 1.46e1.33 (2H, m),
1.22 (3H, d, J¼6.1 Hz, Me); dC (100 MHz, CDCl3) 206.1 (C]O), 141.1
(Cquart.), 138.8 (Cquart.), 136.1 (CH-olef.), 128.5 (2CH-arom.), 127.8
(2CH-arom.), 127.6 (CH-arom.), 74.3 (CH(OBn)Me), 70.7 (CH2), 39.5
(CH2), 35.7 (CH2), 29.6 (CH2), 29.5 (CH2), 26.4 (CH2), 25.8 (CH2),
25.2 (CH2), 20.1 (Me).
4.3.4. endo-7-(5-(Benzyloxy)pentyl)bicyclo[4.1.0]heptan-1-ol (endo-
6c). Yield 16%. Found: C, 79.05; H, 9.81. C19H28O2 requires C, 79.12;
H, 9.78%; Rf (25% EtOAc/petroleum ether) 0.43; nmax (liquid film)
3384, 3088, 3064, 3029, 3006 cmꢀ1
; dH (400 MHz, CDCl3) 7.39e7.22
4.3. General procedure for the preparation of bicyclo[n.1.0]
(5H, m, Ph), 4.51 (2H, s, CH2Ph), 3.47 (2H, t, J¼6.7 Hz, CH2OBn),
2.19e1.96 (2H, m), 1.96e1.78 (2H, m), 1.72e1.54 (2H, m), 1.54e1.03
(11H, m), 1.11 (1H, ddd, J¼10.5, 9.3, 2.2 Hz, H-cycloprop.), 0.94e0.84
(1H, m, H-cycloprop.); dC (100 MHz, CDCl3) 138.8 (Cquart. arom.),
128.5 (2CH-arom.), 127.8 (2CH-arom.), 127.6 (CH-arom.), 73.1 (CH2),
70.6 (CH2), 55.9 (Cquart. cycloprop.), 30.0 (CH2), 29.9 (CH2), 29.1
(CH2), 28.7 (CH cycloprop.), 26.3 (CH2), 23.7 (CH2), 22.5 (CH2), 22.2
(CH2), 21.6 (CH cycloprop.), 19.1 (CH2).
alkan-1-ols 64
Intermediate b-iodoketones 8 were generated by the addition of
an equivalent amount of hydrogen iodide (solution in dry benzene,
ca. 0.5e1.5 M)31 to the solution of unsaturated ketones 7 (25 mmol)
in dry benzene (15 mL). A solution of TiCl(Oi-Pr)3 in THF (1 M,
25 mmol, 25 mL) was added to the suspension of zinc dust32 (3.25 g,
50 mmol) in THF (25 mL) and then a fresh-prepared solution of b-
iodoketone 8 (25 mmol) in dry benzene was added via syringe in
one portion. After few minutes, the reaction mixture spontaneously
4.3.5. exo-9-((R)-2-(Benzyloxy)propyl)bicyclo[6.1.0]nonan-1-ol (exo-
13
6d). Mixture of two diastereomers in a ratio of 1:1. Yield 74%. [
a]
D
Please cite this article in press as: Zubrytski, D. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.032

D.M. Zubrytski et al. / Tetrahedron xxx (2014) 1e7
5
ꢀ11.5 (C 3.0, CHCl3); nmax (CCl4) 3460, 3095, 3067, 3032 cmꢀ1
.
(100 MHz, CDCl3) 139.0 (Cquart. arom.), 128.5 (2CH-arom.), 127.7
(2CH-arom.), 127.6 (CH-arom.), 73.0 (CH2), 70.7 (CH2), 68.9 (Cquart.
cycloprop.), 34.5 (CH2), 29.2 (CH cycloprop.), 28.0 (CH2), 27.0 (CH2),
21.7 (CH2), 21.0 (CH-cycloprop.), 1.2 (SiMe3).
Found: C, 79.07; H, 9.81. C19H28O2 requires C, 79.12; H, 9.78%.
