Catalytic enantioselective alkylative aldol reaction: Efficient multicomponent assembly of dialkylzincs, allenic esters, and ketones toward highly functionalized δ-lactones with tetrasubstituted chiral centers

Article abstract of DOI:10.1021/ja071512h

A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized δ-lactones were produced in the presence of a catalytic amount of the Cu(OAc)₂

Full text of DOI:10.1021/ja071512h

Published on Web 05/16/2007
Catalytic Enantioselective Alkylative Aldol Reaction: Efficient
Multicomponent Assembly of Dialkylzincs, Allenic Esters, and
Ketones toward Highly Functionalized δ-Lactones with
Tetrasubstituted Chiral Centers
Kounosuke Oisaki, Dongbo Zhao, Motomu Kanai,* and Masakatsu Shibasaki*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0013, Japan
Received March 3, 2007; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Abstract: A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the
catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized δ-lactones were pro-
duced in the presence of a catalytic amount of the Cu(OAc)2-DIFLUORPHOS complex through three-
component assembly of dialkylzincs, allenic esters, and unactivated ketones. This CAMCR constructs
two C-C bonds and one tetrasubstituted chiral center simultaneously. Conjugate addition of alkyl-
copper species to an allenic ester produced highly active copper enolate in situ, and the successive
asymmetric aldol addition to ketones followed by lactonization afforded the desired products. The
addition of MS4A and Lewis base (Ph2SdO, DMSO, or HMPA) is important for obtaining a high
yield, with suppression of the undesired R-addition pathway. Control/crossover experiments suggest
that the addition of a Lewis base facilitated the retro-aldol reaction of the R-adducts (proofreading
effect). The ketone and copper enolate generated through the retro-aldol reaction were con-
verted to the desired lactone through the γ-aldol pathway, which was trapped by irreversible lactone
formation.
Introduction
reactions, however, is highly challenging for two main reasons.
(1) The number of possible reaction pathways increases
The development of convergent, concise, functional-
group-compatible, and stereoselective synthetic methodologies
to produce novel carbon skeletons is in high demand.
Such synthetic methodologies should rapidly produce densely
functionalized small organic molecules from relatively
simple reactants. These molecules constitute structurally distinct
components for innovative medicinal/biochemical libraries
with their diverse arrangement of multiple functional
groups.1
exponentially according to the number of reactants in a
multicomponent reaction. (2) Substrates for chiral tetrasubsti-
tuted carbon synthesis (ketones and ketoimines) are relatively
unreactive. Therefore, catalysts promoting such reactions should
be highly active and precisely facilitate one specific desired
reaction pathway out of the many side reaction pathways with
excellent enantioselectivity.
Catalytic asymmetric aldol addition to ketones is one of the
most attractive methodologies for constructing a functionalized
skeletal backbone with a chiral tetrasubstituted center. Three
groups, including ours,6 have reported such reactions between
unactivated ketones and silyl enolates. Although some of those
Catalytic asymmetric multicomponent reactions (CAM-
CRs),2,3 which assemble three or more reagents together to
stereoselectively form chiral molecules, would have a key role
in such methodologies. Although CAMCR development is being
actively studied and significant progress has been made,2 an
asymmetric construction of tetrasubstituted carbon centers by
CAMCR is still in the early stages.4,5 Such methodology could
provide novel chiral building blocks not easily accessible using
the currently existing methodologies. The development of such
(3) General discussion of domino/cascade/tandem reactions: (a) Nicolaou, K.
C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551-564. (b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134-7186. (c) Tietze, L. F. Chem. ReV. 1996, 96, 115-136.
(d) Tietze, L. F.; Haunert, F. In Stimulating Concepts in Chemistry; Vo¨gtle,
F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany,
2000; pp 39-64. (e) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G.
C. Chem. ReV. 2005, 105, 1001-1020.
(4) Selected review for the construction of chiral tetrasubstituted carbon
centers: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388-401. (b) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-
10146. (c) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363-5367. (d) Trost, B. M.; Jiang, C. Synthesis 2006, 369-
396. (e) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873-
888.
(5) Reported CAMCR for the construction of a chiral tetrasubstituted carbon
center: (a) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 10784-10785. (b) Komanduri, V.; Krische, M. J. J. Am.
Chem. Soc. 2006, 128, 16448-16449. See also ref 7b-d.
