Squaramide-catalyzed enantioselective Michael addition of masked acyl cyanides to substituted enones

Article abstract of DOI:10.1021/ja409012q

Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective Michael addition to substituted enones. The reactions are catalyzed by chiral squaramides and afford adducts in high yields (90-99%) and with excellent enantioselectivities (85-98%). The addition products are unmasked to produce dicyanohydrins that, upon treatment with a variety of nucleophiles, provide γ-keto acids, esters, and amides. The use of this umpolung synthon has enabled, in enantiomerically enriched form, the first total synthesis of the prenylated phenol (+)-fornicin C.

Full text of DOI:10.1021/ja409012q

Communication
pubs.acs.org/JACS
Squaramide-Catalyzed Enantioselective Michael Addition of Masked
Acyl Cyanides to Substituted Enones
Kin S. Yang, Antoinette E. Nibbs, Yunus E. Turkmen, and Viresh H. Rawal*
̈
Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States
S
* Supporting Information
ABSTRACT: Masked acyl cyanide (MAC) reagents are
shown to be effective umpolung synthons for enantiose-
lective Michael addition to substituted enones. The
reactions are catalyzed by chiral squaramides and afford
adducts in high yields (90−99%) and with excellent
enantioselectivities (85−98%). The addition products are
unmasked to produce dicyanohydrins that, upon treatment
with a variety of nucleophiles, provide γ-keto acids, esters,
and amides. The use of this umpolung synthon has
Figure 1. Synthesis of 1,4-dicarbonyls via addition of MAC reagents.
enabled, in enantiomerically enriched form, the first total
synthesis of the prenylated phenol (+)-fornicin C.
he importance of umpolung chemistry stems from its
Tcapacity to provide access to functional group arrange-
ments that are difficult to realize through normal chemical
reactivity considerations.1 For example, whereas 1,3-dicarbonyl
compounds are readily synthesized through classical reactivity
(nucleophilic enolate plus an electrophilic carbonyl reactant),
1,4-dicarbonyl compounds, having dissonant connectivity,2 can
prove challenging. An efficient route to such compounds is
through an umpolung strategy, the reaction of an enone with a
masked acyl anion. Given their value in synthesis, many acyl
anion equivalents have been developed and utilized for a variety
of synthesis problems.3 Among useful and versatile umpolung
synthons are protected hydroxyl malononitriles, known as
masked acyl cyanide (MAC) reagents, developed by Yamamoto
and Nemoto.4 Treatment of a MAC reagent with base generates
a nucleophilic acyl anion equivalent that will react with a variety
of electrophilic units. Subsequent unmasking of the MAC unit
produces an acyl cyanide, which can be intercepted to afford
carboxylic acids, esters, or amides.5 Thus, unlike typical acyl
anion equivalents, MAC reagents also harbor masked acid
chloride-like reactivity. This dual capability, found in few acyl
anion equivalents, allows MAC reagents to function as carbon
monoxide equivalents.6 The usefulness of these reagents is
demonstrated by their use in the total syntheses of (−)-bestatin,
cyclotheonamide C, and oseltamivir (tamiflu).7−9 Despite their
importance in synthesis, there appears to be no report of a
catalytic enantioselective reaction of a MAC reagent.10 The ease
of deprotonation of MAC reagents suggested that their reactions
could be rendered enantioselective using a bifunctional chiral
base. In this report, we disclose the first enantioselective
reactions of the MAC family of umpolung synthons.11,12
Specifically, we show that Michael additions of MAC reagents
to enones are efficiently catalyzed by chiral squaramides,
affording adducts in high yields and excellent enantioselectivities
Figure 2. A selection of chiral catalysts examined.
and, upon unmasking, provide ready access to chiral γ-keto-
carboxylic acids, -esters, and -amides (Figure 1).
