Diastereoselective addition of methylmetal reagents to 2-methylaldehydes

Article abstract of DOI:10.1016/S0040-4020(01)00713-X

The preparation of compounds incorporating the 3-hydroxy-2-methyl-1-butyl moiety of high diastereomeric purity is described. These compounds can serve as potential building blocks for the preparation of several kinds of natural products. The diastereoselective addition of a number of methylmetal derivatives to three 3-substituted 2-methylaldehydes in various solvents was studied. An excellent diastereomeric ratio (95:5 anti-Cram/Cram) was obtained with 2-methyl-3-(phenylsulfanyl)propanal (5) and Me₂Zn in the presence of TiCl₄.

Full text of DOI:10.1016/S0040-4020(01)00713-X

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 7541±7548
Diastereoselective addition of methylmetal reagents
to 2-methylaldehydes
p
È
Michael Larsson and Hans-Erik Hogberg
Chemistry, Department of Natural and Environmental Sciences, Mid Sweden University, SE-851 70 Sundsvall, Sweden
Received 1 March 2001; revised 8 June 2001; accepted 5July 2001
AbstractÐThe preparation of compounds incorporating the 3-hydroxy-2-methyl-1-butyl moiety of high diastereomeric purity is described.
These compounds can serve as potential building blocks for the preparation of several kinds of natural products. The diastereoselective
addition of a number of methylmetal derivatives to three 3-substituted 2-methylaldehydes in various solvents was studied. An excellent
diastereomeric ratio +95:5 anti-Cram/Cram) was obtained with 2-methyl-3-+phenylsulfanyl)propanal +5) and Me2Zn in the presence of TiCl4.
q 2001 Published by Elsevier Science Ltd.
1. Introduction
aldehydes of type III could be accomplished, we would
have easy access to synthons of type II for further transfor-
mation to targets of type I.
A number of natural products, such as some pheromones1
and antibiotics2 contain the stereoisomerically pure
3-hydroxy-2-methyl-1-butyl moiety shown in I and II
+Scheme 1) and various approaches are available for the
synthesis of such compounds.1±3 Our interest in the develop-
ment of new methods for the preparation of compounds of
type II is related to the synthesis of pine saw¯y sex pher-
omones, which are esters of pure stereoisomers of type I
+Rˆmethyl branched alkyl group). If an ef®cient and highly
diastereoselective addition of a methyl moiety to chiral
The nucleophilic addition of an organometallic reagent to a
carbonyl group is one of the most powerful and reliable
methods of carbon±carbon bond formation known in
organic synthesis. When the carbonyl compound has
diastereotopic faces, diastereoselective reactions are
possible and they usually proceed according to Cram's
rule.4 Since its introduction in 1952, the models for open
chain systems have been further developed by, among
others, Cornforth, Karabatsos, Felkin and Ahn.5 In simple
systems, all models predict the formation of the same major
diastereomer, the so-called Cram-product. For carbonyl
compounds incorporating a suitably placed heteroatom
+for example O, N or S in the a-, b-, or g-position) chelation
can occur. In such cases, the addition usually proceeds
according to Cram's cyclic model, which leads to the
so-called anti-Cram-product.4,6 Since the introduction of
that latter model, many new chelation-controlled diastereo-
selective carbonyl additions have been developed.7
A frequently used non-chelating substrate for the study of
the diastereoselectivity in 1,2-additions of organometals is
2-phenylpropanal. It has been shown that such reactions
proceed according to Cram's rule.8 Aliphatic 2-methyl-
aldehydes have also been investigated. The diastereo-
selectivity obtained in methyl-Grignard reactions of e.g.
2,6,10-trimethyldodecanal and 2-methylbutanal is 70:30
and 55:45 +Cram/anti-Cram), respectively.1e,9
Scheme 1. Retrosynthetic analysis for target I derived from the isomeri-
cally pure 3-hydroxy-2-methyl synthon II. pˆstereogenic center of de®ned
con®guration +relative or absolute).
2. Results and discussion
Keywords: addition; asymmetric induction; diastereoselection; chelation.
Corresponding author. E-mail: hans-erik.hogberg@kep.mh.se
p
The objective of this investigation was to ®nd a suitable
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020+01)00713-X

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M. Larsson, H.-E. Hogberg / Tetrahedron 57 +2001) 7541±7548
7542
Scheme 2. Preparation of mixtures of the threo and erythro isomers +T and E, respectively) of compounds 3, 4 and 6.
substituent X in compounds of type III and appropriate
reaction conditions for transforming them into diastereo-
merically highly enriched products of type II, which could
then be converted into either of the following three alter-
natives where X is transformed into +a) an electrophilic
carbon e.g. a carbonyl carbon, +b) a good leaving group or
+c) a group which renders the adjacent carbon nucleophilic.
further transformation, could serve as a leaving group,
making the adjacent methylene carbon electrophilic. Alter-
natively, after oxidation to XˆPhSO2, the same carbon
would become nucleophilic after deprotonation.
