Consecutive proline-catalyzed aldol reactions and metal-mediated allylations: Rapid entries to polypropionates

Article abstract of DOI:10.1055/s-2005-864791

A concise method for the rapid construction of polypropionate-type structures by consecutive organocatalytic aldol and metal-mediated allylation reactions is described.

Full text of DOI:10.1055/s-2005-864791

LETTER
751
Consecutive Proline-Catalyzed Aldol Reactions and Metal-Mediated
Allylations: Rapid Entries to Polypropionates
Rapid
Entries
a
to
P
olyprop
r
ionate
s
a Källström,a,1 Anniina Erkkilä,b,1 Petri M. Pihko,*b Rainer Sjöholm,a Reijo Sillanpää,c,2 Reko Leino*a
a
Department of Organic Chemistry, Åbo Akademi University, 20500 Åbo, Finland
Fax +358(2)2154866; E-mail: reko.leino@abo.fi
b
Laboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology,
P. O. Box 6100, 02150 TKK, Finland
Fax +358(9)4512538; E-mail: petri.pihko@tkk.fi
c
Department of Chemistry, University of Jyväskylä, 40351 Jyväskylä, Finland
Received 21 December 2004
aqueous media,15 into a one-pot reaction sequence. Since
the first aldol step is highly enantio- and diastereoselec-
tive, this protocol should be a particularly facile method
for rapid access to polypropionates.
Abstract: A concise method for the rapid construction of polypro-
pionate-type structures by consecutive organocatalytic aldol and
metal-mediated allylation reactions is described.
Key words: aldol reactions, allylations, asymmetric synthesis,
indium, organocatalysis
The one-pot allylation of the propionaldehyde aldol
product 1a,b with indium metal in aqueous conditions
provided a diastereomeric mixture of diol products 4 in
good yield (Table 2, entries 1–3).16 The complete lack of
selectivity in the allylation reaction was quite surprising,
given the precedent set by Paquette and co-workers in
which a-unsubstituted b-hydroxyaldehydes afforded
allylation products with up to 8.5:1 anti:syn selectivity.17
Under the same conditions, the crotylation procedure
afforded a 39:44:17 ratio of diol diastereomers (Table 3,
entry 1). Simple acetonide protection (see below) revealed
that the two major diastereomers possessed an anti,anti
stereochemistry, indicating that the crotylation had pro-
ceeded mainly in an anti-Felkin (and anti-Paquette!) man-
ner. It was therefore not surprising that by using an even
more bulky prenylating reagent under the same condi-
tions, we obtained only the anti-Felkin product, the
anti,anti-diol diastereomer, derived from the anti-aldol
product (Table 4, entries 1 and 2). Unfortunately, this was
achieved in a rather low yield (13%). In addition, the
product was contaminated by the minor anti,syn-dia-
stereomer derived from the initial aldol reaction.18
The controlled construction of open-chain systems bear-
ing consecutive stereocenters is one of the most enduring
challenges for modern asymmetric synthesis.3 Natural and
unnatural targets of medicinal and biological interest of-
ten contain structural motifs of this type. Stereochemical-
ly defined polypropionates are important building blocks
of polyketides such as erythromycin,4 discodermolide5
and other marine metabolites,6 compounds possessing
impressive antibiotic, anticancer and immunosuppressive
bioactivities.
In recent years, asymmetric organocatalysis has emerged
as an impressive tool for stereoselective chemical synthe-
sis.7 For example, the proline-catalyzed intermolecular di-
rect asymmetric aldol reaction, initially developed in the
laboratories of List8 and Barbas9 and further expanded by
the work of MacMillan,10 Jørgensen11 and others,12 allows
the efficient construction of several biologically impor-
tant targets in high enantiomeric excess using metal-free
catalysis under environmentally benign conditions. How-
ever, the resultant aldol products are often very labile, and
this makes the utilization of these building blocks prob-
lematic. This is especially true when the aldol reaction in-
volves the union of two aldehydes, since the product is a
highly unstable aldehyde aldol.13 Thus, their efficient fur-
ther derivatization to more stable products would be high-
ly desirable.14 In an optimal case, such transformations
Table 1 Optimization of the Reaction Conditions of Propionalde-
hyde Dimerization
O
O
OH
O
OH
O
catalyst
solvent
H
H
H
H
1a
1b
2
could be carried out as a one-pot operation with preserva- Entry Catalyst Solvent Time
tion and utilization of the aldol stereochemistry.
