Stereoselective synthesis of 1-methyl-1,2-and 1,3-cyclopentanediols via γ-lactones

Article abstract of DOI:10.1007/s10593-013-1206-4

A method for the synthesis of 1-methylcarbapentofuranose derivatives was developed, where 1,2-cis- and 1,2-trans-4-hydroxymethyl-1- methylcyclopentanediols were obtained from intramolecular opening of a 4-epoxy-4-methyl-γ-lactone. An intramolecular aldol reaction of 4-methyl-4-(2-oxoethyl)-γ-lactone derivatives yielded 1,3-cis- and 1,3-trans-4-hydroxymethyl-1-methylcyclopentanediols.

Full text of DOI:10.1007/s10593-013-1206-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
STEREOSELECTIVE SYNTHESIS OF 1-METHYL-1,2-
AND 1,3-CYCLOPENTANEDIOLS via -LACTONES
1
2
2
2
2
3
2
A. Niidu , A. Paju , A.-M. Müürisepp , I. Järving , T. Kailas , T. Pehk , and M. Lopp *
A method for the synthesis of 1-methylcarbapentofuranose derivatives was developed, where 1,2-cis-
and 1,2-trans-4-hydroxymethyl-1-methylcyclopentanediols were obtained from intramolecular opening
of a 4-epoxy-4-methyl--lactone. An intramolecular aldol reaction of 4-methyl-4-(2-oxoethyl)--lactone
derivatives yielded 1,3-cis- and 1,3-trans-4-hydroxymethyl-1-methylcyclopentanediols.
Keywords: carbaribose, cyclopentane-1,2-diols, cyclopentane-1,3-diols, -lactone derivatives,
oxabicyclo[2.2.1]heptanone, cyclization, epoxide opening.
Substituted cyclopentanediol structural subunits are essential parts of many important natural
compounds and their analogs. Prostaglandins F [1, 2]and phytoprostanes [3], antiviral [4-6] and anticancer [7-9]
carbacyclic nucleoside analogs present only a few examples of such compounds. It is obvious that the synthesis
of differently substituted cyclopentane structures and pentofuranose carba analogs has attained considerable
interest in the last few decades [10-12]. Also, several methods for stereoselective synthesis of compounds with
structures of this type have been published [13-15].
We have been engaged in the synthesis of different 4'-substituted nucleoside analogs [16-18]. Now we
have developed synthetic routes for obtaining 1'-methyl-substituted carbocyclic ribose analogs 5a,b with
controlled regio- and stereoselectivity from the key intermediates 3a,b via bicyclic lactones 4a,b.
O
HO
HO
O
OH
Me
O
O
Me
O
O
OH
Me
5
a
OTBDMS
4
a
Me
3
a
EtO
O
O
O
OH
Me
O
1
O
Me
HO
O
5
b
TBDMSO
Me
3
4
b
b
_
*
______
To whom correspondence should be addressed, e-mail: pehk@kbfi.ee.
1
Cambrex Tallinn AS, 3/1 Teaduspargi, Tallinn 12618, Estonia; e-mail: allan.niidu@gmail.com.
Tallinn University of Technology, 15 Akadeemia tee, Tallinn 12618, Estonia; e-mail: lopp@chemnet.ee.
National Institute of Chemical Physics and Biophysics, 23 Akadeemia tee, Tallinn 12618, Estonia.
2
3
_
_______________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1871-1880, December, 2012.
Original article submitted July 9, 2012.
009-3122/13/4812-1751©2013 Springer Science+Business Media New York
0
1751

The location of the secondary OH group in the cyclopentane ring was determined by the key
intermediate 3: compounds with 2-OH group are obtained from epoxide 3a, and compounds with 3-OH group,
from the aldehyde 3b.
Lactone intermediates 2a,b were prepared starting from ethyl levulinate 1. Thus, addition of vinylic
Grignard reagent to compound 1 [19], followed by intramolecular cyclization, afforded lactone 2a (49% yield
after distillation). The double bond of lactone 2a was epoxidized with m-chloroperbenzoic acid (m-CPBA),
resulting in a diastereomeric mixture of epoxy lactones 3a in the syn/anti isomers ratio of 1.8:1.0, in 40%
overall isolated yield.
O
Vinylmagnesium
m-CPBA
bromide
O
1
3a
THF, 0–10°C
CH Cl , room temp.
2
2
(
40% total)
syn/anti = 1.8 : 1.0
Me CH2
2
a
(
46–49%)
We also intended to obtain lactone aldehyde 3b directly from vinyl lactone 2a (via lactone alcohol 6),
by using a hydroboration–oxidation sequence. Despite our many attempts using Me S·BH in THF at different
2
3
substrate/reactant ratios and reaction conditions, we always obtained a mixture of different products with the
yield of the target lactone alcohol 6 after oxidation of borane with NaBO ·4H O in the range of 25-39%, along
3
2
with compound 7, which very likely formed in 22-39% yield from regioisomer 6a, after a hydroboration–
elimination–rehydroboration sequence [20]. Also, we isolated 9-25% of the reduction product 8. Even using a
sterically bulky boron reagent disiamylborane (Sia BH) (110 mol%, from 0°C to room temperature, 44 h) did
2
not improve the results – compound 6 was formed in only 8% yield after 44 h at room temperature; instead, a
radical coupling reaction of alkene 2a with THF occurred, yielding compound 9 in 35% yield.
