Catalytic enantioselective β-alkylation of α,β-unsaturated aldehydes by combination of transition-metal- and aminocatalysis: Total synthesis of bisabolane sesquiterpenes

Article abstract of DOI:10.1002/chem.201100756

Branching out! The first co-catalytic enantioselective (up to 98:2 e.r.) β-alkylation of α,β-unsaturated aldehydes by combination of simple chiral amine and copper catalysts provides β-branched aldehydes in a one-pot protocol (see scheme). The methodology was applied to the short total syntheses of bisabolane sesquiterpenes (S)-(+)-curcumene, (E)-(S)-(+)-3- dehydrocurcumene and (S)-(+)-tumerone.

Full text of DOI:10.1002/chem.201100756

DOI: 10.1002/chem.201100756
Catalytic Enantioselective b-Alkylation of a,b-Unsaturated Aldehydes by
Combination of Transition-Metal- and Aminocatalysis: Total Synthesis of
Bisabolane Sesquiterpenes
Samson Afewerki,[a] Palle Breistein,[a] Kristian Pirttilꢀ,[a] Luca Deiana,[b, c]
Pawel Dziedzic,[b, c] Ismail Ibrahem,*[a] and Armando Cꢁrdova*[a, b, c]
b-Alkyl substituted aldehydes are constituents of biologi-
cally active natural products (e.g. (S)-citronellal) and valua-
ble chiral building blocks in asymmetric synthesis. For exam-
ple, they can be used as synthons for the total synthesis of
sesquiterpenes and polyketides.[1] In this context, natural
products such as bisabolane sesquiterpenes (e.g., (S)-(+)-
curcumene 1, (S)-(+)-dehydrocurcumene 2, and (S)-(+)-tu-
merone) 3, which exhibit anti-cancer as well as antimicrobial
activities and are used as additives in perfumes, flavors, and
cosmetics,[1a–c,2] could be rapidly assembled according to ret-
rosynthetic analysis from (3S)-b-methyl aldehyde (6k).
metallic reagents to a,b-unsaturated carbonyl compounds
have been achieved.[3] In particular, the enantioselective
copper-catalyzed conjugate addition of organometallic re-
agents using different types of chiral ligand systems on the
metal provides high stereocontrol.[3] This research has
shown that the direct transition-metal-catalyzed enantiose-
lective 1,4-addition of an organometallic reagent to an a,b-
unsaturated aldehyde 5 in the presence of a chiral ligand is
very challenging due to a competing 1,2-addition reaction,
which gives both the b-aldehyde 6 and alcohol 7, respective-
ly (Scheme 1).[4b–c,5]
Scheme 1.
Based on our research on combination of aminocatalysis
and transition-metal catalysis,[6–8] we found that the chiral
amine-catalyzed iminium activation[9] of an a,b-unsaturated
aldehyde 2 can be combined with a copper-catalyzed conju-
gate addition of a silyl nucleophile to achieve the stereose-
À
Recently, major breakthroughs in transition-metal-cata-
lyzed enantioselective conjugate addition (ECA) of organo-
lective C Si-bond formation via transition state
(Scheme 2).[10]
I
According to these findings and a “retrocatalytic” analy-
sis, we envisioned that this type of dual catalysis[10] could be
applied to the asymmetric addition of a carbon nucleophile
(e.g., organozinc reagent R2Zn) to a,b-unsaturated alde-
[a] S. Afewerki, P. Breistein, K. Pirttilꢀ, Prof. I. Ibrahem,
Prof. A. Cꢁrdova
hydes
5 and afford b-alkyl substituted aldehydes 6
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University, 851 70 Sundsvall (Sweden)
E-mail: ismail.ibrahem@miun.se
(Scheme 3). Thus, the key to success would be the ability of
a chiral amine catalyst to lower the LUMO of an enal 5 by
iminium activation in combination with simultaneous
copper-catalyzed conjugate addition of an organometallic re-
agent to this intermediate and favor 1,4-addition over 1,2-
addition. If successful, we planned to employ this potential
co-catalytic stereoselective reaction as the key transforma-
tion for the total synthesis of sesquiterpenes such as 1–3.
Herein we present the asymmetric b-alkylation of a,b-un-
saturated aldehydes by the one-pot combination of a simple
chiral amine and transition-metal catalyst without the use of
a glove box. Next, this novel co-catalytic b-alkylation was
armando.cordova@miun.se
acordova@organ.su.se
[b] L. Deiana, Dr. P. Dziedzic, Prof. A. Cꢁrdova
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
[c] L. Deiana, Dr. P. Dziedzic, Prof. A. Cꢁrdova
The Berzelii Center EXSELENT, Stockholm University
106 91 Stockholm (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100756.
8784
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8784 – 8788

