Allenoate Prenucleophiles: A Triply Diastereoselective Approach to β-Hydroxy Esters Containing All-Carbon α-Quaternary Centers

Article abstract of DOI:10.1021/acs.orglett.9b02930

Allenyl esters activated by titanium(IV) underwent additions to a wide range of aldehydes in high regio- and diastereoselectivities leading to products containing an all-carbon quaternary center bearing an α-vinyl group that was installed with high select

Full text of DOI:10.1021/acs.orglett.9b02930

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Allenoate Prenucleophiles: A Triply Diastereoselective Approach to
β‑Hydroxy Esters Containing All-Carbon α‑Quaternary Centers
Samantha L. Maki,† Pradip Maity, Shannon Dougherty, Jennifer Johns,
and Salvatore D. Lepore*
‡
†
†
,
†
†
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431-0991, United States
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
‡
*
S Supporting Information
ABSTRACT: Allenyl esters activated by titanium(IV) under-
went additions to a wide range of aldehydes in high regio- and
diastereoselectivities leading to products containing an all-
carbon quaternary center bearing an α-vinyl group that was
installed with high selectivity for the Z-geometry. An aldol
product was also converted to an indanone offering a new route
to this important compound class. Product triple diastereose-
lectivity has been rationalized using a concerted transition-state
model.
here is a continuing need for tools to construct highly
substituted acyclic carbon centers, in part due to their
1
T
growing prevalence in the structures of medicinally valuable
2
compounds. In this regard, allenoates have been exploited as
3
useful building blocks under the action of Lewis acid catalysts
4
or Lewis base catalysts, including our own work involving
alkoxide- and fluoride-promoted reactions. Allenoates have
also served as prenucleophiles in addition reactions to
5
6
carbonyl electrophiles in the presence of stoichiometric
7
8
activating agents. For example, Shi, Selig, and most recently,
9
Zhou demonstrated that, under Lewis basic conditions,
heteroatom attack of the allenoate sp carbon led to anion
formation followed by subsequent exclusive addition to the γ-
6
carbon leading to cyclic products (Figure 1). Shibasaki
demonstrated that reducing and nucleophilic alkylating
reagents in a Lewis basic regime also convert allenoates to
nucleophiles that undergo intermolecular γ-additions.
Under Lewis acidic conditions, a nucleophile and its
carbonyl target can in theory be tethered by a chelating
metal to promote α-selective additions; however, only a few
such examples exist. Lam used a Ni catalyst to facilitate aryl
attack of an allenoate followed by its intramolecular α-addition
10
to a carbonyl (Figure 1). An analogous intermolecular
approach was taken by Roush, who activated an allenoate
through reduction with a chiral stoichiometric borane reagent.
Subsequent α-addition to aldehyde was thought to occur by a
Figure 1. Activation strategies for allenoate prenucleophiles.
communication, we describe how allenyl ester prenucleophiles
activated by Ti(IV) reagents led to hydroxy esters A as single
diastereomer products bearing an α-quaternary center. While a
11
boron-chelated six-membered ring transition state. In seeking
alternatives to chiral boron reagents to produce congested
aldol products, we noted the work of Lu, who created α-vinyl-
β-hydroxy ketones using allenyl ketones and zirconium(IV)
chloride, though diastereoselectivities were poor for most
13
variety of multistep strategies such as the Ireland−Claisen
14
and radical cyclization lead to similar congested products, to
our knowledge, the present halo-aldol reaction is the first
1
2
substrates. We reasoned that other Lewis acidic reagents may
be more successful in bringing about an ordered bimolecular
addition of allenoates and aldehydes or ketones. In the present
Received: August 17, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
5
general approach to accomplish this transformation in a
single step. Furthermore, these aldol products are synthetically
useful building blocks; here, we demonstrate their utility in
accessing highly functionalized indanes.
Table 2. Reaction Scope Leading To Vinyl Chloride
a c
−
Products
In our initial studies involving the addition of allenoate 2 to
aliphatic aldehyde 4a, no reaction occurred at −20 °C.
Warming to room temperature overnight led to significant
formation of 6a in high diastereoselectivity; however, we
observed that the ester underwent debenzylation at this
temperature leading to diminished yields (Table 1, entry 1).