Our initial efforts focused on the identification of effective
catalysts and conditions for the enantioselective Michael reaction
between trans-chalcone (1a) and MOM-MAC (2) to afford
adduct 3a (Figure 2).13,14 Although quinine (I) promoted this
reaction, it afforded the adduct with poor enantioselectivity. The
cinchonidine-derived thiourea catalyst (II) gave better enantio-
selectivity but low conversion. On the other hand, the
corresponding squaramide (III) provided both superior
conversion and enantioselectivity. As anticipated, the pseudo-
Received: August 30, 2013
Published: October 3, 2013
© 2013 American Chemical Society
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a
Table 1. Substrate Scope of Squaramide-Catalyzed MAC Addition Reactions
a
c
d
Conditions: reactions performed with 1 (0.36 mmol), 2 or 4 (0.30 mmol), VIc (5 mol %), CH2Cl2 (0.6 mL). Isolated yield. ee determined by
e
chiral stationary phase HPLC. 4 Å MS was used as an additive to avoid hydrolysis.
enantiomeric, quinidine-derived squaramide (IV) provided the
product with comparable selectivity and conversion but enriched
in the opposite enantiomer. Among the other squaramide
catalysts examined, those based on 1,2-diaminocyclohexane
proved most effective, particularly the pyrrolidine catalyst VIc,
which formed 3a at a high rate and with 90% ee.15,16 The
enantiomeric excess improved significantly, to 97%, when the
reaction was carried out at −30 °C. It is noteworthy that
comparable enantioselectivity was observed even at 1 mol %
catalyst loading, albeit with lower conversion. Moreover,
increasing the catalyst loading to 10 mol % did not significantly
increase the conversion over the 5 mol % reaction, presumably
due to the limited solubility of the catalyst.17 Additional solvents
were also investigated for the reaction, but they did not lead to an
improved outcome.
electron-deficient aryl groups at the β-position gave excellent
results (entries 2−3). The more electron-rich substrate, p-
methoxyphenyl enone 1d, required higher reaction temperatures
and provided reduced enantioselection (entry 4). The Michael
addition was also effective with naphthyl enone 1e and various
heteroaryl-substituted enones (entries 5−9). Conjugated enone
1j reacted selectively at the β-position to afford the addition
products in excellent yields and enantioselectivities (entry 10).
The related substituted dienone 1k delivered the addition
product with a notable drop in enantioselectivity, coinciding with
its reduced reactivity (entry 11). The reaction of enone 1l, which
contains a free phenol, is noteworthy as it demonstrates the
tolerance for acidic hydrogen-bond donor groups in the substrate
(entry 12). The successful use of benzotriazole-containing enone
1m (entry 13) is noteworthy.
We next examined the practical utility and substrate scope of
squaramide-catalyzed enantioselective Michael reactions of
MAC reagents (Table 1). In general, high yields and
enantioselectivities were observed for a broad range of enones.
Importantly, the related TBS-MAC reagent (4)4b was also found
to be effective for the enantioselective Michael reaction.
Although 4 displays lower reactivity compared to 2, requiring
higher reaction temperatures and/or longer times for complete
reaction, it provides comparable enantioselectivity while offering
an alternative deprotection protocol (vide infra). Enones having
Enones having β-alkyl-substituents were also found to be
effective substrates for the MAC-Michael reaction.18 The
reaction of both MAC reagents with enones having primary
alkyl substitutents proceeded well, affording the addition
products in near-quantitative yields and with high enantiose-
lectivities (entries 14−16). The more sterically hindered
cyclohexyl-enone 1q (entry 17) required room temperature for
the reaction to proceed but still gave the product with 89% ee.
Cyclopropyl enone 1r, on the other hand, was more reactive and
gave the addition product in excellent yield and selectivity (entry
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a
Scheme 1. Functionalization of MAC Adducts
Scheme 2. Determination of Absolute Stereochemistry
Figure 3. Model for asymmetric induction.
a
Conditions: (a) 1:1 AcOH/DME (0.5 M), (R)-CSA (50 mol %), 60
°C, 2 h; (b) morpholine, Et3N, −40 °C; (c) MeOH, Et3N, −40 °C;
(d) 1:1 AcOH/H2O (0.5 M), (R)-CSA (50 mol %), 15 h; (e) 3HF·
Et3N, THF, −30, 2 h; (f) HN(OMe)Me.HCl, Et3N, −40 °C; (g)
H2NCH2CO2Me·HCl,Et3N, −40 °C; (h) TBAF, H2O:THF:AcOH
(1:1:2), 24 h.
Scheme 3. Total synthesis of Fornicin C
18). The Michael reaction of MOM-MAC and trifluoromethyl-
substituted enone 1s proceeded nicely, providing straightforward
access to chiral units containing the trifluoromethyl group.
Curiously, for reasons that are unclear, the same reaction with
TBS-MAC gave significantly lower selectivity with this substrate.