Yield
(1:2)
1a (ee, %):
1b (ee, %)
(h)
Here we describe our initial efforts in combining two
well-known C–C bond-forming methods, namely the
enantioselective MacMillan aldehyde-aldehyde aldol
addition10 and a Barbier-type metal-mediated allylation in
1
2
3
Pro
DMF
10
75
24
80a
(98:2)
4 (99):1 (36)
5 (>99):1 (87)
7 (>99):1 (95)
Hyp
Hyp
DMF
85b
(97:3)
DMSO
82b
(96:4)
SYNLETT 2005, No. 5, pp 0751–0756
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-864791; Art ID: G47404ST
© Georg Thieme Verlag Stuttgart · New York
a Yield (%), as reported in ref.10a
b Conversion (%), determined by 1H NMR.

752
S. Källström et al.
LETTER
Table 2 The Aldol–Allylation Sequence
anti:anti:
syn:anti:
OH OH
mainly anti
OH
R
O
O
O
Br
4a, R = H
5a, R = Me
catalyst
R
H
H
H
DMF or DMSO
In, additive
H2O
R
acceptor
donor
1, R = H
3, R = Me
OH OH
R
4b, R = H
5b, R = Me
Entry
R
Catalyst
Pro
Additive
Yielda
Ratio (a:b:c:d)b
1
2
3
4
5
H
–
72
64
82
52
54
35:35:13:12
35:45:10:10
37:47:8:8
37:56:4:4
H
Hyp
Hyp
Pro
–
H
NaI
–
Me
Me
Pro
NaI
23:67:4:6
a Yields (%) represent the combined yield of diastereomers.
b a: Anti,anti; b: syn,anti; c: anti,syn, d: syn,syn. The product ratios were determined by 1H NMR analysis of the crude reaction products.
The original MacMillan procedure for the proline-cata- M). By this method, the propionaldehyde dimer 1 was ob-
lyzed dimerization of propionaldehyde in DMF affords 1 tained in 7:1 anti:syn selectivity and >99% ee (entry 3).19
as a 4:1 anti:syn mixture (Table 1, entry 1), thus compli-
cating product purification and analysis after subsequent
transformations. By changing the catalyst to 4-trans-hy-
When we applied these new, optimized reaction condi-
tions to the aldol–allylation reaction cascade we observed
the desired improvement in selectivities (Table 2, entry
4). However, the yield remained the same. Inspired by the
seminal report of Butsugan and co-workers on the indium-
mediated allylations where allyl iodides were used as the
droxy-L-proline (Hyp) we were able to increase the dia-
stereomeric selectivity to 5:1 anti:syn (entry 2).19 Further
improvement in the anti-selectivity was obtained by per-
forming the reaction in DMSO at high concentration (10
allyl source,20 we explored the use of NaI as an additive to
Table 3 The Aldol–Crotylation Sequence
anti:anti:anti:
OH OH
mainly anti
R
O
O
OH
O
Br
catalyst
6a, R = H
R
H
H
H
7a, R = Me
DMF or DMSO
In, additive
H2O
R
syn:anti:anti:
acceptor
donor
1, R = H
OH OH
3, R = Me
R
6b, R = H
7b, R = Me
Entry
R
Catalyst
Pro
Additive
Yielda
20
Ratio (a:b:Sc)b
39:44:17
1
2
3
4
H
–
H
Hyp
Pro
NaI
–
54
34:54:12
Me
Me
33
36:48:16
Pro
NaI
31
37:50:13
a Yields (%) represent the combined yield of diastereomers.
b a: Anti,anti,anti; b: syn,anti,anti; Sc: anti/syn,syn,anti/syn (the stereochemistry of the minor products was not determined). The product ratios
were determined by 1H NMR analysis of the crude reaction products.
Synlett 2005, No. 5, 751–756 © Thieme Stuttgart · New York

LETTER
Rapid Entries to Polypropionates
753
Table 4 The Aldol–Prenylation Sequence
mainly anti
OH
highly anti selective
Br
O
OH OH
O
O
catalyst
R
H
H
H
DMF or DMSO
In, additive
H2O
R
R
acceptor
donor
1, R = H
8, R = H
3, R = Me
9, R = Me
Entry
R
H
Catalyst
Hyp
Additive
Yielda
13
Ratio (a:b:Sc)b
75:<2:25
1
2
3
4
–
H
Hyp
Pro
NaI
–
42c
21c
50
85:<2:15
Me
Me
>95:<3:<3
>95:<3:<3
Pro
NaI
a Yields (%) represent the combined yield of diastereomers.
b a: Anti,anti; b: syn,anti; Sc: anti/syn,syn. The product ratios were determined by 1H NMR analysis of the crude reaction products.
c Yields of the pure 8a and 9a (anti,anti) isomers, respectively.