COMMUNICATION
Table 1. Condition screening.[a]
Entry
Cat.
Ligand
t
Conv.
[%][b]
Ratio
e.r.[d]
[h]
6/7[c]
1
2
3
4
5
6
7
8
–
9a
–
–
12
9
91
29
18
58
53
60
38
>98
75
45
38
8
27
19
11
72
24
23
3:97
22:78
84:16
62:38
8:92
50:50
78:22
7:23
8a[e]
8a
12
12
17
18
17
14
15
12
12
8
11
12
9
16
23
4
8a
8b
8c
8d
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9 f
9a
9a
–
96:4
61:39
90:10
47:53
47:53
62:38
95:5
87:13
76:24
89:11
94:6
48:52
8:92
8e
19:90
12:88
58:42
76:24
77:23
49:51
86:14
36:64
34:66
76:24
16:84
9
8 f
Scheme 2. Chiral amine- and Cu-co-catalyzed enantioselective b-silyla-
tion of enals 5.
10
11
12
13
14
15
16
17
18
8a[f]
8a
8a[g]
8a
8a
8a
82:18
88:12
91:9
8a[h]
8a[i]
8a[j]
71:29
[a] Under N2 atmosphere. [b] Determined by GC analysis of the crude re-
action mixtures. [c] Determined by GC analysis and 1H NMR analysis of
the crude reaction mixtures. [d] Determined by chiral-phase GC analysis.
The enantiomeric excess (ee) value of 7a was 0% for all cases. [e] The re-
action was performed without CuACHTNUTRGNENG(U OTf)2 catalyst.[f] 8a (20 mol%).
[g] The ligand was premixed with the base KOtBu and the reaction per-
formed at RT. [h] Reaction run at RT. [i] CuTC (copper thiophene car-
boxylate, 2 mol%), 9a (4 mol%) at RT. [j] CuCl (10 mol%) at 508C.
Scheme 3.
ratio (e.r.) of 78:22. To our delight, the combination of
chiral amine 8a[13] and Cu
ACHTUNGTRENNUNG
employed as the key step for the expeditious total synthesis
of bisabolane sesquiterpenes.
reaction towards a
84:16) and gave 6a with 77:23 e.r. (Table 1, entry 3).
We began probing the reaction between Et2Zn and cin-
namic aldehyde 5a by using different copper salts and chiral
amines 8 as catalysts. We found that the highest 1,4-selectivi-
ty and enantioselectivity was achieved when copper(II) tri-
To improve the conversion and enantioselectivity of the
asymmetric conjugate addition, we decided to employ Lewis
bases such as organic phosphines and N-heterocyclic car-
benes 9 as ligands for the copper catalyst.[14] In most cases,
the reaction was 1,4-selective and gave 6a with good to high
flate (CuACHTUNGTRENNUNG(OTf)2, 10 mol%) was employed as the transition-
metal co-catalyst and THF as
the solvent at 608C (Table 1).[11]
Key results are shown in
Table 1. The reaction that was
performed without the chiral
amine co-catalyst 8 gave the
corresponding racemic alde-
hyde 6a and alcohol 7a in a
ratio of 3:97 (Table 1, entry 1).
Thus, this reaction was highly
1,2-selective. The reaction per-
formed in the presence of chiral
amine catalyst 8a without
a
copper-catalyst was also 1,2-se-
lective (6a/7a; 22:78; Table 1,
entry 2), however, (S)-6a[12] was
formed with an enantiomeric
Chem. Eur. J. 2011, 17, 8784 – 8788
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www.chemeurj.org
8785