(1) Comprehensive reviews of diversity-oriented synthesis: (a) Schreiber, S.
L. Science 2000, 287, 1964-1969. (b) Kubota, H.; Lim, J.; Depew, K.
M.; Schreiber, S. L. Chem. Biol. 2002, 9, 265-276. (c) Burke, M. D.;
Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613-618. (d) Burke,
M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58.
(2) Recent discussions of (C)AMCRs: (a) Multicomponent Reactions; Zhu,
J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Guo,
H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354-366. (c) Ramo´n,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602-1634. (d) Enders,
D.; Hu¨ttl, M. R.; Grondal, C.; Raabe, G. Nature 2006, 441, 861-863.
9
10.1021/ja071512h CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 7439-7443
7439

A R T I C L E S
Oisaki et al.
Scheme 1. Catalytic Reductive and Alkylative Aldol Reaction of
Table 1. Optimization Using Aromatic Ketone 1a
Allenic Esters
amt of
Cu
temp
C)
yieldb
(%)
eec
(%)
recovered
1ab (%)
entry
ligand
source
(
°
reactions are highly stereoselective (enantio- and diastereose-
lective) and synthetically useful,6c,f preactivation of the nucleo-
philes is necessary.
1
2
DTBM-SEGPHOS
CuOAc
0
0
47 77
43 59
9
8
DTBM-SEGPHOS/ CuOAc
PCy3
tol-BINAP
tol-BINAP
tol-BINAP
DIFLUORPHOS
DIFLUORPHOS
3
CuOAc
CuOAc
Cu(OAc)2
0
0
0
83 79
68 82
86 82
75 94
95 91
8
18
7
20
4
4d
5
In situ metal enolate generation via conjugate addition of a
nucleophile to R,â-unsaturated carbonyl compounds is an
attractive alternative.2b In the case when a metal hydride (or its
equivalent) is used as a nucleophile in the conjugate addition,
a catalytic asymmetric reductiVe aldol reaction is realized
(Scheme 1). Originating from the first intramolecular example
by Lam,7a intermolecular catalytic asymmetric reductive aldol
reactions to unactivated ketones were independently developed
by Riant’s group7b and our group7c,d using acrylate esters and
allenic esters as the prenucleophiles, respectively.
6
Cu(OAc)2 -20
7f
Cu(OAc)2 -20
8e,f DIFLUORPHOS
Cu(OAc)2 -20 >95 90
trace
a Slowly added over 2 h. b Determined by 1H NMR of the crude mixture
on the basis of an internal standard method. c Determined by chiral HPLC.
d A 1.6 equiv sample of Et2Zn was slowly added over 4 h. e A 1.2 equiv
sample of Et2Zn was slowly added over 1.5 h. f (EtO)3SiF (20 mol % in
entry 7 and 30 mol % in entry 8) was used as an additive.
in the first step (conjugate addition),9 such CAMCRs should
be synthetically more useful. Moreover, if ketones are used as
substrates in the second aldol reaction, compounds containing
chiral tetrasubstituted carbons can be constructed. The meth-
odology involving above two, however, is not established.10,11
We report herein the first synthetically useful catalytic
alkylative aldol reaction that assembles alkylzincs, allenic esters,
and unactivated ketones to afford functionalized δ-lactones with
a tetrasubstituted chiral center. An interesting mechanistic insight
with regard to the constitutional selectivity is also described.
On the other hand, if organometallic reagents could be utilized
as a trigger nucleophile, a catalytic asymmetric alkylatiVe aldol
reaction would be realized (Scheme 1).8 There is a remarkable
advantage of this type of reaction over the reductive variant,
because further complex structures are accessible. Currently,
however, catalytic asymmetric alkylative aldol reactions are
restricted to enones as acceptors for the initial conjugate addition
and aldehydes as acceptors for the subsequent aldol reaction. If
more versatile R,â-unsaturated esters can be used as substrates
(6) Catalytic asymmetric aldol reaction to unactivated ketones: (a) Denmark,
S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233-4235. (b) Denmark, S.
E.; Fan, Y.; Eastgate, M. D. J. Org. Chem. 2005, 70, 5235-5248. (c)
Moreau, X.; Tejeda, B.; Campagne, J. -M. J. Am. Chem. Soc. 2005, 127,
7288-7289. (d) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 5644-5645. (e) Oisaki, K.; Zhao, D.; Suto, Y.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2005, 46, 4325-4329. (f) Oisaki, K.;
Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7164-
7165. Recently, a copper-catalyzed asymmetric Mannich-type reaction to
ketoimines was reported: (g) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 500-501.
