Acid-catalyzed aldol-Meerwein-Ponndorf-Verley-etherification reactions - Access to defined configured quaternary stereogenic centers

Article abstract of DOI:10.1016/j.tet.2011.11.069

A novel asymmetric aldol-reduction-etherification process of aliphatic enolizable aldehydes is described. The intermediately formed aldol adducts - β-hydroxyaldehydes - were reduced and transformed into the corresponding 1,3-diol ethers by external secondary alcohols at the same time. Thus, with the help of chiral secondary alcohols an access to optically active 1,3-diol ether is given. Furthermore, asymmetric cross-aldol-Meerwein-Ponndorf reactions of enolizable aldehydes can also be realized under these reaction conditions.

Full text of DOI:10.1016/j.tet.2011.11.069

Tetrahedron 68 (2012) 1137e1144
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Acid-catalyzed aldol-MeerweinePonndorfeVerley-etherification
reactionsdaccess to defined configured quaternary stereogenic centers
*
Andrea Seifert, Kerstin Rohr, Rainer Mahrwald
Institute of Chemistry, Humboldt-University, Brook-Taylor Str. 2, 12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2011
Received in revised form 10 November 2011
Accepted 23 November 2011
Available online 27 November 2011
A novel asymmetric aldol-reductioneetherification process of aliphatic enolizable aldehydes is de-
scribed. The intermediately formed aldol adductsdb-hydroxyaldehydesdwere reduced and transformed
into the corresponding 1,3-diol ethers by external secondary alcohols at the same time. Thus, with the
help of chiral secondary alcohols an access to optically active 1,3-diol ether is given. Furthermore,
asymmetric cross-aldol-MeerweinePonndorf reactions of enolizable aldehydes can also be realized
under these reaction conditions.
Keywords:
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Enolizable aldehydes
MeerweinePonndorf-aldol reactions
Quaternary stereogenic enters
1,3-Diol
1. Introduction
Also, a similar hydride shift is observed in the aldol-Tishchenko
reaction. During this reaction a second molecule of the starting
The MeerweinePonndorfeVerley reduction (MPVR) of ketones
has a prominent significance and a striking usefulness in organic
synthesis. It is reversible, and the reverse reaction is known as the
Oppenauer oxidation (OO). Several highly diastereoselective MPV-
processes1 and their extension to the synthesis of chiral 1,3-
mercapto alcohols2 were reported. On the other hand, examples
of asymmetric MPV-processes are rare and lacking in general ap-
plication.3 Several chiral metal complexes were tested in enantio-
selective execution of the MPV-reaction but they are mostly
devoted to aromatic ketones.4 Satisfying examples of asymmetric
execution in the aliphatic series are still unknown, with the ex-
ception of biocatalytical hydrogen transfer reactions.5 In contrast,
several synthetic enlargements of this important redox process
have been reported, where the MPV-reaction is incorporated into
CeC bond formation processes. These are MPV-aldol condensation
processes,6 and MPV/Brook rearrangement/aldol addition.7 Also,
the formal MPV-alkynylation,8 MPV-cyanation,9 MPV-allylation,10
and MPV-transfer aldol reaction11 should be mentioned here.
During the MeerweinePonndorfeVerley-reaction a 1,5-hydride
shift occurs. A metal ion increases the electrophilic nature of the
carbonyl group and a 1,5-hydride shift occurs from an external
secondary alcohol (mostly isopropanol) to reduce the carbonyl
compound.12 A cyclic six-membered transition state is generally
accepted as the mechanism of this hydride transfer.13
aldehyde generates an acetal intermediate to reduce the ketone by
a 1,5-hydride shift. As a consequence corresponding 1,3-diol esters
were obtained with extremely high degrees of diastereoselectivity.
But again, high enantioselectivities were obtained in these re-
actions only when used with aromatic ketones as substrates.14
When starting with corresponding racemic aldol adducts 1,3-diol
esters were detected with good enantioselectivities.15
Scheme 1. Comparison of 1,5-hydride transfer-reactions.
These findings contrast results we have observed in enantiose-
lective aldol-MeerweinePonndorfeVerley-etherification processes
of enolizable aldehydes.16 In these transformations enolizable
* Corresponding author. Tel.: þ49 30 2093 8397; fax: þ49 30 2093 5553; e-mail
address: rainer.mahrwald@rz.hu-berlin.de (R. Mahrwald).
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.069

1138
A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
aldehydes react in the presence of catalytic amounts of acids and an
external secondary alcohol to give the corresponding 1,3-diol
etherda product derived from an aldol addition, Meer-
weinePonndorfeVerley reduction and etherification sequence.
Again, a 1,5-hydride shift, as is shown in Scheme 1, is observed
under these reaction conditions. As a consequence, the formation of
a primary alcohol followed by etherification is observed. The real
In a following first series we explored the intramolecular version
of this reaction. To this end we reacted several enolizable dia-
ldehydes with cyclopentanol in the presence of LiClO4 and catalytic
amounts of trifluoroacetic acid (TFA). Extremely high degrees of
diastereoselectivities were detected. The 1,3-diol cyclopentyl ethers
4aee were isolated as a single diastereoisomer (Scheme 3). A typical
tendency for preferring the formation of a quaternarycarbon atom is
observed under these reaction conditions, if one compares the re-
sults of intramolecular aldol addition-MPV-etherification of adi-
paldehyde 3a (4a: 11% yield) and heptanedial 3b (4b: 17% yield) with
reaction mechanism is still unknown so far.
A
Meer-
weinePonndorfeVerley reduction of intermediately formed
hemiacetals to give 1,3-diol ethers cannot be excluded.
Herein we expand this novel transformation to a highly stereo-
selective intramolecular version with dialdehydes. Furthermore, we
describe this transformation for both seriesdthe synthesis of R- and
S-configured 1,3-diol methyl ether. In addition, we provide a mild
and useful procedure for the cleavage of resulting methyl ether.
those of a-methyl adipaldehyde 3c (4c: 75% yield).
To analyze the source and fate of hydride deuterated cyclo-
hexanol was deployed in these reactions. Isobutyraldehyde was
reacted with C1-deuterated cyclohexanol in the presence of cata-
lytic amounts of trifluoroacetic acid and lithium perchlorate. The
expected 1,3-diol cyclohexyl ether was isolated in addition to
equimolar amounts of cyclohexanone (Scheme 4).
2. Results and discussion
One equivalent of C1-deuterated cyclohexanol was oxidized to
reduce the assumed intermediate
b-hydroxyaldehyde. A second
During our ongoing studies of the application of LiClO4 in or-
ganic reactions we observed aldol reactions attended by a simul-
taneous hydride transfer. The type of hydride transfer strongly
depends on reaction conditions. When used with bases an aldol-
Tishchenko process is observed. The corresponding syn-config-
ured 1,3-diol monoesters were detected in this case.17 In contrast to
that an aldol addition/MPV-reduction/etherification reaction se-
quence is observed by deployment of acids18 and an external al-
cohol (cyclopentanol for 2a and 2b). The corresponding 1,3-diol
cyclopentyl ethers 2a and 2b were isolated in high yields. By ap-
equivalent of C1-deuterated cyclohexanol was used for the ether-
ification. Subsequent analysis revealed the full incorporation of
deuterium.19,20 Again, one single diastereoisomer was detected by
1H NMR experiments. These interesting findings should offer the
possibility of an enantioselective access to optically active 1,3-diol
ether. To this end several chiral secondary alcohols were tested in
these reactions, but only with moderate success. Racemization of
the starting chiral secondary alcohols was observed under the
conditions of this aldol-MPV process. At that point we decided to
deploy two alcohols in these reactionsdone for the etherification
process and an additional chiral alcohol for the hydride transfer. To
this end we have tested a series or different alcohols in homo-aldol-
MPV-etherification reaction of isobutyraldehyde (Scheme 5).
The results clearly indicate the fundamental role played by the
alcohols deployed in these reactions. The observed yields corre-
spond to the oxidation enthalpies of the according alcohols.21
Cyclopentanol, the alcohol with the lowest oxidation enthalpy, is
oxidized very easily to give cyclopentanone and thus the highest
yields of 1,3-diol ether (2a: 86%). On the other handdmethanol is
the alcohol with the highest oxidation enthalpy in this seriesdis
nearly resistant against oxidation under these reaction conditions.