A. Cꢁrdova, I. Ibrahem et al.
enantiomeric ratios. The highest conversion was achieved
when PPh3 was employed as the additive. Of the screened
catalysts of type 8, the protected diarylprolinol 8a co-cata-
lyzed the asymmetric conjugate addition with the best enan-
tioselectivity. For example, aldehyde 6a was formed with up
to 96:4 e.r. (Table 1, entry 4). Lowering the catalyst loading
of 8a slightly decreased the e.r. of 6a to 95:5 (Table 1,
entry 10). With these results in hand, we decided to probe
the scope of the catalytic ECA of organozinc reagent R2Zn
enals 5b and 5 f gave the corresponding aldehydes 6j and
6k with 98:2 and 97:3 e.r., respectively (Table 2, entries 9
and 10). The co-catalytic asymmetric conjugate addition of
dialklzinc reagent Me2Zn did also work for aliphatic enals 5
as acceptors but gave lower e.r. values (Table 2, entries 11
and 12).
Finally the methodology was applied to the short total
synthesis of (S)-(+)-curcumene 1, (E)-(S)-(+)-3-dehydrocur-
cumene 2, and (S)-(+)-tumerone 3 (Scheme 4), which have
been popular targets for the synthetic community. However,
there have been fewer enantioselective syntheses to date of
tumerone 3.[15] Our syntheses began with the synthesis of al-
dehyde (S)-6k[12] (97:3 e.r.), derived by co-catalytic ECA of
Me2Zn to enal 5 f. The subsequent reduction of 6k, tosyla-
tion and nucleophilic displacement gave iodine 11 in 65%
overall yield (three steps). Grignard addition of 10 to 11
gave curcumene 1 in 57% yield. The synthesis of dehydro-
curcumene 2 began with a Wittig reaction between aldehyde
6k and 12 to give enone 13 in 64% yield. A subsequent
Wittig reaction gave dehydrocurcumene 2 in 68% yield. Tur-
merone 3 was rapidly assembled in 51% overall yield in a
one-pot procedure involving a Grignard addition of 10 with
aldehyde 6k followed by oxidation with tetrapropylammoni-
um perruthenate (TPAP).[16] Thus, this synthesis was com-
pleted in two purification steps from a,b-unsaturated alde-
hyde 5 f and delivered the target compound with 97:3 e.r.
The absolute configuration at C3 of b-alkyl aldehyde 6k
was S (R=Ar) as established by the above enantioselective
total synthesis. Thus, employing (S)-8a as the chiral co-cata-
lyst gave the corresponding b-branched aldehydes (S)-6. We
also investigated the crude reaction with HRMS[17] and
found that iminium intermediates II (Scheme 5) were
formed by condensation between chiral amine 8a and enals
5 (Figure 1). In addition, the iminium intermediate formed
between product 6a and the chiral amine catalyst 8a was
observed. Moreover, the ability of chiral amine 8a to switch
the 1,2-selectivity of the copper-catalyzed organozinc addi-
to a,b-unsaturated aldehydes 5 using CuACTHNURTGNENG(U OTf)2 as the metal
catalyst, 8a as the chiral amine, and 9a as the additive in
THF at 608C (Table 2).
Table 2. The scope of the co-catalyzed ECA of R2Zn to enals 5.[a]
Entry R1
R
Product
t
Yield 6 Ratio e.r.[d]
[h] [%][b]
6:7[c]
1
2
3
4
5
6
7
8
4-MeOC6H4 Et
6b
6c
6d
6e
6 f
6g
6h
6i
13
16
18
13
13
9
83
62
60
47
44
71
44
79
76
65
23[j]
60[j]
85:15 98:2
64:36 98:2
63:37 95:5
78:22 96:4
75:25 98:2
83:17 97:3
79:21 97:3
80:20 98:2
2-naphth
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-iPrC6H4
3-ClC6H4
Et
Et
Et
Et
Et
Et
9
3-MeOC6H4 Et
11
16
14
14
16
9
4-MeOC6H4 Me[f]
6j
6k
91:9
93:7
98:2
97:3
10
11
12
3-MeC6H4
nBu
nBu
Me[f]
Me[g,h] 6l
51:49 92:8
80:20 83:17
Me[g,i]
6l
[a] Under N2 atmosphere. [b] Yield of pure isolated 6 after silica gel
column chromatography. [c] Determined by 1H NMR analysis of the
crude reaction mixture. [d] Determined by chiral-phase HPLC or chiral
GC analyses. The ee value of products 7 is 0%. [f] Reaction run at 228C.
[g] Reaction run at 458C. [h] Me2Zn added at 228C. [i] Me2Zn added at
À788C. [j] Yield determined by GC.
The co-catalytic ECA of
Et2Zn to enals 5 with an aryl
substituent at the b position
proceeded with good 1,4-selec-
tivities and high enantioselec-
tivity to give the corresponding
b-alkylaldehyde products 6a–6i
(Table 2, entries 1–8). The high-
est selectivities for the co-cata-
lytic asymmetric reactions were
achieved when 3-substituted
enals 5 with a 3- or 4-MeOPh
group was used as the sub-
strates (Table 2, entries 1 and
8). The co-catalytic transforma-
tions using Me2Zn as the re-
agent was 1,4-selective and
Scheme 4. a) Me2Zn, cat. 8a, cat. Cu
gave the corresponding product
6 with a high e.r. value. For ex-
AHCTNUGTERN(GNUN OTf)2, cat. 9a, THF, 608C. b) NaBH4, CH2Cl2, MeOH, 08C; c) TsCl, pyri-
dine, CH2Cl2, RT, 5 h; d) NaI, acetone, reflux, 2 h; e) 10, CuI, THF, 08C, 5 h; f) 12, CHCl3, reflux, 16 h;
g) Ph3PMeBr, BuLi, Et2O; h) 10, THF, 08C, 1 h; i) tetrapropylammonium perruthenate (TPAP), N-methylmor-
ample, the ECA of Me2Zn to pholine-N-oxide (NMO), CH2Cl2, MS (4 ꢃ), 3 h.
8786
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Chem. Eur. J. 2011, 17, 8784 – 8788