We have studied the reactions of various methylmetals with
aldehydes 1, 2 and 5 +Scheme 2) in various solvents with or
without added chelating agents +Table 1). In this study,
2-methyl-3-phenylpropanal +1) served as the reference for
a non-chelating substrate. The identi®cation of the dia-
stereomeric products was made by transformation of these
into mixtures of the known1a 3,4-dimethyl-g-butyrolactone
diastereomers.
Many types of aryl groups +XˆAr) can be transformed into
carboxylic acids through oxidation with RuCl3±NaIO4,
which converts the substituent +XˆAr) into an electrophilic
carbonyl group +e.g. XˆCOOR). In the 1,2-additions
studied here, aryl groups are, in general, not able to form
chelated intermediates. However, provided the aryl group is
properly substituted +for example Xˆo-MeOC6H4),
chelation could potentially occur. On the other hand, if X
itself is a donor group +e.g. XˆPhS), chelation might also be
expected to take place. In the latter case, the resulting
addition product would contain a PhS-group, which after
In accordance with earlier results9,10 the reactions of
aldehyde 1 +Table 1: entries 2, 6 and 8) demonstrated that
the steric effects were very small in this case. Karabatsos11
has pointed out that the differences in conformational
energies between the three main conformations are small
Table 1. Diastereomeric ratios +dr) obtained when reacting methylmetal reagents with aldehydes 1, 2 and 5 either with or without added Lewis acids
Entrya
Reagent
Equiv. MeMetal +Lewis acid)
Substrate
Temperature +8C)
Drb T/E +anti-Cram/Cram)
Solvent
1
2
3
MeLi
MeLi
MeLi
MeLi
1.52
1.51
1.52
1.52
270
270
270
2100
250
250
240
240
270
270
270
270
270
270
270
270
270
270
270
60:40
50:50
65:35
60:40
55:45
47:53
46:54
54:46
45:55
39:61
65:35
58:42
56:44
69:31
79:21
95:05
95:05
86:14
Et2O
Et2O
THF/Cumenec
Et2O
Et2O
4
5MeMgBr
6
7
8
1.5
2
MeMgBr
MeTi+O-i-Pr)3
MeTi+O-i-Pr)3
+1)TiCl4, +2)Me2Zn
Me2TiCl2
MeLi
+1)TiCl4, +2)MeLi
MeLi
+1)TiCl4, +2)MeLi
2TiCl2
1.51
1.52
1.51
+1.0)1.6
1.52
1.55
+1.0)1.6
1.55
+1.0)1.6
1.55
+1.01.6)
+2.0)1.6
+0.5)1.6
1.55
Et2O
Et2O
Et2O
CH2Cl2
CH2Cl2
Et2O
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
d
9
2
d
10
11
12
13
14
15Me
16
17
18
19
5
5
d
d
d
d
+1)TiCl4, +2)Me2Zn
+1)TiCl4, +2)Me2Zn
+1)TiCl4, +2)Me2Zn
Me2Zn
5
5
5
d
d
±e
d
±
a
Yields were in range of 40±95%, according to GC and in entry 16 the isolated yield was 85%.
Diastereomeric ratio was determined by GC analysis on the alcohol products 3 and 4, or on the butyrate of alcohol product 6.
Proportions: 10/90.
Mixed with a small amount +3±6 vol%) of the solvent from the methylmetal reagent.
Only starting material was isolated.
b
c
d
e

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M. Larsson, H.-E. Hogberg / Tetrahedron 57 +2001) 7541±7548
7543
in cases like this, thereby leading to transition-states of
similar energy. This could explain the poor selectivity
observed.
improved in some cases +compare e.g. entries 13 and 14)
and not in others +entries 11 and 12).
It is known that dimethylzinc is unable to add to aldehydes
without activation +con®rmed in entry 19).21 However, in
the presence of 1 equiv. of TiCl4 in CH2Cl2 at a low
temperature aldehyde 5 reacted readily with dimethylzinc.
The product 6 was obtained in an excellent diastereomeric
ratio +95:5 6T/6E, entry 16). Using 0.5equiv. of TiCl 4
relative to the substrate +entry 18) gave a lower diastereo-
selectivity, whereas increasing it from 1.0 to 2.0 equiv.
+entry 17) did not in¯uence the selectivity +cf Ref. 16).
These results indicated that a chelating substrate would
probably lead to an improved selectivity. Screening experi-
ments with 3-+2-methoxyphenyl)-2-methylpropanal +2)
were performed. The diastereoselectivity obtained with
aldehyde 2 was in the range from 39:61 to 65:35 +anti-
Cram/Cram, see Table 1). When attacking an aldehyde,
MeTi+O-i-Pr)3 is a known non-chelating reagent.12 In our
hands, this reacted with 2 to give a low preference for the
Cram-product +entry 7). In comparison with the phenyl
substituted aldehyde 1, the substrate 2 should be more
sterically demanding. This could explain the product distri-
butions observed. On the other hand, a good chelating
reagent such as MeMgBr,13 furnished a slightly increased
anti-Cram diastereoselectivity from 47:53 for compound 1
to 55:45 for compound 2 +entry 6 and 5, respectively). When
using some other complex methylmetal reagents or Lewis
acids [e.g. MeYb+OTf)2, MeCeCl2, CeCl3, Me2CuLi,
MeZrCl3, ZrCl4],14 the diastereoselectivity was not
improved. The highest anti-Cram/Cram ratio +65:35) was
observed with MeLi in THF/Cumene +entry 3).
