Highly regio- and stereoselective double Michael addition-cyclization of 2,3-allenoates with organozinc compounds: Efficient synthesis of 5-benzylidenecyclohex-2-enones

Article abstract of DOI:10.1002/anie.200801497

(Chemical Equation Presented) Highly substituted α,β-unsaturated cyclohexenones, a key structural motif in many natural products, were prepared in the title reaction (see scheme). High diastereoselectivity was observed with respect to the two stereogenic centers at the 4-and 6-positions. When optically active starting materials were used, the desired products were formed without evident racemization. A rationale for the observed stereoselectivity is proposed.

Full text of DOI:10.1002/anie.200801497

Angewandte
Chemie
DOI: 10.1002/anie.200801497
Domino Reactions
Highly Regio- and Stereoselective Double Michael Addition–
Cyclization of 2,3-Allenoates with Organozinc Compounds: Efficient
Synthesis of 5-Benzylidenecyclohex-2-enones**
Zhan Lu, Guobi Chai, and Shengming Ma*
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
Table 1: Effects of reaction time and the amount of diethylzinc on the
Highly substituted a,b-unsaturated cyclohexenones, which
addition–cyclization of 2,3-allenoate 1a with diethylzinc.
are found in a wide range of natural products, have caught the
attention of many synthetic organic and medicinal chemists.[1]
For example, (+)-guttiferone, hyperforin, and aristoforin are
inhibitors of the human sirtuins SIRT1 and SIRT2;[1a]
bisorbicillinol exhibits antioxidant activity; bisvertinolone is
an antifungal agent;[1b,c] and garsubellin A has potent neuro-
trophic activity.[1d] a,b-Unsaturated cyclohexenones have also
been used as intermediates to synthesize other natural
products, such as carvone.[2] Herein, we report a highly
regio- and stereoselective double addition–cyclization reac-
tion of two molecules of a 2,3-allenoate with organozinc
compounds providing an efficient route to highly substituted
5-benzylidenecyclohex-2-enone derivatives.
Entry
x
t1 [min]
t2 [h]
Yield of
Yield of
2a [%][a]
3a [%][a]
1[b]
2
3
4
5
3
3
3
2
90
90
15
15
15
6
9
10
10
10
47
61
69
60
58
14
14
5
14
16
1.5
Recently, we reported an iron-catalyzed conjugate addi-
tion reaction of 2,3-allenoates with Grignard reagents to
afford b,g-unsaturated alkenoates with high regio- and
stereoselectivity.[3] When we attempted the reaction of ethyl
2-methyl-4-phenyl-2,3-butadienoate (1a)with diethylzinc
[a] The yield was determined by NMR spectroscopy using CH2Br2 as the
internal standard. [b] Fe(acac)3 (5 mol%) was added as a catalyst. acac=
acetylacetonate.
(3 equiv)under the catalysis of Fe(acac) by treatment at
3
À788C for 1.5 h followed by warming to room temperature
for 6 h, the conjugate addition product ethyl 3-ethyl-2-methyl-
4-phenyl-3-butenoate (3a)was formed in low yield along with
an unknown side product (Table 1, entry 1). Through spec-
troscopic analysis (1H and 13C NMR, MS)and X-ray diffrac-
tion analysis,[4] we identified that the side product contained a
cyclohexenone unit with an exo Z carbon–carbon double
bond, and that the reaction showed excellent diastereoselec-
tivity with respect to the two stereogenic centers at the 4- and
6-positions (Figure 1). A control experiment showed that the
reaction even proceeds in the absence of Fe(acac)3 to afford
2a in 61% yield (Table 1, entry 2). The yield of 2a decreased
[*] Z. Lu, G. Chai, Prof. Dr. S. Ma
Laboratory of Molecular Recognition and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027, Zhejiang (China)
Fax: (+86)21-6416-7510
Figure 1. ORTEP representation of 2a.