As a consequence, the 1,3-diol methyl ether was observed in very
low yield (5a: 12%). Based on these remarkable differences a fol-
lowing comfortable situation appeared: methanol can be used as
the etherification-alcohol and optical pure menthol, a secondary
and competitive sterically demanding alcohol, should serve as the
chiral hydride source.22 By a careful optimization of the reaction
conditions the following protocol was elaborated.
plication of
a-unbranched aldehydes extremely high degrees of
anti-diastereoselectivity were noticed (2b, Scheme 2).
23
The reactions were carried out in the presence of dry LiClO4
and catalytic amounts of trifluoroacetic acid (0.1 mol %) at rt. Best
results with regard to yields were obtained in the absence of any
Scheme 2. Comparison of aldol-Tishchenko reaction and aldol-Meerweine
PonndorfeVerley-etherification reaction.
Scheme 3. Intramolecular aldol-MeerweinePonndorfeVerley-etherification process. Reaction conditions: rt, neat, 6 equiv LiClO4, 1 mol % TFA, 2 equiv cyclopentanol.

A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
1139
Scheme 4. Stereoselective incorporation of deuterium. Reaction conditions: 2 equiv
C1-deuterated cyclohexanol, 10 equiv LiClO4, 1 mol % TFA, rt, 2 h.
Scheme 5. Aldol-MeerweinePonndorfeVerley-etherification with different external
alcohols.
Fig. 1. Transition state models.
solvents. By application of oxygen-containing solvents no reactions
were observed.24 Furthermore, higher yields and shorter reactions
times were obtained by deployment of trimethylsilyl ether of op-
tically pure menthol. An optional and selective access to both en-
antiomers is given by the use of (ꢀ)- or (þ)-menthyl trimethylsilyl
ethers. By application of (ꢀ)-menthyl trimethylsilyl ether S-con-
figured 1,3-diol ethers were obtained. When used with
(þ)-menthyl trimethylsilyl ether R-configured 1,3-diol ethers were
obtained with same results concerning to yields and stereo-
selectivities.20 Also, a slight increasing of yields is noticed when
using with the corresponding trioxane instead of the aldehyde.25
The results of these investigations are shown in Scheme 6.
conditions.
components in every reaction we tried (6a and 6b, Scheme 7). Even
in reactions of two different -branched enolizable aldehydes an
extremely strong differentiation is observed. In these cases, the less
sterically demanding aldehyde acts exclusively as the ene compo-
nent (6c and 6d, Scheme 7). Other cross-aldol adducts or self-aldol
adducts were not detected under these reaction conditions. In ad-
dition, high enantioselectivities were detected.
a-Branched enolizable aldehydes act exclusively as ene
a
Next, the isolated 1,3-diol ethers were transformed into the
corresponding 1,3-diols. The use of methyl ethers as a protecting
group for aliphatic alcohols is often limited by low yields and dif-
Scheme 6. Asymmetric homo-aldol-MeerweinePonndorfeVerley-etherification reactions. aResults obtained by use of freshly distilled aldehydes. bResults obtained when used with
the corresponding trioxanes.
Two bicyclic transition state models are likely to be conceivable
as is depicted in Fig.1. For reasons of simplification these transitions
states are given for the homo-aldol-MPV-etherification reaction of
isobutyraldehyde and (ꢀ)-menthol. Both transition states
explaining the configurative outcomedthe formation of S-config-
ured products. Due to steric interactions of the isopropyl groups
there should be a preference of transition state A over transition
state B (see also Supplementary data).
In a further series reactions of two different enolizable alde-
hydes were investigated. An extremely high differentiation be-
tween the employed aldehydes was observed. The key to the
regioselectivity of this reaction is the preferred formation of eno-
ficulties during the isolation-process of the corresponding alcohols.
Several well-established methods, such as the application of boron
reagents (BF3/AcOH,26 BBr3/NaI27 or BBr3/CH2Cl228) or TMSI29
yielded the expected 1,3-diols in very low yields only (<11%). An
increasing of yields was noticed when used with in situ generated
trimethylsilyl iodide.30 But the expected 1,3-diols were isolated
with yields not higher than 30%. Further optimization revealed
equimolar amounts of Me3SiI in the presence of catalytic amounts
of NaI (1 mol %) as the reagent of choice. Under these conditions the
reaction proceeds very easy and selectively at rt in carbon tetra-
chloride. After 10e16 h the corresponding 1,3-diols 8aee were
isolated in good yields (Scheme 8). Enantioselectivity as well as
diastereoselectivity of the starting methyl ether 5aee were not
lates of
a-branched enolizable aldehydes under these reaction

1140
A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
Scheme 7. Asymmetric cross-aldol-MeerweinePonndorfeVerley ether formation reactions.
Scheme 8. Methyl ether-cleavage.
influenced by the reaction conditions described. This fact was ap-
4.2. General procedure for the synthesis of products 2aec
proved by NMR-spectroscopy of the corresponding Mosher-ester.20
Trifluoroacetic acid (480 mg, 0.0042 mmol) was added to
a mixture of corresponding aldehydes 1a or 1b (4.2 mmol), dry
isopropanol (4.2 mmol for 2c) or dry cyclopentanol (4.2 mmol for
2a or 2b) and dry LiClO4 (2.65 g, 25 mmol). The reaction mixture
was stirred 2 h at rt and monitored by TLC. After completion (DC-
control) the reaction mixture was quenched with saturated aque-
ous solution of Na2CO3 (50 ml) and extracted with diethyl ether
(2ꢂ100 ml). The organic layer was dried (MgSO4), filtrated and the
solvent was removed in vacuo to give crude product. Purification by
column chromatography yielded the products 2aec (hexane/ethyl
acetatee95/5; Rfw0.15e0.2).
3. Conclusions
In summary, we have developed an access to optically active 1,3-
diol ethers. During a new aldol-MeerweinePonndorfeVerley re-
duction etherification process the 1,3-diol ethers were formed with
extremely high degrees of diastereoselectivity. The process can be
performed out intramolecularly as well as intermolecularly. By the
deployment of two different alcoholsdone for the hydride transfer
and one for the etherificationdan access to enantiomerically
enriched 1,3-diol ethers can be realized. An extremely high differ-
entiation of deployed aldehydes is observed in cross-aldol-MPV-
etherification reactions. This differentiation is controlled by steric
interactions. By a following optimization of established protocols of
methyl ether-cleavage we were able to isolate the corresponding
1,3-diols in good yields.
4.2.1. rac-1-Cyclopentoxy-2,2,4-trimethyl-pentan-3-ol
2a. Yield
¼3.78e3.72 (1H, m, CH), 3.22
86%. 1H NMR (CDCl3, 300 MHz):
d
(1H, d, J¼8.7 Hz, CH2), 3.20 (1H, d, J¼2.4 Hz, CH), 3.10 (1H, d,
J¼8.7 Hz, CH2), 1.80 (1H, dsept, J¼2.2, 6.8 Hz, CH), 1.60e1.44 (8H,
m, CH2), 0.93 (3H, d, J¼6.9 Hz, CH3), 0.86 (3H, s, CH3), 0.85 (3H, s,
CH3), 0.43 (3H, d, J¼6.8 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
d
¼83.0, 82.0, 80.0, 38.5, 31.9, 31.9, 29.1, 23.6, 23.4, 23.3, 20.5, 16.4;
HRMS-ESI (m/z): calcd for C13H26O2þHþ: 215.2006, found:
4. Experimental
4.1. General
215.2007.
4.2.2. (3S*,4R*)-3-(Cyclopentyloxymethyl)-2,6-dimethylheptan-4-ol
2b. Yield 68%. 1H NMR (CDCl3, 300 MHz):
d
¼3.88e3.82 (1H, m, CH),
1H NMR and 13C NMR spectra were recorded at 300 and 75 MHz
in CDCl3, respectively, using an AC-300 spectrometer. Chemical
shifts are given in parts per million. HRMS were measured at 70 eV
using an ESI-TOF-spectrometer. Purification of products was ac-
complished by flash-chromatography. Thin layer chromatography
was performed with Merck Silica Gel 60 F254 TLC plates. Aldehydes
were freshly distilled before use. LiClO4 was dried at 140 ꢁC in vacuo
for 10 h before use.