When using Me2TiCl2 as the reagent +entry 15), the diastero-
meric ratio was somewhat lower, probably caused by
competition between the intermolecular addition pathway
+as is the case for entry 16) and an 1,3-intramolecular
migration.22 When using TiCl4 followed by MeLi, we
obtained a low diastereoselectivity. In this case, the poten-
tial cyclic chelate was probably decomposed, leading to an
open chain intermediate and hence a poor selectivity. When
screening other Lewis acids7b±f,14,23 with Me2Zn and
compound 5, either the diastereoselectivity was low or no
product was obtained.
Although chelates might be involved in the transition-state
in some of the reactions with 2-methoxyphenyl substituted
aldehyde 2, the resulting eight-membered ring system
would be relatively ¯exible leading to several possible
transition states of similar energy. This probably explains
the modest improvements in selectivity observed, when
switching from substrate 1 to 2. The product distribution
could also be due to solvent effects15 or the nature of the
Lewis acid used. When for example TiCl4 in CH2Cl2 was
used, a certain extent of complex formation could occur
with binding to the carbonyl oxygen only. This would
lead to a higher population of the Felkin±Ahn conforma-
tion16 in the transition state, which would favor the
formation of the Cram-product.
In order to con®rm the relative con®gurations of the stereo-
genic centres in the major secondary alcohol product 6T, its
1H NMR spectrum was compared with those of the
previously known diastereomers, 6E and 6T. The spectra
of these were previously known to display different
coupling constants for some protons.18,19 Our major product
showed shifts and coupling constants identical with those of
6T. Similarly, the 1H NMR spectrum of the known acetate20
of 6E was also used for stereoisomer assignment. From
these comparisons we concluded that the major diastereo-
mer obtained from the dimethylzinc±TiCl4-reaction with
compound 5 was the anti-Cram-product, 6T.
Because poor diastereofacial control was obtained from the
additions of methylmetal reagents to both substrates 1 and 2,
we turned our attention to another substrate with the poten-
tial for better chelation control. In accordance with earlier
observations made with some substrates containing sulfur,7j
a suitably placed sulfur atom in an aldehyde substrate would
be expected to promote chelation with a Lewis acid. The
readily available 2-methyl-3-+phenylsulfanyl)propanal +5)17
could serve as such a substrate which, in the presence of a
Lewis acid would form a chelate between the carbonyl
oxygen and the sulfur atom. After addition of a methylmetal
reagent, a six-membered ring transition state would form.
This would react to give a building block of type II +Scheme
1), namely compound 6 favoring one diastereomer, either
6T or 6E. The preparation of various stereoisomers of
compound 6 have been described earlier.18±20
This hypothesis was con®rmed experimentally, because in
the reactions of various methylmetal reagents with aldehyde
5, the anti-Cram-product 6T was in excess in all cases
+entries 11±18, Table 1). This indicated that chelation
occurred even in the absence of an added chelating agent.
When adding such an agent, the diastereomeric ratios were
Scheme 3. Isomers 6±9E are epimeric at C2 and are not shown. Reactions:
+a) TBDMSCl, CH2Cl2, Et3N. +b) m-CPBA, CH2Cl2. +c) 3,5-Dinitrobenzoyl
chloride, pyridine, C6H6. +d) 1. n-BuLi, THF, 2788C. 2. Ethyl chloro-
formate. +e) 1. Li, NH3, 2788C. 2. PhCO2Na. 3. MeOH, HCl, Dx.

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M. Larsson, H.-E. Hogberg / Tetrahedron 57 +2001) 7541±7548
7544
Scheme 4. Proposed mechanism for the formation of compound 6T in the TiCl4 catalyzed reaction of aldehyde 5 with dimethylzinc.
In order to obtain a diastereomerically pure derivative of
6T, a crystalline compound was desirable. After oxidation
to the sulfone 7Ta +Scheme 3), the 3,5-dinitrobenzoate was
prepared and recrystallized to give the diastereomerically
pure compound 7Tc +mp 128±1308C). The epimeric dinitro-
benzoate, the erythro-diastereomer 7Ec, is a known
Thus, we have established an ef®cient method for
acquiring a possible building block [the threo-isomer of
the 3-hydroxy-2-methyl-1-butyl moiety II +Scheme 1)],
which should be useful for the preparation of various natural
products. Because the building block we prepared is
racemic, an ef®cient resolution strategy for this is needed.
Lipase catalysis has proved very ef®cient for compounds of
this type. Alternatively, methods for preparing the starting
aldehyde 5 enantiomerically pure should be developed. At
present, we are studying these routes.
