An efficient, practical, and enantioselective method for synthesis of homoallenylamides catalyzed by an aminoalcohol-derived, boron-based catalyst

Article abstract of DOI:10.1021/ja500374p

A practical catalytic method for enantioselective addition of an allene unit to aldimines is disclosed. Transformations are promoted by an in-situ-generated B-based catalyst that is derived from a simple, robust, and readily accessible (in multigram quantities) chiral aminoalcohol. A range of aryl-, heteroaryl-, and alkyl-substituted homoallenylamides can be obtained in 66-91% yield and 84:16 to >99:1 enantiomeric ratio through reactions performed at ambient temperature and in the presence of 0.1-3.0 mol% of the chiral catalyst and a commercially available allenylboron reagent. The catalytic protocol does not require strict anhydrous conditions, can be performed on gram scale, and promotes highly selective addition of an allenyl unit (vs a propargyl group). The utility of the approach is demonstrated through development of succinct approaches to syntheses of anisomycin and epi-cytoxazone.

Full text of DOI:10.1021/ja500374p

Communication
pubs.acs.org/JACS
An Efficient, Practical, and Enantioselective Method for Synthesis of
Homoallenylamides Catalyzed by an Aminoalcohol-Derived, Boron-
Based Catalyst
Hao Wu, Fredrik Haeffner, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
antibacterial)6 and epi-cytoxazone (a member of cytokine
modulator family of compounds).7
ABSTRACT: A practical catalytic method for enantio-
selective addition of an allene unit to aldimines is
disclosed. Transformations are promoted by an in-situ-
generated B-based catalyst that is derived from a simple,
robust, and readily accessible (in multigram quantities)
chiral aminoalcohol. A range of aryl-, heteroaryl-, and alkyl-
substituted homoallenylamides can be obtained in 66−
91% yield and 84:16 to >99:1 enantiomeric ratio through
reactions performed at ambient temperature and in the
presence of 0.1−3.0 mol% of the chiral catalyst and a
commercially available allenylboron reagent. The catalytic
protocol does not require strict anhydrous conditions, can
be performed on gram scale, and promotes highly selective
addition of an allenyl unit (vs a propargyl group). The
utility of the approach is demonstrated through develop-
ment of succinct approaches to syntheses of anisomycin
and epi-cytoxazone.
We recently described the design of aminoalcohol 1 (Scheme
1), which can be used as the precursor to a B-based chiral catalyst
a
Scheme 1. Initial Examination of the Catalytic Process
a
B(pin) = (pinacolato)boron.
that can effect the addition of allyl-B(pin) to phosphinoylimines
and isatins as well as allenyl-B(pin) (2) to the latter set of bicyclic
α-ketoamides.8 Transformations proceeded efficiently and with
exceptional α selectivity. Furthermore, the C−B bond was
directly converted to a C−C bond, which is unlike reactions of
most organometallic complexes where γ addition often
predominates.1 We subsequently envisioned that the transi-
tion-metal-free catalytic system might be readily amenable to
promoting highly α-selective additions of allenyl-B(pin) to
phosphinoylimines. However, we were surprised to find that
such is not the case (Scheme 1). Treatment of imine 3 with 3.0
mol% 1 and 1.5 equiv of 2, under the conditions developed
through the aforementioned initial investigations,8 resulted in a
sluggish and nonselective transformation; only 40% conversion
was observed after 14 h, and a 25:75 mixture of homoallenyl (4)
and homopropargyl (5) amides was formed. Control experi-
ments indicated that a significant portion of 5 is likely formed
through a pathway that does not involve a species that is derived
from 1 (ca. 20% conv, 14 h, 75% 5).9
eliable transformations that furnish N-containing organic
R
molecules are crucial to advances in chemistry, biology, and
medicine. Despite recent progress, several shortcomings are yet
to be fully addressed, among which is the lack of availability of
broadly applicable catalytic processes that afford homoallenyl-
amines in high yield and enantioselectivity.1 The significance of
such protocols partly arises from the growing number of
selectiveand in many cases catalyticprocedures that are
specific to allenes and generate valuable enantiomerically
enriched organic molecules.2,3 Ground-breaking investigations
have led to processes that provide access to homoallenylamides
and derivatives; however, the extant methods are limited in
