Nickel-catalyzed asymmetric Negishi cross-couplings of secondary allylic chlorides with alkylzincs

Article abstract of DOI:10.1021/ja800103z

Complementing previous advances in allylation chemistry, an effective nickel/Pybox catalyst for regioselective asymmetric Negishi cross-couplings of racemic secondary allylic chlorides with readily available organozinc halides has been developed. The method has been applied in two key steps of a formal total synthesis of fluvirucinine A₁. Copyright

Full text of DOI:10.1021/ja800103z

Published on Web 02/08/2008
Nickel-Catalyzed Asymmetric Negishi Cross-Couplings of Secondary Allylic
Chlorides with Alkylzincs
Sunghee Son and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received January 6, 2008; E-mail: gcf@mit.edu
Table 1. Enantioselective Negishi Cross-Couplings of
“Symmetrical” Allylic Chlorides with Alkylzinc Reagents (for the
Reaction Conditions, See eq 1)
Metal-catalyzed enantioselective couplings of allylic electrophiles
with carbon nucleophiles have been intensively studied,1 with most
of the investigations focused on palladium-catalyzed reactions of
allylic esters/carbonates with enolates, copper-catalyzed couplings
of primary allylic electrophiles with Grignard and diorganozinc
reagents (SN2′ substitution),2 and nickel-catalyzed reactions of
certain allylic electrophiles with Grignard reagents.3,4 Although
powerful methods have been developed, there remains room for
improvement, for example, processes that accommodate a broader
range of nucleophiles and that display greater functional-group
compatibility. In this report, we describe a versatile nickel-based
catalyst for asymmetric couplings of racemic secondary allylic
chlorides with readily available alkylzinc halides5 (eq 1; DMA )
N,N-dimethylacetamide), and we apply this method to a formal total
synthesis of fluvirucinine A1.
All data are the average of two experiments. a Isolated yield. b The
production is volatile. The yield was determined by GC versus an internal
standard. c Solvent: DMA/DMF (9:1).
Table 2. Enantioselective Negishi Cross-Couplings of
Unsymmetrical Allylic Chlorides with Alkylzinc Reagents (for the
Reaction Conditions, See eq 1)
Previously, we have reported nickel-catalyzed enantioselective
Negishi reactions of R-bromo amides and benzylic bromides with
organozinc reagents.6 Although the regioselectivity of the carbon-
carbon bond-forming process was not a concern for these families
of substrates, we anticipated that regioselectivity would be an issue
for couplings of allylic electrophiles. To avoid this complication
during our initial studies, we chose to examine the reaction of a
“symmetrical” allylic halide. Under the conditions that we had de-
veloped for enantioselective Negishi couplings of R-bromo amides
and benzylic bromides, we obtained promising results for an allylic
electrophile (eq 2; DMI ) 1,3-dimethyl-2-imidazolidinone).
All data are the average of two experiments. Regioselectivity, >20:1,
except for entry 1. a Isolated yield. b Regioselectivity, 1.9:1; ee of the minor
regioisomer, 88%. c The allylic chloride is a mixture of regioisomers.
Through optimization studies, we were able to significantly im-
prove the enantioselectivity of this Negishi cross-coupling reaction
(87% ee, 95% yield; Table 1, entry 1).7-9 The combination of a
high ee and a high yield establishes that the process is stereocon-
vergent: the two enantiomers of the racemic substrate are trans-
formed into the same enantiomer of the product with good
stereoselectivity.
As the steric demand of the R1 substituent increases, the
enantioselectivity of the cross-coupling decreases (Table 1, entries
1-5). Thus, good ee’s are generally obtained if the group is
unbranched (entries 1-4), but an erosion in stereoselection is
observed for a hindered diisopropyl-substituted allylic chloride
(entry 5). The Ni/Pybox catalyst can achieve an asymmetric Negishi
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10.1021/ja800103z CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Formal Total Synthesis of Fluvirucinine A1 via Two
Catalytic Asymmetric Negishi Reactions of Allylic Chlorides
available in two steps from commercially available ethyl (E)-4-
oxo-2-butenoate, provided compound 3 in excellent yield, regiose-
lectivity, and ee. Reduction and then bromination furnished
intermediate 4, which was converted to the organozinc reagent and
coupled with an allylic chloride to generate 5 in very good yield,
regioselectivity, and stereoselectivity. A reduction/amination se-
quence then afforded target aldehyde 1.
In summary, complementing previous advances in allylation
chemistry, we have developed an effective nickel/Pybox catalyst
for regioselective asymmetric Negishi cross-couplings of racemic
secondary allylic chlorides with readily available organozinc halides.
Furthermore, we have applied this method in two key steps of a
formal total synthesis of fluvirucinine A1. Additional studies of
nickel-catalyzed coupling reactions of alkyl electrophiles are
underway.
Acknowledgment. We thank Hong Shu for important prelimi-
nary studies. Support has been provided by the National Institutes
of Health (National Institute of General Medical Sciences, Grant
R01-GM62871), Merck Research Laboratories, and Novartis.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For reviews, see: (a) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New