3.67 (1H, dd, J¼3.0, 9.4 Hz, CH2), 3.62 (1H, br s, CH), 3.58 (1H, dd,
J¼5.0, 9.4 Hz, CH2), 2.05e1.98 (1H, m, CH), 1.85e1.78 (1H, m, CH),
1.68e1.53 (8H, m, CH2), 1.49e1.44 (1H, m, CH), 1.29e1.12 (2H, m,
CH2), 1.01 (3H, d, J¼6.8 Hz, CH3), 0.95e0.90 (9H, m, CH3); 13C NMR
(CDCl3, 75 MHz):
23.5, 23.3, 22.4, 22.1, 21.3, 19.5. HRMS-ESI (m/z): calcd for
C15H30O2þHþ: 243.2319, found: 243.2319.
d
¼82.0, 70.8, 67.5, 48.9, 45.7, 32.2, 31.9, 26.1, 24.5,

A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
1141
4.2.3. rac-1-Isopropoxy-2,2,4-trimethyl-pentan-3-ol 2c. Yield 44%.
1H NMR (CDCl3, 300 MHz):
Purification by column chromatography yielded products 4aee
(hexane/ethyl acetated95/5; Rfw0.15e0.2).
d
¼3.47 (1H, sept, J¼6.1 Hz, CH), 3.28
(1H, d, J¼8.6 Hz, CH2), 3.25 (1H, d, J¼2.4 Hz, CH), 3.17 (1H, d,
J¼8.6 Hz, CH2), 1.83 (1H, dsept, J¼2.3, 6.8 Hz, CH), 1.11 (3H, d,
J¼6.8 Hz, CH3), 1.09 (3H, d, J¼6.8 Hz, CH3), 0.97 (3H, d, J¼6.9 Hz,
CH3), 0.90 (3H, s, CH3), 0.89 (3H, s, CH3), 0.87 (3H, d, J¼6.8 Hz, CH3);
4.4.1. (1S*,2S*)-2-(Isopropoxymethyl)cyclopentanol 4a. Yield 11%.
1H NMR (CDCl3, 300 MHz):
d
¼4.27 (1H, ddd, J¼3.2, 5.1, 8.1 Hz, CH),
3.90e3.84 (1H, m, CH), 3.58 (1H, dd, J¼4.7, 9.3 Hz, CH2), 3.51 (1H,
13C NMR (CDCl3, 75 MHz):
d
¼83.0, 79.5, 72.5, 38.6, 29.1, 23.7, 23.4,
dd, J¼7.3, 9.3 Hz, CH2), 1.79e1.47 (15H, m, CH, CH2); 13C NMR
21.8, 21.7, 20.6, 16.5. HRMS-ESI (m/z): calcd for C11H24O2þHþ:
(CDCl3, 75 MHz):
d
¼81.8, 74.9, 68.9, 43.9, 34.8, 32.3, 32.0, 26.1, 23.4,
189.1849, found: 189.1849.
22.3. HRMS-ESI (m/z): calcd for C11H20O2þHþ: 185.1536, found:
185.1536.
4.3. General procedure for the synthesis of dialdehydes 3aee
Dialdehydes 3aee were synthesized by the following sequence:
4.4.2. (1S*,2S*)-2-(Cyclopentyloxymethyl)cyclohexanol
17%. 1H NMR (CDCl3, 300 MHz):
4b. Yield
¼4.35 (1H, ddd, J¼3.6, 5.6, 9.0 Hz,
d
CH), 3.93e3.89 (1H, m, CH), 3.64 (1H, dd, J¼4.1, 9.4 Hz, CH2), 3.56
(1H, dd, J¼6.9, 9.1 Hz, CH2), 1.76e1.52 (17H, m, CH, CH2); 13C NMR
(CDCl3, 75 MHz):
d
¼81.9, 75.6, 67.7, 51.5, 33.9, 33.6, 32.4, 32.0, 32.0,
23.5, 21.0, 19.4. HRMS-ESI (m/z): calcd for C12H22O2þHþ: 199.1693,
found: 199.1694.
4.4.3. (1S*,2S*)-2-(Cyclopentyloxymethyl)-2-methylcyclopentanol
4c. Yield 75%. 1H NMR (CDCl3, 300 MHz):
d
¼3.87e3.83 (1H, m, CH),
3.81e3.78 (1H, m, CH), 3.44 (1H, d, J¼9.0 Hz, CH2), 3.32 (1H, d,
J¼9.0 Hz, CH2), 1.70e1.48 (14H, m, CH2), 0.93 (3H, s, CH3); 13C NMR
(CDCl3, 75 MHz):
d
¼82.0, 81.6, 74.5, 45.3, 34.1, 34.0, 32.1, 23.7, 23.4,
21.1. HRMS-ESI (m/z): calcd for C12H22O2þHþ: 199.1693, found:
4.3.1. Adipaldehyde 3a31. (R1¼R2¼R3¼H, n¼1): 51%, 1H NMR
199.1689.
(CDCl3, 300 MHz):
d
¼9.65e9.64 (2H, m, CHO), 2.39e2.34 (4H, m,
CH2), 1.56e1.52 (4H, m, CH2); 13C NMR (CDCl3, 75 MHz):
d¼201.8,
4.4.4. (1S*,2S*,3R*)-2-(Cyclopentyloxymethyl)-3-methylcyclopentanol
4d. Yield 18%. 1H NMR (CDCl3, 300 MHz):
d
¼3.99e3.92 (1H, m, CH),
43.2, 21.2.
3.90e3.86 (1H, m, CH), 3.63 (1H, dd, J¼4.1, 8.8 Hz, CH2), 3.25 (1H, pt,
J¼9.4 Hz, CH2), 1.69e1.50 (14H, m, CH, CH2), 1.00 (3H, d, J¼6.3 Hz,
4.3.2. Heptane-1,7-dial 3b32. (R1¼R2¼R3¼H, n¼2): 89%, 1H NMR
CH3); 13C NMR (CDCl3, 75 MHz):
d
¼81.8, 79.3, 72.1, 54.8, 34.6, 32.3,
(CDCl3, 300 MHz):
d
¼9.63 (2H, t, J¼1.7 Hz, CHO), 2.33 (4H, dt, J¼1.6,
7.2 Hz, CH2), 1.57e1.47 (4H, m, CH2), 1.29e1.21 (2H, m, CH2); 13C
NMR (CDCl3, 75 MHz):
¼202.1, 43.3, 28.2, 21.4.
32.2, 31.8, 31.0, 23.5, 20.0. HRMS-ESI (m/z):calcd for C12H22O2þHþ:
d
199.1693, found: 199.1696.
4.3.3. 2-Methyl-adipaldehyde 3c33. (R1¼Me, R2¼H, R3¼H, n¼1):
4.4.5. (1S*,2R*,5S*)-2-(Cyclopentyloxymethyl)-2-isopropyl-5-
63%, 1H NMR (CDCl3, 300 MHz):
d
¼11.72 (1H, t, J¼1.4 Hz, CHO),
methylcyclopentanol 4e. Yield 32%. 1H NMR (CDCl3, 300 MHz):
11.57 (1H, d, J¼1.7 Hz, CHO), 4.46e4.41 (2H, m, CH2), 4.35e4.26 (1H,
d
¼3.86 (1H, d, J¼5.8 Hz, CH), 3.84e3.80 (1H, m, CH), 3.52 (1H, d,
m, CH), 3.74e3.56 (4H, m, CH2), 3.07 (3H, d, J¼7.0 Hz, CH3); 13C NMR
J¼8.9 Hz, CH2), 3.35 (1H, d, J¼8.9 Hz, CH2), 1.79e1.40 (14H, m, CH,
CH2), 1.00 (3H, d, J¼6.9 Hz, CH3), 0.90 (3H, d, J¼6.8 Hz, CH3), 0.85
(CDCl3, 75 MHz):
d¼204.5, 201.8, 46.0, 43.6, 29.6, 19.3, 13.2.
(3H, d, J¼6.9 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
¼81.9, 80.4, 71.6,
d
4.3.4. 3-Methyl-adipaldehyde 3d34. (R1¼R3¼H, R2¼Me, n¼1): 43%,
52.8, 39.9, 30.3, 32.1, 31.7, 23.4, 18.7, 17.8, 13.5. HRMS-ESI (m/z):
calcd for C15H28O2þHþ: 241.2162, found: 241.2162.