HC
improve the reaction rate in the allylation step (entries 3
HA
R
HB
O
O
O
5
O
3
HC
O
and 5). These modified conditions afforded a clear im-
provement in overall yields, especially in the case of steri-
cally more encumbered crotyl (Table 3, entries 2 and 4)
and prenyl reagents (Table 4, entries 2 and 4).21,22
R
Me
Me
O
HA
HB
100.3 ppm
97.6 ppm
10b
10a/10b
10a
anti:anti
syn:anti
In addition to the propionaldehyde dimerization products,
the crossed-aldol product 3 (>99% ee, 25:1 anti:syn)19 de-
rived from isobutyraldehyde as the acceptor and propi-
onaldehyde as the aldol donor were subjected to the one-
pot aldol-allylation procedure (Table 2, entries 4 and 5,
Table 3 and Table 4, entries 3, 4).23,24 Unfortunately, in
the crossed-aldol reaction the use of Hyp catalyst was not
practical due to the slow reaction rate. Therefore the aldol
step of the sequence was performed using our slightly
modified variant of the MacMillan conditions.14
HA
HC
O
5
O
R
O
O
Me
Me
6
3
97.7 ppm
HB
anti:anti
11a/11b
HA
HC
O
OH
O
5
O
R
O
6
98.2 ppm
97.8 ppm
3
HB
OH
anti:anti
The stereochemistries of the diol products could be readi-
ly ascertained by NMR analysis of the acetonide deriva-
tives. In the case of the acetonides derived from the
allylation product 4, there were two major components
(10a and 10b, Figure 1) with 13C NMR chemical shifts of
d = 100.3 and 97.6 ppm indicating anti- and syn-stereo-
chemistry between diol hydroxyl groups, respectively.25
Since the first aldol step was anti-selective, we can con-
clude that the two major diastereomers obtained have the
syn,anti- and anti,anti-stereochemistry. For 5, the product
of the crossed-aldol–allylation sequence, the major
syn,anti-isomer 5b could also be readily identified by cor-
relation with literature data.26
12a/12b
HA
J
AB = 9.7 Hz
HC
O
O
JBC = 10.2 Hz
R
O
O
Me
97.3 ppm
HB
anti:anti
13
Figure 1 Assignment of the stereochemistry of the products with
the acetonide derivatives
ences between the acetonide methyl groups were in the
range of 10 ppm with both products. Taken together, these
data are clearly indicative of a syn relationship between
the diol hydroxyl groups in both diastereomers.25 There-
fore, it has been concluded that the two major diastereo-
mers have the absolute stereochemistry of anti,anti and
only the stereochemistry of C(6) varies.
Acetonide protection of the major diastereomers of the
crotylation products 6 and 7 enabled us to establish the
relative stereochemistry (Figure 1). 13C NMR of 11a,b
revealed only one major acetal-derived chemical shift at
d = 97.7 ppm but two major products could be observed
according to 1H NMR and 13C NMR chemical shifts of the
allyl group double bonds. Subjection of 11a,b to reductive
ozonolysis27 afforded the corresponding primary alcohols
12a,b, whose 13C NMR acetonide shifts appeared at d =
98.2 and 97.8 ppm. The 13C NMR chemical shift differ-
The C(6) stereochemistry of the major crotylation prod-
ucts 6 and 7 could be determined from the corresponding
benzaldehyde acetal derivatives 14a and 14b. In order to
avoid unfavorable syn-pentane interactions with the equa-
Synlett 2005, No. 5, 751–756 © Thieme Stuttgart · New York

754
S. Källström et al.
LETTER
Ph
Instead, we propose a bicyclic transition state assembly
where the strain might be relieved by a boat-like geometry
for the indium chelate.29
H
B R
Me
Me
HD
J
AB = 9.9 Hz
O
O
O
Ph
O
JBC = 9.8 Hz
JCD = 2.1 Hz
HA
HC
The fact that the crotylation reactions were not particular-
ly selective with regard to the crotyl stereocenter can be
explained by the rapid E/Z-isomerization of the crotylmet-
al species, as observed by Paquette and others.30 However,
it should be noted that the proposed chair-boat and the
boat-boat transition states (see Figure 4) lead to the oppo-
site stereochemical outcome. Thus, if these pathways are
nearly equal in energy, they may constitute an alternative
explanation for the observed lack of selectivity.
