Merging Asymmetric [1,2]-Additions of Lithium Acetylides to Carbonyls with Type II Anion Relay Chemistry

Article abstract of DOI:10.1021/acs.orglett.9b02959

An enantioselective three-component coupling reaction has been developed, enabling the union of a variety of lithium acetylides and electrophiles exploiting an achiral linchpin via an anionic reaction cascade. This Type II Anion Relay Chemistry tactic is initiated via an enantioselective [1,2]-carbonyl addition exploiting BINOL catalysis to access an enantioenriched alkoxide intermediate. Migration of charge across the linchpin via a [1,4]-Brook rearrangement with electrophile capture affords a three-component propargyl ether adduct. Herein, we report the development, scope, and limitations of this reaction sequence.

Full text of DOI:10.1021/acs.orglett.9b02959

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Merging Asymmetric [1,2]-Additions of Lithium Acetylides to
Carbonyls with Type II Anion Relay Chemistry
Kevin T. O’Brien and Amos B. Smith, III*
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States
*
S Supporting Information
ABSTRACT: An enantioselective three-component coupling reaction has been developed, enabling the union of a variety of
lithium acetylides and electrophiles exploiting an achiral linchpin via an anionic reaction cascade. This Type II Anion Relay
Chemistry tactic is initiated via an enantioselective [1,2]-carbonyl addition exploiting BINOL catalysis to access an
enantioenriched alkoxide intermediate. Migration of charge across the linchpin via a [1,4]-Brook rearrangement with
electrophile capture affords a three-component propargyl ether adduct. Herein, we report the development, scope, and
limitations of this reaction sequence.
he challenge of organic synthesis is not only the ability to
synthesize a target but also the efficiency with which the
target is constructed. In this regard, Anion Relay Chemistry
ARC) comprises a one-pot, three-component union tactic in
T
(
which a linchpin component sequentially forms a C−C bond
to each of two other components via an anionic reaction
1
cascade. This tactic permits the assembly of complex
polyketide fragments from simple building blocks, thereby
minimizing the number of synthetic steps required to achieve
the synthetic target. Accordingly, our group has exploited ARC
to permit the total syntheses of several natural products,
2
3
including (−)-nahuoic acid C , (−)-mandelalide A, and
i
4
(
−)-enigmazole A. The Type II ARC protocol is initiated by
1,2]-addition of an organolithium reagent to linchpin 1,
followed in turn by a [1,4]-Brook rearrangement and
[
5
electrophile capture to afford the three-component adduct 2
(
Figure 1a). Here, diastereoselectivity arises via Felkin−Anh
control with the absolute configuration set by the α-methyl
stereogenic center present in 1.
6
,7
While stereoretentive and diastereoselective processes have
been successfully incorporated into the ARC protocol, an
enantioselective variant has yet to be developed. We reasoned
that this could be achieved via initiation of the ARC sequence
with an asymmetric [1,2]-carbonyl addition. Asymmetric
organometallic [1,2]-carbonyl additions commonly employ
Figure 1. (a) Prior ARC Work: Diastereoselectivity; (b) Prior
Asymmetric [1,2]-Addition of Lithium Acetylides to Ketones; (c)
Proposed ARC Tactic
8
Zn acetylides, although Sn, B, Li, and other metals have been
rearrangement of Zn alkoxides remains elusive. Thus, our focus
has been on lithium acetylides.
9
employed. This approach has been exploited by others,
1
0
11
The enantioselective [1,2]-carbonyl addition of a lithium
including Marek and Johnson, to access three-component
couplings initiated by a Zn acetylide. However, these examples
rely on a [1,2]-Brook rearrangement of the [1,2]-addition
intermediate, whereas our envisioned strategy would comprise
a [1,4]-Brook rearrangement; a protocol for the [1,4]-Brook
1
2
acetylide was first disclosed by Mukaiyama and later
Received: August 19, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02959
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
3
a
improved by the Merck group in the synthesis of the HIV-1
reverse transcriptase inhibitor efavirenz. However, these early
examples required several equivalents of ligand to impart high
enantioselectivity. Recently, Nakajima reported a catalytic
method for the asymmetric [1,2]-addition of lithium acetylides
to ketones to yield enantioenriched propargyl alcohols utilizing
Table 2. Optimization of ARC Sequence
14
BINOL derivative (R)-6 (Figure 1b). We sought to utilize
R)-6 in conjunction with a lithium acetylide to access
(
1H NMR ratio (13:14)
entry
variation (BnBr addition)
enantioenriched alkoxide 8 via an asymmetric [1,2]-addition to
achiral linchpin 7 to obtain the enantioenriched three-
component adduct 9 after [1,4]-Brook rearrangement and
electrophile capture (Figure 1c).