(7) Catalytic asymmetric reductive aldol reaction to unactivated ketones: (a)
Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225-4228. (b) Deschamp,
J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed. 2006,
45, 1292-1297. (c) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2006, 47, 1403-1407. (d) Zhao, D.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440-14441.
(8) Recent examples of catalytic asymmetric alkylative aldol reactions: (a)
Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002, 124,
10984-10985. (b) Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R.
Angew. Chem., Int. Ed. 2005, 44, 3874-3879. (c) Brown, M. K.; Degrado,
S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44, 5306-5310. (d)
Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Feringa, B. L. J.
Am. Chem. Soc. 2006, 128, 14977-14985 and references therein. See also
ref 2b.
(9) Several reports of catalytic enantioselecitve conjugate addition of organo-
metallic reagents to R,â-unsaturated esters are present. Cu catalyst with
Grignard reagents: (a) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995,
36, 4275-4278. (b) Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa,
B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-2756. (c) Harutynyan, S.
R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.; Badorrey, R.; Meetsma,
A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103-
9118. (d) Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007,
40, 179-188. (e) Wang, S.-Y.; Ji, S.-J.; Loh, T. -P. J. Am. Chem. Soc.
2007, 129, 276-277. Rh catalyst with arylboron reagents: (f) Xu, F.;
Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
Tetrahedron: Asymmetry 1998, 9, 1651-1655. (g) Takaya, Y.; Senda, T.;
Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999,
10, 4047-4056. (h) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org.
Chem. 2000, 65, 5951-5955. (i) Hayashi, T.; Yamasaki, K. Chem. ReV.
2003, 103, 2829-2844. (j) Navarre, L.; Pucheault, M.; Darses, S.; Geneˆt,
J. -P. Tetrahedron Lett. 2005, 46, 4247-4250. (k) Paquin, J.-F.; Stephenson,
C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7, 3821-3824.
Results and Discussion
To optimize the reaction conditions, we first selected ac-
etophenone (1a), ethyl 2,3-butadienoate (2), and diethylzinc in
hexane (3a) as substrates. At first, the CuOAc-DTBM-
SEGPHOS catalyst, which afforded γ-adduct selectively in the
previous reductive aldol protocol,7c,d was examined. Slow
addition of 3a into a THF solution of 1a, 2, and the catalyst (5
mol %) produced the γ-adduct exclusively. The expected
compound 5a was, however, isolated in only a tiny amount.
The major product was lactone 4aa (77% ee in 47% yield, Table
1, entry 1).12 In constrast to the reductive aldol reaction, the
addition of an achiral phosphine ligand, PCy3, significantly
lowered the enantioselectivity (entry 2). By changing the chiral
ligand to the sterically less demanding tol-BINAP, the reactivity
was improved, and 4aa was obtained in 83% yield with 79%
ee (entry 3). Extending the slow addition time to 4 h resulted
in a decreased yield (entry 4). The use of divalent Cu(OAc)2 as
a copper source slightly improved the enantioselectivity and
(10) Very preliminary results (up to 88% ee and 60% yield, two examples) were
reported in ref 7d.
(11) Catalytic asymmetric intramolecular alkylative aldol reactions to unactivated
ketones (two-component reactions) were reported. Rhodium catalysis: (a)
Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125,
1110-1111. (b) Bocknack, B. M.; Wang, L. -C.; Krische, M. J. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5421-5424. Copper catalysis: (c)
Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
4528-4529.
(12) The noncyclized products were obtained in the previous reductive aldol
reaction (ref 7c,d). The difference is perhaps due to the higher nucleophi-
licity of zinc alkoxide than boron alkoxide.
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Catalytic Enantioselective Alkylative Aldol Reaction
A R T I C L E S
Table 2. Optimization Using Aliphatic Ketone 1b
Table 3. Scope and Limitations
4ba
6
entry
additive (concn, mol %)
yieldb (%)
eec (%)
yieldb (%)
1
2
3
4
5
(EtO)3SiF (30)
44
64
27
94
∼30
∼10
>40
trace
trace
MS4Ad
87
MS4Ad + (EtO)3SiF (30)
MS4Ad + Ph2SdO (20)
Ph2SdO (20)
NDe
87
>95
40f
87
a Slowly added over 1.5 h. b Determined by 1H NMR of the crude mixture
on the basis of an internal standard method. c Determined by chiral HPLC.
d Activated with a heat gun under reduced pressure (5 mmHg). The loading
was 200 mg/mmol of 1b. e Not determined. f Approximately 20% of 1b
remained.
yield (entry 5). Further screening of the chiral ligand led to the
identification of DIFLUORPHOS13 as the best ligand, producing
94% ee product at -20 °C (entry 6).