E-mail: masm@mail.sioc.ac.cn
[**] Financial support was received from the National Natural Science
Foundation of China (20732005) and the Major State Basic
Research Development Program (2006CB806105). Shengming Ma
is a Qiu Shi Adjunct Professor at Zhejiang University. We thank
Guangke He in this research group for reproducing the results
presented in entries 2, 4, 5, and 9 of Table 3.
when less diethylzinc was used (Table 1, entries 3–5). Fur-
thermore, we found that when a solution of diethylzinc in
hexanes was added dropwise to a solution of 1a in toluene at
room temperature, the reaction also afforded 2a in 76% yield
together with 3a in 10% yield (Table 2, entry 1). The solvents
THF, Et2O, Bu2O, CH2Cl2, benzene, and ethylbenzene failed
to give better results (Table 2, entries 2–7). Therefore, for
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801497.
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Table 2: Effect of the solvent on the addition–cyclization of 2,3-allenoate
1a with diethylzinc.
dimethylzinc was used, the product was not formed at room
temperature (Table 3, entry 8); at 100 8C, the corresponding
products were formed in 52–64% yield (Table 3, entries 9–
11).
The reaction of the optically active 2,3-allenoates (R) - or
(S)-1a and 1c[5] with dialkyl zinc reagents afforded the
corresponding optically active cyclohex-2-enones without
racemization (Table 4). The absolute configuration of the
Entry
Solvent
Yield of
Yield of
Recovery of
2a [%][a]
3a [%][a]
1a [%][a]
Table 4: Addition–cyclization of optically active 2,3-allenoates 1 with
dialkyl zinc reagents.[a]
1
2
3
4
5
6
7
toluene
THF
Et2O
76
trace
46
50
57
10
13
20
16
17
8
–
68
10
–
8
–
Bu2O
CH2Cl2
benzene
ethylbenzene
59
72
10
–
[a] The yield was determined by NMR spectroscopy using CH2Br2 as the
internal standard.
Entry
1
R
t [h]
2
Ar
ee
Yield ee
[%][b]
[%][c] [%][b]
further study, we defined the standard reaction conditions to
be the addition of a dialkyl zinc reagent (3 equiv)to a solution
of the 2,3-alkadienoate in toluene at room temperature
(Table 2, entry 1). 1H NMR spectroscopic analysis of the
crude product showed that only one diastereoisomer was
formed.
The scope of the reaction was investigated under these
standard conditions (Table 3). The reaction of a variety of
substituted 2,3-allenoates with dialkyl zinc reagents afforded
the cyclohex-2-enone derivatives with high regio- and stereo-
selectivities. Aryl groups with electron-withdrawing or elec-
tron-donating substituents are tolerated, and the reaction
proceeds when R1 and R2 are alkyl groups. When diethyl- or
dibutylzinc were used, the reaction proceeded at room
temperature (Table 3, entries 1–7 and 12). However, when
1
2
3
4
5
6
7
8
(R)-1a Ph
(S)-1a Ph
(R)-1a Ph
(S)-1a Ph
(R)-1a Ph
(S)-1a Ph
97
96
97
96
98
96
Et
Et
1[d]
3[d]
(4S,6R)-2a 61
(4R,6S)-2a 76
(4S,6R)-2h 51
(4R,6S)-2h 52
(4S,6R)-2k 69
(4R,6S)-2k 73
97
96
95
95
97
96
92
85
Me 12[e]
Me 12[e]
nBu 5[f]
nBu 4[g]
(R)-1c p-BrC6H4 92
(S)-1c p-BrC6H4 86
Et
Et
4.5[d] (4S,6R)-2c 65
3[d]
(4R,6S)-2c 69
[a] The reaction was conducted with Et2Zn in hexanes (0.88m), Me2Zn in
toluene (1.2m), or nBu2Zn in heptane (1.0m). [b] Determined by HPLC
on a chiral phase. [c] Yield of the isolated product. [d] The reaction was
carried out at room temperature. [e] The reaction was carried out at
1008C. [f] The reaction was carried out at room temperature for 3 h, then
at 308C for 2 h. [g] The reaction was carried out at room temperature for
2 h, then at 508C for 2 h.