1
compound +mp 156.5±1588C).20 The H NMR spectra of
the two compounds were very similar except for the peak
at 5.2 ppm, where our compound, 7Tc, displayed an
apparent quintet with a coupling constant of 6.3 Hz whereas
7Ec had been reported20 to display a doublet of quartets
+Jˆ3.8 and 6.6 Hz) at 5.3 ppm.
3. Experimental
In order to establish unambiguously the relative con®gura-
tion of threo-6T and erythro-6E, 3,4-dimethyl-g-butyro-
lactone +9) was synthesized from a mixture of both
+Scheme 3). The alcohol 6 +T/E ratio 61:39) was protected
as its tert-butyldimethylsilylether 6b. After oxidation with
meta-chloroperbenzoic acid, the sulfone 7b was obtained.
Acylation with ethyl chloroformate of the a-sulfonyl
carbanion generated from 7b furnished 8. Removal of the
phenylsulfonyl group was accomplished with lithium in
liquid ammonia. Subsequent hydrolysis gave the target
lactone 9 +trans/cis-ratio: 65:35 by GC, when compared
with authentic samples of both the cis- and trans-lactone
91a).
3.1. General experimental procedure
Commercially available chemicals were used without
further puri®cation unless otherwise stated. Me2Zn was
purchased as a 2.0 M solution in toluene, MeLi as a 1.6 M
solution in Et2O or as a 1.0 M solution in THF/Cumene
+10:90) and MeMgBr as a 3.0 M solution in Et2O. All
dried materials were stored under argon. Commercially
available anhydrous CeCl3 was heated at 1 mbar at 1408C
for 3 h before use. Et2O +LiAlH4), THF +K, benzophenone),
CH2Cl2 +CaH2) and toluene +CaH2) were distilled from the
indicated drying agents. Preparative liquid chromatography
+LC) was performed on straight phase silica gel +Merck 60,
230±400 mesh, 0.040±0.063 mm) employing a gradient
technique using an increasing concentration +0±100%) of
distilled Et2O in distilled pentane or of distilled ethyl acetate
in distilled cyclohexane, as eluent. The progress was
followed by thin layer chromatography or GC. NMR spectra
We demonstrated above that the diastereoselective addition
of Me2Zn to 2-methyl-3-+phenylsulfanyl)propanal +5) with
TiCl4 as a Lewis acid catalyst, furnished the addition
product 6T in an excellent diastereomeric ratio +95:5 anti-
Cram/Cram). Because experiments made it clear that an
equimolar amount of TiCl4 relative to the substrate was
needed, this indicated that the reaction took place via a
1:1 substrate/Lewis acid complex. Because the effect of a
lower amount of Lewis acid was lower selectivity, it
appeared as if the catalyst was still bound as a 1:1 alkoxy-
complex in the product. This complex could in turn function
as a Lewis acid catalyst, but with lower selectivity
explaining the results obtained when using less than an
equimolar amount of the catalyst. We tentatively suggest
that the reaction between compound 5, TiCl4 and
dimethylzinc in CH2Cl2 proceeds via the path described in
Scheme 4.
1
were recorded on a Bruker DMX 250 +250 MHz H and
62.9 MHz 13C) spectrometer using CDCl3 as solvent and
TMS as internal reference. The diastereoisomeric ratio of
the alcohols 3 and 4 were determined using a Varian 3700
gas chromatograph equipped with a CP-Wax 52CB, 30 m,
0.25mm i.d. dfˆ0.25 mm, carrier gas He, 15psi, split 1:30.
+GC programme: 1308C/1 min, 38C/min, 1758C). The cis/
trans ratio of the diastereomeric mixture of 3,4-dimethyl-g-
butyrolactone was determined using a 30 m, 0.25mm i.d.
capillary column coated with CP-Sil 19CB, dfˆ0.25 mm;
carrier gas N2,100 kPa, split 30:1. The diastereoisomeric
ratio of the butyrates of alcohol 6 was determined using a

È
M. Larsson, H.-E. Hogberg / Tetrahedron 57 +2001) 7541±7548
7545
Varian 3700 gas chromatograph equipped with a CP-Sil 88,
50 m, 0.25 mm i.d. dfˆ0.20 mm, carrier gas He, 15psi, split
1:30. +GC programme: 1008C/3 min, 18C/min, 2008C).
Retention time +min): 90.0 +threo isomer, butyrate of 6T)
and 90.6 +erythro isomer, butyrate of 6E). Mass spectra
were recorded on a Saturn 2000 instrument, operating in
the EI or CI +CH3CN as chemical ionization gas) mode,
coupled to a Varian 3800 GC instrument. Boiling points
are uncorrected, and those marked with BTB are given as
air-bath temperatures +bath temperature/mbar) in a bulb-to-
bulb +BTB, BuÈchi-GKR-51) apparatus. Elemental analysis
was performed by Mikrokemi AB, SE-752 28 Uppsala,
Sweden.
priate aldehyde +1.0 mmol) in the speci®ed solvent
+2.0 mL) at the speci®ed temperature +see Table 1). The
reaction was stirred at that temperature for 4 h and worked
up as above.