O
Me OH
O
OH
HO
8
OH
Me
(
9–25% from 2a)
6
1
) Me S·BH
THF
2
3
(
25–39%)
2
a
+
2
) NaBO ·4H O
3 2
O
OH
O
OH
Me
HO
Me
Me
7
Me
(
22–39% from 2a)
6
a
O
1
) Sia BH, THF
2
O
2
a
6 (8%)
+
O
2) NaBO ·4H O
3 2
Me
9
(35%)
Poor chemo- and regioselectivity (only 2:1 in favor of primary alcohol 6, calculated from the 6/7 ratio)
prompted us to pursue another synthetic path towards the key intermediate 3b. Thus, a synthesis via allylic
-lactone 2b was performed. Direct Grignard reaction of ethyl levulinate 1 with allylmagnesium bromide gave
unsatisfactory results, leading to mixtures of monoaddition adduct 2b (after lactonization) and triple addition
adduct 10 in variable ratios. The yield of monoaddition adduct 2b did not exceed 23% in the best case.
1
752

O
CH2
Allylmagnesium
bromide
O
1
+
HO
CH2
CH2
THF, 0°C to room temp.
H C
2
Me
Me
(16–30%)
OH
2
b
10
(
13–23%)
Fortunately, Ti(III)-mediated Barbier type allylation of ethyl levulinate 1 according to Estevez [21] with
.5-fold excess of allyl bromide afforded allylic lactone 2b in 91% yield. Two-step oxidation of -lactone 2b
1
and osmium-catalyzed dihydroxylation followed by NaIO -induced oxidative cleavage [22-24] afforded the key
4
intermediate 3b in 78% overall yield.
1
) cat. OsO , NMO
4
Allyl bromide
t-BuOH–H O (3:1), room temp.
2
1
2b (91%)
3b
Cp TiCl , Mn(0)
2) NaIO (0.65 M)
2
2
4
(78% over 2 steps)
THF, room temp.
CH Cl , room temp.
2
2
There are several reports in the literature where the intramolecular epoxide opening has been used to
construct functionalized cyclopentane structural units. Some of the examples include NaH-assisted synthesis of
the bicyclic skeleton of 9-deoxyenglerin A [25], Lewis acid (BF )-catalyzed intramolecular epoxide opening to
3
synthesize brefeldin A [26], and a radical Ti-catalyzed stereoselective epoxide opening to construct
functionalized cyclopentane structural units of terpenic compounds [27].
We found that lactone epoxide 3a cyclizes smoothly in a regioselective manner by the use of
TBDMSOTf–DIPEA reagent system [28].
OH
OH
O
O
Me
Me
OH
trans-5a
TBDMSOTf
DIPEA
OTBDMS
(
78% from exo-4a)
exo-4a
1
) LiAlH , THF, 
4
3
a
+
CH Cl , room temp.
2
2
O
2) 6 N aq. HCl, THF
MeOH (1:2:2), room temp.
OH
OH
O
(
for trans-5a)
Me
Me
or NaOH, H O
2
(
for cis-5a)
OTBDMS
OH
endo-4a
cis-5a
(
72% from endo-4a)
(
86% total yield)
exo/endo = 1.0 : 1.8
The cyclization afforded stable diastereomeric silyl-protected alcohols 4a in a good yield (86%) as the
primary reaction products, in a similar exo/endo diastereomer ratio as the initial epoxide (1.8:1.0). This result
indicates that the reaction is fully regio- and stereoselective. The diastereomers were easily separated on silica
gel and subjected separately to reduction. Diastereomer exo-4a was treated with LiAlH in refluxing THF,
4
quenched with aqueous NaOH, and deprotected with 6 N HCl in a mixture of MeOH and THF to afford diol
trans-5a in 78% yield over two steps. The compound cis-5a was obtained similarly from compound endo-4a in
7
2% yield after treatment of the reaction mixture with aqueos NaOH solution without the deprotection step.
Cyclization of the second key intermediate 3b was performed under the same conditions used for
compound 3a. After separation on silica gel, isomers exo-4b and endo-4b were obtained in 49% total isolated
yield, with the exo/endo ratio of ~1.0:1.5.
1
753

O
OH
Me
O
HO
Me
HO
trans-5b
(63% from exo-4b)
TBDMSO
TBDMSOTf
DIPEA
exo-4b
1
) LiAlH , THF, 
4
3
b
+
CH Cl , room temp.
2
2
O
2) 6N aq. HCl, THF
MeOH (1:2:2), room temp.
HO
OH
O
(
for trans-5a)
Me
Me
or NaOH, H O
2
(
for cis-5a)
HO
cis-5b
55% from endo-4b)
TBDMSO
endo-4b
(
49% total yield)
(
exo/endo = 1.0 : 1.5
The subsequent transformations were carried out separately with the exo and endo isomers separately.
Thus, compound exo-4b was treated with LiAlH in THF, quenched with aqueous NaOH, followed by
4
deprotection with a 1:2:2 mixture of aqueous 6 N HCl, MeOH, and THF to afford isomer trans-5b in 63% yield
over two steps. A similar transformation of compound endo-4b to isomer cis-5b was achieved in 55% yield by a
direct one-step quenching the mixture with aqueous NaOH.