Our efforts were first directed toward evaluation of the
enantioselectivity of [1,2]-addition of lithium phenyl acetylide
to linchpin 10 to afford propargyl alcohol 11 (Table 1). The
1
2
3
4
5
6
7
8
9
maintained at −78 °C
warmed to −50 °C
warmed to −30 °C
warmed to 0 °C
b
b
54:46
59:41
75:25
63:37
23:77
69:31
60:40
67:33
warmed to rt
warmed to 50 °C
warmed to −30 °C, 24 h
gradually warmed to rt
HMPA added
Table 1. Optimization of Enantioselectivity Utilizing ARC
a
Linchpin
1
0
1.0 equiv of BnBr
a
n-BuLi (1.2 equiv); acetylene (1.0 equiv); (R)-6 (10 mol %); 10 (1
b
equiv); BnBr (2 equiv); 10 added over 10 min. Only 11 observed.
deleterious, as was either addition of HMPA, or reduction of
the BnBr stoichiometry. Additionally, maintaining the temper-
ature of the reaction at −30 °C, the lowest temperature at
which [1,4]-Brook rearrangement was observed, for 24 h did
not increase the formation of 13.
With optimized conditions for the full ARC sequence in
hand, the nucleophile scope was investigated. Reactions were
performed with linchpin 10 and BnBr as the electrophile
a
n-BuLi (2.2 equiv); acetylene (2.0 equiv); (R)-6 (10 mol %); 10 (1
(
Scheme 1). The influence of steric and electronic factors of
b
equiv); HCl (1.5 equiv); [Si] = TMS (11a); TBS (11b). 10 added
over 10 min;
the lithium acetylide on enantioselectivity was clear. Electron-
rich acetylides afforded greater enantioselectivity than electron-
poor acetylides. This trend is most evident in three-component
adducts 16a−16c, wherein enantioselectivity and yield are
reaction was initiated by deprotonation of phenylacetylene in
the presence of (R)-6 at −78 °C, followed by the addition of
linchpin 10 over a period of 10 min. The rate of ketone
addition was examined first. Decreased enantioselectivity was
observed with rapid dropwise addition of linchpin 10, with no
significant difference in enantioselectivity observed when
linchpin 10 was added over a 30 min period. Next, the
influence of silyl substitution on the linchpin was assessed by
comparing TMS and TBS linchpins 10 and 12, respectively.
Greater enantioselectivity was observed for [1,2]-addition to
a
Scheme 1. Nucleophile Scope
1
1
0 than 12. Importantly, reduction of alkyne stoichiometry to
equiv afforded excellent enantioselectivity.
Having optimized the enantioselectivity of the [1,2]-
addition, we turned our attention to the full ARC sequence.
The temperature dependence of the [1,4]-Brook rearrange-
ment and electrophile capture was examined first (Table 2). In
these experiments, benzyl bromide (BnBr) was added to the
reaction mixture after completion of the [1,2]-addition at −78
°C. Upon addition of BnBr (2.0 equiv), the mixture was
warmed to a range of temperatures from −78 to +50 °C and
held at the corresponding temperature for 1 h before the
reaction was quenched. We anticipated the formation of
products 13 and 14, whereby [1,4]-Brook rearrangement is
followed either by alkylation or protonation, respectively. The
[
1,4]-Brook rearrangement was observed at temperatures as
low as −30 °C. The highest ratio of alkylation to protonation
product (13/14) was observed with immediate transfer of the
reaction vessel to a water bath at room temperature. Allowing
the reaction to gradually warm to room temperature was
a
n-BuLi (1.2 equiv); 15 (1.0 equiv); (R)-6 (10 mol %); 10 (1.0
equiv); BnBr (2.0 equiv); 10 added over 10 min; TBAF deprotection
b
c
of crude product. TBS acetylene (15d ). TMS acetylene (15d ).
i
ii
B
DOI: 10.1021/acs.orglett.9b02959
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
positively correlated with the electron-donating character of
the para substituent. Perhaps of greater significance is the
influence of steric encumbrance of the nucleophile on
An effective cascade reaction should afford the final product
in greater yield than that obtained by the sequential execution
of the constituent reactions. The ARC cascade was therefore
divided into a two-pot sequence for comparison. The first step
of the ARC sequence is [1,2]-addition of lithium phenyl-
acetylide to linchpin 10 to arrive at alkoxide 19. A [1,4]-Brook
rearrangement of alkoxide 19 is then thermally triggered with
subsequent electrophile capture terminating the standard one-
pot ARC sequence (Scheme 3). Alternatively, alkoxide 19 can
15
enantioselectivity. Bulky nucleophiles such as 15d (TBS
i
acetylene) and 15dii (TMS acetylene) afforded 16d with
modest to moderate enantiomeric ratios of 72:28 and 90:10,
respectively. This steric influence was further exemplified in
the comparison of cyclic and linear aliphatic lithium acetylides,
wherein a greater enantiomeric ratio was observed for 16f than
1
6e. Pleasingly, the use of benzyl propargyl ether was well
tolerated, providing access to diversifiable three-component
adduct 16g in good yield and excellent enantioselectivity.
