α-Silyl Amides: Effective Bifunctional Lynchpins for Type i Anion Relay Chemistry

Article abstract of DOI:10.1021/acs.orglett.7b03142

Lynchpins comprising α-silyl amides have been validated for type I anion relay chemistry (ARC) to permit ready access to γ-ketoamides. Importantly, the ARC protocol can be run at ambient temperature without the need of additional reagents to trigger the [

Full text of DOI:10.1021/acs.orglett.7b03142

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
α‑Silyl Amides: Effective Bifunctional Lynchpins for Type I Anion
Relay Chemistry
Thomas D. Montgomery and Amos B. Smith, III*
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
*
S Supporting Information
ABSTRACT: Lynchpins comprising α-silyl amides have been
validated for type I anion relay chemistry (ARC) to permit
ready access to γ-ketoamides. Importantly, the ARC protocol
can be run at ambient temperature without the need of
additional reagents to trigger the [1,4] Brook rearrangement.
he rapid and efficient construction of complex molecular
While we and others have employed type I ARC, the
available lynchpins remain limited, with dithiane-based
T
architecture has been a longstanding hallmark for the total
synthesis of natural products. A protocol developed in our
laboratory, termed anion relay chemistry (ARC), has proven
highly effective toward this end via the construction of
polyketide natural products. The ARC tactic can be categorized
3
lynchpins by far the most common. Other effective ASGs
8
9
10
for type I lynchpins include bischloro, cyano, and allyl. Use
of dithianes as anion-stabilizing groups followed by the Brook
rearrangement is, however, limited to oxidative or reductive
removal, resulting in a ketone or methylene moiety. In an effort
to expand the scope of the ARC tactic to different connectivity
patterns, we reasoned that a carbonyl-based ASG would permit
access to 1,4 oxygenation patterns. This tactic becomes even
more appealing due to the comparative difficulty in preparing
1
2
into through-bond and through-space negative charge3
migration, the later further divided into type I and type II.
Type I ARC involves the generation of an anion adjacent to an
anion stabilizing group (ASG); following addition to a reactive
4
electrophile, a [1,n]-Brook rearrangement returns the derived
anion to the originating site, which can then be captured with a
second suitable electrophile to yield a three-component
product in a single flask. We first reported the use of type I
11
such compounds given incompatibility with the typical aldol
12
or Michael reactions (Scheme 2). Significant work has been
done relating to the synthesis of 1,4-dicarbonyls involving
5
ARC in 1997, employing dithianes as the anion-stabilizing
13
14
metal-catalyzed couplings and Stetter reactions and through
groups as a strategic step in our total synthesis of spongistatins
15
the use of umpolung synthons.
6
1
and 2 (Scheme 1, entry 1).
With this constraint in mind, we turned to amide-based
16
lynchpins as a potential carbonyl bifunctional lynchpin.
Scheme 1. Anion Relay Chemistry
Importantly, Rathke and co-workers early on had demonstrated
that C-silylated amides can be prepared and reacted at the α-
Scheme 2. Typical 1,3-Oxygen Spacing
In 2004, we extended the ARC tactic via the use of
bifunctional lynchpins. In this case, the first step involves
addition of a nucleophile to a suitable oxygen-containing
electrophile which can lead by migration of the derived anion
via a Brook rearrangement to a new carbon center bearing an
anion-stabilizing group. The reaction can then be terminated by
reaction of the new anion with a suitable electrophile. This
tactic was termed type II ARC and has subsequently been
employed to great advantage in a number of total syntheses,
including our recent synthesis of mandelalide A (Scheme 1,
Received: October 9, 2017
7
entry 2).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
7
18
a
carbon with both aldehydes and epoxides. We therefore
postulated that after amide deprotonation of 1 the enolate
would open the epoxide at ambient temperature. A
spontaneous Brook rearrangement of the resultant alkoxide
could then ensue, migrating the negative charge to be captured
with an appropriate electrophile (Scheme 3).
Table 2. Substrate Scope for Electrophile Component
Scheme 3. Amide-Based Lynchpin
Gratifyingly, exposure of the anion derived from lynchpin 1
to butylene oxide at ambient temperature led both to ring
opening of the epoxide and subsequent [1,4] thermal Brook
rearrangement to furnish 2 (R = H) (Table 1, entry 1).
a
Table 1. Initial Results and Optimization
b
entry
solvent
THF
electrophile
base
LDA
NMR yield (%)
H O+
80
c
1
2
3
4
5
6
7
8
9
3
Et O
2
H O+
LDA
0
69
72
3
toluene
DCM
THF
THF
THF
THF
THF
H O+
LDA
3
H O+
LDA
3
c
