Regio- and enantiospecific rhodium-catalyzed allylic substitution with an acyl anion equivalent

Article abstract of DOI:10.1021/ol402336u

The construction of enantiomerically enriched acyclic quaternary substituted ketones via the regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of chiral nonracemic tertiary alcohols with cyanohydrin pronucleophiles is described. This approach provides an alternative method to the α-arylation and vinylation of acyclic disubstituted ketone enolates, which remains a challenging endeavor. The combination of the allylic alkylation with ring-closing metathesis facilitates the preparation of enantiomerically enriched 2,2-disubstituted naphthalene-1-ones, which have proven very difficult to prepare using a more conventional dearomatization strategy.

Full text of DOI:10.1021/ol402336u

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5626–5629
Regio- and Enantiospecific Rhodium-
Catalyzed Allylic Substitution with an Acyl
Anion Equivalent
P. Andrew Evans*,† and Samuel Oliver‡
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON, K7L 3N6,
Canada, and Department of Chemistry, University of Liverpool, Crown Street,
Liverpool L69 7ZD, United Kingdom
andrew.evans@chem.queensu.ca
Received August 14, 2013
ABSTRACT
The construction of enantiomerically enriched acyclic quaternary substituted ketones via the regio- and enantiospecific rhodium-catalyzed allylic
alkylation reaction of chiral nonracemic tertiary alcohols with cyanohydrin pronucleophiles is described. This approach provides an alternative
method to the R-arylation and vinylation of acyclic disubstituted ketone enolates, which remains a challenging endeavor. The combination of the
allylic alkylation with ring-closing metathesis facilitates the preparation of enantiomerically enriched 2,2-disubstituted naphthalene-1-ones, which
have proven very difficult to prepare using a more conventional dearomatization strategy.
The asymmetric synthesis of R-substituted carbonyl
compounds, particularly those that contain quaternary
carbon stereogenic centers, remains a particularly impor-
tant area of investigation for synthetic organic chemistry.1
This can be attributed to the challenges associated with the
installation of this type of structural motif in important
biologically active pharmaceutical agents and natural
products.2 Ingeneral, themostcommonapproach towards
the asymmetric construction of these types of compounds
involves the functionalization of prochiral enolate nucleo-
philes, typically by alkylation,3 arylation,4 and vinylation.5
However, in addition to the inherent stereoelectronic
restrictions placed on the regioselective formation and
alkylation of an unsymmetrical enolate, a critical limita-
tion with these reactions is that they are generally optimal
for cyclic substrates, which circumvents the problems
associated with controlling the enolate geometry. For
instance, the deprotonation of an acyclic R,R-disubstituted
ketone almost invariably leads to a mixture of (E)- and
(Z)-enolates, which upon facially selective electrophilic
trapping generates a mixture of enantiomers. Although a
couple of notable examples have been devised that success-
fully address the problem with acyclic R,R-disubstituted
enolates, a universal solution to this problem has not been
forthcoming. For example, the chiral auxiliary pseudoephed-
rine Xψ facilitates the formation of a stereodefined enolate
that undergoes diastereoselective alkylation (Scheme 1A),6
† Queen's University.
‡ University of Liverpool.
(1) For recent reviews on the catalytic enantioselective construction
of quaternary carbon stereogenic centers, see: (a) Christoffers, J.; Mann,
A. Angew. Chem., Int. Ed. 2001, 40, 4591. (b) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105. (c) Trost, B. M.; Jiang, C. Synthesis 2006,
369. (d) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593.
(2) For reviews on the asymmetric synthesis of natural products
containing quaternary carbon stereogenic centers, see: (a) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b) Hong,
A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2745.
(3) For recent reviews on the enantioselective enolate alkylation reac-
tion, see:(a) Stoltz, B. M.;Mohr, J. T. InScience of Synthesis;DeVries, J. G.,
Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart, 2010; Vol. 3, p 567. (b)
Oliver, S.; Evans, P. A. Synthesis 2013, 45, doi: 10.1055/s-0033-1338538.
(4) For recent examples of asymmetric transition metal-catalyzed
enolate arylation reactions, see: (a) Ahman, J.; Wolfe, J. P.; Troutman,
M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918.
(b) Chen, G.; Kwong, F. Y.; Chan, H. O.; Yu, W.-Y.; Chan, A. S. C.
(5) For recent examples of asymmetric transition metal-catalyzed
enolate vinylation reactions, see: (a) Chieffi, A.; Kamikawa, K.; Ahman,
J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897. (b) Huang, J.;
Bunel, E.; Faul, M. M. Org. Lett. 2007, 9, 4343. (c) Taylor, A. M.;
Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900.
Chem. Commun. 2006, 1413. (c) Garcıa-Fortanet, J.; Buchwald, S. L.
´
Angew. Chem., Int. Ed. 2008, 47, 8108. (d) Liao, X.; Weng, Z.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 195. (e) Ge, S.; Hartwig, J. F. J. Am.
Chem. Soc. 2011, 133, 16330.
r
10.1021/ol402336u
Published on Web 11/01/2013
2013 American Chemical Society

