Asymmetric conjugate addition of alkylzirconium reagents to α,β-unsaturated lactones

Article abstract of DOI:10.1021/ol501292x

The asymmetric synthesis of β-substituted lactones by catalytic asymmetric conjugate addition of alkyl groups to α,β-unsaturated lactones is reported. The method uses alkylzirconium nucleophiles prepared in situ from alkenes and the Schwartz reagent. Enantioselective additions to 6- and 7-membered lactones proceed at rt, tolerate a wide variety of functional groups, and are readily scalable. The method was used in a formal asymmetric synthesis of mitsugashiwalactone.

Full text of DOI:10.1021/ol501292x

Letter
pubs.acs.org/OrgLett
Terms of Use
Asymmetric Conjugate Addition of Alkylzirconium Reagents to
α,β‑Unsaturated Lactones
Eleanor E. Maciver,† Rebecca M. Maksymowicz,† Nancy Wilkinson, Philippe M. C. Roth,
and Stephen P. Fletcher*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: The asymmetric synthesis of β-substituted lactones by catalytic asymmetric conjugate addition of alkyl groups to
α,β-unsaturated lactones is reported. The method uses alkylzirconium nucleophiles prepared in situ from alkenes and the
Schwartz reagent. Enantioselective additions to 6- and 7-membered lactones proceed at rt, tolerate a wide variety of functional
groups, and are readily scalable. The method was used in a formal asymmetric synthesis of mitsugashiwalactone.
he development of Cu-catalyzed asymmetric conjugate
Taddition (ACA) reactions to α,β-unsaturated carbonyl
derivatives has received tremendous attention for over 25 years.
This work has led to a number of highly enantioselective
methods,1 and a few of these are now so sufficiently robust that
they can be used in complex molecule synthesis.1e,2 These
reactions have for the most part been developed with a small
number of model substrates with the major focus on simple linear
and cyclic enones,3,4 and additions to some substrate types are
surprisingly underrepresented1b,4,5 and extensions will require a
step change in current asymmetric methodology.
Lactones superficially resemble cyclic ketones but differ in key
properties such as conformation and strain energy.6,7 They are an
important substrate class for which generally useful Cu-catalyzed
ACA reactions have not been developed. The ACA of alkyl
nucleophiles to α,β-unsaturated lactones would directly provide
Figure 1. Asymmetric 1,4-addition of alkyl nucleophiles to lactones.
enantiomerically enriched lactones, but development of a
broadly useful method has been elusive. As previously pointed
out,8 early methods involve a high catalyst loading,9 reactions
that report only conversion,10 or a very limited scope.11 Using
reactions between intermediate enolates and starting lactone
dialkylzinc reagents, Hoveyda reported the first effective ACAs to
α,β-unsaturated lactones (Figure 1a)8 and applied this method in
the synthesis of clavirolide C.2e High yields are observed when
the reaction is carried out in the presence of an aldehyde which
traps the ACA product as an aldol adduct, and a subsequent
retroaldol step is used to release the desired product.2e,8,12
Hoveyda et al. attribute the low yields observed in the absence of
an aldehyde to adventitious ketene formation or intermolecular
Michael addition.8 Feringa et al. developed a Grignard based
procedure which (Figure 1a)13 gives high yields under
pseudoinfinite dilution conditions, where a solution of lactone
is slowly added to a cold solution of the catalyst and nucleophile.
Taken together, these two reports suggest that intermolecular
need to be suppressed to develop high yielding procedures.
Here, we report a direct method for 1,4-addition of alkyl units
to α,β-unsaturated lactones (Figure 1b). We reasoned that strong
group IV metal−oxygen bonds (Figure 1c)14,15 would make
zirconium enolates less nucleophilic, and proceeded to examine
the ACA of alkylzirconium reagents2p,16 to lactones. Alkenes,
when treated with the Schwartz reagent,17 undergo hydro-
metalation to alkylzirconium nucleophiles.18 Conditions pre-
viously used for the addition of 4-phenyl-1-butene 1 to
cyclohexenone16a were applied to 5,6-dihydropyran-2-one 2a
Received: May 6, 2014
© XXXX American Chemical Society
A
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Letter
(Scheme 1), and we obtained the 1,4-addition product 3a with
7, 89% ee) with the exception of CH2Cl2 (entry 10), which gave
91% ee but without full conversion in this solvent with only a low
isolated yield (<10%). Keeping the reaction conditions of entry
7, but varying the temperature (not shown), did not appreciably
increase the enantioselectivity. Copper perchlorate and copper
triflimidate salts gave excellent enantioselectivity (93% ee, entry
16) in the absence of TMSCl. However, reaction yields with
these counterions were always low (<10%) even though full
conversion was observed. Extensive attempts to optimize these
yields were not fruitful. Although the combination of (CuOTf)2·
PhH and F gave a slightly lower enantioselectivity (89 vs 93%
ee), we could consistently obtain over 75% isolated yield using
this system.