To assign the configurations of bicyclic intermediates 4a,b, well-known NMR spectral features of
related bicyclo[2.2.1]heptane derivatives were used [29-31]. It is known that when C-5 or C-6 atoms in such
1
3
compounds have an oxygen-derived exo substituent, the C NMR signal of the C-7 carbon is shifted upfield
32, 33]. In the case of compound 4a, the C-7 atom signal had a chemical shift of 40.7 ppm for the exo isomer
and 42.7 ppm for the endo isomer, and in the case of compound 4b the corresponding values were 41.9 and
[
1
3
3
4
3.4 ppm. In the H NMR spectra, J
H-5x,H-4
was always larger than JH-5n,H-4. In the case of compound 4b, the
corresponding values were 4.3 and 1.3 Hz, thus revealing the configuration of the H-5 proton. In the case of
3
compound 4a, both H-5 protons exhibited J
constants of 4.6 Hz (for the endo isomer) and 4.3 Hz (for the
H-5x,H-4
3
exo isomer) and J
constants of 0.6 and 0.7 Hz, respectively (Fig. 1).
H-5n,H-4
3J5x,4 coupling constant
is always larger than 3J5n,4
Ha 7 Hs
4JHn,Hs coupling constant
H
5
is always larger than 4J
Hx,Hs
cis-Vicinal coupling constant
3
O
Hx
Hx
4
3
(
J ) is always larger than
5,6
1
O
Me
Hn – endo proton
Hx – exo proton
Ha – anti proton
Hs – syn proton
trans-vicinal coupling constant
6
Hn
endo-4b
Fig. 1. Relevant interactions for the structure determination.
(
TBDMSO group at position 5n is not shown)
3
As a rule, the vicinal proton-proton coupling constants J have higher values when the protons were cis-
oriented. In the case of compounds 4a, the H-5x and H-5n protons being assigned, the relative configuration of
3
H-6 was revealed by inspecting the relevant J coupling constants of H-5x,H-6 and H-5n,H-6, which for the
isomer exo-4a were 2.7 and 6.6 Hz and for the isomer endo-4a 9.0 and 3.3 Hz, respectively. Equally informative
1
in H NMR spectrum for the purpose of establishing the configuration of compounds 4a and 4b were
4
J constants between H-7s and H-6 (and H-5) endo protons, which were always larger in the case of endo
protons than in the case of exo protons [29]. The H-6n proton of compound 4a was found to be coupled to H-7s
with J = 1.6 Hz, whereas the H-5n proton of compound 4b was coupled to H-7s with J = 1.3 Hz.
1
754

Taking into account all the relevant information given above, we determined unambiguously the relative
configuration of bicyclic compounds 4a,b, thus letting us establish also the relative configurations of diols 5a,b.
On the other hand, the relative configuration of compound 5a could have been determined based on our
1
3
previous observation [34] that the C chemical shifts of 1-methyl-substituted vicinal diols are dependent on the
1
3
cis-trans substitution pattern. The methyl group should have C chemical shift upfield in trans-diol relative to
cis-diol; in the case of the isomer trans-5a, the methyl group had a 22.1 ppm chemical shift, and 25.2 ppm in the
case of isomer cis-5a. Furthermore, the C-1 and C-2 carbons in compound 5a should have chemical shifts
moved upfield when cis substitution is observed relative to the trans-substituted diol. Indeed, the chemical shifts
for C-1 and C-2 carbons in the isomer cis-5a were 79.1 and 78.6 ppm, whereas in the isomer trans-5a the
corresponding shifts were 81.8 and 81.1 ppm. These results correlated with the observation that reduction of
compounds exo-4a and endo-4a should yield triols trans-5a and cis-5a, respectively, and thus confirmed the
assignment of the relative configuration for bicyclic intermediates 4a.
Thus, through unprecedented use of the TBDMSOTf–DIPEA reagent system, a regio- and stereospecific
epoxide opening reaction was investigated and efficiently applied to the synthesis of novel methyl branched
cyclopentane derivatives via heterocyclic bicyclo[2.2.1]heptanes. Appropriate substrate selection allowed us to
achieve the synthesis of regioisomeric 5- and 1-methyl-6-silyloxy-2-oxa-bicyclo[2.2.1]heptan-3-one derivatives,
starting from (2-methyl-5-oxotetrahydrofuran-2-yl)acetaldehyde and 5-methyl-5-oxiranyldihydrofuran-2-one,
respectively.
EXPERIMENTAL
The IR spectra were measured on a Perkin-Elmer Spectrum BX FTIR spectrometer. The NMR spectra
were determined in CDCl or CD OD on Bruker Avance USLA 400 or Bruker Avance 800 spectrometers.
3
3
Residual solvent signals were used for reference. Mass spectra were recorded on Hitachi M80B or Shimadzu
GCMSQP2010 spectrometers using EI ionization (70 eV). High-resolution mass spectra were recorded on an
Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS spectrometer utilizing AJ-ESI or APCI ion
sources. Elemental analyses were performed on a Perkin-Elmer C,H,N,S-Analyzer 2400. Precoated silica gel 60
F254 plates from Merck were used for TLC, whereas for column chromatography silica gel KSK40-100 μm was
used. All reactions sensitive to moisture or oxygen were carried out under Ar atmosphere in oven-dried
glassware. Vinyl lactone 2a and allyl lactone 2b were synthesized according to previously published methods
(
except that, for allylation reaction, allyl bromide instead of allyl chloride was used as alkylating reagent) and
their physical and spectroscopic properties were in accordance with data given in the literature [19, 21].
Epoxides 3a were synthesized by the literature method [35]. Chemicals were purchased from Aldrich Chemical
Co. or Alfa Aesar and were used as received. MeOH was distilled from sodium. DCM was distilled over CaH2
and stored on the 4Å molecular sieves pellets. THF was distilled from sodium benzophenone complex.
