Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One-Pot Synthesis of Differentiated 1,3-Diketones, Pyrans, and Spiroketals

Article abstract of DOI:10.1002/anie.201509342

The design, synthesis, and validation of new highly effective bifunctional linchpins for type II anion relay chemistry (ARC) has been achieved. The mechanistically novel negative-charge migration that comprises the Brook rearrangement is now initiated by a stabilized tetrahedral intermediate, which is generated by nucleophilic addition to a Weinreb amide, rather than by a simple oxyanion that is generated from an epoxide. As a result, the linchpin preserves the carbonyl functionality in the ARC adducts, thus permitting access to functionally complex systems in a single flask without the need for further chemical manipulations. This tactic was validated with the one-pot preparation of monoprotected 1,3-diketones as well as pyran and spiroketal scaffolds, depending on the choice of nucleophile, electrophile, and work-up conditions.

Full text of DOI:10.1002/anie.201509342

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International Edition: DOI: 10.1002/anie.201509342
German Edition: DOI: 10.1002/ange.201509342
Brook Rearrangement
Hot Paper
Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb
Amide Linchpins for the One-Pot Synthesis of Differentiated
1,3-Diketones, Pyrans, and Spiroketals
Mark Farrell, Bruno Melillo, and Amos B. Smith III*
Abstract: The design, synthesis, and validation of new highly
effective bifunctional linchpins for type II anion relay chemis-
try (ARC) has been achieved. The mechanistically novel
negative-charge migration that comprises the Brook rearrange-
ment is now initiated by a stabilized tetrahedral intermediate,
which is generated by nucleophilic addition to a Weinreb
amide, rather than by a simple oxyanion that is generated from
an epoxide. As a result, the linchpin preserves the carbonyl
functionality in the ARC adducts, thus permitting access to
functionally complex systems in a single flask without the need
for further chemical manipulations. This tactic was validated
with the one-pot preparation of monoprotected 1,3-diketones
as well as pyran and spiroketal scaffolds, depending on the
choice of nucleophile, electrophile, and work-up conditions.
Scheme 1. a) Type I and b) type II anion relay chemistry. ASG=anion-
stabilizing group.
I
n an attempt to mimic Natureꢀs elegant synthesis of complex
laboratory,[5] we have continued to design and validate new
ARC linchpins. To this end, we envisioned a new class of
type II linchpins that would permit access to multicomponent
adducts bearing monoprotected 1,3-dicarbonyl functional
groups by means of a mechanistically new ARC tactic.
Specifically, we turned to the introduction of a carboxylic acid
derivative at the electrophilic terminus of the linchpin (1;
Scheme 2), reasoning that the relative stability of the derived
tetrahedral intermediate resulting from nucleophilic addition
(see 2; Scheme 2) would permit the desired Brook rearrange-
molecules, the concept of anion relay chemistry (ARC) has
been developed and validated as a versatile synthetic plat-
form for the union of complex fragments to furnish multi-
component adducts in an effective and stereocontrolled
fashion.[1] ARC methods can be categorized based on the
nature of the negative-charge migration: “Through-bond”
ARC (e.g., conjugate addition) has been widely exploited in
organic chemistry, whereas “through-space” ARC has come
to fruition only over the past two decades. Our interests in this
area focus on the development and implementation of
“through-space” ARC, which can be subdivided into type I
and type II tactics. Type I ARC was developed based on the
precedent set by the groups of Matsuda and Tietze,[2] wherein
linchpins react with 2 equivalents of an epoxide to furnish
symmetric tricomponent adducts. Later, by controlling the
timing of the Brook rearrangement through a change in
solvent polarity, counterion, or temperature, the formation of
unsymmetric tricomponent adducts was achieved, thus
increasing the utility of the tactic for complex-molecule
synthesis (Scheme 1a).[3] Subsequently, we designed and
validated the type II ARC tactic, which involves charge
migration across a bifunctional linchpin, again through
a controlled Brook rearrangement, resulting in a distinct
class of tricomponent adducts (Scheme 1b).[4]
Scheme 2. Type II anion relay chemistry linchpin: a new concept.
Whereas both the type I and II ARC tactics have been
exploited in a number of total synthetic ventures in our
ment to outcompete premature collapse to the ketone (5),
thereby preventing over-addition of the initiating nucleophile.