14a: anti:anti:anti
Ph
H
B R
H
JAB = 9.8 Hz
JBC = 9.8 Hz
JCD = 2.3 Hz
O
O
O
Me
HD
Ph
O
HA
HC
Me
14b: syn:anti:anti
NOESY cross-peak
The Paquette model...
Figure 2 Stereochemical proof of crossed-aldol crotylation
products and diagnostic NOESY cross-peaks
L
L
H
L
In
OH OH
In
O
O
O
R
torial methyl at C(4), the crotyl side chain prefers the con-
formation shown in Figure 2. This conformation is also
supported by the coupling constant data as well as
NOESY cross-peaks between the C(4) methyl group and
C(6) methine proton, observable in both diastereomers.
The key difference are the diagnostic NOESY cross-peaks
between the C(4) methyl group and the terminal alkene
proton, revealing 14b is the isomer with the syn,anti,anti-
stereochemistry. This interaction was not observed in the
anti,anti,anti-diastereomer 14a. The stereochemistry of
6a and 6b were analogously deduced from the corre-
sponding benzaldehyde acetals.
O
L
R
H
R
H
anti (1,3)
... may break down with additional substituents
L
L
H
R
L
OH OH
In
In
O
O
O
O
L
R
H
H
R
H
steric hindrance
anti (1,3)
The observed syn(1,3)-selectivity may result from a boat TS:
O
RZ
OH OH
R
In
The stereochemistry of the prenylation products 8 and 9
RE
O
OH
O
R
1
X
were similarly determined from H NMR coupling con-
RE
RZ
chair
boat
H
R
stants of the acetonide (13, see Figure 1) or the benzalde-
hyde acetal derivatives. This analysis was further
supported by X-ray single crystal analysis of 9, confirm-
ing the anti,anti-stereochemistry (Figure 3).
syn (1,3)
or
+
RZ
OH OH
O
RE
RZ
RE
X
R
R
In
O
RZ
RE
X
boat
boat
syn (1,3)
Figure 4 The anti-Felkin stereochemistry might result from a boat
transition state
In this Letter, we have described a viable method for the
construction of polypropionate-type structures in a rapid
manner by consecutive, one-pot proline-catalyzed aldol
and metal-mediated allylation reactions. Noteworthy fea-
tures of this study are: 1) The anti-selectivity of the propi-
onaldehyde dimerization was increased by changing the
catalyst, and further improved by changing the solvent. 2)
Improved yields were obtained in the allylation step by
using sodium iodide as an additive. 3) Most importantly,
it was found that the Paquette model breaks down with
additional substituents, as shown by the crotylation and
prenylation products providing significant anti-Felkin
and anti-Paquette selectivity. The access to the anti,anti-
stereotriad is noteworthy as this particular array is
known to be the most challenging to achieve by chemical
synthesis.31
Figure 3 X-ray structure of 928
The observed anti-Felkin and anti-Paquette selectivity in
the crotylation and prenylation reactions was rather unex-
pected. We suggest that the Paquette model might break
down with additional substituents (Figure 4) as a result of
increasing steric clashes between the methyl groups of
the crotyl/prenyl group and the a-aldehyde substituent.
Synlett 2005, No. 5, 751–756 © Thieme Stuttgart · New York

LETTER
Rapid Entries to Polypropionates
755
(10) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
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(b) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A.
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(12) For recent examples, see: (a) Nyberg, A. I.; Usano, A.;
Pihko, P. M. Synlett 2004, 1891. (b) Casas, J.; Sundén, H.;
Córdova, A. Tetrahedron Lett. 2004, 45, 6117.
(13) b-Hydroxyaldehydes are notorious for the facility by which
they undergo oligomerization, elimination and other
decomposition reactions. For recent documented examples,
see: (a) Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003,
68, 1319. (b) Lautens, M.; Stammers, T. A. Synthesis 2002,
1993.