Diastereomer 1: Rf (20% EtOAc/petroleum ether) 0.67; dH
(400 MHz, CDCl3) 7.37e7.22 (5H, m, Ph), 4.63 (1H, d, J¼11.5 Hz,
CH2Ph), 4.46 (1H, d, J¼11.5 Hz, CH2Ph), 3.63e3.53 (1H, m, CH(OBn)
Me), 3.27 (1H, br s, OH), 2.54e2.18 (1H, m), 2.02e1.85 (2H, m),
1.82e0.88 (10H, m), 1.18 (3H, J¼6.1 Hz, Me), 0.84e0.69 (1H, m),
0.50e0.41 (1H, m, H-cycloprop.), 0.22 (1H, ddd, J¼10.1, 5.7, 4.3 Hz,
H-cycloprop.); dC (100 MHz, CDCl3) 138.4 (Cquart. arom.), 128.5
(2CH-arom.), 128.1 (2CH arom.), 127.8 (CH-arom.), 76.3 (CH(OBn)
Me), 71.1 (CH2), 58.7 (Cquart. cycloprop.), 36.4 (CH2), 34.2 (CH2), 31.2
(CH cycloprop.), 29.2 (CH2), 28.7 (CH2), 27.5 (CH cycloprop.), 26.5
(CH2), 26.3 (CH2), 25.3 (CH2), 19.8 (Me).
4.4.2. exo-7-(2-(Benzyloxy)ethyl)-1-trimethylsiloxybicyclo[4.1.0]hep-
tane (exo-9b). Yield 92%. Found: C, 71.57; H, 9.51. C19H30O2Si re-
quires C, 71.64; H, 9.49%; Rf (2.4% EtOAc/petroleum ether) 0.36; nmax
(CCl4) 3089, 3067, 3031, 3006 cmꢀ1
; dH (400 MHz, CDCl3) 7.40e7.20
(5H, m, Ph), 4.56 (1H, d, J¼12.2 Hz, CH2Ph), 4.52 (1H, d, J¼12.2 Hz,
CH2Ph), 3.61e3.50 (2H, m, CH2OBn), 2.11e2.02 (1H, m), 2.02e1.92
(1H, m), 1.92e1.79 (2H, m), 1.60e1.50 (1H, m), 1.49e1.38 (2H, m),
1.32e1.17 (2H, m), 1.16e1.01 (1H, m), 0.72 (1H, ddd, J¼7.4, 6.0,
1.4 Hz, H-cycloprop.), 0.52 (1H, dt, J¼7.9, 6.0 Hz, H-cycloprop.), 0.14
(9H, s, SiMe3); dC (100 MHz, CDCl3) 139.0 (Cquart. arom.), 128.5 (2CH-
arom.), 127.7 (2CH-arom.), 127.5 (CH-arom.), 72.9 (CH2), 70.7 (CH2),
59.4 (Cquart. cycloprop.), 33.2 (CH2), 28.6 (CH2), 25.2 (CH cycloprop.),
25.0 (CH cycloprop.), 24.5 (CH2), 21.8 (CH2), 21.7 (CH2), 1.5 (SiMe3).
Diastereomer 2: Rf (20% EtOAc/petroleum ether) 0.58; dH
(400 MHz, CDCl3) 7.41e7.19 (5H, m, Ph), 4.62 (1H, d, J¼12.0 Hz,
CH2Ph), 4.47 (1H, d, J¼12.0 Hz, CH2Ph), 3.72e3.62 (1H, m, CH(OBn)
Me), 3.21 (1H, br s, OH), 2.11e2.03 (1H, m), 2.02e1.87 (2H, m),
1.84e1.11 (10H, m), 1.23 (3H, d, J¼6.1 Hz, Me), 1.11e0.72 (1H, m),
0.55e0.45 (1H, m, H-cycloprop.), 0.34 (1H, dt, J¼10.4, 5.2 Hz, H-
cycloprop.); dC (100 MHz, CDCl3) 138.7 (Cquart. arom.), 128.5 (2CH-
arom.), 127.7 (3CH-arom.), 74.6 (CH(OBn)Me), 70.5 (CH2), 58.8
(Cquart. cycloprop.), 34.5 (CH2), 34.2 (CH2), 31.6 (CH cycloprop.), 29.2
(CH2), 28.8 (CH2), 26.5 (CH2), 26.4 (CH2), 25.4 (CH2), 24.8 (CH
cycloprop.), 18.1 (Me).