Table 3: Addition–cyclization of 2,3-allenoates
1 with dialkyl zinc
reagents.[a]
products was established by X-ray diffraction analysis of (À)-
(4S,6R)-2c by using the two bromine atoms as the reference
(Figure 2).[4,6] The reactions of (À)-(R)-1a (97% ee)and ( +)-
Entry Ar
R1
R2
R
T [8C] t [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
Ph
Ph
p-BrC6H4
p-ClC6H4
p-FC6H4
p-MeOC6H4 Me Et (1 f)
Ph
Ph
Ph
Me Et (1a)
Me Me (1b) Et
Me Et (1c)
Me Et (1d)
Me Et (1e)
Et
RT
RT
RT
RT
RT
RT
RT
1
23
3
3
8
65 (2a)
79 (2b)
63 (2c)
69 (2d)
65 (2e)
57 (2 f)
47 (2g)
Et
Et
Et
Et
Et
2
3
Et
Et (1g)
[c]
Me Et (1a)
Me Et (1a)
Me Me (1b) Me 100
Me Et (1d)
Me Et (1a)
Me RT
Me 100
13
18
24
12
3
–
52 (2h)
64 (2i)
60 (2j)
82 (2k)
10
11
12
Ph
p-ClC6H4
Ph
Me 100
nBu RT
[a] The reaction was conducted with Et2Zn in hexanes (0.88m), Me2Zn in
toluene (1.2m), or nBu2Zn in heptane (1.0m). [b] Yield of the isolated
product. [c] The substrate 1a was recovered in 60% yield.
Figure 2. ORTEP representation of (À)-(4S,6R)-2c.
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(S)-1a (96% ee)proceeded even with Me 2Zn at
1008C to give the products (À)-(4S,6R)-2h and
(+)-(4R,6S)-2h with 95% ee (Table 4, entries 3 and
4).
A model to predict the stereochemical outcome
of this reaction is shown in Scheme 1. In the first
step, the regio- and stereoselective Michael addi-
tion[7] of Et2Zn to (À)-(R)-1a affords the optically
active a-zincated 2-alkenoate 4.[8]
A second
Michael addition[7] of the g-carbon atom of inter-
mediate 4 to the center carbon atom of the allene
moiety in (À)-(R)-1a affords 5A with high stereo-
Scheme 2. Mechanistic study. Yields and recoveries were determined by NMR
spectroscopy using CH2Br2 as the internal standard.
ZnBr2 (0.5 equiv)at À788C. The reaction of this zinc 1,3-
dienolate with the remaining 0.5 equivalents of (À)-(R)-1a
afforded the cyclic product 2a in 7% yield with 0% ee
(Scheme 2). This result ruled out the possibility that the
racemic[11] zinc 1,3-dienolate reacts with (À)-(R)-1a to afford
the optically active cyclic product 2.[9] Further study is
required to determine the true mechanistic nature of this
transformation.[12]
In summary, we have developed a highly regio- and
stereoselective double Michael addition–cyclization of two
molecules of a 2,3-allenoate with organozinc compounds. The
(Z)-5-benzylidenecyclohex-2-enones were produced with
high diastereoselectivity with respect to the two stereogenic
centers at the 4- and 6-positions. The aromatic group at the 4-
position may increase the reactivity of 2,3-allenoates towards
organozinc compounds. When optically active 2,3-allenoates
were employed, optically active (Z)-5-benzylidenecyclohex-
2-enones were produced without racemization. Owing to the
relatively low reactivity of dialkyl zinc reagents in terms of
[7a]
=
conjugate addition to C C bonds,
this study should
stimulate new research in the chemistry of organozinc
compounds. We are conducting further studies in this area.
Scheme 1. Model for the prediction of the stereochemical outcome of
the reaction.
selectivity. Its conformer 5B then undergoes an intramolec-
ular 1,2-addition reaction to form the six-membered ring.