While optimization of selectivities and yields will be re-
quired for greater reaction efficiency, these results prove
that the aldol–allylation reaction cascade allows rapid ac-
cess to synthetic stereotriads and stereotetrads, and thus
may enable efficient construction of polyketide building
blocks.
Acknowledgment
Financial support from the Academy of Finland (Combined Orga-
nocatalysis and Metal-Mediated Reactions, project numbers
203283 and 203287), the National Technology Agency of Finland
(TEKES), Research Foundation of Orion Corporation, Magnus
Ehrnrooth Foundation, TKK, European Science Foundation (COST
D-28), and Research Institute of the Åbo Akademi University Re-
search Foundation is gratefully acknowledged.
We thank Professors Kyösti Kontturi and Ari Koskinen (both at
TKK) for access to chiral GC and for material support, Professor
Jorma Mattinen (ÅA) for financial support, Dr. Jari Koivisto (TKK)
and MSc Mattias Roslund (ÅA) for NMR assistance, Markku
Reunanen (ÅA) for HRMS assistance, Ms. Inkeri Majander (TKK)
for experimental assistance, and Dr. Melanie Clarke (TKK) for a
careful reading of the manuscript.
(14) Pihko, P. M.; Erkkilä, A. Tetrahedron Lett. 2003, 44, 7607.
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Maier, T. C. Synthesis 2003, 633. (e) Denmark, S. E.; Fu, J.
Chem. Rev. 2003, 103, 2763.
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(16) For the propionaldehyde dimerization–allylation sequence,
the following procedure is illustrative. To L-proline (5.8 mg,
0.05 mmol, 10 mol%) in DMF (0.5 mL), was added
propionaldehyde (72 mL, 1.0 mmol, 200 mol%) at 0 °C. The
reaction mixture was stirred 10 h at 4 °C. Then, to the
reaction mixture were added H2O (0.5 mL), indium (68.9
mg, 0.6 mmol, 120 mol%), and allyl bromide (52 mL, 0.6
mmol, 120 mol%). The reaction mixture was stirred for
additional 3 h at r.t. The reaction mixture was then extracted
with EtOAc (2 × 3 mL). The combined organic layers were
dried over anhyd Na2SO4, concentrated in vacuo, and
purified by flash chromatography (50% MTBE in hexanes)
to yield 57 mg (72%) of 1 as a mixture of diastereomers.
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(18) In addition to indium, tin and zinc were also screened as
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(19) The enantioselectivity was determined by GC analysis of the
5,5-dimethyl-1,3-dioxane derivatives of 1 or 3 as described
in ref.14 Conditions: Supelco g-DEXTM 120 column (30 m ×
0.25 mm, 0.25 mm film). The carrier has a velocity of 28
cm/s, FID detection (300 °C) (110 °C isotherm 45 min, then
raised to 180 °C at a rate of 2 °C/min); (a) for GC analysis
of the dimer 1: (2S,3S)-anti-isomer tR = 50.0 min, (2R,3R)-
anti-isomer tR = 52.3 min, (2R,3S)-syn-isomer tR = 47.7 min,
(2S,3R)-syn-isomer tR = 48.1 min; (b) GC analysis of the
cross aldol product 3: anti-isomer tR = 55.1 min, anti-isomer
tR = 56.0 min, syn-isomer tR = 54.2 min, syn-isomer
tR = 55.1 min.
(f) Thayumanavan, R.; Tanaka, F.; Barbas, C. F. III. Org.
Lett. 2004, 6, 3541.
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756
S. Källström et al.
LETTER
(20) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53,
1833.