Table 1. Optimization of the One-Pot Regio- and Enantiospe-
cific Rhodium-Catalyzed Allylic Substitution with an Acyl
Anion Equivalenta
Scheme 1. Comparison of Stereoselective Enolate Alkylation
with Metal-Catalyzed Allylic Substitution for the Preparation
of Enantiomerically Enriched Acyclic Quaternary Stereocenters
acyclic ketone 3a
entry
L
b:lb
P(O-2,4-di-tBuC6H3)3 g19:1
% yieldc
erd
cee15
1
2
3
4
5
66
72
78
80
87
91:9
85
19
61
85
91
P(OTBS)3
P(OPh)3
g19:1
g19:1
g19:1
g19:1
59:41
79:21
91:9
P(OMe)3
P(OCH2CF3)3
95:5
a All reactions were performed on a 0.5 mmol reaction scale using
1 equiv of nBuLi, 1 equiv of MeOCOCl, 2.5 mol % [RhCl(COD)]2,
10 mol % L, 1.3 equiv of 2a, and 1.8 equiv of LiHMDS in THF (5 mL) at
À10 °C for ca. 16 h, followed by the addition of 4 equiv of TBAF at room
temperature. b Regioselectivity was determined by 500 MHz 1H NMR
on the isolated product 3a. c Isolated yields. d Determined by chiral
HPLC on the isolated product 3a.
whereas a chiral chromium salen catalyst results in a highly
enantioselective alkylation of a mixture of enolate stereo-
isomers (Scheme 1B).7 Nevertheless, we envisioned an
alternative approach to this problem, which circumvents
the formation of an enolate and thereby provides almost
unparalleled scope with respect to the electrophile.
R-vinyl ketones, which remain challenging substrates for
conventional enolate alkylation reactions.
A critical component for this process is the ability to
readily access highly enantiomerically enriched tertiary
allylic alcohols. In this context, an array of chiral non-
racemic aryl tertiary alcohols 1 were readily prepared by a
threestepprocedurereportedbyAggarwalandco-workers
for the stereodivergent construction of aryl-substituted
tertiary alcohols.13 Interestingly, the attempted activation
of the tertiary allylic alcohol 1a (Ar = Ph) with methyl
chloroformate led to the rearrangement to the achiral
linear regioisomer during purification by column chroma-
tography.14 Hence, to circumvent this problem, we devel-
oped a convenient and efficient one-pot procedure in which
the reactive allylic carbonate was generated in situ, and
then directly treated with the anion of the cyanohydrin 2 in
the presence of the rhodium catalyst, to provide the
enantiomerically enriched ketone 3 upon deprotection of
the resultant cyanohydrin adduct with fluoride.
Table 1 outlines the effect of the phosphite ligand on
enantiospecificity. Interestingly, the bulky aryl phosphite
that was optimal for regioselectivity in the previous study
afforded the acyclic ketone 3a in moderate yield and
stereospecificity (entry 1). A survey of various phosphite
ligands indicates that the regioselectivity is consistent with
an array of stereoelectronically diverse ligands, whereas
the level of stereospecificity is optimal with a smaller
electron-deficient phosphite ligand, namely tris(2,2,2-
trifluoroethyl) phosphite (entry 5). Presumably, the
In this context, we recently reported a novel method for
the construction of acyclic quaternary carbon stereogenic
centers via the rhodium-catalyzed allylic substitution of
tertiary allylic alcohol derivatives with an acyl anion
equivalent (Scheme 1C), namely a tert-butyldimethylsilyl-
protected cyanohydrin.8 The cyanohydrin pronucleophile
is readily prepared by the addition of tert-butyldimethylsi-
lyl cyanide to the corresponding aldehyde9 and unmasked
in situ with fluoride to afford the acyclic ketone. Addition-
ally, this study also provided proof-of-concept for the first
stereospecific rhodium-catalyzed allylic substitution of a
chiral nonracemic tertiary allylic alcohol derivative, which
proceeds via a classical double inversion process to facil-
itate good chirality transfer, albeit slightly lower than the
corresponding secondary alcohol derivatives.10À12 Herein,
we describe a general method for the enantiospecific
synthesis of a variety of acyclic quaternary R-aryl and
(6) Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.;
Myers, A. G. J. Am. Chem. Soc. 2008, 130, 13231.
(7) Doyle, A. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46,
3701.
(8) Evans, P. A.; Oliver, S.; Chae, J. J. Am. Chem. Soc. 2012, 134,
19314.
(9) Kurono, N.; Yamaguchi, M.; Suzuki, K.; Ohkuma, T. J. Org.
Chem. 2005, 70, 6530.
(10) Evans, P. A.; Leahy, D. K. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005;
Chapter 10, pp 191À214.
(13) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778. (b) Bagutski, V.; French, R. M.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2010, 49, 5142.
(11) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(12) For an example of a stereospecific iron-catalyzed allylic sub-
stitution of a tertiary allylic carbonate, see: Jegelka, M.; Plietker, B. Org.
Lett. 2009, 11, 3462.
(14) Fora related process involvingallylic acetates, see:Serra-Muns, A.;
ꢀ
Guerinot, A.; Reymond, S.; Cossy, J. Chem. Commun. 2010, 46, 4178.
Org. Lett., Vol. 15, No. 22, 2013
5627

