A highly stereoselective organocatalytic approach to Lilial and muguesia

Article abstract of DOI:10.1055/s-0032-1318220

The stereoselective alkylation of aldehydes with benzodithiolylium tetrafluoborate gave a straightforward access to key compounds for the synthesis of fragrances and flavors. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318220

LETTER
▌449
lAetteHr ighly Stereoselective Organocatalytic Approach to Lilial® and Muguesia
Organocatalytic Enantioselective Access to Fragrance
Andrea Gualandi,* Marco Giuseppe Emma, Jessica Giacoboni, Luca Mengozzi, Pier Giorgio Cozzi
Alma Mater Studiorum – Università di Bologna, Dipartimento di Chimica ‘G. Ciamician’, Via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: andrea.gualandi10@unibo.it
Received: 09.01.2013; Accepted: 25.01.2013
addition of nucleophilic organometallic methyl reagents
Abstract: The stereoselective alkylation of aldehydes with benzo-
to chiral aldeidic precursors, the behavior of the chiral al-
dehydes 11a,b towards the addition of several different
nucleophiles was investigated.
dithiolylium tetrafluoborate gave a straightforward access to key
compounds for the synthesis of fragrances and flavors.
Key words: organocatalysis, MacMillan catalysts, enamine, alkyl-
ation, aldehydes
The approach to Lilial® is depicted in the Scheme 1. The
aldehyde 6, also known as odorants with the name of
Bourgeonal, is not commercially available8 and it was
prepared by a Wittig reaction between the commercially
available 4-tert-butylbenzaldehyde (3) and the commer-
cially available phosphorane 4. The successive reduction
with DIBAL-H of the amide 5 gave the α,β-unsaturated
aldehyde in good yield that was reduced by hydrogen to 6
by a standard procedure.9
Perception of odor is a process based on molecular recog-
nition: as consequence shape and chirality of molecules
are important for the olfactory properties.1 Although the
olfactory mechanism is still not clarified, the structural
and chiral features of a molecule are recognized by our
brain as a definite and characteristic odor sensation.2 The
spatial distribution of substituents around stereogenic
centers is therefore crucial when a process of molecular
recognition is involved. In fact, as the recognition is deter-
mined by chiral protein the enantiomers of chiral odorants
can be perceived in different ways by our olfaction.3 It is
therefore important to prepare different enantioenriched
chiral odorant in order to test, recognize, and evaluate
their potential behavior pure or as a mixture of stereoiso-
mers.4 Two of the most important odorants are Lilial® (1,
Figure 1) the most widely employed lily-type flavor, and
Muguesia (2, Figure 1). (R)-Lilial® (95% ee) was de-
scribed as stronger and more aggressive than the race-
mate,5 while (S)-Lilial® (93% ee) was found less
expressive than the racemate. Muguesia (2) is commer-
cially available by IFF Inc. as mixtures of two racemic dia-
stereoisomers.6 In the IFF catalogue online, Muguesia is
described as floral, rosy, and minty. Several stereoselec-
tive synthesis of 1 and 2 were described,5,6 especially with
enzymatic methods.6b,d
Me
N
O
CH2Cl2
r.t.
CHO
Ar
Me
+
Ar
N
OMe
4
3, Ar = 4-t-BuC6H4
PPh3 OMe
O
5, 98%
Me
1. DIBAL-H
THF, –40 °C
Ar
Ar
N
OMe
2. H2 (1 atm)
10% Pd/C, MeOH
5
O
O
6, 62%
Scheme 1 Synthesis of aldehyde 6
The aldehyde 6 obtained in 62% yield was used for the
enantioselective organocatalytic alkylation reaction with
the commercially available 1,3-benzodithiolylium tetra-
fluoroborate 7 (Scheme 2)7e in the presence of the
MacMillan’s catalyst 8.10
Me
N
1.
O
CHO
Ar
OH
Ar
N
H
OH
∗
Bn
⋅PhCOOH
8 (20 mol%)
NaH2PO4
6, Ar = 4-t-Bu-Ph
S
S
CHO
+
∗
∗
S
S
–
BF4
H2O–MeCN
t-Bu
Lilial® (1)
Muguesia (2)
7
2. NaBH4, MeOH
9, 91%, 95% ee
Figure 1 Lilial® and Muguesia structures
1. H2 (1 atm), Raney-Ni, EtOH
Ar
9
O
2. Dess–Martin periodinane
CH2Cl2
Recently, we have reported a straightforward and practi-
cal organocatalytic alkylation of aldehydes based on SN1-
type reaction.7 In this report, we described the application
of our methodology to the synthesis of 1 and 2. In addi-
tion, as in the Muguesia synthesis we have considered the
Lilial (1) 85%
Scheme 2 Enantioselective synthesis of 1
The desired product 9 was obtained in good yield and very
high enantiomeric excess. The successive treatment of 9
with Raney-Nickel11 and hydrogen removed the benzodi-
thiol in quantitative yield. The intermediate alcohol was
directly oxidized with Dess–Martin periodinane to Lilial®
SYNLETT 2013, 24, 0449–0452
Advanced online publication: 07.02.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318220; Art ID: ST-2013-B0031-L
© Georg Thieme Verlag Stuttgart · New York