If effective, the Brook rearrangement would reveal a nucle-
ophilic carbanion, which in turn could add to an electrophile
and thereby construct a multicomponent adduct (Scheme 2).
Although precedent can be found for the capture of
a tetrahedral intermediate by N-to-O and S-to-O silyl
[*] Dr. M. Farrell, B. Melillo, Dr. A. B. Smith III
Department of Chemistry, University of Pennsylvania
231 S. 34th Street, Philadelphia, PA 19104 (USA)
E-mail: smithab@sas.upenn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509342.
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Table 1: Electrophile scope with linchpin 15.[a]
migrations,[6] the potential for premature collapse of the
tetrahedral intermediate in the polar medium typically
required to trigger the Brook rearrangement (i.e., C-to-O
silyl group migration) would have to be overcome to realize
our goal.
To explore the envisioned new ARC tactic, we first
constructed the prospective linchpins 12–15 (Scheme 3).
Carboxylic acid 12 and ethyl ester 13 were prepared in
analogous fashion, namely by nucleophilic addition of TMS-
Scheme 3. Linchpin synthesis and preliminary studies.
[a] Reaction conditions: i) 15, THF, À788C, then slow addition of nBuLi;
ii) electrophile, HMPA, THF, À788C to À308C; iii) sat. aq. NH4Cl.
dithiane to lithium bromoacetate and ethyl bromoacetate,
respectively.[7] In turn, amide coupling of 12 with the HCl salts
of N,N-dimethylamine and N,O-dimethylhydroxylamine pro-
vided amide linchpins 14 and 15; the latter compound is
a Weinreb amide (Scheme 3).[8] With the first linchpins 12 and
13 in hand, the feasibility of the proposed ARC tactic was
explored in THF at À788C, using n-butyl lithium (nBuLi) as
the nucleophile and benzyl bromide (BnBr) as the electro-
phile; hexamethylphosphoramide (HMPA) was employed to
trigger the Brook rearrangement. Unfortunately, the reaction
sequence resulted in the formation of complex mixtures, with
only minor amounts of the desired product 16 (< 16%).
Pleasingly, however, when 14 and 15 were subjected to the
aforementioned reaction conditions, the desired product 16
could be isolated in good to excellent yield after protic
workup and flash chromatography. The superiority of the
Weinreb amide linchpin 15, relative to congener 14, suggests
that the stabilization of the tetrahedral intermediate imparted
by the N-methoxy moiety, presumably by chelation of lithium,
prevents premature Brook rearrangement and is pivotal to
the success of this ARC tactic.[8]
provide adduct 22 in 71% yield. Finally, when epichlorohy-
drin was employed as the terminating electrophile, epoxide 23
was obtained in good yield, resulting as expected from
nucleophilic attack at the terminal epoxide carbon atom
rather than direct displacement of the chloride.[9]
Next, we explored the nature of the nucleophilic compo-
nent of the ARC reaction, employing benzyl bromide as the
electrophilic species (Table 2). Again, the ARC reactions
proceeded in good yield with alkyl, alkenyl, alkynyl, allyl, and
aryl lithium nucleophiles (entries 1–7). The addition of softer
nucleophiles was also explored (entries 8–10). To achieve
these transformations, greater control over the timing of the
Brook rearrangement was required: Key to success was the
addition of a solution of benzyl bromide in THF to the
tetrahedral intermediate, followed by the slow addition of
a precooled HMPA/THF solution. With this procedure, the
reactions furnished the desired tricomponent adducts in
generally good yields.
Excited by the initial results, we proceeded to analyze the
scope and utility of this new ARC tactic with linchpin 15 and
diverse electrophiles and nucleophiles (Tables 1 and 2).