relatively small size and increased π-acidity of this ligand
serves to increase the rate of nucleophilic alkylation rela-
tive to πÀσÀπ isomerization and thereby minimize the
equilibration of the enyl intermediate.
Scheme 2. Scope for the Stereospecific Rhodium-Catalyzed
Allylic Substitution with an Acyl Anion EquivalentaÀd
Scheme 2 summarizes the application of the optimized
reaction conditions (Table 1, entry 5) to aryl cyanohydrins
and tertiary allylic alcohol derivatives. A range of electron-
rich and electron-poor aryl cyanohydrins provide the
acyclic ketones 3aÀi in good to excellent yield and with
uniformly high conservation of enantiomeric excess
(entries 1À9),15 albiet disubstituted derivatives provide
slightly lower stereospecificities (entries 8 and 9). In addi-
tion, several tertiary arylallylic alcohols 1 provide excellent
stereoretention in this process (entries 10À15). Interest-
ingly, in the case of both the ortho-fluorinated aryl cyano-
hydrin and tertiary aryl allylic alcohol, trimethyl phosphite
provided optimal selectivity at room temperature (entries
4 and 15). A particularly attractive feature with this
method is the ability to obtain consistently high chirality
transfer for an array of R-quaternary substituted aryl
ketones, which is almost independent of the substitution
pattern of cross-coupling components. Overall, this
reaction currently provides access to a diverse array
of acyclic R-quaternary ketones bearing pendant alkyl,
aryl and vinyl groups, in which the latter provides a
particularly versatile functional handle for target direc-
ted synthesis.
To highlight the substrate scope of this method further,
we elected to examine the rhodium-catalyzed allylic alky-
lation of the linalool-derived allylic carbonate 4 (96:4 er)
with the cyanohydrin 2a (eq 1). Gratifyingly, the alkyl-
substituted allylic carbonate 4 was as efficient as the
aryl-substituted analogs, providing the ketone 5 in excel-
lent yield and enantiospecificity (91:9 er, 89% cee) in
the presence of lithium chloride. Interestingly, in the
absence of lithium chloride the reaction furnished 5 with
slightly reduced stereospecificity (88:12 er, 85% cee). This
additive presumably serves to deaggregate the lithiated
cyanohydrin, thereby providing a more reactive nucleo-
phile, which undergoes alkylation at an increased rate
relative to πÀσÀπ isomerization of the chiral allylic elec-
trophile to afford enhanced stereospecificity. In contrast,
the one-pot protocol serendipitously generates lithium
chloride from the acylation of the allylic alcohol 1, which
presumably explains the consistently high stereospecifici-
ties (Scheme 2). Although alkyl-substituted tertiary allylic
alcohols are generally more difficult to prepare than the
corresponding aryl derivatives, this reaction provides
proof-of-concept for this important process.
a All reactions were performed on a 0.5 mmol reaction scale using
1 equiv of nBuLi, 1equivofMeOCOCl, 2.5mol%[RhCl(COD)]2, 10mol%
P(OCH2CF3)3, 1.3 equiv of 2, and 1.8 equiv of LiHMDS in THF
(5 mL) at À10 °C for ca. 16 h, followed by the addition of 4 equiv
of TBAF at room temperature. b Regioselectivity was determined by
500 MHz 1H NMR on the isolated products. c Isolated yields. d En-
antiomeric ratios (er) values were determined by chiral HPLC on the
isolated products. e P(OMe)3 was used at room temperature.
for the total synthesis of a variety of natural products.16
Nevertheless, despite some exciting developments in this
field, particularly in the area of hypervalent iodine
(15) The term conservation of enantiomeric excess (cee) = (ee of
product/ee of starting material) Â 100. Evans, P. A.; Robinson, J. E.;
Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761.
The asymmetric construction of cyclohexadienone deri-
vatives via the enantioselective oxidative dearomatization
of phenols and naphthols provides an important strategy
ꢀ
(16) For a recent review, see: Pouysegu, L.; Deffieux, D.; Quideau, S.
Tetrahedron 2010, 66, 2235.
5628
Org. Lett., Vol. 15, No. 22, 2013