+c) Entries 9, 12, 14 and 16±18, Table 1. TiCl4 +1.0 mmol,
except for entries 17 and 18 there the equivalents of Lewis
acid were 2.0 and 0.5mmol, respectively) was added to the
appropriate aldehyde +1.0 mmol) in the speci®ed solvent
+15mL) at 2708C. After the mixture was stirred at that
temperature for 20 min, a solution +see above) of the appro-
priate methylmetal reagent +1.6 mmol) was added dropwise
at 2788C and stirred for 4 h and worked up as above.
3.2. Preparation of starting materials
3.4. Description of speci®c compounds
3.2.1. 3-*2-Methoxyphenyl)-2-methylpropanal *2). o-Anis-
aldehyde +50 g, 368 mmol) was added to a solution of KOH
+21 g, 370 mmol) in EtOH +300 mL, 95%) and cooled to
08C. Propanal +35g, 606 mmol) was added at a speed so
that the temperature did not exceed 108C and then stirred for
3 h. After addition of HCl +50 mL, 6 M, aq.) and extraction
with Et2O +3£75mL) the organic layer was dried +MgSO 4)
and concentrated to give an oil. After distillation, +bp 125±
1308C/3.0 mbar), +2E)-3-+2-methoxyphenyl)-2-methylprop-
2-enal +44.0 g, 68%) was obtained. This +30.0 g, 170 mmol)
in MeOH +500 mL) was stirred with a suspension of Raney
nickel in water +,20 g) under H2 at room temperature
during 15h. The suspension was ®ltered and the solid
collected was washed thoroughly with MeOH +5£50 mL).
The solvent was evaporated off and the resulting mixture,
containing the product and remaining starting material, was
dissolved in Et2O +250 mL) and shaken with Na2S2O5
+11£35mL, sat. aq.). The pH of the combined aqueous
phase was adjusted to ,9 using NaOH +5M, aq.,
,50 mL). Extraction with ether +3£100 mL) followed by
drying +MgSO4) and concentration furnished a colorless
oil +14.0 g, 46%), 98% pure by GC. Bp 80±858C/2.0 mbar
3.4.1. 3-Methyl-4-phenylbutan-2-ol *3). +Entry 6, erythro/
threo, 3E/3T, 53:47). n21 1.5164 +lit.29 1.519), bp 858C/
D
0.5mbar +BTB) +lit. 29 1248C/14.7 mbar). 1H NMR: d
7.32±7.16 +5H, m), 3.79±3.67 +1H, m), 2.92±2.78 +1H,
m), 2.44±2.30 +1H, m), 1.88±1.73 +1H, m), 1.36 +1H, br
s, OH), 1.21 +1.41H, d, Jˆ6.3 Hz), 1.20 +1.59H, d,
Jˆ6.3 Hz), 0.86 +1.59H, d, Jˆ6.9 Hz), 0.83 +1.41H, d,
1
Jˆ6.8 Hz) ppm. H NMR was similar to that reported in
the literature.30 13C NMR: 141.3, 129.2, 128.3, 125.8,
71.4, 70.3, 42.3, 41.8, 39.3, 39.1, 20.6, 19.8, 14.6,
13.5ppm. MS +EI): m/z 146 +100) +M2H2O)1, 131 +68),
91 +13). Retention time +min.): 14.6 and 15.2 for erythro
+3E) and threo +3T), respectively.
3.4.2. 4-*2-Methoxyphenyl)-3-methylbutan-2-ol *4). +Entry
5, threo/erythro, 4T/4E, 5 5 :45n2)1.D 1.5210. Bp 1308C/
0.7 mbar +BTB). H NMR: d 7.23±7.11 +2H, m,), 6.94±
1
6.85+2H, m), 3.84 +3H, d, Jˆ1.6 Hz), 3.67±3.54 +1H, m),
2.90±2.74 +1H, m), 2.55 +0.45H, dd, Jˆ7.7 and 13.4 Hz),
2.39 +0.55H, dd, Jˆ7.0 and 13.3 Hz), 2.20 +1H, br s, OH),
1.86±1.68 +1H, m), 1.17 +1.35H, d, Jˆ6.3 Hz), 1.12 +1.65H,
d, Jˆ6.4 Hz), 0.93 +1.65H, d, Jˆ6.8 Hz), 0.85+1.35H, d,
Jˆ6.9 Hz) ppm. 13C NMR: 157.3, 131.3, 131.0, 129.3,
127.2 +2C), 120.8, 120.4, 110.3 +2C), 71.2, 68.6, 55.4, 41.1,
40.9, 33.5, 33.1, 19.9, 19.7, 15.3, 13.5 ppm. MS +EI): m/z 194
+100) +M1), 177 +27), 121 +44). Anal. Calcd for C12H18O2: C
74.2; H 9.3. Found: C 74.5; H 9.4.