In the course of reaction optimization, a small amount of
ketone 1a was always recovered. On the basis of the previous
studies of the copper-catalyzed aldol reaction,6d,f we speculated
that the ketone recovery was due to competitive enolization
promoted by the highly basic intermediate copper alkoxide
species (CuOEt or copper aldolate; see Scheme 3). In the
previous case, the addition of (EtO)3SiF effectively shortened
the lifetime of copper aldolate and enolization of ketones was
sufficiently suppressed. Thus, we added a catalytic amount of
(EtO)3SiF in the present system. As expected, recovery of ketone
was significantly suppressed, and 4aa was produced in 95%
yield with a minimum loss of enantioselectivity (entry 7). The
loading of diethylzinc could be reduced to up to 1.2 equiv of
ketone (entry 8). In this system, organometallic reagents other
than dialkylzinc produced less satisfactory results; EtMgBr and
Et3B resulted in no reaction, and Et3Al afforded inferior results
on both conversion and enantioselectivity (20% yield, 23% ee
under the conditions shown in entry 4).
a Slowly added over 1.5 h. b Activated with a heat gun under reduced
pressure (5 mmHg). The loading was 200 mg/mmol of 1. c Isolated yield.
d Determined by chiral HPLC analysis. e A 10 mol % concentration of the
Cu source, 12 mol % ligand, and 1.6 equiv of dialkylzinc (slowly added
over 1.5 h) were used. f CuTC was used instead of Cu(OAc)2. g The absolute
configuration was determined to be R.
reconvert the kinetic R-aldolates to the thermodynamically stable
lactone 4ba through an iterative retro-aldolization-aldolization
process.14
When the above optimized conditions were applied to
aliphatic ketone 1b, however, lactone 4ba was obtained in only
44% yield with concomitant production of a significant amount
of R-adducts 6 as a diastereomixture (Table 2, entry 1). To
promote the desired γ-addition pathway, we screened the
additives again. The addition of activated MS4A was promising
(Table 2, entry 2): the yield of 4ba increased to 64%, while
the generation of 6 was decreased to ca. 10% yield. On the
other hand, the addition of (EtO)3SiF accelerated the R-addition
pathway (entry 3). We speculated that the R-adducts (the
corresponding copper or zinc aldolates) were the kinetic products
and (EtO)3SiF trapped the kinetic R-aldolates. The R-aldolates,
however, would be labile if they were not trapped under the
reaction conditions. We expected that it would be possible to
On the basis of this assumption, we studied the effects of
Lewis base additives that can facilitate the retro-aldol reaction
by activating the metal-O bond of metal aldolate. As expected,
the addition of diphenyl sulfoxide (Ph2SdO) suppressed the
generation of R-adducts (entry 4). TLC monitoring of the
reaction profile suggested that Ph2SdO facilitated reconversion
of the initially formed R-adducts to the lactone through in situ
destruction (i.e., retro-aldol reaction) of R-products 6 (proof-
reading effect). At the beginning of the reaction (after slow
addition of Et2Zn, 1.5 h), a significant amount of R-products 6
was observed in both the presence and the absence of Ph2Sd
O. The R-products disappeared completely, however, after 12
h in the presence of Ph2SdO, and lactone 4ba was detected as
the major product on TLC. Reconversion of 6 to 4ba was slower
(13) (a) Jeulin, S.; de Paule, S. D.; Ratovelomanana-Vidal, V.; Geneˆt, J. -P.;
Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320-325. For
other asymmetric catalyses in which DIFLUORPHOS works as an excellent
chiral ligand, see: (b) Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc.
2005, 127, 14556-14557. (c) Sibi, M.; Tatamidani, H.; Patil, K. Org. Lett.
2005, 7, 2571-2573.
(14) In the case of aromatic ketone 1a (Table 1), R-adducts were observed in
only trace amounts. A retro-aldol reaction of the R-aldolates derived from
aromatic ketones might be faster than the silyl trap. Alternatively, the
γ-adduct might be the kinetic product from aromatic ketones.