80% ee and >50% yield as determined by 1H NMR.
Scheme 1. Initial ACA of Alkylzirconiums to Lactones
We examined copper sources in combination with phosphor-
amidite ligands and solvents (Table 1). Copper sources gave
We next prepared catalyst complex G (Figure 2; see
Supporting Information (SI)), composed of CuOTf and ligand
a
Table 1. Representative Optimization Reactions
Figure 2. Lactones and catalyst complex used here.
F. This complex is more convenient than (CuOTf)2·PhH and
was used for the rest of these studies. G is readily made on a >1 g
scale, can be weighed out in air, and is stable for at least a month if
stored on the bench under argon.
We examined the hydrometalation−ACA of simple alkenes to
2a (Table 2, entries 1−6). These experiments allowed a
comparison to previous methods for ACA to lactones. Simple
linear (entries 1−4) and hindered (entries 5 and 6) alkenes are
well tolerated. In the case of volatile 3b, the alkene (ethylene)
used is a gas and the hydrozirconation is performed under a
balloon atmosphere of ethylene (see SI).
When we examined lactones of different ring sizes and
substitution patterns (Figure 2) we found that 5-membered rings
are difficult substrates; 2b was rapidly and completely consumed,
and no desired product was recovered, while, conversely, 2c was
recovered unchanged. These conditions are also unsuitable for
acyclic α,β-unsubstituted esters. These results, in combination
with those obtained using triflimidate and perchlorate salts
(Table 1, entries 14−19) suggest that it is the combination of the
catalyst and reactive enolate that leads to low yields. When more
reactive substrate−catalyst combinations are used (i.e., 2b or
more Lewis acidic catalysts) very low yields are observed,
presumably due to enolate attacking lactones activated by the
catalyst.15b As this system is unsuitable for 5-membered ring
substrates, Hoveyda’s 1,4-addition/aldol/retroaldol procedure8
is the only currently viable method for ACA of alkyl units to 2b.
The addition of alkyl groups to 7-membered lactones 2d and 2e
goes smoothly, with good yields and high enantioselectivities
observed (entries 7 and 8).
entry
Cu source
ligand
additive
solvent
Et2O
ee (%)
1
2
3
4
5
6
7
8
(CuOTf)2·C6H6
[Cu(MeCN)4·OTf]
[Cu(MeCN)4·PF6]
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
AgNTf2 + CuCl
AgNTf2 + CuCl
AgNTf2 + CuCl
AgClO4 + CuCl
AgClO4 + CuCl
AgClO4 + CuCl
B
B
B
C
D
E
F
F
F
F
F
F
F
F
F
F
F
F
F
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
−
(S)-80
(S)-67
0
Et2O
Et2O
Et2O
(S)-79
(S)-75
(S)-55
(R)-89
(R)-83
(R)-80
(R)-91
(R)-86
(R)-88
(R)-70
0
Et2O
Et2O
Et2O
Et2O
c
9
TMSCl
CH2Cl2
c
10
−
−
11
12
13
TMSCl
TMSCl
−
TMSCl
TMSCl
−
2-MeTHF
t-BuOMe
t-BuOMe
CH2Cl2
Et2O
bc
,
14
15
16
17
18
19
bc
,
(R)-44
(R)-93
(R)-89
(R)-78
(R)-94
bc
,
CH2Cl2
Et2O
bc
,
−
bc
,
TMSCl
Et2O
bd
,
18-crown-6 CH2Cl2
a
Conditions: 4-phenyl-1-butene (2.5 equiv), Cp2ZrHCI (2 equiv), 5,6-
dihydropyran-2-one (1 equiv), copper (10 mol %), Ligand (10 mol
%), Additive (5 equiv), rt, >50% yield by crude H NMR. Silver (15
mol %), precipitate filtered before use. Less that 10% yield observed.