+lit.24 113±1148C/6.7 mbar), n21 1.5195. The 1H NMR
D
spectral data was similar to that reported in the literature.25
3.3. General procedures for the methylmetal addition
reactions
3.3.1. 3-Methyl-4-phenylbutan-2-ol *3), 4-*2-methoxy-
phenyl)-3-methylbutan-2-ol *4) and 3-methyl-4-*phenyl-
sulfanyl)butan-2-ol *6). +a) Entries 1±6, 11, 13 and 19,
Table 1. The appropriate aldehyde +1.0 mmol) in freshly
distilled dry solvent +2.0 mL) was added dropwise to the
methylmetal reagent +1.5mmol) in the same solvent
+5.0 mL) at a given temperature +see Table 1). The reaction
was stirred at that temperature for 10 min and at room
temperature for 1.5h. NH 4Cl +5mL, sat. aq.) was added
followed by HCl +3 mL, 3 M, aq.). Extractive work-up
with Et2O +3£10 mL), NaHCO3 +20 mL, sat. aq.), H2O
+20 mL) and brine +20 mL), followed by drying +MgSO4)
and solvent removal in vacuo furnished the product.
The racemic threo-isomer 4T of the alcohol can be
separated from the erythro-one +4E) through LC. The
diastereomers were identi®ed by comparison of H NMR
1
of the mixture to that of the pure threo isomer. GC-retention
time +min): 22.6 and 24.4 for 4T and 4E, respectively.
Identi®cation of the erythro-/threo-isomers of 4 +and also
of 3) was performed through a preparation of 3,4-dimethyl-
g-butyrolactone from the alcohol4 +and 3) via acylation,
followed by RuCl3/NaIO4 oxidation and acid catalysed
lactone formation following a reaction sequence described
for a different 3-aryl-2-methylalcohol.31 The retention times
of the lactone stereoisomers so obtained were compared
with those of authentical lactone samples.
3.4.3. *2Rp,3Sp)-4-*2-Methoxyphenyl)-3-methylbutan-2-
26
+b) Entries 7±8, 10 and 15, Table 1. TiCl4 or TiCl+O-i-
27
Pr)3 +1.5mmol) was dissolved in freshly distilled solvent
ol *4T). +threo/erythro, 4T/4E, .200:1). n21 1.5212. Bp
1108C/0.9 mbar +BTB). H NMR: d 7.23±7.12 +2H, m),
D
1
+10 mL) and cooled to 2708C. Dropwise addition of a MeLi
or Me2Zn28 +entries 10 and 15) solution +see Section 3.1)
+1.5mmol), followed by dropwise addition of the appro-
6.94±6.85+2H, m), 3.84 +3H, s), 3.67±3.60 +1H, m), 2.85
+1H, dd, Jˆ8.4 and 13.3 Hz), 2.39 +1H, dd, Jˆ6.9 and

È
M. Larsson, H.-E. Hogberg / Tetrahedron 57 +2001) 7541±7548
7546
13.3 Hz), 2.19 +1H, d, OH, Jˆ4.1 Hz), 1.78±1.68 +1H, m),
1.13 +3H, d, Jˆ6.5Hz), 0.93 +3H, d, Jˆ6.9 Hz) ppm. 13C
NMR: 157.4, 131.0, 129.3, 127.2, 120.8, 110.3, 68.6, 55.4,
40.9, 33.6, 19.9, 13.5ppm. MS +EI): m/z 194 +100) +M1),
177 +27), 121 +46).
pyridine +64 mL, 0.79 mmol) and benzene +2 mL) was
mixed with 3,5-dinitrobenzoyl chloride +152 mg,
0.66 mmol) at 08C. Stirring over night at room temperature
followed by extractive work-up with HCl +10 mL, 6 M),
Na2CO3 +10 mL, sat. aq.), brine +10 mL), drying +Na2SO4)
and solvent removal in vacuo gave a solid, which after
recrystallization from ethanol and toluene furnished the
title compound +50 mg, 27%) as colorless crystals; mp
128±1308C +Lit.20 156.5±1588C for the erythro-isomer)
3.4.4. *2Rp,3Rp)-3-Methyl-4-*phenylsulfanyl)butan-2-ol
*6T). Entry 16. 2-Methyl-3-+phenylsulfanyl)propanal17 +5,
12.0 g, 66.7 mmol), was dissolved in CH2Cl2 +500 mL)
and stirred and cooled to 2708C and then TiCl4 +8.1 mL,
74 mmol) was added dropwise via a syringe. An orange
viscous solution was obtained and this was kept at 2708C.
After stirring for 1 h, Me2Zn [49.5mL +2 M in toluene),
99 mmol] was added dropwise followed by stirring at
2708C. After stirring over night, at which point the
temperature had reached 108C, water +200 mL) was added
and the phases were separated. The aqueous phase was
extracted with Et2O +3£100 mL) and the combined ether
extract was washed with NaHCO3 +2£100 mL, sat. aq.),
dried +Na2SO4). ®ltered and the solvent was evaporated
off, furnishing a yellowish oil +11.0 g, 85%) after LC
+EtOAc gradient in cyclohexane), 99% pure by GC.