450
A. Gualandi et al.
LETTER
(1), obtained in 85% yield and without loss of enantiopu- were tested, and a few results obtained are reported in Ta-
rity. The two enantiomers of Lilial® can be obtained with ble 1 (entries 1–4). Unfortunately, we found that the con-
the same synthetic strategy by choosing the appropriate trol on the diastereoselectivity exercised by the
enatiomer of 8 (S or R). On the other hand, the synthetic benzodithiol group was rather poor for methylating re-
approach to Muguesia (2) started with the commercially agents such as MeMgBr under various reaction condi-
available hydrocinnamaldehyde (10a), that was easily al- tions. The best results of diastereoselectivity in favor of
kylated to the derivative 11a by organocatalytic stereose- anti product 12aa were achieved when MeLi was used as
lective SN1 reaction. Differently from the synthesis of 1, nucleophile at –78 °C (entry 3) but we observed a modest
the aldehyde 11a was isolated in good yield and without conversion, probably due to metalation of the benzodithi-
racemization by using the MacMillan’s catalyst (8, ol group.7e
Scheme 3). Similarly, the adduct 11b, obtained in high
yield and enantioselectivity, was prepared starting from
propanal (10b).
OH
OH
R1
S
CHO
S
R1
S
R1
S
R2
anti
R2
syn
R2M
+
R
S
CHO
11a: R = Bn, 85%, 95% ee
R
CHO
S
S
10a,b
8 (20 mol%)
+
S
11b: R = Me, 96%, 96% ee
NaH2PO4
H2O–MeCN
S
S
–
BF4
12aa–ad
12ba–bc
11a,b
7
Scheme 4 Addition of organometallic reagents to aldehydes 11a,b
Scheme 3 Preparation of aldehydes 11a,b
As chiral α- and β-thioaldehydes were found behaving rel-
atively well when chelating Lewis acids were used in pro-
moting the addition of nucleophiles,12 we considered the
addition of Me2Zn in the presence of TiCl4.13 Pleasantly,
we obtained good results (Table 1, entry 4), and the de-
In order to prepare Muguesia, we performed the addition
of different nucleophilic methyl reagents (Scheme 4,
R2 = Me) to aldehydes 11a,b with the aim to introduce the
second stereogenic center in a diastereoselective fashion.
Different methyl nucleophilic organometallic reagents
Table 1 Addition of Organometallic Reagents to 11a,ba
Entry
R1
R2M
Conditions
Product
Conversion (%)b drb,c
1
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
MeMgBr
MeMgBr
MeLi
THF, 0 °C
12aa
12aa
12aa
12aa
12ab
12ac
12ac
12ad
12ba
12ba
12ba
12ba
12bb
12bb
12bc
98 (93)d
93
50:50
THF, –78 °C
52:48
64:36
9:91
3
THF, –78 °C
42
4
Me2Zn
TiCl4, CH2Cl2, –78 °C
THF, –78 °C
99 (91)d
86 (82)d
98
5
PhC≡CLi
allylSnBu3
allylSnBu3
vinylMgBr
MeMgBr
MeMgBr
MeLi
75:25
73:27
38:62
52:48
56:44
50:50
58:42
34:66
75:25
83:17
62:38
6
BF3·OEt2, CH2Cl2, –78 °C
TiCl4, CH2Cl2, –78 °C
Et2O, –78 °C
7
98
8
97
9
THF, 0 °C
79
10
11
12
13
14
15
THF, –78 °C
67
THF, –78 °C
62
Me2Zn
TiCl4, CH2Cl2, –78 °C
THF, 0 °C
95
PhC≡CLi
PhC≡CLi
allylSnBu3
99
THF, –78 °C
81 (76)d
97
BF3·OEt2, CH2Cl2, –78 °C
a To a solution of aldehyde (0.1 mmol) in the desiderate solvent (1 mL) and at the desiderate temperature, a solution of the organometallic re-
agent (2 equiv) was slowly added.
b Determined by 1H NMR spectroscopy.
c Diastereomeric ratio given as anti/syn.
d Isolated yield.
Synlett 2013, 24, 449–452
© Georg Thieme Verlag Stuttgart · New York