4.4.3. exo-7-(5-(Benzyloxy)pentyl)-1-trimethylsiloxybicyclo[4.1.0]
heptane (exo-9c). Yield 90%. Found: C, 73.21; H, 10.09. C22H36O2Si
requires C, 73.28; H, 10.06%; Rf (2.4% EtOAc/petroleum ether) 0.36;
nmax (liquid film) 3089, 3065, 3030, 3002 cmꢀ1
; dH (400 MHz,
CDCl3) 7.42e7.23 (5H, m, Ph), 4.51 (2H, s, CH2Ph), 3.48 (2H, t,
J¼6.7 Hz, CH2OBn), 2.12e1.92 (2H, m), 1.91e1.80 (1H, m), 1.73e1.58
(2H, m), 1.57e1.33 (7H, m), 1.30e1.16 (3H, m), 1.15e1.03 (1H, m),
0.66 (1H, ddd, J¼7.5, 5.9, 1.4 Hz, H-cycloprop.), 0.37 (1H, dt, J¼8.1,
5.9 Hz, H-cycloprop.), 0.14 (9H, s, SiMe3); dC (100 MHz, CDCl3) 138.9
(Cquart. arom.), 128.5 (2CH-arom.), 127.7 (2CH-arom.), 127.6 (CH-
arom.), 73.0 (CH2), 70.7 (CH2), 59.7 (Cquart. cycloprop.), 33.3 (CH2),
29.9 (CH2), 29.6 (CH2), 28.2 (CH cycloprop.), 28.0 (CH2), 26.3 (CH2),
25.3 (CH cycloprop.), 24.6 (CH2), 21.9 (CH2), 21.8 (CH2), 1.5 (SiMe3).
4.3.6. endo-9-((R)-2-(Benzyloxy)propyl)bicyclo[6.1.0]nonan-1-ol
(endo-6d). Mixture of two diastereomers in a ratio of 1:1. Yield 13%.
Found: C, 79.08; H, 9.79. C19H28O2 requires C, 79.12; H, 9.78%; Rf
18
(20% EtOAc/petroleum ether) 0.41; [
a
]
ꢀ7.5 (C 2.0, CHCl3); nmax
D
(liquid film) 3400, 3088, 3064, 3030 cmꢀ1
; dH (400 MHz, CDCl3)
7.40e7.23 (5H, m, Ph), 4.59 (0.5H, d, J¼11.8 Hz, CH2Ph), 4.58 (0.5H,
d, J¼12.0 Hz, CH2Ph), 4.49 (0.5H, d, J¼11.8 Hz, CH2Ph), 4.48 (0.5H, d,
J¼12.0 Hz, CH2Ph), 3.58e3.47 (1H, m, CH(OBn)Me), 2.64 (1H, q,
J¼7.1 Hz), 1.97e1.25 (11H, m), 1.22 (3H, d, J¼6.1 Hz, Me), 1.10 (2H, t,
J¼7.2 Hz), 1.05e0.94 (1H, m), 0.94e0.73 (2H, m); dC (100 MHz,
CDCl3) 139.2 (2Cquart. arom.), 128.5 (2CH-arom.), 128.4 (2CH-arom.),
127.9 (2CH-arom.), 127.8 (2CH-arom.), 127.6 (CH-arom.), 127.5 (CH-
arom.), 75.4 (CH(OBn)Me), 75.1 (CH(OBn)Me), 70.6 (CH2), 70.5
(CH2), 58.6 (Cquart. cycloprop.), 58.6 (Cquart. cycloprop.), 46.3 (CH2),
46.3 (CH2), 31.2 (CH2), 31.2 (CH2), 28.9 (CH2), 28.4 (CH2), 28.3 (CH2),
27.9 (2CH cycloprop.), 26.6 (CH2), 26.2 (CH2), 26.2 (CH2), 24.9
(2CH2), 24.4 (CH cycloprop.), 24.2 (CH cycloprop.), 23.3 (2 CH2), 19.8
(Me), 19.7 (Me).