Next, the scope of electrophiles was evaluated using lithium
phenyl acetylide as the nucleophile and ketone linchpin 10 to
afford 18 (Scheme 2). Benzyl and allyl bromide electrophiles
Scheme 3. Comparison of One-Step and Two-Step ARC
Approaches
a
a
Scheme 2. Electrophile Scope
a
b
TBAF deprotection of products. n-BuLi (1.2 equiv), 10 (1.0 equiv)
c
THF, −78 °C 2 h; PhCHO (2.0 equiv). 11 (1.0 equiv), n-BuLi (1.2
equiv), THF, −78 °C 30 min, then PhCHO (2.0 equiv); both (R)-6
and no catalyst yielded identical results.
be acidified at −78 °C to afford alcohol 11. In the two-pot
protocol, purified alcohol 11 enters the ARC sequence via
deprotonation to 19. The one-pot and two-pot methods were
compared for the ARC sequence employing linchpin 10 with
phenylacetylene and benzaldehyde serving as the nucleophile
and electrophile, respectively, to afford three-component
adduct 18i. A drastic difference in the product distribution
was observed between the one- and two-pot methods. Whereas
the one-pot protocol provided 18i in good yield (73%), the
two-pot process provided only trace 18i with most of the
recovered material consisting of quenched product 14 (89%)
and benzyl alcohol (48%). We suspect the reduction of
benzaldehyde to benzyl alcohol occurs via a single-electron
transfer (SET) process that is favored by the two-pot reaction
sequence. The role of the two-pot approach in favoring a
SET pathway is unclear but may be a consequence of a
different aggregation state that occurs via access of 19 by an
alternate route. Thus, this one-pot asymmetric three-
component union tactic circumvents the undesired reactivity
and is more efficient than the sum of its parts.
a
n-BuLi (1.2 equiv); acetylene (1.0 equiv); (R)-6 (10 mol %); 10 (1.0
16
equiv); El (2.0 equiv); 10 added over 10 min; crude TBAF
deprotection. No TBAF used. (S)-epichlorohydrin was used as
electrophile 17f.
b
c
provided the desired three-component adducts 18a and 18b in
good yield. Diyne product 18c was obtained from the
corresponding silyl propargyl bromide after TBAF depro-
tection, albeit in modest yield. While an excellent yield of 18d
was achieved using MeI, a poor yield was observed for 5-
bromo-1-pentene, likely due to the competing elimination
reaction. Epoxide electrophiles were found to be viable,
affording adducts 18f−18h in modest to good yield, permitting
inclusion of an additional stereocenter. In each case, the
product was observed by H/ C NMR as a single
diastereomer. Benzaldehyde was also successfully employed,
proceeding with high enantioselectivity (99:1 er) to yield 18i
as an expected mixture of diastereomers (1.5:1).
Having demonstrated the generality of the one-pot protocol
with respect to acetylides and electrophiles, we examined the
viability of aldehyde linchpins 24a and 24b to afford secondary
alcohol 25 with phenylacetylene and BnBr serving as the
nucleophile and electrophile, respectively (Scheme 4).
Pleasingly, good yields and moderate enantioselectivities
were achieved employing aldehyde linchpins 24a and 24b.
As opposed to ketone linchpins 10 and 12 (Table 1), the size
of the silyl substituent did not affect the enantiomeric ratio of
the corresponding three-component adducts 25. Thus, either
silyl ether product can be obtained at no expense of
enantioselectivity, permitting convenient integration into a
protecting group strategy.
1
13
C
DOI: 10.1021/acs.orglett.9b02959
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Organic Letters
Letter
a
Scheme 4. Aldehyde Linchpin
ketone linchpin 10. Reduced enantioselectivity observed with
highly sterically encumbered acetylenes can be attenuated with
increased catalyst loading to permit good to excellent
enantioselectivity. This tactic enables effective diversity-
oriented synthesis by virtue of not only a three-component
nature but also the control over absolute configuration that is
exerted via the application of either (S)-Ph BINOL-6 or (R)-
2
Ph BINOL-6.
2
a
n-BuLi (1.2 equiv); acetylene (1.0 equiv); (R)-6 (10 mol %); 24 (1.0
equiv); BnBr (2.0 equiv); 24 added over 10 min; crude TBAF
ASSOCIATED CONTENT
■
b
c
deprotection. 24a. 24b.
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02959.
The greatest limitation to the generality of this tactic with
respect to enantioselectivity is derived from the steric factors of
the acetylene. Although many lithium acetylide substrates
enabled excellent enantioselectivity with linchpin 10, syntheti-
cally useful silyl acetylenes afforded moderate enantioselectiv-
ity for three-component adduct 16d (Scheme 1). To overcome
this limitation, the relationship between catalyst loading and
enantioselectivity was investigated (Figure 2). First, we
General experimental procedures, optimization studies,
1
13
characterization data, H NMR/ C NMR spectra, and
SFC chromatographs (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: smithab@sas.upenn.edu.
ORCID
Kevin T. O’Brien: 0000-0002-9584-9589
Amos B. Smith, III: 0000-0002-1712-8567
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the National Institute of
Health National Cancer Institute through Grant No. CA-
■
1
9033 and the National Foundation for Cancer Research. We
thank Dr. C. Ross III at the University of Pennsylvania for
assistance with HRMS analysis.
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Figure 2. Catalyst loading experiments with hindered silyl acetylenes.
■
2
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