1 equiv of 18-crown-6 was used, and ca. 30% isolated yield was
obtained.
b
1
c
d
vastly different results (from racemic to 80% ee) depending on
the counterion and solvating species, with (CuOTf)2·PhH giving
the highest ee (entry 1). Switching from ligand B19 to 2-naphthyl-
substituted C had little effect on enantioselectivity (79% ee,
Table 1 entry 4); however, an isomer bearing an achiral amine
moiety (ligand F,16b entry 7) appreciably increased the
enantioselectivity to 89% ee. Upon looking at different solvents
in the presence or absence of TMSCl (entries 7−13), diethyl
ether + TMSCl gave the highest level of enantioselectivity (entry
The use of functionalized nucleophiles in Cu-catalyzed ACAs
remains a major challenge,1b,c,20 and with lactones the previous
nucleophile scope is extremely limited (see Figure 3). The use of
starting materials incorporating functional groups offers
extensive opportunities to further elaborate the products.
We found a range of functional groups could be added (Figure
4). Alkenes bearing aromatic rings (3a,j,k,m,o and 4b), internal
olefins (3h), ethers and protected alcohols (3i,j,k,l,o and 4b),
stereogenic centers (3h,o), halogens (3m,o), multiple structural
B
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Letter
a
ee). All reactions were performed at rt and are typically complete
within a few hours.
Table 2. Asymmetric Addition of Alkyl Groups
One possible drawback of the methodology is the use of excess
alkene and Schwartz reagent relative to the lactone substrate, and
so when we examined the formation of product 3l (bearing a
silyl-protected alcohol) on a preparative scale (Scheme 2) we
arbitrarily reduced the ratios of the alkene (to 2 equiv) and
Schwartz reagent (to 1.7 equiv). On an 8-mmol scale we obtained
0.872 g of 3l (76% yield, 90% ee).
Scheme 2. Preparative Scale and Ring-Opening Reactions
Ring opening of enantioenriched 3a (89% ee) with primary
and secondary amines (Scheme 2) was also examined.
Trimethylaluminum mediated ring opening in CH2Cl2 gave
functionalized amides 6a and 6b.
We next prepared a compound previously used in natural
product synthesis (Scheme 3). Racemic 8 is a late-stage
a
Scheme 3. Formal Asymmetric Synthesis of
Mitsugashiwalactone
Conditions: alkene (2.5 equiv), Cp2ZrHCI (2 equiv), lactone (1
b
equiv), complex G (10 mol %), TMSCI (5 equiv), Et20, rt. Isolated
yield. c Ee determined by derivitization and HPLC; see SI. d Volatile. e
Ee determined directly by HPLC.
Figure 3. Alkyl nucleophiles previously used in ACA to lactones.
intermediate in the syntheses of rac-mitsugashiwalactone.21,22
Asymmetric syntheses of mitsugashiwalactone have been
reported from a chiral pool23 and enantiomerically resolved
materials,24 but not (to our knowledge) from material where
asymmetry is introduced in a catalytic asymmetric approach.
Access to 8 represented a much more demanding test of the
method than the examples we had examined thus far. We
suspected that an appropriately functionalized lactone 7 could be
converted to 8 by dehydrative condensation, but the stability of
the lactone ring, the stereochemical integrity of the tertiary
center during cyclization, and the ability to access 7 were all
unclear.
Figure 4. Products obtained by ACA using functionalized alkenes as
starting materials. a Isolated as a mixture of diastereoisomers.
features (3o) and an electron-rich styrene (3m) and allylsilane
(3n) uniformly gave high levels of enantiomeric excess (85−92%
C
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Fletcher, S. P. Chem. Commun. 2013, 49, 4211. (q) Endo, K.; Hamada,
D.; Yakeishi, S.; Shibata, T. Angew. Chem., Int. Ed. 2013, 52, 606.
(3) For example more than 4000 relevant asymmetric additions to
cyclohexenone have been reported; see ref 4.