scope, requiring specially activated substrates and/or aryl-
substituted imines,4 or furnish the corresponding silyl-
substituted products.5
Here, we outline a practical approach to catalytic enantio-
selective synthesis of aryl-, heteroaryl-, and alkyl-substituted
homoallenylamides. Reactions can be performed at room
temperature in the presence of 0.1−3.0 mol% of a readily
accessible and robust chiral aminoalcohol and commercially
available (pinacolato)allenylboron [allenyl-B(pin)], proceeding
to completion in 2−14 h; the desired products are obtained often
with complete group selectivity (5.0−10% propargyl addition in
some cases), in 66−91% yield after purification and 84:16 to
>99:1 enantiomeric ratio (er). The utility of the approach is
illustrated in the context of applications to enantioselective
synthesis of natural product anisomycin (antitumor and
́
To gain additional insight vis-a-vis the origin of the
unexpectedly low efficiency, we carried out a series of DFT
calculations.10 These investigations revealed that, in contrast to
an allylboron intermediate, transformation via a propargyl−
boron compound (II vs I, Scheme 2) is energetically more
demanding, thus allowing the competitive uncatalyzed process to
Received: January 19, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Communication
The transformation leading to 7a can be performed with as
little as 0.1 mol% 1, affording the desired product in 90% yield,
95:5 er (Scheme 4); none of the propargyl addition product was
Scheme 2. Key Results of DFT Calculations
a
Scheme 4. Enantioselective Allene Additions to Aryl Imines
become the major product-generating pathway. We conjectured
that this complication might partly arise from the strain in the six-
membered-ring transition state and/or the diminution in the
degree of overlap between the appropriate alkyne π and imine π*
orbitals. To compensate for the diminished reactivity, we
considered the use of Boc-imines, substrates believed to be
somewhat more electrophilic11 and that contain a less sterically
hindered CN unit (vs phosphinoylimines); moreover and
importantly, carbamates are capable of establishing an H-bond
contact within the active binary complex.8
With carbamate 6a as the starting material, under otherwise
identical conditions (cf. Scheme 1), there was 56% conversion to
7a (31% yield), which was generated in 90:10 er (Scheme 3);
a
Scheme 3. Reaction with a Boc-Imine Substrate
a
Reactions were performed under N2 atmosphere. Conversion was
determined by analysis of 1H NMR spectra of the unpurified products
( 2%); <2% propargyl addition, unless noted otherwise. Yields are of
purified homoallenyl products, except for 7g and 7j ( 5%).
Enantioselectivities were determined by GC or HPLC analysis.
b
c
∼5% propargyl addition product formed. ∼10% propargyl addition
product formed. See the Supporting Information for details.
detected. Catalytic processes can be performed with different
aryl-substituted imines, including those that carry an ortho (cf.
7b,c), meta (cf. 7d), or para (cf. 7e,f) substituent. Trans-
formations with electron-donating groups proceed at a
diminished rate: whereas p-trifluoromethylphenyl-substituted
7e was obtained in 80% yield and 94:6 er with 0.1 mol% 1 after
2.0 h, the p-methoxyphenyl-containing homoallenylamide 7f
required 3.0 mol% catalyst loading and 14 h to proceed to 85%
conversion, and ca. 5% of the corresponding homopropargyl side
product was formed (74% yield, 97:3 er; see below for more
details). Syntheses of furyl- and thienyl-substituted products 7g−
j demonstrate that heterocyclic Boc-imines can serve as effective
substrates; the expected homoallenylamides were isolated in 83−
89% yield and 95:5−99:1 er, albeit, in certain instances, along
with formation of ca. 5−10% of the propargyl addition side
product. One shortcoming of the method is that additions to
pyridyl imines proceed readily but are less enantioselective; as an
example, transformation of 7k in the presence of 3.0 mol% 1 and
EtOH (otherwise the same as shown in Scheme 4) delivers the
homoallenylamide in 77% yield and 84:16 er (ca. 10%
homopropargylamide formed). Kinetic studies indicate that the
C−C bond-forming addition is likely the turnover-limiting step
a
1
Conversion was determined by analysis of H NMR spectra of the
unpurified product mixtures ( 2%). Yields are of purified homoallenyl
products ( 5%). Enantioselectivities were determined by GC analysis.