1H NMR (CDCl3, 300 MHz):
d
¼9.66e9.63 (2H, m, CHO), 2.40e1.92
(5H, m, CH, CH2), 1.65e1.36 (2H, m, CH2), 0.86 (3H, d, J¼6.7 Hz,
CH3); 13C NMR (CDCl3, 75 MHz):
27.1, 19.3.
d¼202.0, 201.9, 50.4, 41.1, 28.3,
4.5. General procedure for the synthesis of methyl ethers
5aee
4.3.5. 2-Isopropyl-5-methyl-adipaldehyde 3e35. (R1¼Me, R2¼H,
R3¼iPr, n¼1): 43%, 1H NMR (CDCl3, 300 MHz):
¼9.61e9.60 (1H, d,
d
Trifluoroacetic acid (480 mg, 0.0042 mmol) was added to
a mixture of corresponding aldehydes 1aee (4.2 mmol), (þ)- or
(ꢀ)-menthyl TMS-ether (12.6 mmol), dry methanol (4.2 mmol),
and dry LiClO4 (2.65 g, 25 mmol). The reaction mixture was stirred
2 h at rt and monitored by TLC. After completion the reaction
mixture was quenched with saturated aqueous solution of Na2CO3
(50 ml) and extracted with diethyl ether (2ꢂ100 ml). The organic
layer was dried (MgSO4), filtrated, and the solvent was removed in
vacuo to give crude products. Purification by column chromatog-
raphy yielded products 5aee (hexane/ethyl acetated95/5;
Rfw0.15e0.2).
J¼3.0 Hz, CHO), 9.56 (1H, d, J¼2.0 Hz, CHO), 2.30 (1H, dsept, J¼2.1,
6.9 Hz, CH), 2.08e1.93 (2H, m, CH2), 1.72e1.58 (2H, m, CH2),
1.48e1.40 (1H, m, CH), 1.30e1.20 (1H, m, CH), 1.07 (3H, d, J¼7.1 Hz,
CH3), 0.93 (3H, d, J¼6.6 Hz, CH3), 0.91 (3H, d, J¼6.6 Hz, CH3); 13C
NMR (CDCl3, 75 MHz):
20.1, 19.6, 13.3.
d¼205.2, 204.6, 58.2, 46.3, 28.4, 28.2, 23.0,
4.4. General procedure for the synthesis of products rac-4aee
Trifluoroacetic acid (480 mg, 0.0042 mmol) was added to
a mixture of corresponding aldehyde 3aee (4.2 mmol), dry cyclo-
pentanol (4.2 mmol), and dry LiClO4 (2.65 g, 25 mmol). The reaction
mixture was stirred 2 h at rt and monitored by TLC. After com-
pletion the reaction mixture was quenched with saturated aqueous
solution of Na2CO3 (50 ml) and extracted with diethyl ether
(2ꢂ100 ml). The organic layer was dried (MgSO4), filtrated, and the
solvent was removed in vacuo to give the crude products.
4.5.1. (S)-1-Methoxy-2,2,4-trimethyl-pentan-3-ol (S-5a). Yield 52%,
76% ee. 1H NMR (CDCl3, 300 MHz):
d
¼3.27 (1H, d, J¼8.7 Hz, CH2),
3.27 (3H, s, OMe), 3.24 (1H, d, J¼2.3 Hz, CH), 3.09 (1H, d, J¼8.7 Hz,
CH2), 1.83 (1H, dsept, J¼2.3, 6.8 Hz, CH), 0.95 (3H, d, J¼6.9 Hz, CH3),
0.90 (3H, s, CH3), 0.87 (3H, s, CH3), 0.86 (3H, d, J¼6.4 Hz, CH3); 13
C
NMR (CDCl3, 75 MHz):
d
¼83.4, 82.4, 59.1, 38.9, 29.0, 23.4, 23.4, 20.7,

1142
A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
16.4. HRMS-ESI (m/z): calcd for C9H20O2þHþ: 161.1536, found:
4.5.9. (3R,4S,5S)-3-Methoxymethyl-3,5-dimethylheptan-4-ol
161.1534. ½a 2D5
ꢃ
(76% ee) ꢀ16.3 (c 1.0 g/100 ml, CH2Cl2).
(3R,4S,5S-5e). Yield 31%, 64% de, 68% ee. 1H NMR (CDCl3, 300 MHz):
d
¼3.39 (1H, d, J¼1.5 Hz, CH), 3.34 (1H, d, J¼8.9 Hz, CH2), 3.28 (3H, s,
4.5.2. (R)-1-Methoxy-2,2,4-trimethyl-pentan-3-ol
(R-5a). Yield
¼3.29 (1H, d, J¼8.8 Hz,
OMe), 3.16 (1H, d, J¼9.0 Hz, CH2), 1.59e1.31 (5H, m, CH, CH2),
48%, 81% ee. 1H NMR (CDCl3, 300 MHz):
d
0.92e0.84 (9H, m, CH3), 0.76 (3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
CH2), 3.28 (3H, s, OMe), 3.23 (1H, d, J¼2.3 Hz, CH), 3.07 (1H, d,
J¼8.7 Hz, CH2), 1.83 (1H, dsept, J¼2.3, 6.8 Hz, CH), 0.95 (3H, d,
J¼6.9 Hz, CH3), 0.90 (3H, s, CH3), 0.87 (3H, s, CH3), 0.85 (3H, d,
d
¼79.9, 79.3, 59.0, 41.1, 35.0, 30.2, 28.6, 18.3, 13.9, 12.0, 7.8. HRMS-
ESI (m/z): calcd for C11H24O2þHþ: 189.1849, found: 189.1849. ½a 2D5
ꢃ
(68% ee) ꢀ17.5 (c 1.0 g/100 ml, CH2Cl2).
J¼6.4 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
¼83.4, 82.3, 59.0, 38.8,
d
28.9, 23.4, 23.3, 20.6, 16.3. ½a D25
ꢃ
(81% ee) þ17.6 (c 1.0 g/100 ml,
4.5.10. (3S,4R,5R)-3-Methoxymethyl-3,5-dimethylheptan-4-ol
CH2Cl2).
(3S,4R,5R-5e). Yield 25%, 61% de, 68% ee. 1H NMR (CDCl3, 300 MHz):
d
¼3.40 (1H, d, J¼1.4 Hz, CH), 3.35 (1H, d, J¼9.0 Hz, CH2), 3.29 (3H, s,
4.5.3. (3R,4S)-3-Methoxymethyl-2,6-dimethylheptan-4-ol (3R,4S-
OMe), 3.17 (1H, d, J¼9.0 Hz, CH2), 1.60e1.16 (5H, m, CH, CH2),
5b). Yield 29%, de >99%, 95% ee. 1H NMR (CDCl3, 300 MHz):
0.93e0.84 (9H, m, CH3), 0.77 (3H, s, CH3); 13C NMR (CDCl3,
d
¼3.81 (1H, ddd, J¼4.3, 8.9, 13.6 Hz, CH), 3.61 (1H, dd, J¼3.1, 9.5 Hz,
75 MHz):
d
¼79.9, 79.3, 59.0, 40.9, 35.0, 30.2, 28.5, 18.3, 13.9, 12.0,
CH2), 3.55 (1H, dd, J¼4.9, 9.5 Hz, CH2), 3.30 (3H, s, OMe), 1.96 (1H,
dsept, J¼2.7, 7.1 Hz, CH), 1.85e1.72 (1H, m, CH), 1.50e1.40 (1H, m,
CH), 1.24e1.11 (2H, m, CH2), 0.97 (3H, d, J¼6.8 Hz, CH3), 0.91e0.87
7.8. ½a 2D5
ꢃ
(68% ee) þ17.9 (c 1.0 g/100 ml, CH2Cl2).
4.6. General procedure for the synthesis of methyl ethers
6aed
(9H, m, CH3); 13C NMR (CDCl3, 75 MHz):
d
¼71.9, 70.7, 59.0, 49.2,
45.7, 26.3, 24.6, 23.5, 22.0, 21.3, 19.6. HRMS-ESI (m/z): calcd for
C11H24O2þHþ: 189.1849, found: 189.1849 ½a 2D5
ꢃ
(92% ee) ꢀ13.2 (c
Trifluoroacetic acid (480 mg, 0.0042 mmol) was added to
a mixture of corresponding aldehydes 1aee (4.2 mmol/2.1 mmol
of each aldehyde), (þ)- or (ꢀ)-menthyl TMS-ether (12.6 mmol), dry
methanol (4.2 mmol), and dry LiClO4 (2.65 g, 25 mmol). The re-
action mixture was stirred 2 h at rt and monitored by TLC. After
completion the reaction mixture was quenched with saturated
aqueous solution of Na2CO3 (50 ml) and extracted with diethyl
ether (2ꢂ100 ml). The organic layer was dried (MgSO4), filtrated,
and the solvent was removed in vacuo to give crude products. Pu-
rification by column chromatography yielded products 6aed
(hexane/ethyl acetated95/5; Rfw0.15e0.2).