5
-Methyl-5-oxiranyldihydrofuran-2-one (3a) (Mixture of Diastereomers). m-CPBA (551.3 mg,
2
2
.46 mmol, 1.22 equiv) was added portionwise at 22°C to a solution of -vinyl lactone 2a (253.6 mg,
.01 mmol) in CH Cl (5 ml). The resulting solution was stirred at 22°C for 25 h, during which precipitation
2
2
occurred. A second portion of m-CPBA (764.4 mg, 3.10 mmol) was added, and stirring was continued for
another 19 h (44 h total). The reaction was quenched with successive addition of 10% aqueous solution of
Na S O (5 ml) and 5% aqueous solution of NaHCO (5 ml) with vigorous stirring. The layers were separated
2
2
3
3
and the water phase extracted with CH Cl (4×10 ml). The combined organic phases were washed sequentially
2
2
with NaHCO (10 ml) and saturated NaCl (10 ml), then dried over Na SO . Filtration and evaporation of
3
2
4
volatiles afforded the crude product, from which, after purification by flash chromatography (silica gel, CH Cl –
2
2
MeOH, 200:1), diastereomeric epoxides 3a were obtained as a light-yellow oil (112 mg, 40%, syn/anti =
-
1
1
1
.8:1.0). IR spectrum (thin layer), , cm : 2984 (CH), 1778 (CO). H NMR spectrum (400 MHz, CDCl ), δ,
3
ppm (J, Hz): 3.20 (0.36H, J = 4.2, J = 2.7, 2'-CH anti); 3.03 (0.64H, dd, J = 4.0, J = 2.8, 2'-CH syn); 2.84
1
755

(
0.36H, t, J = 4.3, 3'-CH
A
anti); 2.80 (0.64H, dd, J = 5.0, J = 2.6, 3'-CH
A A
syn); 2.78-2.69 (1.28H, m, 3-CH syn,
3
2
'-CH syn); 2.66-2.57 (1.08H, m, 3-CH anti, 3'-CH anti); 2.55-2.39 (1.28H, m, 3-CH syn, 4-CH syn); 2.13-
B
2
B
B
A
.01 (1H, m, 4-CH syn, 4-CH anti); 1.90-1.78 (0.36H, m, 4-CH anti); 1.50 (1.92H, s, CH syn); 1.48 (1.08H,
B
A
B
3
1
3
s, CH anti). C NMR spectrum (101 MHz, CDCl ), δ, ppm: 176.5 (C-2 syn); 176.2 (C-2 anti); 84.7 (C-5 anti);
3
3
8
2
1.6 (C-5 syn); 56.7 (C-2' syn); 55.3 (C-2' anti); 43.6 (C-3' anti); 43.5 (C-3' syn); 32.5 (C-4 syn); 29.0 (C-3 syn);
+
9.0 (C-3 anti); 27.7 (C-4 anti); 23.5 (CH anti); 23.3 (CH syn). Mass spectrum, m/z (I , %): 142 [M] (1), 127
3
3
rel
+
+
+
[M-CH ] (2), 112 [M-CH O] (1), 99 [M-C H O] (100). Found, %: C 58.90; H 7.09. C H O . Calculated, %:
3 2 2 3 7 10 3
C 59.14; H 7.09.
2-Methyl-5-oxotetrahydrofuran-2-yl)acetaldehyde (3b). OsO in t-BuOH (2.5%, 2.2 ml, 0.175 mmol)
(
4
and N-methylmorpholine N-oxide (NMO) (50% in water, 1.1 ml, 5.32 mmol) were consecutively added to a
solution of -allyl lactone 2b (93%, 536.3 mg, 3.55 mmol) in t-BuOH (8.9 ml) and H O (3.0 ml). After stirring
2
at 22°C for 23 h, the reaction mixture was treated with 20% aqueous Na SO (10 ml) and Florisil (1 g) at the
2
3
same temperature for 45 min. The resulting slurry was filtered through a pad of Celite and the latter washed
with acetone (3×15 ml). The organic volatiles were evaporated, and 1 M NaHSO (2 ml) was added to the
4
residue to adjust the pH to 2. The water phase was extracted with EtOAc (15×15 ml, NaCl (2 g) was added to
the water phase after the 10th extract), dried over MgSO , and filtered through a short pad of silica to yield
4
crude 5-(2,3-dihydroxypropyl)-5-methyldihydrofuran-2-one (562.5 mg) as a 1:1 mixture of diastereomers,
1
which was used in the next synthetic step without further purification. H NMR spectrum (400 MHz, CDCl ), δ,
3
ppm (J, Hz): 3.98-3.89 (1H, m, 2'-CH); 3.62-3.52 (1H, m) and 3.49-3.40 (1H, m, 3'-CH ); 2.72-2.55 (2H, m,
2
3
-CH ); 2.49-2.21 (1H, m) and 2.12-1.99 (1H, m, 4-CH ); 1.92-1.71 (2H, m, 1'-CH ); 1.49 (1.5H, s) and 1.47
2 2 2
1
3
(
(
(
1.5H, s, CH ). C NMR spectrum (101 MHz, CDCl ), δ, ppm: 177.0 (C-2); 86.1 and 85.9 (C-5); 68.4 and 67.9
3 3
C-2'); 66.6 and 66.6 (C-3'); 42.7 and 42.6 (C-1'); 33.4 and 32.7 (C-4); 28.7 and 28.5 (C-3); 26.4 and 25.6
CH3).