4.4.4. exo-9-((R)-2-(Benzyloxy)propyl)-1-trimethylsiloxybicyclo
[6.1.0]nonane (exo-9d). Mixture of two diastereomers in a ratio of
1:1. Yield 90%. Found: C, 73.23; H, 10.08. C22H36O2Si requires C,
13
73.28; H, 10.06%; Rf (2.4% EtOAc/petroleum ether) 0.36; [
a
]
ꢀ6.2
D
(C 3.0, CHCl3); nmax (CCl4) 3090, 3067, 3031 cmꢀ1
;
dH (400 MHz,
CDCl3) 7.40e7.22 (5H, m, Ph), 4.61 (0.5H, d, J¼11.7 Hz, CH2Ph), 4.53
(1H, s, CH2Ph), 4.48 (0.5H, d, J¼11.7 Hz, CH2Ph), 3.66e3.54 (1H, m,
CH(OBn)Me), 2.25e2.12 (1H, m), 2.01e1.85 (1.5H, m), 1.82e1.57
(3.5H, m), 1.57e1.35 (4H, m), 1.25 (3H, t, J¼6.1 Hz, Me), 1.33e1.03
(3H, m), 0.91e0.69 (1H, m), 0.44e0.28 (1.5H, m, H-cycloprop.),
0.26e0.19 (0.5H, m, H-cycloprop.), 0.17 (4.5H, s, SiMe3), 0.16 (4.5H,
s, SiMe3); dC (100 MHz, CDCl3) 139.3 (2Cquart. arom.), 128.5 (4CH-
arom.), 127.8 (2CH-arom.), 127.7 (2CH-arom.), 127.5 (CH-arom.),
127.5 (CH-arom.), 76.1 (CH(OBn)Me), 75.7 (CH(OBn)Me), 70.8 (CH2),
70.4 (CH2), 63.3 (Cquart. cycloprop.), 63.1 (Cquart. cycloprop.), 36.7
(CH2), 35.1 (CH2), 34.3 (CH2), 34.2 (CH2), 30.6 (CH cycloprop.), 30.6
(CH cycloprop.), 28.9 (CH2), 28.9 (2 CH2), 28.8 (CH2), 26.9 (CH
cycloprop.), 26.5 (CH2), 26.5 (CH2), 26.3 (2 CH2), 25.9 (CH cyclo-
prop.), 25.8 (CH2), 25.8 (CH2), 20.2 (Me), 19.9 (Me), 2.0 (2 SiMe3).
4.4. General procedure for the preparation of trimethylsilyl
ethers 9
Trimethylchlorosilane (6.27 mL, 49.5 mmol) was added to the
cooled (0ꢁC) and stirred solution of cyclopropanol 6 (16.5 mmol)
and triethylamine (9.18 mL, 66 mmol) in anhydrous THF (55 mL).
The resulted mixture was stirred until the completion of the re-
action (TLC-monitoring) and then was treated with water (15 mL).
The aqueous layer was separated and extracted with ethyl acetate
(2ꢂ10 mL). The combined organic phases were washed with brine
(5 mL) and dried (Na2SO4). Evaporation and chromatography of the
residue (1:40 ethyl acetate/n-hexane) gave compounds 9aed as
colorless liquids.
4.5. General procedure for the preparation of diols 3
A solution of trimethylsilyl ether 9 (13.2 mmol) in a mixture of
THF (200 mL) and water (10 mL) was stirred under a hydrogen
atmosphere at room temperature in the presence of 10% palladium
on charcoal (0.702 g, 0.660 mmol, 5% mol.) until the completion of
the reaction (TLC-monitoring, approximately 1 h). Then the catalyst
was filtered off and washed cautiously with ethyl acetate, the fil-
trate was dried (Na2SO4) in the presence of a few drops of trie-
thylamine. Evaporation and chromatography of the residue (from
1:5 to 1:1 ethyl acetate/petroleum ether) gave the title compounds
as colorless liquids (3aec and one of the diastereomers of 3d) or
a colorless solid (one of the diastereomers of 3d).
4.4.1. exo-6-(2-(Benzyloxy)ethyl)-1-trimethylsiloxybicyclo[3.1.0]hex-
ane (exo-9a). Yield 80%. Found: C, 70.95; H, 9.29. C18H28O2Si re-
quires C, 71.00; H, 9.27%; Rf (2.4% EtOAc/petroleum ether) 0.36; nmax
(liquid film) 3088, 3064, 3029 cmꢀ1
; dH (400 MHz, CDCl3) 7.45e7.23
(5H, m, Ph), 4.56 (1H, d, J¼12.2 Hz, CH2Ph), 4.52 (1H, d, J¼12.2 Hz,
CH2Ph), 3.60e3.51 (2H, m, CH2OBn), 2.04e1.78 (4H, m), 1.68e1.48
(3H, m), 1.20e1.03 (1H, m), 0.94 (1H, t, J¼4.0 Hz, H-cycloprop.), 0.77
(1H, ddd, J¼9.0, 5.7, 4.0 Hz, H-cycloprop.), 0.14 (9H, s, SiMe3); dC
Please cite this article in press as: Zubrytski, D. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.032

6
D.M. Zubrytski et al. / Tetrahedron xxx (2014) 1e7
4.5.1. exo-6-(2-Hydroxyethyl)bicyclo[3.1.0]hexan-1-ol
(exo-
solution). After the completion of the reaction (TLC-monitoring,
3a). Yield 91%. Found: C, 67.49; H, 9.94. C8H14O2 requires C, 67.57;
H, 9.92%; Rf (50% EtOAc/petroleum ether) 0.32; nmax (liquid film)
usually within 15 min) the reaction mixture was washed with
NaHCO3 solution (2ꢂ50 mL, satd aq), brine (2ꢂ10 mL) and dried
(Na2SO4). Evaporation and chromatography of the residue (from
pure petroleum ether to 1:20 ethyl acetate/petroleum ether) gave
compounds 5aed as colorless liquids.