1.0 g/100 ml, CH2Cl2).
4.5.4. (3S,4R)-3-Methoxymethyl-2,6-dimethylheptan-4-ol
(3S,4R-
¼3.82
5b). Yield 31%, de >99%, 95% ee. 1H NMR (CDCl3, 300 MHz):
d
(1H, ddd, J¼4.3, 8.9 Hz, CH), 3.62 (1H, dd, J¼3.1, 9.5 Hz, CH2), 3.56
(1H, dd, J¼4.9, 9.5 Hz, CH2), 3.32 (3H, s, OMe), 1.99 (1H, dsept, J¼2.8,
7.0 Hz, CH), 1.88e1.75 (1H, m, CH), 1.53e1.41 (1H, m, CH), 1.27e1.15
(2H, m, CH2), 0.99 (3H, d, J¼6.7 Hz, CH3), 0.93 (3H, d, J¼6.8 Hz, CH3),
0.92 (3H, d, J¼6.7 Hz, CH3), 0.89 (3H, d, J¼6.7 Hz, CH3); 13C NMR
(CDCl3, 75 MHz):
d
¼71.9, 70.8, 59.0, 49.2, 45.7, 26.3, 24.6, 23.5, 22.0,
21.3, 19.6. ½a 2D5
ꢃ
(95% ee) þ15.0 (c 1.0 g/100 ml, CH2Cl2).
4.6.1. (4S,5R)-5-(Methoxymethyl)-2,5-dimethylheptan-4-ol (4S,5R-
4.5.5. (S)-Cyclohexyl-(1-methoxymethyl-cyclohexyl)-methanol (S-5c).
Yield 29%, 56% ee. 1H NMR (CDCl3, 300 MHz):
¼3.48 (1H, d, J¼9.2 Hz,
CH2), 3.34 (1H, d, J¼9.2 Hz, CH2), 3.27 (3H, s, OMe), 3.20 (1H, br s, CH),
1.71e1.19 (21H, m, CH, CH2); 13C NMR (CDCl3, 75 MHz):
6a). Yield 21%, 77% de, 72% ee. 1H NMR (CDCl3, 300 MHz):
d¼3.50
d
(1H, dd, J¼1.8, 10.6 Hz, CH), 3.36 (1H, d, J¼9.0 Hz, CH), 3.31 (3H, s,
OMe), 3.23 (1H, d, J¼9.0 Hz, CH), 1.93e1.83 (1H, m, CH), 1.52e1.14
(5H, m, CH, CH2), 0.94 (3H, d, J¼6.7 Hz, CH3), 0.88 (3H, d, J¼6.5 Hz,
CH3), 0.84 (3H, t, J¼7.5 Hz, CH3), 0.74 (3H, s, CH3); 13C NMR (CDCl3,
d¼82.9, 78.0,
59.1, 40.8, 38.5, 34.2, 31.6, 30.6, 27.4, 27.1, 26.6, 26.3, 26.2, 21.7, 21.2.
HRMS-ESI (m/z): calcd for C15H28O2þHþ: 241.2162, found: 241.2161.
75 MHz):
d¼79.6, 74.9, 59.2, 40.9, 40.4, 28.1, 24.6, 24.3, 21.4, 17.5, 7.7.
½
a 2D5
ꢃ
(56% ee) ꢀ10.1 (c 1.0 g/100 ml, CH2Cl2).
HRMS-ESI (m/z): calcd for C11H24O2þHþ: 189.1849, found:
189.1856. ½a 2D5
(72% ee) ꢀ16.5 (c 1.0 g/100 ml, CH2Cl2).
ꢃ
4.5.6. (R)-Cyclohexyl-(1-methoxymethyl-cyclohexyl)-methanol
(R-5c). Yield 31%, 52% ee. 1H NMR (CDCl3, 300 MHz):
d¼3.49 (1H, d,
4.6.2. (4R,5S)-5-(Methoxymethyl)-2,5-dimethylheptan-4-ol (4R,5S-
6a). Yield 19%, 78% de, 75% ee. 1H NMR (CDCl3, 300 MHz):
J¼9.2 Hz, CH2), 3.35 (1H, d, J¼9.2 Hz, CH2), 3.28 (3H, s, OMe), 3.19
d¼3.50
(1H, m, CH), 1.69e1.17 (21H, m, CH, CH2); 13C NMR (CDCl3, 75 MHz):
(1H, dd, J¼1.7, 10.6 Hz, CH), 3.36 (1H, d, J¼9.0 Hz, CH), 3.30 (3H, s,
CH3), 3.23 (1H, d, J¼9.0 Hz, CH), 1.92e1.83 (1H, m, CH), 1.53e1.23
(5H, m, CH, CH2), 0.95 (3H, d, J¼6.7 Hz, CH3), 0.88 (3H, d, J¼6.5 Hz,
CH3), 0.84 (3H, t, J¼7.5 Hz, CH3), 0.73 (3H, s, CH3); 13C NMR (CDCl3,
d
¼82.9, 78.0, 59.1, 40.7, 38.5, 34.2, 31.6, 30.6, 27.4, 27.2, 26.6, 26.3,
26.2, 21.7, 21.2. ½a D25
(52% ee) þ8.9 (c 1.0 g/100 ml, CH2Cl2).
ꢃ
4.5.7. (2R,3S)-2-Benzyl-1-methoxy-5-phenyl-pentan-3-ol
(2R,3S-
75 MHz):
d¼79.6, 74.8, 59.2, 40.8, 40.3, 28.1, 24.6, 24.3, 21.3, 17.4, 7.7.
5d). Yield 23%, 87% de, 92% ee. 1H NMR (CDCl3, 300 MHz):
½
a 2D5
ꢃ
(75% ee) þ16.9 (c 1.0 g/100 ml, CH2Cl2).
d
¼7.31e7.18 (10H, m, ph), 3.66 (1H, ddd, J¼4.2, 8.6 Hz, CH), 3.60
(1H, dd, J¼3.3, 9.4 Hz, CH2), 3.34 (1H, dd, J¼4.3, 9.4 Hz, CH2), 3.30
4.6.3. (3S)-1-Methoxy-2,2,5-trimethylhexan-3-ol (S-6b). Yield 30%,
95% ee. 1H NMR (CDCl3, 300 MHz):
(3H, s, OMe), 2.92e2.85 (2H, m, CH2), 2.78e2.69 (2H, m, CH2),
d¼3.47 (1H, dd, J¼1.9, 10.6 Hz,
1.92e1.81 (3H, m, CH, CH2); 13C NMR (CDCl3, 75 MHz):
d¼142.4,
CH), 3.33 (3H, s, CH3), 3.30 (1H, d, J¼8.7 Hz, CH2), 3.18 (1H, d,
J¼8.8 Hz, CH2), 1.90e1.80 (1H, m, CH), 1.36e1.27 (1H, m, CH2),
1.16e1.07 (1H, m, CH2), 0.93 (3H, d, J¼6.7 Hz, CH3), 0.88 (3H, d,
J¼6.5 Hz, CH3), 0.87 (3H, s, CH3), 0.86 (3H, s, CH3); 13C NMR (CDCl3,
140.4, 129.1, 128.4, 128.3, 128.2, 125.9, 125.7, 73.6, 72.9, 59.1, 45.1,
37.9, 35.4, 32.4. HRMS-ESI (m/z): calcd for C19H24O2þHþ: 285.1849,
found: 285.1850 ½a D25
(92% ee) ꢀ35.9 (c 1.0 g/100 ml, CH2Cl2).
ꢃ
75 MHz):
d
¼82.9, 76.4, 59.3, 40.9, 38.1, 24.5, 24.3, 22.8, 21.3, 19.4.