To the obtained intermediate diol (479 mg, 2.75 mmol) dissolved in CH Cl (55.0 ml), NaIO (0.65 M,
2
2
4
5
.3 ml) and silica (5.22 g) were added at 22°C. The resulting slurry was stirred for 40 min and then filtered
through a pad of silica. The solids on the filter were washed with CH Cl (3×25 ml) and EtOAc (2×25 ml), and
2
2
the solvents were evaporated to yield the crude aldehyde 3b as a light-brown liquid. Yield 392.4 mg (78%). IR
-
1
1
spectrum (CHCl ), , cm : 1766 (CO), 1723 (CO). H NMR spectrum (400 MHz, CDCl ), δ, ppm (J, Hz): 9.79
3
3
(
3
1H, t, J = 1.9, CHO); 2.85 (2H, qd, J = 16.7, J = 1.8, CH CHO); 2.71–2.62 (2H, m, 4-CH ); 2.30–2.16 (2H, m,
2
2
1
3
-CH ); 1.52 (3H, s, CH ). C NMR spectrum (101 MHz, CDCl ), δ, ppm: 198.6 (CHO); 175.7 (C-5); 83.2
2 3 3
+
(
[
C-2); 53.3 (CH CHO); 33.0 (C-4); 28.3 (C-3); 26.3 (CH ). Mass spectrum, m/z (I , %): 143 [M+H] (1), 127
2 3 rel
+
+
+
+
M-CH ] (8), 114 [M+H-CH O] (27), 99 [M-C H O] (92). Found, m/z: 165.0521 [M+Na] . C H O Na.
3
2
2
3
7
10
3
Calculated, m/z: 165.0522.
Synthesis of Cyclization Products exo-4a, endo-4a, exo-4b and endo-4b (General Method).
-(tert-Butyldimethylsilyloxy)-1-methyl-2-oxabicyclo[2.2.1]heptan-3-one (4a). To the mixture of
DIPEA (255 l, 1.45 mmol) and TBDMSOTf (340 l, 1.45 mmol) in CH Cl (6 ml), a solution of a
6
2
2
diastereomeric mixture of epoxides 3a (69 mg, 0.49 mmol) in CH Cl (3 ml) was added dropwise at 25°C over a
2
2
period of 10-15 min. The resulting solution (0.06 M of substrate) was stirred for 0.5 h at 25°C, after which the
reaction mixture was added to a saturated aqueous NH Cl solution, and the layers were separated. The organic
4
phase was extracted with CH Cl (4×10 ml), dried over MgSO , filtered, and the filtrate concentrated in vacuo.
2
2
4
The residue was purified by column chromatography (silica gel, heptane–acetone, 40:1 to 10:1) to yield
compounds exo-4a (66.6 mg, 54%) and endo-4a (39.0 mg, 32%) in the form of light-yellow oils.
6
-exo-(tert-Butyldimethylsilyloxy)-1-methyl-2-oxabicyclo[2.2.1]heptan-3-one (exo-4a). IR spectrum
-
1
1
(
thin layer), , cm : 1776 (CO). H NMR spectrum (800 MHz, CDCl ), δ, ppm (J, Hz): 3.82 (1H, ddd, J = 6.6,
3
J = 2.7, J = 1.6, 6-CHn); 2.72 (1H, dddd, J = 4.3, J = 1.6, J = 1.2, J = 0.7, 4-CH); 2.17 (1H, dddd, J = 13.2,
J = 6.6, J = 2.3, J = 0.7, 5-CHn); 1.98 (1H, dd, J = 10.6, J = 1.2, 7-CHa); 1.88 (1H, ddt, J = 10.6, J = 2.3,
J = 1.6, 7-CHs); 1.59 (1H, ddd, J = 13.2, J = 4.3, J = 2.7, 5-CHx); 1.47 (3H, s, 1-CH ); 0.87 (9H, s, C(CH ) );
3
3 3
1
3
0
.06 (3H, s) and 0.05 (3H, s, Si(CH ) ). C NMR spectrum (400 MHz, CDCl ), δ, ppm: 178.1 (C-3); 90.8
3 2 3
1
756

(
(
1
3 3 3 3 3
C-1); 73.3 (C-6); 41.1 (C-4); 40.7 (C-7); 36.2 (C-5); 25.6 (SiC(CH ) ); 17.8 (SiC(CH ) ); 15.6 (1-CH ); -4.8
+
+
+
SiCH ); -5.1 (SiCH ). Mass spectrum, m/z (I , %): 257 [M+H] (1), 241 [M-CH ] (2), 211 [M-COOH] (1),
3 3 rel 3
+
+
+
+
99 [M-t-Bu] (31), 171 [M-t-Bu-CO] , (41), 155 [M-t-Bu-COOH] (26), 141 [M-TBDMS] (1), 127 [M+1-
+
+
+
TBDMS-CH ] (9), 115 [TBDMS] (28), 75 [C H SiO] (100). Found, %: C 60.81; H 9.48. C H O Si.
3
2
7
13 24
3
Calculated, %: C 60.89; H 9.43.
6
-endo-(tert-Butyldimethylsilyloxy)-1-methyl-2-oxabicyclo[2.2.1]heptan-3-one
(endo-4a).