The optimized conditions are suitable for the preparation of
gram quantities of the Michael adducts. For example, the reaction
with chalcone 1a was scaled up to produce 1 g of product, formed
in the same yield and enantioselectivity as noted in entry 1.
Additionally, in large-scale reactions the low solubility of the
catalyst makes it convenient to recover most of it (84%) from the
ether extracts by simple filtration. Such recovered catalyst can be
used multiple times without measurable loss in efficacy.
We recognized that the above reactions would be of value only
if the MAC group in the Michael adducts could be transformed
into useful functional groups without eroding enantioselectivity.
A careful examination of hydrolysis conditions allowed us to
identify mild, efficacious conditions for unmasking the MAC
moiety. For the MOM-MAC adduct 3a, excellent results were
obtained if the intermediate acyl cyanide, which is prone to
racemization, was intercepted at a relatively low temperature (ca.
−40 °C).19 Thus, treatment of the labile dicyanohydrin (6),
formed upon removal of the MOM group, at −40 °C with
MeOH/Et3N or morpholine/Et3N, gave ketoester 7 or
ketoamide 9, respectively, in high yields and with little or no
enantiomeric excess loss (Scheme 1). Ketoacid (8) can be
formed directly by treating the MOM-adduct with CSA in
aqueous acetic acid. Conditions were also developed for the
efficient transformation of the TBS-MAC adduct 5a to methyl
ester 7, Weinreb amide 10, and glycine-derived amide 11 as well
as for its direct transformation to ketoacid 8.20
chalcone, which in turn is activated through hydrogen bonding.
Analogous models have been posited for thiourea- and
squaramide-catalyzed asymmetric reactions.14b,h
The utility of the above enantioselective methodology is
demonstrated through the total synthesis of prenylated phenol
(+)-fornicin C (Scheme 3). Isolated from Ganoderma fornicatum,
extracts of which are reported in Chinese medicine to have
health-promoting properties,22 fornicin C displays moderate in
vitro cytotoxic activity against the human larynx carcinoma cell
line Hep-2 (23 μg/mL). Triol 17 can be prepared directly from
the aldol reaction of the trianion of 2,5-dihydroxyacetophenone
(14) with geraniol-derived aldehyde 16 in ca. 50% yield23 or in a
higher yield via the Mukaiyama aldol reaction of silyl enol ether
15 with 16. Dehydration to the enone was an unforeseen
challenge since basic conditions promoted cyclization to a
chromanone, while strongly acidic conditions introduced
complications through reactions with the geranyl side chain.
Furthermore, with dehydrating agents such as Martin’s sulfurane
or Burgess’ reagent, the phenols competed with the secondary
alcohol. We found that sulfur trioxide-pyridine complex was
effective in achieving the dehydration of triol 17 to enone 18.24
Addition of TBS-MAC (4) to enone 18 provided adduct 19 with
92% ee.25 When subjected to AcOH-buffered TBAF, 19 was
successfully unmasked to reveal (+)-fornicin C in 51% overall
yield, with complete retention of ee.
The absolute stereochemistry induced during the Michael
reaction was determined by taking advantage of the unique
reactivity of acyl benzotriazoles.21 The MAC addition product of
cinnamyl-benzotriazole (1m) catalyzed by (R,R)-VIc was first
converted to methyl ester 12, unmasking of which generated the
known succinate ester 13, enriched in the S enantiomer (Scheme
2). The observed asymmetric induction is consistent with a
pretransition state assembly shown in Figure 3, wherein the
ammonium salt directs nucleophilic addition of MAC anion to
To summarize, we have developed the first catalytic,
enantioselective reaction of the MAC family of umpolung
synthons. We have shown that chiral squaramide VIc catalyzes
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(11) Selected examples of acyl anion equivalents in enantioselective
the conjugate addition reactions of MAC reagents 2 and 4 to a
collection of electronically and structurally diverse enones to
afford adducts in high yields and with excellent enantioselectiv-
ities. The addition products can be unmasked to afford γ-keto-
carboxylic acids, -esters, and -amides, all formed in excellent
yields and with near complete retention of enantiomeric
excesses. We have utilized this methodology for the total
synthesis of (+)-fornicin C, prepared in five steps from known
aldehyde 16, in 51% overall yield and 92% ee. The development
of other enantioselective reactions of MAC and related
umpolung reagents is expected to be of great value in organic
synthesis.
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(a) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
vrawal@uchicago.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Institutes of Health
(R01GM069990) is gratefully acknowledged.
REFERENCES
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