(4) Alexakis, A., Krause, N., Woodward, S., Eds. Copper-Catalyzed
Asymmetric Synthesis; Wiley-VCH: 2014.
To synthesize 7, we chose to investigate the hydrometalation−
ACA of isoprene 9 to lactone 2a (Scheme 3). This conjugated
diene, a substrate type that we had not yet examined, showed
excellent chemoselectivity between the mono- and disubstituted
olefins and gave 3p with high enantioselectivity at rt on a 6.0
mmol scale (78% yield, 83% ee). Using isoprene as a starting
material is attractive because it is readily available and
inexpensive. Cleavage of the olefin in 3p by ozonolysis gave
(−)-7a quantitatively, and cyclization to (−)-8 was accomplished
using tosylic acid under Dean−Stark conditions (81% yield from
3p) with no detectable loss of enantiopurity.
In conclusion, a new method has been developed for Cu-
catalyzed ACA of alkyl nucleophiles to α,β-unsaturated lactones.
The nucleophiles are generated in situ from alkenes and the
Schwartz reagent. We applied the method in a formal asymmetric
synthesis of mitsugashiwalactone. Our laboratory is currently
investigating extensions and applications of alkylzirconium
addition reactions.
(5) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Chem.
Soc. Rev. 2009, 38, 1039.
(6) For example, the 6-membered δ-valerolactone has an overall strain
energy that is substantially greater than other 6-ring alicyclic
compounds. The 6-membered lactone also has higher strain than the
5-membered lactone by about 7.5 kJ/mol, the reverse order of strain
energies generally observed for alicyclic compounds.
(7) Luisa, M.; Pilcher, G.; Yang, M. Y.; Brown, J. M.; Conn, A. D. J.
Chem. Thermodyn. 1990, 22, 885.
(8) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2005, 44, 5306.
ASSOCIATED CONTENT
* Supporting Information
All procedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
(9) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275.
(10) (a) Yan, M.; Zhou, Z. Y.; Chan, A. S. C. Chem. Commun. 2000,
115. (b) Reetz, M. T.; Gosberg, A.; Moulin, D. Tetrahedron Lett. 2002,
43, 1189. (c) Liang, L.; Yan, M.; Li, Y. M.; Chan, A. S. C. Tetrahedron:
Asymmetry 2004, 15, 2575. (d) Naeemi, Q.; Robert, T.; Kranz, D. P.;
Velder, J.; Schmalz, H. G. Tetrahedron: Asymmetry 2011, 22, 887.
(11) (a) Liang, L.; Su, L. M.; Li, X. S.; Chan, A. S. C. Tetrahedron Lett.
2003, 44, 7217. (b) Feringa, B. L.; Badorrey, R.; Pena, D.; Harutyunyan,
S. R.; Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834.
(c) Clavier, H.; Coutable, L.; Guillemin, J. C.; Mauduit, M. Tetrahedron:
Asymmetry 2005, 16, 921. (d) Rix, D.; Labat, S.; Toupet, L.; Crevisy, C.;
Mauduit, M. Eur. J. Inorg. Chem. 2009, 1989.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stephen.fletcher@chem.ox.ac.uk.
Author Contributions
†E.E.M. and R.M.M. contributed equally.
Notes
̌
́ ̌ ́ ́ ́
J.; Meciarova, M.; Almassy, A.; Horvath, B.; Sebesta,
(12) Csizmadiova,
R. J. Organomet. Chem. 2013, 737, 47.
(13) Mao, B.; Fananas-Mastral, M.; Feringa, B. L. Org. Lett. 2013, 15,
286.
The authors declare no competing financial interest.
(14) It is well established that Zr−O single and ZrO double bonds in
relevant zirconcene complexes are anomalously short, reflecting a
significant ionic contribution. See ref 15.
(15) Isolatable zirconium ester enolates have been characterized, and
their ability to initiate polymerization was studied in detail by the Chen
group: (a) Howard, W. A.; Parkin, G. J. Am. Chem. Soc. 1994, 116, 606.
(b) Zhang, Y.; Ning, Y.; Caporaso, L.; Cavallo, L.; Chen, E. Y. X. J. Am.
Chem. Soc. 2010, 132, 2695.
(16) (a) Maksymowicz, R. M.; Roth, P. M. C.; Fletcher, S. P. Nat.