IR
-
1
1
spectrum (thin layer), , cm : 1779 (CO). H NMR spectrum (800 MHz, CDCl ), δ, ppm (J, Hz): 4.14 (1H, dd,
3
J = 9.0, J = 3.3, 6-CHx); 2.79 (1H, dddd, J = 4.6, J = 1.9, J = 1.0, J = 0.6, 4-CH); 2.31 (1H, ddd, J = 13.3,
J = 9.0, J = 4.6, 5-CHx); 1.95 (1H, ddd, J = 10.8, J = 3.4, J = 1.9, 7-CHs); 1.72 (1H, dd, J = 10.8, J = 1.0,
7
-CHa); 1.50 (1H, dtd, J = 13.3, J = 3.3, J = 0.6, 5-CHn), 1.48 (3H, s, 1-CH ); 0.88 (9H, s, C(CH ) ); 0.06 (s, 3H)
3 3 3
13
and 0.04 (s, 3H, Si(CH ) ). C NMR spectrum (400 MHz, CDCl ), δ, ppm: 178.2 (C-3); 90.1 (C-1); 74.6 (C-6); 43.6
3
2
3
(
C-4); 42.7 (C-7); 35.6 (C-5); 25.6 (SiC(CH ) ); 18.0 (SiC(CH ) ); 16.1 (1-CH ), -4.7 (SiCH ); -5.0 (SiCH ). Mass
3
3
3 3
3
+
3
3
+
+
+
spectrum, m/z (I , %): 241 [M-CH ] (1), 211 [M-COOH] (1), 199 [M-t-Bu] (12), 171 [M-t-Bu-CO] (23), 155
rel
+
3
+
+
+
[M-t-Bu-COOH] (46), 141 [M-TBDMS] (1), 127 [M+1-TBDMS-CH ] (13), 115 [TBDMS] (22), 75
3
+
[C H SiO] (100). Found, %: C 60.89; H 9.48. C H O Si. Calculated, %: C 60.89; H 9.43.
2 7 13 24 3
5
-(tert-Butyldimethylsilyloxy)-1-methyl-2-oxabicyclo[2.2.1]heptan-3-one (4b) was obtained using
aldehyde 3b as starting material on a 2.75 mmol scale. Yield of isomer exo-4b 143 mg (20%), light-yellow
liquid. Yield of isomer endo-4b 204 mg (29%), light-yellow amorphous solid.
5
-exo-(tert-Butyldimethylsilyloxy)-1-methyl-2-oxabicyclo[2.2.1]heptan-3-one (exo-4b). IR spectrum
-
1
1
(
CHCl ), , cm : 1783 (CO). H NMR spectrum (400 MHz, CDCl ), δ, ppm (J, Hz): 4.33 (1H, ddt, J = 6.6,
3
3
J = 2.0, J = 1.3, 5-CHn); 2.79 (1H, quint, J = 1.3, 4-CH); 2.25 (1H, dd, J = 10.4, J = 1.4, 7-CHa); 2.25 (1H, ddd,
J = 13.8, J = 6.6, J = 2.8, 6-CHn); 1.98 (1H, ddt, J = 10.4, J = 2.8, J = 1.3, 7-CHs); 1.59 (3H, s, 1-CH ); 1.59
3
1
3
(
1H, ddd, J = 13.8, J = 2.0, J = 1.3, 6-CHx); 0.88 (9H, s, C(CH ) ); 0.08 (3H, s) and 0.07 (3H, s, Si(CH ) ). C
3 3 3 2
NMR spectrum (101 MHz, CDCl ), δ, ppm: 176.5 (C-3); 90.2 (C-1); 70.2 (C-5); 53.3 (C-4); 47.0 (C-6); 41.9
3
(
2
C-7); 25.7 (C(CH ) ); 18.7 (1-CH ); 17.9 (C(CH ) ); -4.8 (SiCH ); -5.0 (SiCH ). Mass spectrum, m/z (I , %):
3 3 3 3 3 3 3 rel
+
+
+
+
+
56 [M] (1), 241 [M-CH ] (1), 199 [M-t-Bu] (33), 171 [M-t-Bu-CO] (4), 155 [M-t-Bu-COOH] (7), 115
3
+
+
+
[TBDMS] (2), 75 [C H SiO] (100). Found, m/z: 279.1391 [M+Na] . C H NaO Si. Calculated, m/z:
2 7 13 24 3
2
79.1387.
-endo-(tert-Butyldimethylsilyloxy)-1-methyl-2-oxabicyclo[2.2.1]heptan-3-one
5
(endo-4b).
IR
-
1
1
spectrum (KBr), , cm : 1776 (CO). H NMR spectrum (400 MHz, CDCl ), δ, ppm (J, Hz): 4.54 (1H, ddd,
3
J = 8.7, J = 4.3, J = 3.1, 5-CHx); 2.92 (1H, dt, J = 4.3, J = 1.4, 4-CH); 2.10 (1H, dd, J = 13.7, J = 8.7, 6-CHx);
1
.96 (1H, ddd, J = 10.7, J = 3.9, J = 1.6, 7-CHs); 1.65 (1H, dd, J = 10.7, J = 1.2, 7-CHa); 1.64 (1H, ddd,
J = 13.7, J = 3.9, J = 3.1, 6-CHn); 1.51 (3H, s, 1-CH ); 0.87 (9H, s, C(CH ) ); 0.09 (s, 3H) and 0.06 (s, 3H,
3
3 3
1
3
Si(CH ) ). C NMR spectrum (101 MHz, CDCl ), δ, ppm: 174.8 (C-3); 88.6 (C-1); 70.6 (C-5); 51.7 (C-4); 43.7
3
2
3
(
(
[
C-6); 43.4 (C-7); 25.7 (C(CH ) ); 19.3 (CH ); 18.0 (C(CH ) ); -4.8 (SiCH ); -5.0 (SiCH ). Mass spectrum, m/z
3 3 3 3 3 3 3
+
+
+
+
I , %): 241 [M–CH ] (1), 199 [M–t-Bu] (30); 171 [M–t-Bu–CO] (8); 155 [M–t-Bu–COOH] (6); 75
rel
3
+
+
C H SiO] (100). Found (ESI), m/z: 279.1392 [M+Na] . C H NaO Si. Calculated, m/z: 279.1387.