Table 1. Optimization Study
a
b
entry
temp (°C)
Lewis acid (equiv)
% yield
50
dr
1
2
3
4
5
−20 to rt
1.2 (1 M)
1.2 (1 M)
1.2 (1 M)
0.3 (1 M)
1.2 (neat)
1.2 (1 M)
>20:1
>20:1
93:7
c
0
rt
0
0
0
88
82
d
20
39
70
92:8
e
6
93:7
a
b
1
Isolated yields. Diastereomeric ratio determined by H NMR of
c
d
crude reaction mixture. The yield was 54% after 6 h. Optimal
reaction time here was 6 h; longer times led to some debenzylation.
e
Normally, LA was added last in this reaction. In this case, the order
a
Reaction conditions: 1 (1.0 equiv), 4 (0.9−0.96 equiv), TiCl (1 M
4
of addition was allene and LA first followed by aldehyde.
in DCM, 1.2 equiv), and DCM (0.2 M). TiCl was added after 10 min
to a mixture of allene and aldehyde. Isolated yield of major
diastereomer. Diastereomeric ratio determined by H NMR of the
crude reaction mixture. Underwent dehydration under the reaction
4
b
c
1
16
Although the use of less labile esters solved this problem, we
sought to develop conditions for benzyl esters owing to the
wide utility of this protecting group. Debenzylation side
product formation was avoided by performing the reaction at 0
d
conditions.
°
C, which afforded optimal yields of 6a provided the reaction
Table 3. Reaction Scope Leading To Vinyl Bromide
a−c
was allowed to proceed for 24 h (entry 2). We also examined
this transformation with a substoichiometric amount of
titanium tetrachloride; however, the isolated yield was
significantly lower than when a full equivalent (1.2 equiv)
was added (entry 4). In these reactions, optimal yields were
obtained by adding the Ti(IV) reagent as a dichloromethane
Products
(
DCM) solution (1 M) once all other reaction components
were present. Significantly lower yields were observed when
neat titanium tetrachloride was added (entry 5) or when the
Lewis acid was added to allene prior to aldehyde addition
(
entry 6). We also examined the use of tetrabutylammonium
17
bromide as an additive (not shown in table), which led to
significantly diminished yields of chloride 6a and a minimal
amount of its bromo analogue (9a).
After establishing the optimal conditions, we explored the
reaction scope with respect to various aldehydes (Tables 2 and
3
). In general, a wide range of aldehydes react with allenes 1−3
to give α-chlorovinyl-β-hydroxy esters in good isolated yields.
Reactions leading to products with quaternary centers (6 and
7
) led to single diastereomers (no minor isomer detected by
a
NMR). In contrast, addition reactions with allene 1 led to
products containing a tertiary center in comparatively
moderate diastereoselectivities (usually 6:1). Not surprisingly,
dehydration product is observed when electron-donating
aromatic aldehydes are used in the formation of product
containing an α-tertiary center. This method can also be
extended to additions of acetone leading to products 6d and
Reaction conditions: 1 (1.0 equiv), 4 (0.9−0.96 equiv), TiCl
(1 M
4
was added after 10 min
in DCM, 1.2 equiv), and DCM (0.2 M). TiCl
to a mixture of allene and aldehyde. Isolated yield of major
diastereomer. Diastereomeric ratio determined by H NMR of the
crude reaction mixture. Underwent dehydration under the reaction
4
b
c
1
d
conditions.
7
d possessing two contiguous quaternary centers, which to our
B
DOI: 10.1021/acs.orglett.9b02930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
18
coupling revealed by 1H NMR was 10.3 Hz, strongly
suggesting the anti conformation.
knowledge, is virtually unprecedented in acyclic systems. To
our surprise, titanium tetrabromide as the halogen source also
efficiently led to aldol products 8, 9, and 10 (Table 3). Despite
1
9
its greater Lewis acidity, good yields and high anti-
diastereoselectivity were achieved, especially with α-substituted
allenoates 2 and 3, using the same conditions as TiCl4.