(s, 3 H), 1.02 (s, 3 H), 0.98 (d, 3 H, J = 6.9 Hz), 0.86 (d, 3 H,
J = 7.0 Hz), 0.83 (d, 3 H, J = 6.8 Hz). 13C NMR (150 MHz,
CDCl3): d = 145.9, 113.2, 83.8, 79.1, 43.1, 36.5, 29.7, 23.3,
22.9, 20.6, 19.0, 14.2. Anal. Calcd for C12H24O2: C, 72.0; H,
12.1. Found: C, 71.9; H, 12.5.
(21) For the trans-4-hydroxyproline-catalyzed aldol-prenylation
sequence, the following procedure is illustrative. To 4-
hydroxy-L-proline in dry DMSO (0.1 mL), was added
propionaldehyde (72 mL, 1.0 mmol, 200 mol%) at 0 °C. The
reaction mixture was stirred for 24 h at 4 °C and then
allowed to warm to r.t. H2O (0.5 mL) was added, followed
by indium (86.5 mg, 0.75 mmol, 150 mol%), NaI (112.9 mg,
0.75 mmol, 150 mol%) and prenyl bromide (88 mL, 0.75
mmol, 150 mol%). The reaction mixture was stirred for 2 h
at r.t. EtOAc (5 mL) was added and the resulting mixture
was acidified with 6 M HCl and extracted with EtOAc (2 ×
5 mL). The combined organic extracts were washed with
brine (5 mL), dried over anhyd Na2SO4, and concentrated in
vacuo. The crude product was purified by flash
(23) For the crossed-aldol–allylation sequence, the following
procedure is illustrative. To L-proline (11.7 mg, 0.1 mmol,
10 mol%) and isobutyraldehyde (185 mL, 2.0 mmol, 200
mol%) in DMF (0.5 mL), was added with syringe pump a
solution of propionaldehyde (72 mL, 1.0 mmol, 100 mol%)
in DMF (0.5 mL) at 4 °C during 30 h. The reaction mixture
was stirred for additional 10 h at 4 °C. Then, to the reaction
mixture were added H2O (1.0 mL), In (229.6 mg, 2.0 mmol,
200 mol%), and allyl bromide (175 mL, 2.0 mmol, 200
mol%). The reaction mixture was stirred for additional 2 h at
r.t. The reaction mixture was extracted with EtOAc (2 ×
5 mL). The combined organic layers were dried over anhyd
Na2SO4, concentrated in vacuo, and purified by flash
chromatography (50% MTBE in hexane) to yield 109 mg
(63%) of 4 as a mixture of diastereomers.
(24) The original anti:syn isomer ratio (ca. 25:1) of the aldol
products 6a/6b derived from 3 is eroded slightly in the
allylation step, possibly as a result of enrichment due to
kinetic differences in the rate of the reaction. It should be
noted that in the corresponding aldol–prenylation sequence
the original anti:syn ratios were faithfully preserved.
(25) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.
1993, 58, 3511.
(26) Tenenbaum, J. M.; Woerpel, K. A. Org. Lett. 2003, 5, 4325.
(27) Bracher, F.; Litz, T. Bioorg. Med. Chem. 1996, 4, 877.
(28) (a) Data for 9 has been deposited with the CCDC entry
number 258398. X-ray crystallographic data collection and
processing: Crystallographic data were collected at 173 K on
a Nonius Kappa CCD area-detector diffractometer using
graphite monochromatized MoKa radiation (l = 0.71073
Å). The data collection was performed using j and w scans.
The data were processed using DENZO-SMN v0.93.0. The
structures were solved by direct methods using the SHELXS
program and full-matrix least-squares refinements on F2
were performed using SHELXL-97 program. All heavy
atoms were refined anisotropically. The CH hydrogen atoms
were included at the fixed distances with fixed displacement
parameters from their host atoms, except the vinyl
hydrogens, which were refined with fixed displacement
parameters. The figure was drawn with Ortep-3 for
Windows. (b) Otwinowski, Z.; Minor, W. Methods in
Enzymology, Volume 276: Macromolecular
chromatography (30% MTBE in hexane) to yield 39.3 mg
(42%) of pure 8a.
(22) Selected characterization data:
2,4-Dimethyloct-7-ene-3,5-diol (5, Table 2, Entries 4 and
5).
Mixture of diastereomers; Rf = 0.26 (50% MTBE in hexane).