4.5.8. (2S,3R)-2-Benzyl-1-methoxy-5-phenyl-pentan-3-ol
(2S,3R-
HRMS-ESI (m/z): calcd for C10H22O2þHþ: 175.1693, found:
5d). Yield 25%, 87% de, 93% ee. 1H NMR (CDCl3, 300 MHz):
175.1696. ½a 2D5
(95% ee) ꢀ9.0 (c 1.0 g/100 ml, CH2Cl2).
ꢃ
d
¼7.35e7.20 (10H, m, Ph), 3.67 (1H, ddd, J¼4.1, 8.6 Hz, CH), 3.63
(1H, dd, J¼3.3, 9.4 Hz, CH2), 3.36 (1H, dd, J¼4.3, 9.4 Hz, CH2), 3.32
4.6.4. (3R)-1-Methoxy-2,2,5-trimethylhexan-3-ol (R-6b). Yield 31%,
94% ee. 1H NMR (CDCl3, 300 MHz):
CH), 3.34 (1H, d, J¼8.7 Hz, CH2), 3.34 (3H, s, CH3), 3.18 (1H, d,
J¼8.8 Hz, CH2), 1.90e1.79 (1H, m, CH), 1.33e1.20 (1H, m, CH2),
1.19e1.13 (1H, m, CH2), 0.91 (3H, d, J¼6.7 Hz, CH3), 0.86 (3H, d,
(3H, s, OMe), 2.99e2.66 (2H, m, CH2), 2.79e2.71 (2H, m, CH2),
d
¼3.48 (1H, dd, J¼1.8, 10.5 Hz,
1.96e1.80 (3H, m, CH2); 13C NMR (CDCl3, 75 MHz):
d¼142.3, 140.3,
129.1, 128.4, 128.3, 128.2, 125.9, 125.6, 73.5, 72.8, 59.0, 45.0, 37.9,
35.4, 32.4. ½a 2D5
(93% ee) þ36.2 (c 1.0 g/100 ml, CH2Cl2).
ꢃ

A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
1143
J¼6.5 Hz, CH3), 0.85 (3H, s, CH3), 0.84 (3H, s, CH3); 13C NMR (CDCl3,
C
10H22O2þHþ: 175.1693, found: 175.1689. ½a D
ꢃ
25 (93% ee) ꢀ5.7 (c 1.0 g/
75 MHz):
a 2D5
d
¼82.4, 75.9, 59.0, 40.6, 37.9, 24.2, 24.0, 22.5, 21.1, 19.3.
100 ml, CH2Cl2).
½
ꢃ
(94% ee) þ8.8 (c 1.0 g/100 ml, CH2Cl2).
4.7.3. (S)-Cyclohexyl-1-(hydroxymethyl-cyclohexyl)-methanol
(S-7c)38. Yield 47%, 49% ee. 1H NMR (CDCl3, 300 MHz):
4.6.5. (3S,4R)-1-(Methoxymethyl)-2,4-dimethylhexan-3-ol (3S,4R-
d¼3.84 (1H,
6c). Yield 43%, de >99%, 88% ee. 1H NMR (CDCl3, 300 MHz):
d
¼3.37
d, J¼11.0 Hz, CH2), 3.62 (1H, d, J¼10.3 Hz, CH2), 3.32 (1H, br s, CH),
(1H, d, J¼1.4 Hz, CH), 3.30 (1H, d, J¼8.7 Hz, CH), 3.30 (3H, s, OMe),
3.13 (1H, d, J¼8.7 Hz, CH), 1.59e1.51 (1H, m, CH), 1.45e1.13 (2H, m,
2.82 (2H, s, OH), 1.78e1.16 (21H, m, CH, CH2); 13C NMR (CDCl3,
75 MHz):
d¼84.3, 67.3, 40.9, 38.4, 34.2, 31.0, 29.7, 27.5, 27.0, 26.4,
CH2), 0.94 (3H, s, CH3), 0.89 (3H, s, CH3), 0.90e0.85 (6H, m, CH3); 13
C
26.3, 26.2, 21.6, 21.2. HRMS-ESI (m/z): calcd for C14H26O2þHþ:
NMR (CDCl3, 75 MHz):
d
¼83.4, 80.7, 59.1, 38.9, 35.5, 29.9, 23.5, 21.0,
227.2006, found: 227.2003. ½a D25
(49% ee) ꢀ13.2 (c 1.0 g/100 ml,
ꢃ
13.8, 12.0. HRMS-ESI (m/z): calcd for C10H22O2þHþ: 175.1693,
CH2Cl2).
found: 175.1697. ½a D25
(88% ee) ꢀ1.2 (c 1.0 g/100 ml, CH2Cl2).
ꢃ
4.7.4. (2R,3S)-2-Benzyl-5-phenyl-pentan-1,3-diol (2R,3S-7d)39. Yield
52%, 92% ee. 1H NMR (CDCl3, 300 MHz):
3.96 (1H, dd, J¼2.8, 10.9 Hz, CH2), 3.78 (1H, ddd, J¼4.3, 8.9 Hz, CH),
3.63 (1H, dd, J¼4.4,10.9 Hz, CH2), 2.90e2.67 (4H, m, CH2), 2.60 (2H, s,
OH), 2.05e1.90 (2H, m, CH2),1.86e1.78 (1H, m, CH); 13C NMR (CDCl3,
4.6.6. (3R,4S)-1-(Methoxymethyl)-2,4-dimethylhexan-3-ol (3R,4S-
6c). Yield 38%, de >99%, 88% ee. 1H NMR (CDCl3, 300 MHz):
d¼7.34e7.20 (10H, m, ph),
d¼3.35
(1H, d, J¼1.5 Hz, CH), 3.30 (1H, d, J¼8.7 Hz, CH2), 3.28 (3H, s, OMe),
3.12 (1H, d, J¼8.7 Hz, CH2), 1.59e1.49 (1H, m, CH2),1.43e1.11 (2H, m,
CH2), 0.92 (3H, s, CH3), 0.90e0.86 (6H, m, CH3), 0.87 (3H, s, CH3); 13
C
75 MHz):
d¼141.9, 140.2, 129.1, 128.4, 128.4, 128.4, 126.1, 125.9, 74.4,
NMR (CDCl3, 75 MHz):
d
¼83.3, 80.6, 59.1, 38.8, 35.4, 29.8, 23.4, 20.9,
62.9, 46.1, 37.6, 35.1, 32.3. HRMS-ESI (m/z): calcd for C18H22O2þHþ:
13.7, 11.9. ½a 2D5
ꢃ
(88% ee) þ1.0 (c 1.0 g/100 ml, CH2Cl2).
271.1693, found: 271.1693. ½a D
ꢃ
25 (92% ee) ꢀ4.7 (c 1.0 g/100 ml, CH2Cl2).
4.6.7. (1S)-1-Cyclohexyl-3-methoxy-2,2-dimethylpropan-1-ol
6d). Yield 55%, 33% ee. 1H NMR (CDCl3, 300 MHz):
(S-
4.7.5. (2R,3S,4R)-2-Ethyl-2,4-dimethylhexan-1,3-diol (2R,3S,4R-7e)40
Yield 53%, 79% ee. 1H NMR (CDCl3, 300 MHz):
.
d
¼3.29 (1H, d,
d
¼3.68 (1H, d,
J¼8.6 Hz, CH2), 3.29 (3H, s, CH3), 3.19 (1H, d, J¼1.8 Hz, CH), 3.11 (1H,
d, J¼8.7 Hz, CH2),1.90e1.09 (11H, m, CH, CH2), 0.93 (3H, s, CH3), 0.90
J¼10.8 Hz, CH2), 3.53 (1H, br s, CH), 3.48 (1H, d, J¼10.9 Hz, CH2), 2.68
(2H, s, OH), 1.70e1.62 (1H, m, CH), 1.53e1.45 (2H, m, CH2), 1.40e1.28
(2H, m, CH2), 0.96 (3H, d, J¼6.7 Hz, CH3), 0.91e0.87 (6H, m, CH3), 0.79
(3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
d
¼83.4, 82.7, 59.1, 39.5, 33.4,
27.0, 26.9, 26.4, 26.3, 23.4, 20.7, 16.4. HRMS-ESI (m/z): calcd for
(3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
d
¼80.2, 69.8, 41.3, 35.0, 30.1,
C12H24O2þHþ: 201.1849, found: 201.1850. ½a 2D5
ꢃ
(33% ee) ꢀ3.6 (c
28.1, 17.5, 13.9, 12.0, 7.7. HRMS: ESI (m/z): calcd for C10H22O2þHþ:
1.0 g/100 ml, CH2Cl2).