Perhaps more significantly, trisubstituted allenoates 11−13
underwent addition to cyclohexane carboxaldehyde to afford
aldol products 14−17 bearing trisubstituted double bonds with
Scheme 1. Assignment of Relative Stereochemistry
high Z-selectivity (Table 4). Reactions mediated by TiBr led
4
Although we are actively investigating the mechanism for the
present halo aldol reaction, our current hypothesis is that the
reaction proceeds via a closed transition state, which is
Table 4. Addition Reactions with Trisubstituted
Allenoates
,
a b
21
common for titanium(IV) enolates. Others have hypothe-
sized an open-transition-state model for similar reactions
2
2
involving Al(III) reagents; however, in our work, TiX4
coordinates allenyl ester to deliver halide in an intramolecular
fashion. Titanium coordination geometry also allows for
aldehyde chelation, setting up a favorable six-membered ring
transition state (Figure 3a). In this concerted model where
a
Reaction conditions: 1 (1.0 equiv), 4 (0.9−0.96 equiv), TiBr (1 M
4
in DCM, 1.2 equiv), and DCM (0.2 M). TiBr was added after 10 min
to a mixture of allene and aldehyde. Isolated yield of major
diastereomer. Diastereomeric ratio determined by H NMR of crude
reaction mixture.
4
b
c
1
Figure 3. Current mechanistic hypothesis.
to products with nearly complete triple diastereoselectivity. To
our knowledge, there are very few reports in which acyclic
products with this degree of selectivity are assembled in one
halogenation occurs at the same time as carbon−carbon bond
formation, relative stereochemistry is established by the
3
2
0
orientation of the aldehydic substituent (R ). To minimize
step. This same reaction with benzaldehyde led to compound
7 possessing complete relative anti-stereochemistry but
steric interactions with the forming vinyl unit, we argue that
1
3
the R substituent orients itself closer to the ester group to
diminished Z-selectivity.
favor transition state C, which leads to the observed
To determine the relative stereochemistry of the major
products resulting from these halo aldol reactions, we obtained
an X-ray crystal structure of product 9g, which indicated anti-
stereochemistry (Figure 2). We were unable to crystallize a
product containing an α-tertiary center and thus turned to
NMR experiments to elucidate relative configuration. To this
end, ester 5a was reduced to form the corresponding diol
predominance for antiproducts (Figure 3a). Additionally,
2
2
3
substituted allenes (R ≠ H) prefer to avoid R /R interaction
in B and thus favor Z-alkene formation as observed. The
observed lower Z-selectivity in product 17 can be explained by
2
3
a less repulsive R /R interaction. Despite using slight excesses
of both allene and titanium tetrahalide, we have not observed
byproducts formed by the addition of halogen to allenes
3
followed by conversion to acetal 18 (Scheme 1). The J
(
Figure 3b). This finding seems consistent with our concerted
mechanistic model.
To explore some of the potential applications of the present
halo aldol products, we sought to convert compound 17 to an
indane in the presence of a palladium catalyst inspired by a C−
23
H activation method developed by Liu. Our initial efforts led
to numerous side products; however, oxidation of alcohol
followed by palladium-catalyzed coupling led to alkylidene
indanone 19 (Scheme 2). Although related indanones have
24
been efficiently synthesized by Kwon, our approach leads to
a novel compound not readily accessible using currently known
methods.
Figure 2. Crystal structure of product 9g showing the anti
configuration.
C
DOI: 10.1021/acs.orglett.9b02930
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Jeong, H.; Lee, J.; Ryu, J. Y.; Kim, J.; Yu, C.-M. Org. Lett. 2018, 20,
Scheme 2. Elaboration of 17 into a Novel Alkylidene
Indanone
1
521−1525.
4) (a) Nallapati, S. B.; Chuang, S.-C. Asian J. Org. Chem. 2018, 7,
743−1757. (b) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38,
102−3116.
5) (a) Jana, S.; Roy, A.; Lepore, S. D. Chem. Commun. (Cambridge,
(
1
3
(
U. K.) 2017, 53, 5125−5127. (b) Maity, P.; Lepore, S. D. Angew.
Chem., Int. Ed. 2011, 50, 8338−8341.
(
6) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2
(
(
(
007, 129, 7439−7443.
7) Zhao, G.-L.; Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 4527−4530.
8) Selig, P.; Raven, W. Org. Lett. 2014, 16, 5192−5195.
9) Yao, C.; Bao, Y.; Lu, T.; Zhou, Q. Org. Lett. 2018, 20, 2152−
In conclusion, β-hydroxy esters containing either tertiary or
all-carbon quaternary α-centers were constructed using a
variety of substituted allenoates as prenucleophiles. High
diastereoselectivity was achieved for tertiary and especially
quaternary center-containing products. Trisubstituted alle-
noates led to especially congested aldol products in good
triple diastereoselectivity. Although mechanistic studies are
ongoing, the relative stereochemistry of addition products
appear to support a closed-transition-state mechanism. Our
efforts on adapting this reaction to produce nonracemic
products as well as an expansion of the indanone synthesis
methodology will be published in due course.