chemistry, the asymmetric alkylation reactions are parti-
cularly challenging both in terms of efficiency and
selectivity.17
Scheme 3. Asymmetric Synthesis of Naphthoid Cyclohexa-2,4-
dienone 8 via the Sequential Stereospecific Rhodium-Catalyzed
Allylic Substitution/Ring-Closing Metathesis Reaction
We envisaged an alternative approach to these com-
pounds, as outlined in Scheme 3, which combines the
allylic alkylation with ring-closing metathesis. In this con-
text, the rhodium-catalyzed allylic alkylation of the chiral
nonracemic tertiary carbonate derived from 1a with the
carbanion of the vinyl-substituted cyanohydrin 6 furn-
ished, upon deprotection, the diene 7, which was treated
with Grubbs second-generation catalyst to afford the
naphthoid cyclohexa-2,4-dienone 8 in 85% overall yield
and with 84% cee.18
In conclusion, the regio- and enantiospecific rhodium-
catalyzed allylic substitution of chiral nonracemic tertiary
alcohols with trialkylsilyl-protected cyanohydrins pro-
vides a general and convenient method for the construction
of enantiomerically enriched acyclic R-quaternary substi-
tuted ketones. Additionally, the ability to extend the scope
of this transformation to acyclic alkyl-substituted tertiary
allylic alcohols illustrates the synthetic utility beyond aryl-
substituted allylic alcohol derivatives. The asymmetric
synthesis of a dearomatized naphthoid cyclohexa-2,4-
dienone, which remains a challenging endeavor for
more conventional dearomatization strategies, further
highlights the synthetic potential for this process. Hence,
this method provides a viable alternative to the catalytic
asymmetric R-arylation and vinylation of acyclic disub-
stituted ketone enolates, which are particularly chal-
lenging substrates.
Acknowledgment. We would like to thank NSERC for
a Discovery Grant and a Tier 1 Canada Research Chair
(P.A.E.). We also acknowledge EPSRC and AstraZeneca
(Alderley Park) for a Ph.D. Studentship (S.O.). Dr. Paul
Kemmitt (AZ) is thanked for his support and helpful
discussions. We are also grateful to the EPSRC National
Mass Spectrometry Service Centre (Swansea, UK) for
high-resolution mass spectrometry.
(17) For a recent example of asymmetric spirolactonization of
1-naphthols catalyzed by a spirobiindane-based chiral hypervalent
iodine species, see: Dohi, T.; Takenaga, N.; Nakae, T.; Toyoda, Y.;
Yamasaki, M.; Shiro, M.; Fujioka, H.; Maruyama, A.; Kita, Y. J. Am.
Chem. Soc. 2013, 135, 4558.
(18) Although this particular compound has been prepared in race-
mic form by the oxidative arylation of 1-naphthol using Ph2ICl, the
efficiency of this reaction is poor; see: Ozanne-Beaudenon, A.; Quideau,
S. Angew. Chem., Int. Ed. 2005, 44, 7065.
Supporting Information Available. Experimental pro-
cedures, characterization data, and spectra are included.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5629