2
7
13 24
3
1
,2-trans-4-Hydroxymethyl-1-methylcyclopentane-1,2-diol (trans-5a). LiAlH (91 mg, 2.28 mmol)
4
was suspended in THF, and a solution of compound exo-4a (167 mg, 0.65 mmol) in THF (10 ml) was added at
°C. The resulting suspension was heated to reflux for 1 h, then the reaction mixture was cooled to 0°C and
0
water was added (100 l). Stirring was continued for 0.5 h with gradual rise of temperature to 23°C. Then
aqueous 10% NaOH (100 l) at 23°C was added, and the stirring continued for an additional 0.5 h to complete
the precipitation. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to yield the crude
+
+
+
protected diol. Mass spectrum, m/z (I , %): 243 [M+H-H O] (1), 227 [M-H O-CH ] (1), 203 [M-t-Bu] (12),
1
rel
2
2
3
+
+
+
85 [M-H O-t-Bu] (42), 129 [M+H-H O-TBDMS] (2), 75 [C H SiO] (100).
2 2 2 7
To a solution of the protected diol (130.3 mg, 0.50 mmol) in a mixture of THF (2 ml) and MeOH (2 ml),
N HCl (1 ml) was added dropwise at 25°C. The resulting solution was stirred for 1 h at 25°C, then the
6
volatiles were evaporated to yield the crude product as a light-yellow oil. Further purification was achieved by
1
757

2 2
flash chromatography on silica gel eluting with CH Cl –MeOH, 10:1. Yield 57 mg (78%). Colorless oil. IR
-
1
1
spectrum (thin layer), , cm : 3341 (OH), 1118 (C–O), 1038 (C–O). H NMR spectrum (400 MHz, CD OD), δ,
3
ppm (J, Hz): 3.75 (1H, dd, J = 5.6, J = 3.3, 2-CH); 3.47 (2H, d, J = 6.0, CH OH); 2.44–2.27 (1H, m, 4-CH);
2
1
.98-1.80 (2H, m, 3-CH , 5-CH ); 1.77-1.65 (1H, m, 3-CH ); 1.43 (1H, dd, J = 13.7, J = 5.3, 5-CH ); 1.25 (3H,
A A B B
1
3
s, CH ). C NMR spectrum (101 MHz, CD OD), δ, ppm: 81.8 (C-1); 81.1 (C-2); 67.6 (CH OH); 41.5 (C-5);
3
CH OH] (28), 98 [M+H-H O-CH OH] (17), 97 [M-H O-CH OH] (37). Found, m/z: 169.0829 [M+Na] .
3
3
2
+
+
8.4 (C-4); 36.2 (C-3); 22.1 (CH ). Mass spectrum, m/z (I , %): 146 [M] (1), 128 [M-H O] (3), 115 [M-
3 rel 2
+
+
+
+
2
2
2
2
2
C H NaO . Calculated, m/z: 169.0835.
7
14
3
1
,2-cis-4-Hydroxymethyl-1-methylcyclopentane-1,2-diol (cis-5a). LiAlH (50 mg, 1.29 mmol) was
4
suspended in THF (7 ml), and a solution of the compound endo-4a (88 mg, 0.34 mmol) in THF (7 ml) was
added at 0°C. The resulting suspension was heated to reflux for 1 h, then the reaction mixture was cooled to 0°C
and water (100 l) was added. Stirring was continued for 0.5 h with gradual rise of temperature to 23°C. Then
aqueous 10% NaOH (100 l) at 23°C was added, and the stirring continued for an additional 0.5 h to complete
the precipitation. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to yield the crude
diol cis-5a, which was purified by flash chromatography on silica gel, eluent CH Cl –MeOH, 10:1. Yield 36.4
2
2
-
1
1
mg (72%). Light to colorless oil. IR spectrum (thin layer), , cm : 3381 (OH), 1086 (C–O), 1043 (C–O). H
NMR spectrum (400 MHz, CD OD), δ, ppm (J, Hz): 3.63 (1H, dd, J = 7.9, J = 6.4, 2-CH); 3.48 (2H, d, J = 6.0,
3
CH OH); 2.17-2.01 (2H, m, 4-CH, 3-CH ); 1.79 (1H, dd, J = 13.8, J = 9.3) and 1.56 (1H, dd, J = 13.8, J = 5.7,
2
A
1
3
5
-CH ); 1.48 (1H, dt, J = 12.7, J = 7.5, 3-CH ); 1.22 (3H, s, CH ). C NMR spectrum (101 MHz, CD OD), δ,
2 B 3 3
ppm: 79.1 (C-1); 78.6 (C-2); 67.7 (CH OH); 41.2 (C-5); 36.4 (C-4); 35.6 (C-3); 25.2 (CH ). Mass spectrum, m/z
2
3
+
+
+
+
(
I , %): 146 [M] (1), 128 [M-H O] (5), 115 [M-CH OH] (32), 98 [M+H-H O-CH OH] (14), 97 [M-H O-
rel 2 2 2 2 2
+
+
CH OH] (36). Found, m/z: 169.0828 [M+Na] . C H NaO . Calculated, m/z: 169.0835.