Chem. 2012, 4, 649. (b) Sidera, M.; Roth, P. M. C.; Maksymowicz, R. M.;
Fletcher, S. P. Angew. Chem., Int. Ed. 2013, 52, 7995. (c) Maksymowicz,
R. M.; Sidera, M.; Roth, P. M. C.; Fletcher, S. P. Synthesis 2013, 45, 2662.
(d) Roth, P. M. C.; Sidera, M.; Maksymowicz, R. M.; Fletcher, S. P. Nat.
Protoc. 2014, 9, 104.
ACKNOWLEDGMENTS
We thank the EPSRC for funding (Career Acceleration
Fellowship to SF [EP/H003711/1]).
■
REFERENCES
■
(1) Selected reviews: (a) Christoffers, J.; Koripelly, G.; Rosiak, A.;
Rossle, M. Synthesis 2007, 1279. (b) Alexakis, A.; Backvall, J. E.; Krause,
N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796.
(c) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Chem. Rev. 2008, 108, 2824. (d) Thaler, T.; Knochel, P.
Angew. Chem., Int. Ed. 2009, 48, 645. (e) Wang, S. Y.; Loh, T. P. Chem.
Commun. 2010, 46, 8694.
(2) Selected examples of Cu-catalyzed ACA in natural product
synthesis: (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem.
Soc. 2001, 123, 755. (b) Arnold, L. A.; Naasz, R.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841. (c) Alexakis, A.; March,
S. J. Org. Chem. 2002, 67, 8753. (d) Howell, G. P.; Fletcher, S. P.; Geurts,
K.; ter Horst, B.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 14977.
(e) Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904.
(f) Casas-Arce, E.; ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem.
Eur. J. 2008, 14, 4157. (g) Bates, R. W.; Sridhar, S. J. Org. Chem. 2008,
73, 8104. (h) Lum, T.-K.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2008, 10,
761. (i) Pereira, C. L.; Chen, Y.-H.; McDonald, F. E. J. Am. Chem. Soc.
2009, 131, 6066. (j) Wang, S.-Y.; Song, P.; Chan, L.-Y.; Loh, T.-P. Org.
Lett. 2010, 12, 5166. (k) Hartmann, E.; Oestreich, M. Angew. Chem., Int.
Ed. 2010, 49, 6195. (l) Weiss, M. E.; Carreira, E. M. Angew. Chem., Int.
Ed. 2011, 50, 11501. (m) Mendoza, A.; Ishihara, Y.; Baran, P. S. Nat.
Chem. 2012, 4, 21. (n) Gartner, M.; Qu, J. P.; Helmchen, G. J. Org. Chem.
2012, 77, 1186. (o) Mak, J. Y. W.; Williams, C. M. Chem. Commun. 2012,
48, 287. (p) Maksymowicz, R. M.; Roth, P. M. C.; Thompson, A. L.;
(17) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B. Org. Synth. 1993, 71,
77.
(18) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853. (b) Sebesta, R.
ChemCatChem 2013, 5, 1069.
(19) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(20) Howell, G. P. Org. Process Res. Dev. 2012, 16, 1258.
(21) Saeki, M.; Toyota, M. Heterocycles 2011, 82, 1705.
(22) (a) Liang, K.-W.; Chandrasekharam, M.; Li, C.-L.; Liu, R.-S. J. Org.
Chem. 1998, 63, 7289. (b) Bouyssi, D.; Monteiro, N.; Balme, G.
Tetrahedron Lett. 1999, 40, 1297.
(23) (a) Takacs, J. M.; Myoung, Y. C. Tetrahedron Lett. 1992, 33, 317.
(b) Weinges, K.; Ziegler, H. J.; Maurer, W.; Schmidbauer, S. B. Liebigs
Ann. Chem. 1993, 1029. (c) Takacs, J. M.; Myoung, Y.-C.; Anderson, L.
G. J. Org. Chem. 1994, 59, 6928. (d) Nangia, A.; Prasuna, G. Tetrahedron
1996, 52, 3435.
(24) Yamane, T.; Takahashi, M.; Ogasawara, K. Synthesis 1995, 444.
D
dx.doi.org/10.1021/ol501292x | Org. Lett. XXXX, XXX, XXX−XXX