Owing to the steric interaction between the Ar group (in this
case phenyl)of the 2,3-allenoate and the approaching allylic
Experimental Section
Synthesis of (Æ )-2a: Allene 1a (83.6 mg, 0.4 mmol)and toluene
(5 mL)were added sequentially to a dried Schlenk tube under a
nitrogen atmosphere at room temperature. A solution of Et2Zn in
hexanes (1.36 mL, 1.2 mmol, 3 equiv)was then added to the reaction
mixture with a syringe over 3–5 min at room temperature. When the
reaction was complete (as monitored by TLC), it was quenched by the
dropwise addition of saturated NH4Cl (1 mL)and then water (5 mL)
at room temperature. The mixture was extracted with diethyl ether
(3 ” 30 mL), and the organic layer was washed with dilute aqueous
HCl (1%), a saturated aqueous solution of NaHCO3, and brine, and
dried over anhydrous Na2SO4. Evaporation and column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 20:1)
=
group in 4, the Z stereoselectivity for the exo C C bond is
high.[3] Of course, 4 may be further converted into the
optically active atropisomeric zinc 1,3-dienolate 6,[9] which
would be transformed into racemic 7 or 5A upon reaction
with H+ or (À)-(R)-1a, respectively. However, the fact that
the zinc 1,3-dienolate formed by transmetalation with ZnBr2
of the magnesium 1,3-dienolate (prepared by the iron-
catalyzed conjugate addition of a Grignard reagent to (Æ )-
1a)[3] reacted with 2,3-allenoate (Æ )-1a to afford (Æ )-2a in
less than 3% yield (as determined by NMR spectroscopy)
indicated the low reactivity of the zinc dienolate intermediate
6 towards 1a[10] (Scheme 2). In a further test reaction, a
magnesium 1,3-dienolate was formed by the Fe(acac)3-
catalyzed Michael addition reaction of (À)-(R)-1a with
EtMgBr (0.5 equiv)at À788C and subsequently converted
into a zinc 1,3-dienolate of type 6 by transmetalation with
afforded (Z)-2a (0.0520 g, 65%)as
a solid. M.p.: 125–126 8C
(hexane); IR (neat): n˜ = 2975, 2939, 1744, 1667, 1641, 1599, 1492,
1449, 1366, 1223, 1193, 1098 cmÀ1; H NMR (300 MHz, CDCl3): d =
1
7.35–7.17 (m, 8H), 7.17–7.09 (m, 2H), 6.86 (s, 1H), 4.47 (s, 1H), 3.60–
3.47 (m, 1H), 3.30–3.15 (m, 1H), 2.70–2.50 (m, 1H), 2.22–2.10 (m,
1H), 2.00 (s, 3H), 1.20–1.10 (m, 6H), 0.90 ppm (t, J = 7.1 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d = 197.3, 170.4, 157.7, 141.5, 141.4,
136.0, 131.4, 129.0, 128.63, 128.58, 127.9, 127.6, 127.2, 127.1, 60.9, 58.6,
54.3, 27.4, 24.2, 13.4, 11.9, 11.6 ppm; MS: m/z (%): 388 (M+, 61), 315
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Communications
(100); elemental analysis: calcd (%) for C 26H28O3: C 80.38, H 7.26;
found: C 80.45, H 7.10.
[4] Crystal data for 2a: C26H28O3, Mr = 388.51, monoclinic, P121/c1,
MoKa, final R indices (I > 2s(I)): R1 = 0.0491, wR2 = 0.1028, a =
10.4687(8), b = 14.8999(10), c = 14.6133(10)Š, a = 90, b =
103.0580(19), g = 908, V= 2220.5(3)Š 3, Z = 4, number of reflec-
tions measured/unique: 5052/1585 (Rint = 0.061), number of
observations: 5051 (I > 2s(I)), 291 parameters. CCDC 672093
(2a)and CCDC 672094 (( À)-(4S,6R)-2c)contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of (+)-(4R,6S)-(Z)-2a: The treatment of (+)-(S)-1a
(0.0404 g, 0.2 mmol, 96% ee; [a]2D0 = + 285.3 degcm3 gÀ1 dmÀ1 (c =
0.82 gdLÀ1, CHCl3))[1d] in toluene (2.5 mL)with a solution of Et Zn
2
in hexanes (0.88m, 0.70 mL, 0.6 mmol, 3 equiv)afforded ( +)-(4R,6S)-
(Z)-2a (0.0297 g, 76%, 96% ee). The ee value was determined by
HPLC (chiralcel AD-H, n-hexane/iPrOH = 95:5, 0.7 mLminÀ1, n =
230 nm,
tR(minor) = 7.8 min,
tR(major) = 8.7 min).