IR (thin film): 3342, 2966, 2938, 1642, 1460, 1333, 1138,
1035, 968, 913 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.73–
5.93 (m, 1 H), 5.09–5.17 (m, 2 H), 3.97 (ddd, 1 H, J = 7.2,
5.2, 2.1 Hz), 3.89 (ddd, 1 H, J = 7.6, 5.6, 2.1 Hz), 3.85 (ddd,
1 H, J = 7.8, 5.6, 2.0 Hz), 3.83 (ddd, 1 H, J = 8.5, 5.0, 2.2
Hz), 3.75 (ddd, 1 H, J = 7.8, 5.9, 1.8 Hz), 3.67 (dt, 1 H,
J = 8.1, 3.0 Hz), 3.64 (dt, 1 H, J = 8.7, 3.3 Hz), 3.53–3.59
(m, 1 H, J = 9.5, 2.0 Hz), 3.40 (dd, 1 H, J = 8.9, 2.6 Hz), 3.29
(t, 1 H, J = 6.1 Hz), 2.11–2.56 (m, 2 H), 1.46–1.91 (m, 2 H),
0.78–1.01 (m, 9 H). 13C NMR (150 MHz, CDCl3): d = 135.5,
135.3, 135.2, 135.0, 118.3, 118.2, 117.9, 117.8, 81.0, 80.9,
80.4, 78.8, 76.4, 75.7, 75.4, 71.9, 40.9, 40.3, 40.1, 39.6, 38.8,
37.9, 37.8, 37.5, 34.8, 34.7, 31.8, 31.6, 31.0, 30.1, 27.1, 22.8,
20.4, 19.8, 19.1, 17.3, 14.3, 14.1, 13.1, 11.6. The major
isomer could be readily correlated with literature data (see
ref.25). HRMS (benzaldehyde acetal derivative): m/z calcd
for C17H24O2: 260.1775; found: 260.1775.
(3S,4S,5S)-4,6,6-Trimethyl-oct-7-ene-3,5-diol (8a, Table
4, Entries 1 and 2).
Rf = 0.26 (30% MTBE in hexane). [a]D –5.4 (c 0.5, CH2Cl2).
IR (thin film): 3467, 3019, 2966, 2935, 1638, 1464, 1414,
1130, 1030, 692 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.86
(dd, 1 H, J = 17.5, 10.7 Hz), 5.08 (dd, 1 H, J = 1.3, 10.7 Hz),
5.05 (dd, 1 H, J = 1.3, 17.5 Hz), 3.58 (dt, 1 H, J = 3.1, 8.2
Hz), 3.27 (d, 1 H, J = 5.5 Hz), 1.74–1.67 (m, 1 H), 1.64 (ddq,
1 H, J = 3.1, 7.3, 14.3 Hz), 1.39 (ddq, 1 H, J = 7.3, 8.2, 14.3
Hz), 1.04 (s, 6 H), 0.96 (t, 3 H, 7.3 Hz), 0.89 (d, 3 H, 7.0 Hz).
13C NMR (100 MHz, CDCl3): d = 145.7, 113.1, 83.3, 76.0,
42.8, 38.6, 27.5, 23.1, 22.3, 18.7, 9.4. HRMS (ESI): m/z
calcd for C11H22O2Na: 209.1517; found: 209.1507.
(3S,4S,5S)-2,4,6,6-Tetramethyloct-7-ene-3,5-diol (9,
Table 4, Entries 3 and 4).
Mp 74–75 °C; Rf = 0.33 (30% MTBE in hexane); [a]D –3.2
(c 0.8, CHCl3). IR (thin film): 3316, 2965, 2934, 1642, 1469,
1382, 1262, 1100, 1060, 990 cm–1. 1H NMR (600 MHz,
CDCl3): d = 5.87 (dd, 1 H, J = 17.6, 10.9 Hz), 5.06 (dd, 1 H,
J = 10.7, 1.0 Hz), 5.03 (dd, 1 H, J = 17.8, 1.2 Hz), 3.45 (dd,
1 H, J = 9.0, 2.8 Hz), 3.26 (d, 1 H, J = 5.6 Hz), 1.85 (dq, 1
H, J = 7.0, 3.0 Hz), 1.76 (ddq, 1 H, J = 9.0, 5.6, 7.0 Hz), 1.03
Crystallography, Part A; Carter, C. W. Jr.; Sweet, R. M.,
Eds.; Academic Press: New York, 1997, 307–326.
(c) Sheldrick, G. M. SHELX-97; University of Göttingen:
Germany, 1997.
(29) A similar boat-chair transition state geometry has been
proposed by Chemler and Roush to account for the anti-
selectivity of the reactions between crotyltrifluorosilanes
and b-hydroxyaldehydes. See ref. 13a.
(30) (a) Isaac, M. B.; Chan, T.-H. Tetrahedron Lett. 1995, 36,
8957. (b) Paquette, L. A.; Mitzel, T. M. J. Org.Chem. 1996,
61, 8799.
(31) For informative discussions, see: (a) Hoffmann, R. W.;
Dahlmann, G.; Andersen, M. W. Synthesis 1994, 629.
(b) Ref. 13a.
Synlett 2005, No. 5, 751–756 © Thieme Stuttgart · New York