3305 cmꢀ1
;
dH (400 MHz, CDCl3) 3.79 (1H, ddd, J¼10.0, 4.4, 3.5 Hz,
CH2OH), 3.63 (1H, ddd, J¼10.9, 10.0, 2.9 Hz, CH2OH), 3.42 (2H, br s, 2
OH), 2.13e1.77 (4H, m), 1.72e1.46 (3H, m), 1.18e1.00 (1H, m), 0.95
(1H, t, J¼4.0 Hz, H-cycloprop.), 0.77 (1H, dt, J¼10.2, 4.0 Hz, H-
cycloprop.); dC (100 MHz, CDCl3) 62.8 (CH2), 46.1 (Cquart. cycloprop.),
34.4 (CH2), 30.6 (CH2), 30.1 (CH cycloprop.), 26.9 (CH2), 23.5 (CH
cycloprop.), 21.6 (CH2).
4.6.1. trans-Oxacyclonon-6-ene-2-one (trans-5a). Yield 60% (from
exo-3a). Spectral data are in accordance with those previously
reported.9
4.5.2. exo-7-(2-Hydroxyethyl)bicyclo[4.1.0]heptan-1-ol
(exo-
4.6.2. trans-Oxacyclodec-7-ene-2-one (trans-5b). Yield 74% (from
exo-3b). Spectral data are in accordance with those previously
reported.9
3b). Yield 94%. Found: C, 69.13; H, 10.35. C9H16O2 requires C, 69.19;
H, 10.32%; Rf (50% EtOAc/petroleum ether) 0.32; nmax (CCl4) 3487,
2976 cmꢀ1
;
dH (400 MHz, CDCl3) 3.90 (1H, br s, OH), 3.75 (1H, ddd,
trans-9-(2,2,2-Trifluoroacetoxy)non-6-enoic acid and trans-9-
((9-(2,2,2-trifluoroacetoxy)non-6-enoyl)oxy)non-6-enoic acid in
a ratio of about 1.25:1 were isolated as minor products. Yield 25%
(from exo-3b). Rf (50% EtOAc/petroleum ether) 0.30; nmax (CCl4)
J¼10.0, 4.4, 3.8 Hz, CH2OH), 3.60 (1H, ddd, J¼10.8, 10.0, 3.1 Hz,
CH2OH), 2.98 (1H, br s, OH), 2.08e1.93 (3H, m), 1.93e1.84 (1H, m),
1.58e1.42 (2H, m), 1.42e1.33 (1H, m), 1.28e1.15 (2H, m), 1.13e0.98
(1H, m), 0.78 (1H, ddd, J¼7.7, 5.7, 1.7 Hz, H-cycloprop.), 0.50 (1H,
ddd, J¼10.1, 5.7, 4.6 Hz, H-cycloprop.); dC (100 MHz, CDCl3) 62.7
(CH2), 56.8 (Cquart. cycloprop.), 32.9 (CH2), 31.2 (CH2), 27.4 (CH
cycloprop.), 25.7 (CH cycloprop.), 24.5 (CH2), 21.9 (CH2), 21.7 (CH2).
3107, 1789, 1737, 1711, 970 cmꢀ1
; dH (400 MHz, CDCl3) 10.53 (ca. 2H,
br s, COOH), 5.65e5.29 (6.5H, m, H-olef.), 4.34 (4.5H, t, J¼6.7 Hz,
CH2OCOCF3), 4.06 (2H, t, J¼6.8 Hz, CH2OCOCH2), 2.55e2.25 (13H, m,
CH2), 2.09e1.96 (6.5H, m, CH2), 1.70e1.54 (6.5H, m, CH2), 1.47e1.31
(6.5H, m, CH2).