175.1693, found: 175.1690. ½a D25
(79% ee) ꢀ12.3 (c 1.0 g/100 ml,
ꢃ
CH2Cl2).
4.6.8. (1R)-1-Cyclohexyl-3-methoxy-2,2-dimethylpropan-1-ol
(R-
¼3.29 (3H, s,
6d). Yield 53%, 31% ee. 1H NMR (CDCl3, 300 MHz):
d
Acknowledgements
CH3), 3.28 (1H, d, J¼8.7 Hz, CH2), 3.20 (1H, d, J¼1.9 Hz, CH), 3.11 (1H,
d, J¼8.8 Hz, CH2), 1.90e1.10 (11H, m, CH, CH2), 0.91 (3H, s, CH3), 0.88
The authors thank Deutsche Forschungsgemeinschaft, Bayer-
Schering Pharma AG, Bayer Services GmbH, BASF AG and Sasol
GmbH for financial support.
(3H, s, CH3); 13C NMR (CDCl3, 75 MHz):
d
¼83.4, 82.7, 82.4, 59.1, 39.4,
33.4, 27.0, 26.4, 26.2, 23.4, 20.7, 16.3. ½a D25
(31% ee) þ3.1 (c 1.0 g/
ꢃ
100 ml, CH2Cl2).
Supplementary data
4.7. General procedure for the synthesis of diols 7aee
Results of optimization work is provided. Spectral data of
cyclohexyl and deuterated cyclohexyl ethers are provided. Proofs of
relative configuration and determination of absolute configuration
are given.1H NMR data for Mosher-esters of both series, R- as well as
S-configured 5aee and 6aed and for diols 7aee are described. 1H
and 13C NMR spectra are given for compounds 2aec, dialdehydes
3aee, cyclopentyl ethers 4aee, methyl ethers 5aee, 6aed and diols
7aee. These supplementary data can be found in the online version
at doi:10.1016/j.tet.2011.11.069.
Me3SiI (0.6 mmol) and dry NaI (0.005 mmol) were added to
a solution of 1,3-diol methyl ether 5aee (0.5 mmol) in CCl4. The
reaction mixture was stirred overnight at rt and monitored by TLC.
After completion the reaction mixture was quenched with saturated
aqueous solution of Na2CO3 (50 ml) and extracted with diethyl ether
(2ꢂ100 ml). The organic layer was dried (MgSO4), filtrated, and the
solvent was removed in vacuo to give crude products. Purification by
column chromatography yielded the 1,3-diols 7aee.
4.7.1. (3S)-2,2,4-Trimethyl-pentan-1,3-diol (S-7a)36. Yield 70%, 75%
References and notes
ee. 1H NMR (CDCl3, 300 MHz):
d
¼3.53 (1H, d, J¼10.6 Hz, CH2), 3.39
(1H, d, J¼10.6 Hz, CH2), 3.36 (1H, d, J¼2.4 Hz, CH), 3.29 (2H, s, OH),
1.90 (1H, dsept, J¼2.4, 6.8 Hz, CH), 0.97 (3H, d, J¼6.9 Hz, CH3), 0.92
(3H, d, J¼6.7 Hz, CH3), 0.91 (3H, s, CH3), 0.90 (3H, s, CH3); 13C NMR
1. (a) Ishihara, K.; Hanaki, N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 10695; (b)
Yin, J.; Huffman, M. A.; Conrad, K. M.; Armstrong, J. D., III. J. Org. Chem. 2006, 71,
840; (c) Dilger, A. K.; Gopalsamuthiram, V.; Burke, S. D. J. Am. Chem. Soc. 2007,
129, 16273.
(CDCl3, 75 MHz):
d
¼83.1, 73.3, 39.0, 29.1, 23.2, 19.6, 16.6. HRMS-ESI
2. (a) Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem. Soc. 1996, 118, 13103;
(b) Shiraki, H.; Nishide, K.; Node, M. Tetrahedron Lett. 2000, 41, 3437; (c)
Nishide, K.; Ozeki, M.; Kunishige, H.; Shigeta, Y.; Patra, P. K.; Hagimoto, Y.; Node,
M. Angew. Chem., Int. Ed. 2003, 42, 4515; (d) Ozeki, M.; Nishide, K.; Teraoka, F.;
Node, M. Tetrahedron: Asymmetry 2004, 15, 895; (e) Ozeki, M.; Hashimoto, D.;
Nishide, K.; Kajimoto, T.; Node, M. Tetrahedron: Asymmetry 2005, 16, 1663.
3. For reviews, see (a) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J.
Synthesis 1994, 1007; (b) Nishide, K.; Node, M. Chirality 2002, 14, 759; (c)
Graves, C. R.; Campbell, E. J.; Nguyen, S. B. T. Tetrahedron: Asymmetry 2005, 16,
3460; (d) Cha, J. S. Org. Process Res. Dev. 2006, 10, 1032; (e) Chuah, G. K.; Jae-
nicke, S.; Zhu, Y. Z.; Liu, S. H. Curr. Org. Chem. 2006, 10, 1639; (f) Zaidlewicz, M.;
Pakulski, M. M. Sci. Synth., Stereosel. Synth. 2011, 2, 59.
(m/z): calcd for C8H18O2þHþ: 147.1380, found: 147.1380. ½a 2D5
ꢃ
(75%
ee) ꢀ9.5 (c 1.0 g/100 ml, CH2Cl2).
4.7.2. (2R,3S)-2-Isopropyl-5-methylhexan-1,3-diol (2R,3S-7b)37. Yield
49%, 93% ee. 1H NMR (CDCl3, 300 MHz):
d¼3.96e3.89 (2H, br s, CH
and 1ꢂ CH2), 3.79 (1H, dd, J¼5.2, 10.9 Hz, CH2), 3.26 (2H, s, OH), 1.95
(1H, sept, J¼6.8 Hz, CH),1.81e1.68 (1H, m, CH),1.52 (1H, dd, J¼5.1, 9.1,
13.9 Hz, CH2),1.30 (1H, ddd, J¼3.9, 8.9,12.9 Hz, CH2),1.10 (1H, m, CH),
0.99 (1H, d, J¼6.7 Hz, CH3), 0.92 (3H, d, J¼6.0 Hz, CH3), 0.90 (6H, d,
4. Sm: (a) Evans, D. A.; Nelson, S. G.; Gagne, M. R.; Muci, A. R. J. Am. Chem. Soc.
1993, 115, 9800; (b) Ding, Z.-B.; Cheng, K.-J.; Wu, S.-H. Chin. J. Chem. 1996, 14,
561; (c) Ohno, K.; Kataoka, Y.; Mashima, K. Org. Lett. 2004, 6, 4695; (d) Zeror, S.;
J¼6.5 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
¼71.9, 61.5, 50.3, 45.5,
d
25.9, 24.5, 23.5, 21.9, 21.3, 19.3. HRMS-ESI (m/z): calcd for

1144
A. Seifert et al. / Tetrahedron 68 (2012) 1137e1144
Collin, J.; Zouioueche, L. A. Inorg. Chim. Acta 2009, 362, 2402 Al: (e) Campbell, E.
M.; Stodulski, A.; Suszcynska, A.; Frelek, J. Chem.dEur. J. 2006, 2, 8158; (h)
Stodulski, M.; Jazwinski, J.; Mlynarski, J. Eur. J. Org. Chem. 2008, 5553; (i)
Stodulski, M.; Maminska, A.; Mlynarski, J. Tetrahedron: Asymmetry 2011, 22,
464 Chiral lanthan complexes: (j) Gnanadesikan, V.; Horiuchi, Y.; Oshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7782; (k) Horiuchi, Y.; Gnanade-
sikan, V.; Ohshima, T.; Masu, H.; Katagiri, K.; Sei, Y.; Yamaguchi, K.; Shibasaki,
M. Chem.dEur. J. 2005, 11, 5195 Zirconium complexes: (m) Schneider, C.;
Hansch, M. Synlett 2003, 837; (n) Schneider, C.; Hansch, M.; Sreekumar, P.
Tetrahedron: Asymmetry 2006, 17, 2738 Chiral titanium complexes: see Refs.
11l and 15.