2
7
14
3
1
,3-trans-4-Hydroxymethyl-1-methylcyclopentane-1,3-diol (trans-5b). LiAlH (41 mg, 1.06 mmol)
4
was suspended in THF (2.5 ml), and a solution of the compound exo-4b (130.3 mg, 0.51 mmol) in THF (2.5 ml)
was added at 0°C. The resulting suspension was heated to reflux for 1 h, then the reaction mixture was cooled to
0
°C, and water (41 l) was added. Stirring was continued for 0.5 h with gradual rise of temperature to 23°C.
Then aqueous 10% NaOH (41 l) at 23°C was added, and the stirring was continued for an additional 0.5 h,
upon which water (123 l) was added. The reaction mixture was filtered, and the filtrate was concentrated
in vacuo to yield the crude protected diol, which was dissolved in CH Cl (5 ml), and 6 N HCl (200 l) was
2
2
added. The resulting two-phase system was stirred vigorously for 5 min and then the volatiles were removed in
vacuo to yield the crude diol trans-5b, which was purified by flash chromatography on silica gel, eluent
-
1
CH Cl –MeOH, 20:1 to 10:1. Yield 46.7 mg (63%). Light-yellow oil. IR spectrum (thin layer), , cm : 3331
2
2
1
(
OH), 1057 (C–O), 1031 (C–O). H NMR spectrum (400 MHz, CD OD), δ, ppm (J, Hz): 4.10 (1H, dd, J = 13.6,
3
J = 7.6, 3-CH); 3.68 (1H, dt, J = 9.5, J = 5.9) and 3.58-3.55 (1H, m, CH OH); 2.07 (1H, ddd, J = 13.2, J = 7.1,
2
1
3
J = 1.4, 4-CH); 2.01-1.94 (2H, m) and 1.67-1.52 (2H, m, 2,5-CH ); 1.33 (3H, s, CH ). C NMR spectrum (101
2
3
MHz, CD OD), δ, ppm: 77.8 (C-1); 75.2 (C-3); 65.4 (CH OH); 50.8 (C-4); 50.7 (C-2); 43.8 (C-5); 29.5 (CH ).
3
2
3
+
+
+
Mass spectrum, m/z (I , %): 128 [M-H O] (1), 113 [M-H O-CH ] (15), 98 [M+H-H O-CH OH] (11), 97 [M-
H O-CH OH] (4). Found, m/z: 169.0824 [M+Na] . C H NaO . Calculated, m/z: 169.0835.
rel
2
2
3
2
2
+
+
2
2
7
14
3
1
,3-cis-4-hydroxymethyl-1-methylcyclopentane-1,3-diol (cis-5b). LiAlH (43.5 mg, 1.12 mmol) was
4
suspended in THF (2.5 ml), and a solution of the compound endo-4b (135.2 mg, 0.53 mmol) in THF (2.5 ml)
was added at 0°C. The resulting suspension was heated to reflux for 1h, then the reaction mixture was cooled to
0
°C, and water (44 l) was added. Stirring was continued for 0.5 h with gradual rise of temperature to 19°C.
Then aqueous 10% NaOH (100 l) was added at 19°C, and the stirring continued for an additional 0.5 h, upon
which water (132 l) was added. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to
yield the crude diol cis-5b which was purified by flash chromatography on silica gel, eluent CH Cl –MeOH
2
2
-
1
4
0:1 to 20:1 mixture. Yield 44.3 mg (55%). Light-yellow oil. IR spectrum (thin layer), , cm : 3383 (OH), 1033
1
(
C–O). H NMR spectrum (400 MHz, CD OD), δ, ppm (J, Hz): 4.26 (1H, td, J = 4.9, J = 2.8, 3-CH); 3.79 (1H,
3
dd, J = 10.7, J = 7.5) and 3.66-3.58 (1H, m, CH OH); 2.20–2.10 (1H, m, 4-CH); 1.90-1.81 (3H, m, 2-CH ,
2
2
1
758

1
3
5
-CH
A B 3 3
); 1.77-1.68 (1H, m, 5-CH ); 1.30 (3H, s, CH ). C NMR spectrum (101 MHz, CD OD), δ, ppm: 79.4
(
1
C-1); 74.8(C-3); 63.2 (CH OH); 50.8 (C-2); 47.7 (C-4); 43.8 (C-5); 29.8 (CH ). Mass spectrum, m/z (I , %):
2
3
rel
+
+
+
+
47 [M+H] (1), 128 [M-H O] (2), 113 [M-H O-CH ] (2), 98 [M+H-H O-CH OH] (10), 97 [M-H O-
2 2 3 2 2 2
+
+
CH OH] (5). Found, m/z: 169.0825 [M+Na] . C H NaO . Calculated, m/z: 169.0835.
2
7
14
3
We are grateful to the Estonian Ministry of Education and Research (grant No. 0140060s12), the
Estonian Science Foundation (grants Nos. 5628, 7114, and 8880), EU European Regional Development Fund
TAR 8103 (3.2.0101.08-0017), and the Competence Center for Cancer Research for financial support.
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(
(
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