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A R T I C L E S
Oisaki et al.
Scheme 2. Control and Crossover Experimentsa
1
a The yield is determined by H NMR of the crude mixture on the basis of an internal standard method.
Scheme 3. Proposed Catalytic Cycle
when the Lewis base additive was absent. In the absence of
MS4A (entry 5), a significant amount (ca. 20%) of ketone 1b
was recovered. Therefore, the combined use of MS4A and
Ph2SdO was essential to efficiently promote the desired
δ-lactone-forming pathway.15
Next, we investigated the scope and limitations of the reaction
under the optimized conditions. We used different Lewis base
additives depending on the substrates. In some cases (Table 3,
entries 1-4, 9, and 12), DMSO or HMPA was favorable
because isolation of lactone 4 from Ph2SdO was often
problematic due to their very similar Rf values. In the case of
entries 6-8 and 13, retroreaction of R-adducts was sluggish at
the indicated temperature in the presence of Ph2SdO. Thus,
we selected a more Lewis basic additive (DMSO). In some
cases, utilization of CuTC (copper thiophene-2-carboxylate)16
as a stable Cu(I) source was favorable (entries 6, 7, and 11-
14). Excellent enantioselectivity was generally obtained from
both aromatic and aliphatic ketones with various dialkylzincs.17
To obtain insight into the reversibility from R-products, we
examined the following experiments using isolated R-adducts
6 (0% ee). In the presence of a catalytic amount of CuTC-
DIFLUORPHOS complex and Ph2SdO, 6 was treated with 1.2
equiv of diethylzinc at -20 °C (Scheme 2, eq 1). After 12 h,
R-adduct 6 completely disappeared and lactone 4ba (65% yield,
88% ee) and noncyclized 5b (12% yield) were produced. This
(16) CuTC was prepared following the published procedure: Gallagher, W. P.;
Maleczka, R. E., Jr. J. Org. Chem. 2003, 68, 6775-6779.
(15) MS4A might shorten the lifetime of copper alkoxides in the catalytic cycle
by facilitating the alkoxide ligand exchange between Cu and Zn (from IV
to I in Scheme 3), thus minimizing undesired reactions catalyzed by copper
alkoxides (including enolization of the ketone). MS3A, MS5A, and MS13X
showed similar effects.
(17) (a) Propiophenone (14 h, 76% yield, 17% ee in the presence of HMPA)
and benzalacetone (16 h, 83% yield, 35% ee in the presence of HMPA)
were unsatisfactory substrates. (b) At this stage, this catalytic system is
not applicable to dialkenylzincs, diarylzincs, dialkynylzincs, or monoalky-
lzinc halide (no reaction).
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Catalytic Enantioselective Alkylative Aldol Reaction
A R T I C L E S
result clearly demonstrated that there is a retro-aldol reaction
from R-zinc aldolates (7 in Scheme 3) and the undesired
R-aldolates were converted to the stable and desired lactone
(the proofreading effect). Interestingly, in the absence of a
copper catalyst, the retro-aldol process barely proceeded,
although Ph2SdO was present (eq 2), suggesting that involve-
ment of the Cu catalyst is important for the proofreading effect.
Next, a crossover experiment was conducted in the presence of
acetophenone (1a) and 6 (eq 3). As a result, both 4aa and 4ba
were obtained with high enantioselectivity via complete cross-
over. This result demonstrated that the retro-aldol reaction of 6
produced ketone 1b and vinylogous copper enolate in situ and
an intermolecular recombination of ketone and copper enolate
can proceed.
tion of ketones) could proceed. The γ-cycle involves an
irreversible lactonization step and the intersection with the
reversible R-cycle with the copper enolate II. Consequently,
all copper enolate II is consumed to convert ketones 1 to lactone
4 in the whole process.
Conclusions
We report herein the development of a Cu-DIFLUORPHOS
complex-catalyzed asymmetric alkylative aldol reaction produc-
ing highly functionalized chiral δ-lactones via a three-component
assembly of ketones, allenic esters, and alkylzincs. The reaction
can be applied to a wide range of substrates. The addition of a
Lewis base additive (Ph2SdO, DMSO, and HMPA) and MS4A
was essential for the high product yield. Mechanistic studies
suggest that the Lewis base additive accelerated the retro-aldol
reaction of the undesired R-product (proofreading effect). This
new CAMCR entry for the construction of a chiral tetrasubsti-
tuted center will be useful for a convergent, concise, and
diversity-oriented approach toward the development of innova-
tive medicinal/biochemical libraries.