2155.
(10) Panchal, H.; Clarke, C.; Bell, C.; Karad, S. N.; Lewis, W.; Lam,
H. W. Chem. Commun. (Cambridge, U. K.) 2018, 54, 12389−12392.
11) Kister, J.; Ess, D. H.; Roush, W. R. Org. Lett. 2013, 15, 5436−
(
12) Zhang, C.; Lu, X. Tetrahedron Lett. 1997, 38, 4831−4834.
(13) Crimmins, M. T.; Knight, J. D.; Williams, P. S.; Zhang, Y. Org.
Lett. 2014, 16, 2458−2461.
14) Duplessis, M.; Waltz, M.-E.; Bencheqroun, M.; Cardinal-David,
B.; Guindon, Y. Org. Lett. 2009, 11, 3148−3151.
15) Zhong, Y.-L.; Cleator, E.; Liu, Z.; Yin, J.; Morris, W. J.; Alam,
(
(
M.; Bishop, B.; Dumas, A. M.; Edwards, J.; Goodyear, A.; Mullens, P.;
Song, Z. J.; Shevlin, M.; Thaisrivongs, D. A.; Li, H.; Sherer, E. C.;
Cohen, R. D.; Yin, J.; Tan, L.; Yasuda, N.; Limanto, J.; Davies, A.;
Campos, K. R. J. Org. Chem. 2019, 84, 4780−4795.
ASSOCIATED CONTENT
Supporting Information
■
(
16) See the Supporting Information for haloaldol results involving
phenethyl 2,3-butenoate.
17) Uehira, S.; Han, Z.; Shinokubo, H.; Oshima, K. Org. Lett. 1999,
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02930.
(
1, 1383−1385.
(18) Tanabe, Y.; Matsumoto, N.; Higashi, T.; Misaki, T.; Itoh, T.;
Yamamoto, M.; Mitarai, K.; Nishii, Y. Tetrahedron 2002, 58, 8269−
Characterization data for all new compounds and
experimental procedures (PDF)
8280.
(
19) Hilt, G.; Puenner, F.; Moebus, J.; Naseri, V.; Bohn, M. A. Eur. J.
Org. Chem. 2011, 2011, 5962−5966.
20) Bai, D.-C.; Yu, F.-L.; Wang, W.-Y.; Chen, D.; Li, H.; Liu, Q.-R.;
Ding, C.-H.; Chen, B.; Hou, X.-L. Nat. Commun. 2016, 7, 11806pp.
Accession Codes
(
CCDC 1903943 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
(
21) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527−8.
22) Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.;
Headley, A. D. Org. Lett. 2003, 5, 329−331.
(23) Song, J.; Li, Y.; Sun, W.; Yi, C.; Wu, H.; Wang, H.; Ding, K.;
Xiao, K.; Liu, C. New J. Chem. 2016, 40, 9030−9033.
(24) Fan, Y. C.; Kwon, O. Org. Lett. 2015, 17, 2058−2061.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: slepore@fau.edu.
ORCID
Samantha L. Maki: 0000-0001-6917-3602
Pradip Maity: 0000-0001-8493-3171
Salvatore D. Lepore: 0000-0002-8824-6114
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the NIH (GM110651) for financial support.
We also thank Dr. Animesh Roy for helpful discussions.
■
REFERENCES
■
(
(
1) Feng, J.; Holmes, M.; Krische, M. J. Chem. Rev. (Washington, DC,
U. S.) 2017, 117, 12564−12580.
2) Ling, T.; Rivas, F. Tetrahedron 2016, 72, 6729−6777.
(
3) (a) Tap, A.; Blond, A.; Wakchaure, V. N.; List, B. Angew. Chem.,
Int. Ed. 2016, 55, 8962−8965. (b) Bang, J.; Kim, H.; Kim, J.; Yu, C.-
M. Org. Lett. 2015, 17, 1573−1576. (c) Bang, J.; Oh, C.; Lee, E.;
D
DOI: 10.1021/acs.orglett.9b02930
Org. Lett. XXXX, XXX, XXX−XXX