allyl bromide
allyl bromide
allyl bromide
allyl bromide
allyl bromide
LDA
45
n-BuLi
s-BuLi
LiHMDS
NaH
60
c
89
56
0
a
Amide (1.00 equiv), base (1.10 equiv), butylene oxide (1.05 equiv),
b
1
electrophile (1.60 equiv), solvent (0.2 M). H NMR yield determined
by reference to internal standard. Isolated yield.
a
c
Amide (1.00 equiv), sec-BuLi (1.10 equiv), butylene oxide (1.05
b
equiv), electrophile (1.60 equiv), THF (0.2 M). Diastereomeric ratio
determined from crude H NMR. PCC oxidation. Dess−Martin
periodinane oxidation. Swern oxidation.
1
c
d
e
Following this initial success, we screened a series of commonly
used solvents (entries 2−4) with THF providing the best yield,
although both toluene and DCM were tolerated. We
subsequently performed the reaction with allyl bromide as
the terminal electrophile for the ARC protocol to capture the
generated amide stabilized anion. Pleasingly, following aqueous
workup, we were able to isolate alcohol 2 (R = allyl) in modest
yield (entry 5). Capitalizing on this result, we next examined
several bases to affect the deprotonation of 1; s-BuLi gave the
cleanest reaction, providing the product in 89% yield (entry 7).
With optimized reaction conditions in hand, we turned to
explore the scope of this type I ARC tactic employing butylene
oxide (Table 2). While the yields were generally good to
excellent, the diastereoselectivities of the intermediate amide
enolates proved only modest. Efforts to improve this selectivity
though increased steric bulk at the nitrogen or via the
proceeded in good to excellent yield (entries 7 and 8); similar
oxidation led to γ-ketoamides 9 and 10.
At this point, we examined which epoxide structures would
be compatible with the bifunctional amide lynchpin (Table 3).
Styrene oxide proved to be an excellent substrate; the allyl,
benzyl, and propargyl targets were also available in good to
excellent yield (entries 1−3). Subsequent oxidation provided
the phenyl derivatives 11−13. We next examined the impact of
a heteroatom substituent and were delighted to find the
compatibility of both benzyl and TBS protected glycidol ethers
(entries 4−7). This group of adducts could be similarly
oxidized to the corresponding γ-ketoamides, and in the case of
compounds 16 and 17, selective cleavage of the TMS group
preceded oxidation. Finally, an aryl sulfide could be
incorporated to yield 18 in moderate yield following oxidation.
With the scope of this type I ARC tactic secure, we next
examined the inherent reactivity of the derived products. One
such reaction comprises the direct cyclization of the γ-
19
employment of chiral auxiliaries led to limited success.
To demonstrate more fully the synthetic utility of this
method, we oxidized the derived alcohols to the γ-ketoamides
2
0
(
3−10). Along with the unsubstituted compound (entry 1),
21
various allyl bromides were well tolerated producing 4−6 after
oxidation. Similarly, both propargyl and benzyl bromides were
also tolerated (entries 5 and 6), in the ARC tactic, with both
subsequently oxidized in high yields to furnish 7 and 8. Finally,
alkylation with either a secondary or primary alkyl halide
hydroxyamides to furnish γ-lactones (Scheme 4). To this
end, lynchpin 1 was combined with (R)-(−)-benzyl glycidol
ether 19 to furnish 20 in good yield with modest levels of
diastereoselectivity. Following exposure to triflic anhydride, the
22
known lactone 21 was isolated in 80% yield.
B
DOI: 10.1021/acs.orglett.7b03142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Substrate Scope for Epoxide Component
Scheme 5. Functionalization of Amide Portion
3
,4
compounds to trigger the Brook rearrangement. Further
studies into this and related lynchpins are ongoing in our
laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03142.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: absmith@sas.upenn.edu.
ORCID
Thomas D. Montgomery: 0000-0002-6526-8564
Amos B. Smith III: 0000-0002-1712-8567
Notes
The authors declare no competing financial interest.
a
Amide (1.00 equiv), secBuLi (1.10 equiv), butylene oxide (1.05
b
ACKNOWLEDGMENTS
equiv), electrophile (1.60 equiv), THF (0.2 M). Diastereomeric ratio
determined from crude H NMR. Dess−Martin periodinane
oxidation. Swern oxidation.
■
1
c
Financial support was provided by the NIH through Grant No.
CA-19033. We thank Dr. Charles W. Ross III (University of
Pennsylvania), Director: Automated Synthesis, and laboratory
research associates, Sung-Eun Suh (University of Pennsylva-
nia), and Joo Myung Jun (University of Pennsylvania) for
providing chromatographic and mass spectral method develop-
ment, analyses, and data interpretation.
d
Scheme 4. Lactone Formation and Relative Stereochemistry
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DOI: 10.1021/acs.orglett.7b03142
Org. Lett. XXXX, XXX, XXX−XXX