LETTER
Organocatalytic Enantioselective Access to Fragrance
451
sired 12aa was isolated in 91% yield and a diastereomeric compounds 1 and 6 present also toxicological and biolog-
ratio of 91:9 in favor of syn diastereoisomer.14 The com- ical activities in addition to their odorous properties.20
pound 12aa was transformed into the desired 2 by a hy-
drogenation performed in the presence of Nickel-Raney,
as depicted in Scheme 5. The facial control displayed by
Acknowledgment
Financial support for these researches came from Bologna Univer-
sity, PRIN (Rome) and European Project: BioCHEMLig, and
CATAFLU.OR project.
the benzodithiol in the diastereoselective methylation re-
action is probably determined by the chelation exercised
by the titanium Lewis acid on the sulfur atoms.12 To gain
more information about the diastereoselective addition of
nucleophiles to the chiral aldehydes 11a,b various or-
Supporting Information for this article is available online at
ganometallic reagents were employed (Table 1, entries 5– http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfooimgrattr
o
nSupprigI
o
tnnofrmat
15). Remarkably lithium phenylacetylide is favoring the
anti diastereoisomer probably through a Felkin–Anh
transition state, and similar results15 were obtained by the
addition of allylstannane promoted by the non-chelating
Lewis acid BF3.16
References and Notes
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12aa
(syn/anti 91:9)
2, 93%
(syn/anti 92:8)
Scheme 5 Reductive removal of the benzodithiol group to give
Muguesia (2)
Finally, we investigated the addition of thioester enolate
derivatives to 11a,b by using two different protocols
(Scheme 6).17 The silyl ketene thioacetal of tert-butyl
thioacetate was added to the chiral aldehydes in the pres-
ence of BF3. We obtained a moderate diasteromeric ratio
with aldehyde 11b in favor of the anti diastereoisomer.18
The opposite syn diastereoisomer was obtained in moder-
ate amount when the addition of the titanium enolate of
the tert-butyl thioacetate was considered.19
OH
O
R
S
CHO
S
R
S
St-Bu
S
(3R,4S) / (3S,4S)
method A or B
13a method A: 61%, 60
13b method A: 73%, 81
13b method B: 84%, 39
:
:
:
40
19
71
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79.
11a,b
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method B:
St-Bu, BF3⋅OEt2, CH2Cl2, –78 °C
O
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by comparison of 1H NMR signals (see ref. 6b) of compound
2 obtained after removal of the benzodithiol group.
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Haudrechy, A. Chem. Rev. 2006, 106, 2355. For theoretical
studies which support the polar Felkin–Anh model, see:
St-Bu, TiCl4, Et3N, CH2Cl2, –78 °C
Scheme 6 Addition of thioester enolates to aldehydes 11a,b
In conclusion, we have prepared, in a very straightforward
and rapid manner, two key compounds for the synthesis of
fragrances by the use of our organocatalytic SN1-type ap-
proach in the key step. Studies towards the application of
this methodology towards the synthesis of natural prod-
ucts are in progress in our laboratory. It is noteworthy that
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 449–452

452
A. Gualandi et al.
LETTER
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Synlett 2013, 24, 449–452
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