[a]2D0
=
+ 74.6 degcm3 gÀ1 dmÀ1 (c = 1.49 gdLÀ1, CHCl3). The analytical and
spectroscopic data of (+)-(4R,6S)-(Z)-2a were identical to those of
racemic (Z)-2a.
[5] S. Ma, S. Wu, Chem. Commun. 2001, 441.
[6] Crystal data for (À)-(4S,6R)-2c: C26H26Br2O3, Mr = 546.30,
monoclinic, P1211, MoKa, final R indices (I > 2s(I)): R1 =
0.0635, wR2 = 0.1966, a = 7.3758(4), b = 24.7978(13), c =
Received: March 30, 2008
Revised: April 30, 2008
Published online: July 9, 2008
14.0258(7)Š,
a = 90,
b = 90.2228(14),
g = 908,
V=
2565.4(2)Š 3, Z = 4, number of reflections measured/unique:
5956/3461 (Rint = 0.073), number of observations: 5956 (I >
2s(I)), 561 parameters.
Keywords: allenes · cyclization · esters · Michael addition ·
.
[7] For a monograph on carbozincation, see: a)E. Lorthiois, C.
Meyer, The Chemistry of Organozinc Compounds (Eds.: Z.
Rappoport, I. Marek), Wiley, Chichester, 2006, pp. 863 – 977; for
the uncatalyzed Michael addition of tBu2Zn to conjugated
alkynes, see: b)J. Auger, G. Courtois, L. Miginiac, J. Organomet.
Chem. 1977, 133, 285; c)G. Courtois, L. Miginiac, J. Organomet.
Chem. 1980, 194, 13; d)L. Miginiac, J. Organomet. Chem. 1982,
238, 235; for the anti addition of nucleophiles to allenoates, see:
e)Y. Naruse, S. Kakita, A. Tsunekawa, Synlett 1995, 711.
[8] In the reported crystal structure of the Reformatsky reagent
organozinc reagents
[1] a)C. Gey, S. Kyrylenko, L. Hennig, L.-N. D. Nguyen, A. Büttner,
H. D. Pham, A. Giannis, Angew. Chem. 2007, 119, 5311; Angew.
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giannakis, K. B. Simonsen, P. S. Baran, Y.-L. Zhong, V. P. Vidali,
E. N. Pitsinos, E. A. Couladouros, J. Am. Chem. Soc. 2000, 122,
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the catalytic enantioselective alkylative aldol reaction of allenic
esters and ketones with dialkyl zinc reagents towards the
synthesis of functionalized d-lactones, see: h)D. Zhao, K.
Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128,
14440.
À
(BrZnCH2COOtBu·THF)2, the C Zn bond was clearly visible:
a)J. Dekker, P. H. M. Budzelaar, J. Boersma, G. J. M. van der
Kerk, A. L. Spek, Organometallics 1984, 3, 1403; see also: b)J.
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van der Kerk, A. L. Spek, A. J. M. Duisenberg, J. Organomet.
Chem. 1987, 320, 1; for the configurational stability of organo-
zinc reagents, see: S. Klein, I. Marek, J. F. Normant, J. Org.
Chem. 1994, 59, 2925.
[9] We thank one of the referees for suggesting this mechanistic
possibility.
[10] The fact that we did not observe the formation of the six-
membered product 2 during the studies described in ref. [3]
indicates the lower reactivity of magnesium 1,3-dienolates
towards 2,3-allenoates.
[11] The reaction of optically active (À)-(R)-2a with RMgBr
provided the racemic products of conjugate addition.
[12] For an uncatalyzed addition of a dialkyl zinc reagent to 2-
alkenoates with a radical mechanism, see: F. Denes, S. Cutri, A.
Perez-Luna, F. Chemla, Chem. Eur. J. 2006, 12, 6506.
[2] a)A. Srikrishna, D. H. Dethe, Org. Lett. 2004, 6, 165; b)A.
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