The probable catalytic cycle of the present reaction system
is shown in Scheme 3. At first, Cu(II) is reduced to Cu(I) in
the presence of alkylzinc to produce alkylcopper-phosphine
complex I.18 Conjugate addition of alkylcopper I to allenic ester
2 affords copper enolate II, which is likely to be the actual active
nucleophile of the following aldol reaction.19 In the aldol
reaction step, two kinds of copper aldolates γ-III and R-III,
could be produced. R/γ-Selectivity seems to be highly dependent
on the substrates and conditions.20 Successive reaction of R-III
with dialkylzinc affords R-zinc aldolate 7 and alkylcopper I.
This R-cycle is inherently reversible, and copper enolate II can
be regenerated via a retro-aldol reaction from 7 (supported by
the results shown in Scheme 2, eq 1). The Lewis base additive
(sulfoxide and phosphoramide) facilitates this retroreaction by
destabilizing R-III with coordination to the zinc atom. On the
other hand, from γ-III, successive lactonization produces the
desired lactone 4 and copper ethoxide IV. In the absence of
MS4A, regeneration of active species I might be slow. As a
result, Bro¨nsted base-promoted side reactions (such as enoliza-
Experimental Section
Typical Procedure for Catalytic Alkylative Aldol Reaction to
Ketones. A catalyst solution was generated from Cu(OAc)2 (0.01 mmol,
5.0 mol %), (R)-DIFLUORPHOS (0.012 mmol, 6.0 mol %), a Lewis
base additive (0.04 mmol, 20 mol %), and activated MS4A (40 mg,
200 mg/mmol of 1) in THF (0.25 mL) under stirring at room
temperature for 10 min. Ethyl 2,3-butadienoate (2; 0.3 mmol, 1.5 equiv)
and ketone 1 (0.2 mmol) were then added successively to the catalyst
solution. After 10 min, dialkylzinc solution 3 (0.24 mmol, 1.2 equiv)
was added slowly to the reaction mixture via a syringe pump for 1.5
h at -20 °C. The mixture was allowed to stir for the indicated time.
MeOH was added to quench the reaction, and then the generated
precipitate was filtered over a Celite pad. After evaporation of the
1
solvent, the NMR yield was determined by H NMR analysis of the
crude product with 1,1,2,2-tetrachloroethane as the internal standard.
Purification by silica gel column chromatography (eluent AcOEt/
hexane) gave the analytically pure lactone 4. The enantiomeric excess
was determined by chiral HPLC analysis with 220 nm UV.
(18) (a) Alexakis proposed a bridging role of the carboxylate ligand for a mixed
zinc cuprate complex in a copper-catalyzed enantioselective conjugate
addition. See: Alexakis, A.; Benhaim, C.; Rosset, S.; Human, M. J. Am.
Chem. Soc. 2002, 124, 5262-5263. Noyori also pointed out that a
sulfonamide has a similar role. See: Kitamura, M.; Miki, T.; Nakano, K.;
Noyori, R. Bull. Chem. Soc. Jpn. 2000, 73, 999-1014. (b) In the present
reaction, Cu(OAc)2 produced significantly higher enantioselectivity and
product yield than CuCl or CuBr. These results support a special role of
the acetate ligand, which might derive from the bridging effect between
copper and zinc atoms. (c) The possibility that a cuprate species is the
actual nucleophile in the conjugate addition cannot be excluded.
(19) Copper enolate should exist under rapid equilibrium between C-enolate
(C-II) and O-enolate (O-II). This equilibrium is suggested by the fact that
the major diastereomer was independent of the geometry of the ketene silyl
acetal in the previous copper-catalyzed aldol reaction to ketones (ref 6f),
which proceeded via a copper enolate species.
Acknowledgment. This paper is dedicated to the memory of
Professor Yoshihiko Ito. Financial support was provided by a
Grand-in-Aid for Specially Promoted Research of MEXT. K.O.
thanks JSPS for research fellowships.
Supporting Information Available: Experimental procedures
and characterization of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) For a recent review of catalytic asymmetric vinylogous aldol reactions,
see: Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2005, 44, 4682-4698.
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