4.5.3. exo-7-(5-Hydroxypentyl)bicyclo[4.1.0]heptan-1-ol
(exo-
3c). Yield 91%. Found: C, 72.60; H,11.20. C12H22O2 requires C, 72.68;
H, 11.18%; Rf (50% EtOAc/petroleum ether) 0.30; nmax (liquid film)
4.6.3. trans-Oxacyclotridec-7-en-2-one (trans-5c). Yield 16% (from
exo-3c). Spectral data are in accordance with those previously
reported.33
3350 cmꢀ1
; dH (400 MHz, CDCl3) 3.71e3.58 (2H, m, CH2OH),
2.10e2.01 (1H, m), 2.00e1.92 (1H, m), 1.92e1.82 (2H, m), 1.64e1.52
(3H, m), 1.52e1.31 (8H, m), 1.27e1.17 (2H, m), 1.13e1.00 (1H, m),
0.67 (1H, ddd, J¼7.8, 6.0, 1.7 Hz, H-cycloprop.), 0.41 (1H, dt, J¼6.4,
6.0 Hz, H-cycloprop.); dC (100 MHz, CDCl3) 63.1 (CH2), 58.1 (Cquart.
cycloprop.), 33.0 (CH2), 32.7 (CH2), 29.8 (CH2), 29.3 (CH cycloprop.),
27.5 (CH2), 25.5 (CH2), 25.0 (CH cycloprop.), 24.6 (CH2), 22.0 (CH2),
21.6 (CH2).
4.6.4. trans-(12R)-Methyloxacyclododec-9-ene-2-one (trans-5d, (R)-
(þ)-recifeiolide). Yield 76% (from exo-3d) and 64% ee. Rf (9% EtOAc/
18
petroleum ether) 0.59; [
a]
þ40 (c 1.0, CHCl3) 64% ee; lit:24a
[a]
D
D
þ70 (c 1.0, CHCl3) 100% ee. dH (400 MHz, CDCl3) 5.27 (m, 2H, CH
olef.), 5.15 (m, 1H, MeCHO), 2.05e2.42 (m, 5H, CH2), 1.96 (m, 1H,
CH2),1.80 (m,1H, CH2),1.30e1.57 (m, 5H, CH2),1.23 (d, J¼6.3 Hz, 3H,
Me), 1.14 (m, 2H, CH2); dC (100 MHz, CDCl3) 173.5 (CO), 133.6 (CH),
127.1 (CH), 68.6 (CH), 41.1 (CH2), 33.0 (CH2), 30.4 (CH2), 25.0 (CH2),
24.8 (CH2), 24.3 (CH2), 23.3 (CH2), 20.7 (Me). Spectral data are in
accordance with those previously reported.24e,f
4.5.4. exo-9-((R)-2-Hydroxypropyl)bicyclo[6.1.0]nonan-1-ol
3d). mixture of two diastereomers in a ratio of 1:1. Yield 92%. [
(exo-
18
a
]
D
ꢀ9.1 (C 2.9, CHCl3); Found: C, 72.58; H, 11.21. C12H22O2 requires C,
72.68; H, 11.18%.
Diastereomer 1: colorless solid, mp 73e74ꢁC. Rf (50% EtOAc/
Acknowledgements
petroleum ether) 0.63; nmax (CCl4) 3488 cmꢀ1
; dH (400 MHz, CDCl3)
3.87e3.76 (1H, m, CH(OH)Me), 3.52 (1H, br s, OH), 2.87 (1H, br s,
OH), 2.08 (1H, dt, J¼14.6, 3.5 Hz), 1.96 (1H, dq, J¼14.3, 3.5 Hz, 1H),
1.89 (1H, ddd, J¼14.6, 4.4, 2.6 Hz), 1.82e1.55 (3H, m), 1.54e1.08 (7H,
m), 1.16 (3H, d, J¼6.1 Hz, Me), 0.88e0.69 (1H, m), 0.46 (1H, ddd,
J¼12.0, 5.8, 3.3 Hz, H-cycloprop.), 0.22 (1H, ddd, J¼10.3, 5.8, 4.5 Hz,
H-cycloprop.); dC (100 MHz, CDCl3) 68.8 (CH(OH)Me), 59.1 (Cquart.
cycloprop.), 37.6 (CH2), 34.1 (CH2), 31.2 (CH cycloprop.), 29.1 (CH2),
28.6 (CH2), 27.7 (CH cycloprop.), 26.5 (CH2), 26.4 (CH2), 25.3 (CH2),
24.3 (Me).