1
The H NMR spectrum was similar with that reported in
the literature for the erythro-isomer,20 except for the peak
at 5.2 ppm, where our compound displayed an apparent
quintet with a coupling constant of 6.3 Hz. 13C NMR:
161.8, 148.7 +2C), 139.5, 134.0, 133.8, 129.5 +2C), 129.4,
127.9 +2C), 122.5+2C), 76.1, 58.8, 33.4, 16.7, 16.3 ppm. MS
+CI, CH3CN): m/z 423 +5) +M1H)1, 211 +30), 143 +100),
125+63).
3.4.7. tert-Butyl-*1,2-dimethyl-3-*phenylsulfonyl)propoxy)-
dimethylsilane *7b). Compound 6a +0.5g, 2.55mmol; 6T/
6E-ratio: 69:31) in 5mL of CH 2Cl2 was mixed with triethyl-
amine +0.7 mL, 5.1 mmol) and tert-butylchlorodimethyl-
silane +0.77 g, 5.1 mmol) at room temperature, followed
by re¯ux over night. Extractive work-up with Et2O
+3£15mL), NH 4Cl +20 mL, sat. aq.), brine +20 mL)
followed by drying +Na2SO4) and solvent removal in
vacuo gave a colorless oil +6b) +0.50 g, 63%) after distilla-
tion, 98% pure by GC. Bp 1258C/0.7 mbar +BTB). This
+0.35g, 1.13 mmol) was oxidized as described above 32
+Section 3.4.6) to give the title compound +0.36 g, 93%),
1
+threo/erythro; 95:05). H NMR: d 7.37±7.13 +5H, m),
4.04±3.94 +0.05H, m), 3.77 +0.95H, app. quintet,
Jˆ6.3 Hz), 3.21 +1H, dd, Jˆ4.6 and 12.8 Hz), 2.79 +1H,
dd, Jˆ8.2 and 12.8 Hz), 1.87±1.74 +1H, m), 1.59 +1H, br
s, OH), 1.20 +3H, d, Jˆ6.4 Hz), 1.04 +3H, d,
Jˆ6.8 Hz) ppm. 13C NMR: 136.9, 128.9 +4C), 125.8, 71.1,
40.2, 37.3, 20.4, 15.4 ppm. MS +EI): m/z 196 +100) +M1),
1
179 +10), 123 +2), 109 +4). The H NMR and 13C NMR
1
spectral data were similar to those reported in the literature
for the threo-isomer.19
98% pure by GC. H NMR: d 8.10±7.89 +2H, m), 7.69±
7.40 +3H, m), 3.83 +0.31H, dq, Jˆ3.6 and 6.3 Hz), 3.65
+0.69H, dq, Jˆ4.2 and 6.2 Hz), 3.34 +1H, dd, Jˆ2.7 and
14.5Hz), 2.89±2.78 +0.31H, m), 2.83 +0.69H, dd, Jˆ9.3
and 14.4 Hz), 2.18±1.93 +1H, m), 1.21±0.92 +1.86H, m),
1.10 +2.07H, d, Jˆ6.9 Hz), 1.02 +2.07H, d, Jˆ6.2 Hz),
0.80 +5.49H, s), 0.79 +3.51H, s), 0.01 +3H, s), 20.01 +3H,
s) ppm. MS +CI, CH3CN): m/z 343 +30) +M1H)1, 211 +100),
143 +30), 125+20). The 1H NMR spectrum was similar to
that reported in the literature for the enantiomerically pure
threo isomer.33
3.4.5. Acetate of *2Rp,3Rp)-3-methyl-4-*phenylsulfanyl)-
butan-2-ol *acetate of 6T). Into a solution of 6T +50 mg,
0.26 mmol) in CH2Cl2 +2 mL) acetyl chloride +0.09 mL,
1.3 mmol) was added and the mixture was stirred for 6 h
at room temperature. The crude product was concentrated
and subjected to LC which gave the product +57 mg, 92%),
.99% pure by GC +threo/erythro; 95:5). 1H NMR: d 7.36±
7.14 +5H, m), 5.07±4.98 +0.05H, m), 4.90 +0.95H, app.