Pleasingly, the ARC reactions proceeded smoothly in good
yield with methyl iodide and allyl bromide (entries 1 and 2,
Table 1), whereas the yields achieved with homoallylic,
alkynyl, and alkyl bromides were somewhat lower than with
the corresponding iodide congeners (entries 3–5). The reac-
tion with chlorotriethylsilane also proceeded effectively to
To demonstrate the utility of the monoprotected 1,3-
diketone motif that is now readily accessible by this ARC
tactic, we studied the one-pot construction of substituted
pyran and spiroketal scaffolds from structurally simple
components (Scheme 4).[10] Initial attempts at the single-
flask ARC cyclization method entailed use of nBuLi as the
initiating nucleophile with ethylene oxide as the terminating
electrophile; 41 was isolated in good yield after protic workup
and chromatography (entry 1, Table 3). Use of (R)-benzyl
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Table 2: Nucleophile scope with linchpin 15.[a]
Table 3: Preparation of cyclic systems utilizing 15.[a]
[a] Reaction conditions: i) 15, Et2O, À788C, then slow addition of NuLi;
ii) BnBr, HMPA, Et2O, À788C to À308C; iii) quench A with sat. aq. NH4Cl
or quench B with 48% aq. HF, then NaHCO3.
glycidyl ether as the terminating electrophile led to lactol 42
also in good yield, whereas simply altering the workup
procedure (i.e., more acidic conditions; quench B, Table 3)
led to dihydropyran 43. Next, an alkyl lithium reagent bearing
a terminal TBS ether, which was envisioned to undergo in situ
deprotection, was employed as the initiating nucleophile with
benzyl bromide as the terminating electrophile. Upon reac-
tion completion (determined by TLC), addition of aqueous
HF furnished 45 in 60% yield. Similarly, the use of ethylene
oxide resulted in the formation of spiroketal 46. Turning to
nucleophile 47 and (R)-benzyl glycidyl ether as the electro-
phile, followed by silyl group removal, led to spiroketal 48 in
67% yield. Treatment of 46 and 48 with Raney nickel under
[a] Reaction conditions: i) 15, THF, À788C, then slow addition of NuLi;
ii) BnBr, HMPA, THF, À788C to À308C; iii) sat. aq. NH4Cl. [b] i) 15, THF,
À788C, then slow addition of NuLi; ii) BnBr, THF, then slow addition of
HMPA/THF solution, À788C to À308C; iii) sat. aq. NH4Cl.
a
hydrogen atmosphere furnished (Æ)-olean (49) and
SPIKET-P (50) respectively.[11,12]
Finally, we have also achieved the construction of complex
aldehydes in a similar manner to that presented for the
preparation of tricomponent ketones and ketals. Treatment of
15 with a nucleophilic hydride (LiAlH4) and subsequent
addition of BnBr in a HMPA/THF solution did not result in
the formation of the envisioned adduct (Scheme 5, 52).
Whereas this was not the desired outcome, we envisioned
that the addition of lithium N,O-dimethylhydroxylamine 54 to
Scheme 4. Proposed preparation of cyclic compounds.
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in the preparation of di- and tetrahydropyrans as well as
spiroketals in one-pot processes.
Acknowledgements
Financial support was provided by the NIH (GM-29028). We
thank Dr. G. Furst and Dr. R. Kohli at the University of
Pennsylvania for assistance in obtaining NMR and high-
resolution mass spectra, respectively.
Scheme 5. Preparation of aldehyde-containing adducts.
Keywords: anion relay chemistry · Brook rearrangement ·
1,3-diketones · spiroketals · Weinreb amides
53 would permit formation of intermediate 51;[13] subsequent
Brook rearrangement, electrophile addition, and protic work
up would then yield adduct 55. Gratifyingly, addition of 54 to
53 followed by a solution of benzyl bromide in HMPA/Et2O
and protic workup provided aldehyde 56 in 78% yield
(Table 4, entry 1). In similar fashion, use of ethylene oxide
and (R)-benzyl glycidyl ether as the terminating electrophiles
permitted the preparation of 57 and 58 in good yields
(entries 2 and 3).
How to cite: Angew. Chem. Int. Ed. 2016, 55, 232–235
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[a] Reaction conditions: i) 51, Et2O, À788C, then slow addition of NuLi;
ii) BnBr, HMPA, Et2O, À788C to À308C; iii) sat. aq. NH4Cl.
In summary, we have designed, synthesized, and validated
Weinreb amide 15 as a new type II ARC linchpin for the
efficient preparation of architecturally complex scaffolds.
This linchpin showcases a novel ARC tactic that permits the
ready construction of differentiated 1,3-diketones and deriv-
atives while circumventing the requirement for protecting-
group and oxidation-state manipulations. In turn, we have
illustrated the utility of this new ARC linchpin, most notably
Received: October 6, 2015
Revised: October 27, 2015
Published online: November 20, 2015
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