Support from the Ministry of Education of the Republic of
Belarus is acknowledged.
References and notes
1. Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597; (b) Kulinkovich, O. G. Eur. J. Org.
Chem. 2004, 4517; (c) Haym, I.; Brimble, M. A. Org. Biomol. Chem. 2012, 10, 7649.
2. Rubottom, G. M.; Beedle, E. C.; Kim, C.-W.; Mott, R. C. J. Am. Chem. Soc. 1985, 107,
4230.
3. (a) Kirihara, M.; Yokoyama, S.; Kakuda, H.; Momose, T. Tetrahedron Lett. 1995,
36, 6907; (b) Momose, T.; Nishio, T.; Kirihara, M. Tetrahedron Lett. 1996, 37,
4987; (c) Kirihara, M.; Yokoyama, S.; Kakuda, H.; Momose, T. Tetrahedron 1998,
54, 13943.
Diastereomer 2: colorless liquid. Rf (50% EtOAc/petroleum ether)
0.49; nmax (CCl4) 3473 cmꢀ1
; dH (400 MHz, CDCl3) 4.02e3.87 (1H, m,
CH(OH)Me), 3.40 (1H, br s, OH), 2.83 (1H, br s, OH), 2.15e2.06 (1H,
m), 2.04e1.92 (1H, m), 1.87e1.08 (11H), 1.18 (3H, d, J¼6.1 Hz, Me),
0.89e0.70 (1H, m), 0.48 (1H, ddd, J¼11.9, 5.5, 3.5 Hz, H-cycloprop.),
0.27 (1H, dt, J¼9.4, 5.5 Hz, H-cycloprop.); dC (100 MHz, CDCl3) 67.3
(CH(OH)Me), 59.0 (Cquart. cycloprop.), 35.9 (CH2), 33.9 (CH2), 31.3
(CH cycloprop.), 29.1 (CH2), 28.7 (CH2), 26.5 (CH2), 26.3 (CH2), 25.2
(CH2), 24.7 (CH cycloprop.), 22.1 (Me).
4. Kananovich, D. G.; Zubrytski, D. M.; Kulinkovich, O. G. Synlett 2010, 1043.
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4.6. General procedure for the preparation of trans-alkeno-
lides 5
ꢀ
12. (a) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086; (b) Yu,
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Nature 2011, 479, 88.
13. An alternative procedure for the synthesis of cyclopropanols, involving the
Phenyliodine(III) bis(trifluoroacetate) PhI(OCOCF3)2 (2.71 g,
6.30 mmol) was added in one portion to the stirred solution of exo-
diol 3 (6.00 mmol) in dry dichloromethane (200 mL, 0.03 M
reaction of
b-iodoketones with zinc dust in the presence of trimethyl-
chlorosilane (see Ref. 4), was not as successful. Trimethylsilyl ether of cyclo-
propanol exo-6b was obtained under these conditions in only 47% yield.
Please cite this article in press as: Zubrytski, D. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.032

D.M. Zubrytski et al. / Tetrahedron xxx (2014) 1e7
7
14. Stereochemical configuration was confirmed by 1D NOESY experiments. Low
values of 3J coupling constants between the cyclopropyl protons (for example,
J¼4.0 Hz for exo-6a) were also in agreement with the stereochemical
assignment.
was isolated in 25% yield after the completion of the reaction (after approx.
24 h; see Experimental part).
22. (a) Taub, D.; Girotra, N. N.; Hoffsommer, R. D.; Kuo, C. H.; Slates, H. L.; Weber, S.;
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Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996, 61, 4560.
15. Similarly, the coordination of a metal atom with oxygen-functionalized sub-
stituents in the reactions between esters and alkoxytitanacyclopropane re-
agents leads to the formation of trans-1,2-disubstituted cyclopropanols as
major products: (a) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 6079; (b)
Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291; (c) Sav-
chenko, A. I.; Kulinkovich, O. G. Zh. Org. Khim. 1997, 33, 913; Russ. J. Org. Chem.