Catalytic Enantioselective b-Alkylation of a,b-Unsaturated Aldehydes
COMMUNICATION
approaches the less sterically hindered Si face (R=Ar) of
the chiral iminium intermediate III and performs the selec-
tive 1,4-addition of the carbon nucleophile at its b carbon to
give intermediate IV (Scheme 5). Subsequent hydrolysis of
iminium intermediate IV regenerates the chiral catalyst 8 as
well as the active copper catalyst complex 14. Aqueous
work up gives the desired b-alkyl aldehyde product 6.
In summary, we disclose the first example of enantioselec-
tive b-alkylation of a,b-unsaturated aldehydes by combina-
tion of aminocatalysis and transition-metal catalysis. The co-
catalyzed asymmetric 1,4-addition gave the corresponding b-
alkyl aldehydes with up to 98:2 e.r. Thus, simple bench-
stable chiral amines can be used as catalyst in combination
with a copper salt without the use of a glove box to achieve
catalytic asymmetric addition of dialkylzinc reagents to
enals with high enantioselectivity. The novel co-catalytic re-
action was utilized as the key step for the expeditious total
synthesis of bisabolane sesquiterpenes. Further development
of this class of co-catalytic asymmetric conjugate additions
and its application in total synthesis is ongoing in our labo-
ratories.
Acknowledgements
Financial support was provided by the Mid Sweden University and The
Swedish National Research Council (VR). I. I. is grateful for repatria-
tion funding from VR. We are grateful to Hꢄkan Norberg for help in set-
ting up the lab. The Berzelii Center EXSELENT is financially supported
by VR and the Swedish Governmental Agency for Innovation Systems
(VINNOVA).
Keywords: aldehydes · alkylation · asymmetric conjugate
additions · enantioselectivity · co-catalysis · zinc
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Chem. Eur. J. 2011, 17, 8784 – 8788
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8787

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Received: March 11, 2011
Published online: July 5, 2011
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