J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. 2002, 41, 1020; (f) Ooi, T.; Miura,
T.; Maruoka, K. Angew. Chem., Int. Ed. 1998, 37, 2347; (g) For asymmetric re-
duction of imines see: Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett. 2006,
8, 1229; (h) Graves, C. R.; Zhou, H.; Stern, C. L.; Nguyen, S. T. J. Org. Chem. 2007,
72, 9121; (i) Onar, H. C.; Hasdemir, B.; Yusufoglu, A. J. Serb. Chem. Soc. 2007, 72,
421; (k) Campbell, E. J.; Zhou, H.; Nguyen, S. T. Org. Lett. 2001, 3, 2391 Zr: (l)
Krohn, K.; Knauer, B. Recl. Trav. Chim. Pays-Bas 1996, 115, 140 Er: (m) Xianming,
H.; Kellogg, R. M. Recl. Trav. Chim. Pays-Bas 1996, 115, 410 Ln: (n) Huskens, J.; de
Graauw, C. F.; Peters, J. A.; van Bekkum, H. Recl. Trav. Chim. Pays-Bas 1994, 113,
488 Ru: (o) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
5. For current reviews see (a) Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N.
Acc. Chem. Res. 2007, 40, 1412; (b) Matsuda, T.; Yamanaka, R.; Nakamura, K.
Tetrahedron: Asymmetry 2009, 20, 513; (c) De Wildeman, S. M. A.; Sonke, T.;
Schoemaker, H. E.; May, O. Acc. Chem. Res. 2007, 40, 1260.
6. Mahrwald, R.; Schick, H. Synthesis 1990, 592.
7. (a) Geszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827; (b) Xin, L.; Satterfield, A.
15. Rohr, K.; Herre, R.; Mahrwald, R. J. Org. Chem. 2009, 74, 3744.
16. Seifert, A.; Scheffler, U.; Markert, M.; Mahrwald, R. Org. Lett. 2010, 12, 1660.
17. (a) Markert, M.; Mahrwald, R. Synthesis 2004, 1429; (b) Arnold, A.; Markert, M.;
Mahrwald, R. Synthesis 2006, 1099.
18. For rate enhancement of the MeerweinePonndorfeVerly reaction in the
presence of protonic acids see Kow, R.; Nygren, R.; Rathke, M. W. J. Org. Chem.
1977, 42, 826.
D.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128, 9302.
19. For similar experiments but without any stereoselection see Kamitanaka, T.;
8. (a) Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.; Maruoka, K. Org. Biomol. Chem.
2004, 2, 3312; (b) Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.; Maruoka, K. Tet-
rahedron 2001, 57, 867; (c) Ooi, T.; Takaya, K.; Miura, T.; Maruoka, K. Synlett
2000, 69; (d) Ooi, T.; Miura, T.; Maruoka, K. J. Am. Chem. Soc. 1998, 120, 10790.
9. (a) Watanabe, A.; Matsumoto, K.; Shimada, Y.; Katsuki, T. Tetrahedron Lett. 2004,
45, 6229; (b) Ooi, T.; Takaya, K.; Miura, T.; Ichikawa, H.; Maruoka, K. Synlett
2000, 1133; (c) Mori, A.; Kinoshita, K.; Osaka, M.; Inoue, S. Chem. Lett. 1990,
1171; (d) Mori, A.; Osaka, M.; Inoue, S. Chem. Lett. 1993, 375.
Matsuda, T.; Harada, T. Tetrahedron 2007, 63, 1429.
20. See Supplementary data.
21. Kamitanaka, T.; Ono, Y.; Morishima, H.; Hikida, T.; Matsuda, T.; Harada, T. J.
Supercrit. Fluids 2009, 49, 221.
22. A similar differentiated deployment of methanol and secondary alcohols in
intermolecular hydroalkoxylation of vinylphenols without any selectivity is
described by Zhang, Y.; Sigman, M. S. Org. Lett. 2006, 8, 5557.
23. Several other lithium salts were tested but without any success. For the use of
LiBr in MPV-reduction processes see also Mojtahedi, M. M.; Akbarzadeh, E.;
Sharifi, R.; Abaee, M. S. Org. Lett. 2007, 9, 2791.
10. Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S.-i. J. Am. Chem. Soc. 2000, 122,
1310.
11. (a) Simpura, I.; Nevalainen, V. Tetrahedron Lett. 2001, 42, 3905; (b) Simpura, I.;
Nevalainen, V. Tetrahedron 2003, 59, 7435; (c) Xi, B.; Nevalainen, V. Tetrahedron
Lett. 2006, 47, 2561; (d) Xi, B.; Nevalainen, V. Tetrahedron Lett. 2006, 47, 7133; (e)
Chandrasekhar, S.; Narsihmulu, C.; Reddy, N. R.; Sultana, S. S. Chem. Commun.
2004, 2450; (f) Schneider, C.; Weide, T. Chem.dEur. J. 2005, 11, 3010; (g)
Schneider, C.; Klapa, K.; Hansch, M. Synlett 2005, 91; (h) Schneider, C.; Hansch,
M. Chem. Commun. 2001, 1218; (i) Rohr, K.; Herre, R.; Mahrwald, R. Org. Lett.
2005, 7, 4499.
12. With the exception of a recent report: metal-free medium by deployment of
Brønsted acids: Matsuo, J.-i.; Hattori, Y.; Ishibashi, H. Org. Lett. 2010, 12, 2294.
13. Warnhoff, E. W.; Reynolds-Warnhoff, P.; Wong, M. Y. H. J. Am. Chem. Soc. 1980,
102, 5956.
24. These observations are consistent with results obtained in Michael additions by
Saidi, M. R.; Azizi, N.; Akbari, E.; Ebrahimi, F. J. Mol. Catal. A: Chem. 2008, 292,
44.
25. The trioxanes of the corresponding aldehydes were synthesized by a procedure
of Auge, J.; Gil, R. Tetrahedron Lett. 2002, 43, 7919.
26. (a) Youssefyeh, R. D.; Mazur, Y. Tetrahedron Lett. 1962, 1287; (b) Narayanan, C.
R.; Iyer, K. N. Tetrahedron Lett. 1964, 759.
27. Ohno, K.; Nishiyama, H.; Nagase, H. Tetrahedron Lett. 1979, 4405.
28. Demuynck, M.; De Clercq, P.; Vandevalle, M. J. Org. Chem. 1979, 42, 131.
29. Jung, M. E.; Lyster, M. A. Org. Synth. 1979, 59, 35.
30. Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. Angew. Chem., Int. Ed. Engl.
1981, 20, 690.
14. Chiral lithium BINOLates: (a) Loog, O.; Maeorg, U. Tetrahedron: Asymmetry
1999, 10, 2411; (b) Ichibakase, T.; Nakajima, M. Org. Lett. 2011, 13, 1579 Chiral
ytterbium complexes: (c) Morken et al. described an asymmetric aldol Tish-
chenko reaction catalyzed by chiral yttrium-salen complexes: Mascarenhas,
C. M.; Miller, S. P.; White, P. S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40,
601 During these investigations the authors used isobutyraldehyde as the
ene-component and aromatic aldehydes as carbonyl compounds; (d) Mly-
narski, J.; Mitura, M. Tetrahedron Lett. 2004, 45, 7549; (e) Mlynarski, J.; Jan-
kowska, J.; Rakiel, B. Tetrahedron: Asymmetry 2005, 16, 1521; (f) Mlynarski, J.;
Jankowska, J.; Rakiel, B. Chem. Commun. 2005, 4854; (g) Mlynarsyki, J.; Rakiel,
31. Lopez, S.; Fernandez-Trillo, F.; Castedo, L.; Saa, C. Org. Lett. 2003, 5, 3725.
32. Hong, B.-C.; Tseng, H.-C.; Chen, S.-H. Tetrahedron 2007, 63, 2840.
33. Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110, 4735.
34. Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010, 12, 1552.
35. Huckel, W.; Kummerle, K. J. Prakt. Chem. 1942, 160, 74.
36. Villacorta, G.; San Filippo, J., Jr. J. Org. Chem. 1983, 48, 1151.
37. Kulpinski, M. S.; Nord, F. F. J. Org. Chem. 1943, 8, 256.
38. Marschall, H.; Muehlenkamp, W. B. Chem. Ber. 1976, 109, 2785.
39. Tong, S.-T.; Brimble, M. A.; Barker, D. Tetrahedron 2009, 65, 4801.
40. Neustadter, V. Monatsh. Chem. 1906, 27, 879.