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1729; (e) Epstein, O. L.; Kulinkovich, O. G. Tetrahedron Lett. 2001, 42, 3757; (f)
Quan, L. G.; Kim, S. H.; Lee, J. C.; Cha, J. K. Angew. Chem., Int. Ed. 2002, 41, 2160;
(g) Racouchot, S.; Silvestre, I.; Ollivier, J.; Kozyrkov, Yu. Yu.; Pukin, A.; Ku-
linkovich, O. G.; Salaun, J. Eur. J. Org. Chem. 2002, 2160.
23. Vesonder, R. F.; Stodola, F. H.; Wickerham, L. J.; Ellis, J. J.; Rohwedder, W. K. Can.
J. Chem. 1971, 49, 2029.
24. For other approaches to the synthesis of recifeiolide, see: (a) Gerlach, H.; Oertle,
K.; Thalmann, A. Helv. Chim. Acta 1976, 59, 755; (b) Narasaka, K.; Yamaguchi,
M.; Mukaiyama, T. Chem. Lett. 1977, 6, 959; (c) Utimoto, K.; Uchida, K.; Yamaya,
M.; Nozaki, H. Tetrahedron Lett. 1977, 18, 3641; (d) Kaino, M.; Naruse, Y.; Ishi-
hara, K.; Yamamoto, H. J. Org. Chem. 1990, 55, 5814; (e) Hanaki, N.; Ishihara, K.;
Kaino, M.; Naruse, Y.; Yamamoto, H. Tetrahedron 1996, 52, 7297; (f) Okuma, K.;
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dron 1998, 54, 4243.
16. (a) Shan, M.; O’Doherty, G. A. Org. Lett. 2008, 10, 3381; (b) Shan, M.; O’Doherty,
G. A. Synthesis 2008, 19, 3171.
25. Yotagai, M.; Ohnuki, T. J. Chem. Soc., Perkin Trans. 1 1990, 1826.
17. Coupling constants were obtained after transformation of the corresponding
multiplets to doublets with the aid of 1H homodecoupling experiments, irra-
diating the signals of the allylic methylene groups.
26. Gathirwa, J. W.; Maki, T. Tetrahedron 2012, 68, 370.
27. Compounds exo-3d, exo- and endo-6d were obtained as equimolecular mix-
tures of diastereomers.
18. High yields of alkenolide trans-5b were attained when the reaction was carried
out in a dilute solution (0.03 M concentration of the substrate). When more
concentrated (ca. 1 M) solution was used, the yield of lactone trans-5b dropped
to 60%, according to 1H NMR spectroscopy, whereas the content of acyclic by-
products increased (see Ref. 21).
19. The smaller isolated yield of trans-5a, compared to that of trans-5b, may
have been due to its greater volatility and losses due to evaporation during
isolation.
28. The enantiomeric purity of the obtained (R)-(þ)-recifeiolide trans-5d was de-
termined by its alkaline hydrolysis, followed by transformation of the resulting
hydroxy acid to the corresponding Mosher esters and 1H NMR analysis of their
diastereomeric composition.
29. Reetz, M. T. In Organometallics in Synthesis; Schlosser, M., Ed.; Wiley: New York,
NY, 2002; p 817.
30. Varvoglis, A. Hypervalent Iodine in Organic Synthesis. Best Synthetic Methods;
Academic Press: San Diego, 1997.
20. The formation of mixed anhydrides in the reaction of TMS-derivatives of cy-
clopropanols 1 with PhI(OAc)2 in acetic acid was observed by Kirihara et al. (see
Ref. 3a).
21. In the case of the oxidative fragmentation of cyclopropanol exo-3b under the
used conditions, the mixture of trans-9-(2,2,2-trifluoroacetoxy)non-6-enoic
acid and trans-9-((9-(2,2,2-trifluoroacetoxy)non-6-enoyl)oxy)non-6-enoic acid
31. Prepared by passing a stream of gaseous HI, generated by dropping 57% HI upon
P2O5 (see: Dillon, R. T.; Young, W. G. J. Am. Chem. Soc. 1929, 51, 2389 ). The
concentration of HI in the obtained solution was determined after its aqueous
workup by titration with sodium hydroxide.
32. Zinc dust was activated with a few drops of TMSCl.
33. Hon, Y.-S.; Wong, Y.-C.; Chang, C.-P.; Hsieh, C.-H. Tetrahedron 2007, 63, 11325.
Please cite this article in press as: Zubrytski, D. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.032