quintet, Jˆ6.4 Hz), 3.11 +0.95H, dd, Jˆ4.3 and 12.9 Hz),
3.07 +0.05H, dd, Jˆ5.2 and 12.9 Hz), 2.66 +1H, dd, Jˆ9.0
and 12.9 Hz), 2.03 +3H, s), 1.99±1.89 +1H, m), 1.20 +3H, d,
Jˆ6.4 Hz), 1.07 +0.15H, d, Jˆ6.9 Hz), 1.05+2.8H5 , d,
3.4.8. 3,4-Dimethyl-g-butyrolactone *9). We applied the
acylation protocol of Gannet et al.34 to compound 7b
+0.18 g, 0.54 mmol) +7Tb/7Eb-ratio: 69:31) dissolved in
dry THF +2.5mL) and stirred at 2788C. n-Butyllithium in
hexane +0.82 mL, 1.19 mmol, 1.45M) was added and the
resulting solution was stirred at 2208C for 0.5h and then
cooled to 2788C. Ethyl chloroformate +0.15mL,
1.62 mmol) in THF +2 mL) was added. The resulting
mixture was stirred at 08C for 2 h and then at room tempera-
ture over night. Addition of NH4Cl +5mL, sat. aq.) followed
by extractive work-up with Et2O +3£15mL), brine +20 mL)
and then drying +MgSO4) and solvent removal in vacuo
followed by LC gave 3-methyl-2-phenylsulfonyl-4-tert-
butyldimethylsilanyloxy-pentanoic acid ethyl ester +8)
+0.080 g, 0.19 mmol; 70% pure by GC), MS +CI, CH3CN):
m/z 413 +5) +M2H)1, 283 +75), 223 +32), 141 +100). With-
out further puri®cation the crude product was subjected to
phenylsulfonyl group removal performed according to a
slightly modi®ed protocol compared with that described in
Trost et al.35 Thus compound 8 +0.054 g, 0.13 mmol) in
Et2O +1 mL) was added to a slurry of Li +0.1 g,
1
Jˆ6.8 Hz) ppm. The H NMR spectral data was identical
to that reported in the literature for the erythro-isomer20
except for the peak at 4.9 ppm, where our ester displayed
an apparent quintet with a coupling constant of 6.4 Hz,
whereas a doublet of quartets +Jˆ4.0 and 6.6 Hz) at
5.0 ppm was reported for the acetate of 6E.
3.4.6. *1Rp,2Rp)-1,2-Dimethyl-3-*phenylsulfonyl)propyl-
3,5-dinitrobenzoate *7Tc). The oxidation protocol of
Nicolau et al.32 was applied to 6Ta +1.0 g, 5.10 mmol; 6T/
6E-ratio: 93:7), which was dissolved in CH2Cl2 +15mL) and
mixed with m-CPBA +2.1 g, 12.8 mmol) in CH2Cl2 +6 mL)
and stirred for 6 h at re¯ux temperature. Extractive work-up
with NaHCO3 +20 mL, sat. aq.), Et2O +3£15mL), brine
+20 mL), followed by drying +Na2SO4) and solvent removal
in vacuo furnished crude 3-methyl-4-+phenylsulfonyl)-
butan-2-ol +7Ta). Without puri®cation and using the proto-
col of Liu et al.20 this compound +0.1 g, 0.44 mmol) in

È
M. Larsson, H.-E. Hogberg / Tetrahedron 57 +2001) 7541±7548
7547
Obata, R.; Zhuorong, L.; Takamatsu, S.; Komiyama, K.;
Omura, S. Tetrahedron Lett. 1994, 35, 2635±2636.
+f) Middleton, R. F.; Foster, G.; Cannell, R. J. P.; Sidebottom,
P. J.; Taylor, N. L.; Noble, D.; Todd, M.; Dawson, J.;
Lawrence, G. C. J. Antibiot. 1995, 48, 311±316. +g) Marino,
S. D.; Iorizzi, M.; Palagiano, E.; Zollo, F.; Roussakis, C.
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14.5mmol) in freshly distilled NH 3 +10 mL) at 2788C.
After stirring for 10 min at 2788C, 10 min at 2308C and
recooling to 2788C, solid sodium benzoate was added until
the blue color discharged. NH4Cl +5mL, sat. aq.) and Et 2O
+5mL) were added and the ammonia was allowed to evapo-
rate over night. Extractive work-up with Et2O +3£15mL),
brine +20 mL), drying +MgSO4) and solvent removal in
vacuo furnished the crude product, the TBDMS protected
ethyl ester, 3-methyl-4-tertbutyldimethylsilanyloxy-penta-
noic acid ethyl ester +0.019 g, 0.07 mmol). To this, which
was used without further puri®cation, MeOH +2 mL) and
HCl +0.5mL, 6 M) were added and the reaction was kept
under re¯ux for 12 h, followed by extractive work-up with
Et2O +5£5mL).After washing with brine +10 mL) and
drying +MgSO4), the solvent was distilled off through a
column. After careful evaporation of the residual solvent a
small amount of the lactone 9 in a diastereomeric ratio of
65:35 +trans/cis by GC) was obtained. The lactone 9 is very
water soluble and therefore dif®cult to extract from water.
Hence, the isolated yield was low. The isomer ratio in our
material was established by using GC and GC-MS
performed with our material and with authentic samples
of cis- and trans-3,4-dimethyl-g-butyrolactone +9).1a Reten-
tion time [GC see Section 3.1: isothermal 1008C]: 7.58 and
9.00 min for trans-9 and cis-9, respectively. The mass spec-
tra obtained from the isomers present in our sample were
identical with those obtained from the the authentical
samples of lactone 9.
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Acknowledgements
This work was supported by the Swedish Natural Science
Research Council +NFR), Mid Sweden University and the
Commission of the European Communities, Agriculture and
Fisheries +FAIR), speci®c RTD programme, contract No.
FAIR1-CT95-0339, `Pine saw¯y pheromones for sustain-
able management of European forests'. +This study does
not necessarily re¯ect the Commission's view and in no
way anticipates its future policies in this area.)
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