York, 1999; Vol. 2, Chapter 24. (b) Trost, B. M.; Van Vranken, D. L.
Chem. ReV. 1996, 96, 395-422. See also: Kar, A.; Argade, N. P. Synthesis
2005, 2995-3022.
(2) For reviews, see: (a) Alexakis, A.; Malan, C.; Lea, L.; Tissot-Croset, K.;
Polet, D.; Falciola, C. Chimia 2006, 60, 124-130. (b) Yorimitsu, H.;
Oshima, K. Angew. Chem., Int. Ed. 2005, 44, 4435-4439. Studies to date
have focused largely on couplings of primary allylic electrophiles that
generate terminal olefins (or, symmetrical secondary electrophiles). For
reactions with organozinc reagents, use of RZnX has been reported to be
problematic (for example, see: Du¨bner, F.; Knochel, P. Angew. Chem.,
Int. Ed. 1999, 38, 379-381 and Goldsmith, P. J.; Teat, S. J.; Woodward,
S. Angew. Chem., Int. Ed. 2005, 44, 2235-2237); instead, an excess of
ZnR2 (e.g., 2-6 equiv) is typically employed, resulting in the transfer of
e25% of the available R groups.
(3) For example, see: (a) Consiglio, G.; Morandini, F.; Piccolo, O. J. Chem.
Soc., Chem. Commun. 1983, 112-114. (b) Gomez-Bengoa, E.; Heron,
N. M.; Didiuk, M. T.; Luchaco, C. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1998, 120, 7649-7650.
(4) Progress with nucleophiles that exhibit greater functional-group tolerance
has been relatively modest. For examples, see: (a) Chung, K.-G.; Miyake,
Y.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 15-18. (b) Chen,
H.; Deng, M.-Z. J. Organomet. Chem. 2000, 603, 189-193. (c) Novak,
A.; Fryatt, R.; Woodward, S. C. R. Chim. 2007, 10, 206-212.
(5) Huo, S. Org. Lett. 2003, 5, 423-425.
(6) (a) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-4595. (b)
Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482-10483.
(7) The addition of NaCl has a pronounced effect on the rate of the cross-
coupling, but little impact on the ee. Two of the possible roles of NaCl
are to increase the ionic strength of the reaction mixture (the use of more
polar solvents is generally advantageous) and to activate the organozinc
reagent. For a review of halide effects in transition-metal catalysis, see:
Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26-47.
(8) BnCH2-Pybox can be prepared in two steps from homophenylalanine.
Under otherwise identical conditions, commercially available i-Pr-Pybox
furnishes 78% ee and 92% yield.
reaction of a 1,2,3-trisubstituted allylic electrophile with excellent
enantioselectivity (entry 6). An unactivated alkyl chloride is
essentially inert to these conditions (entry 4).
Next, we turned our attention to enantioselective Negishi
reactions of unsymmetrical allylic chlorides. Perhaps not surpris-
ingly, the regioselection is only modest when the catalyst must
differentiate between an n-butyl and a methyl group (1.9:1
selectivity in favor of reaction proximal to the methyl substituent;
Table 2, entry 1); nevertheless, the ee’s are substantial (major
regioisomer, 83% ee; minor regioisomer, 88% ee), and the
combined yield is excellent. For a variety of other electrophiles,
the asymmetric Negishi couplings proceed with excellent regiose-
lectivity (>20:1; entries 2-7).10 Thus, an isopropyl/methyl- and a
t-Bu/methyl-substituted allylic chloride undergo cross-coupling at
the less hindered site with fairly good ee and in high yield (entries
2 and 3, respectively). Negishi reactions of conjugated electrophiles
occur with a strong preference for carbon-carbon bond formation
at the γ position and with excellent enantioselection (g90% ee;
entries 4-7).11
We have applied this nickel/Pybox-catalyzed asymmetric Negishi
cross-coupling to a formal total synthesis of fluvirucinine A1.12 In
1999, Suh reported the first synthesis of this macrocycle, via
aldehyde 1 (Scheme 1), which he generated in 16 steps through
use of stoichiometric chiral-auxiliary chemistry introduced by
Evans.13 We have developed an eight-step catalytic enantioselective
route to intermediate 1 wherein the two tertiary stereocenters are
produced via asymmetric Negishi reactions of racemic secondary
allylic chlorides. Thus, cross-coupling of chloride 2, which is
(9) Notes: (a) Under our standard conditions, if a simple allylic acetate or
tosylate is employed as the electrophile, or if NiCl2•glyme or the Pybox
ligand is absent, then essentially no cross-coupling is observed; cross-
couplings of certain cyclic allylic chlorides proceed in high ee but low
yield; if R2 is bulky (eq 1), coupling is inefficient. (b) For each Negishi
reaction, the product is generated with >20:1 E:Z selectivity.
(10) The regioisomeric distribution of the cross-coupling product is independent
of the regioisomeric composition of the allylic chloride (Table 2, entries
1-3). This contrasts with most copper-catalyzed reactions of allylic
electrophiles, which exhibit a strong preference for formation of the
regioisomer derived from SN2′ substitution (see ref 2).
(11) With a modified procedure, cross-couplings of aryl-substituted (R1 ) aryl,
Table 2) allylic chlorides can be achieved in excellent ee and moderate
yield (g94% ee; see the Supporting Information).
(12) For applications of enantioselective metal-catalyzed allylations in total
synthesis, see: Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921-
2943.
(13) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo, B.-
A.; Kim, H.-S. Angew. Chem., Int. Ed. 1999, 38, 3545-3547.
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