See the Supporting Information for details. Boc = tert-butyloxycar-
bonyl.
significant amounts of homopropargylamide 8 (17% conv) and
hemiaminal 9 (25% conv) were observed as well. To discourage
the processes that are likely promoted by Lewis basic NaOMe,
leading to the formation of rac-8 and adventitious addition of the
alcohol to the imine to generate 9, we substituted MeOH with
the more hindered i-PrOH. Under the modified conditions, 7a
was obtained as the exclusive product in 97% yield and 95:5 er
(Scheme 3).
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Journal of the American Chemical Society
Communication
of the catalytic cycle;10 such findings support the contention
regarding the positive influence of the more reactive Boc-imine
substrates on reaction efficiency.
6, carried out with 1.80 g of aldimine 6f, is noteworthy for several
other reasons: (1) Rigorous exclusion of air and moisture was not
Catalytic α-selective and enantioselective additions extend to
alkyl-substituted imines (cf. 11a−f, Scheme 5a); 0.1 mol% 1 is
Scheme 6. Catalytic Enantioselective Allenyl Addition on
Gram Scale
a
a
Scheme 5. Enantioselective Allene Additions to Alkyl Imines
a
See the Supporting Information for details.
required. (2) The desired product was isolated in 90% yield (1.90
g) and 97:3 er. That is, the efficiency of the reaction improved
compared to the smaller-scale run (ca. 40−50 mg of 6f, Scheme
4) and despite the lower catalyst loading (0.5 mol% vs 3.0 mol%
for 14 h; cf. Scheme 4). (3) Contrary to the smaller-scale
experiments, on the occasions when the process was performed
on ≥0.5 g scale, <2% of the undesired homopropargylamide was
detected (vs ca. 5% in Scheme 4). The above findings suggest
that the efficiency and selectivity of catalytic allene additions to
Boc-imines are likely to be higher as the scale of a transformation
is increased.
The feasibility of preparing gram quantities of homoallenyl-
amides efficiently and in high enantiomeric purity, and the
increasing variety of ways through which an allene can be
functionalized, means that an assortment of valuable N-
containing molecules can be accessed readily and in meaningful
quantities. The enantioselective synthesis of epi-cytoxazone14 is a
case in point (Scheme 7). Subjection of 1.13 g of 7f (97:3 er) to
1.0 equiv of iodine15 at ambient temperature for 15 min led to the
formation of diiodide 14 with >98% site selectivity as an
a
For reaction conditions, see Scheme 4. Yields refer to purified
b
products. See the Supporting Information for details. 2.0−5.0%
propargyl addition product observed. TBDPS = t-Bu(Ph)2Si.
again sufficient for the transformations to proceed to >98%
conversion at 22 °C after 14 h. The expected homoallenylamides,
including those that contain functional groups such as a silyl
ether, an alkene, or an amide, were obtained with exceptional
enantioselectivity (99:1 er). Only in the case of 11d was 2−5% of
the propargyl addition product detected (<2% otherwise). It
should be noted that the present set of additions are substantially
more efficient than those involving alkyl-substituted imines and
allyl-B(pin) reagents.8
Scheme 7. Application to Enantioselective Synthesis of epi-
a
Cytoxazone
To demonstrate utility, the catalytic enantioselective addition
to p-methoxybenzyl-substituted imine 12 was carried out;
homoallenylamide 13, formerly used in an enantioselective
synthesis of anisomycin,12,13 was isolated in 66% yield and 96:4
er (Scheme 5b). The previously reported route13 for obtaining
enantiomerically enriched 13 entails a six-step sequence
commencing from the aldehyde precursor, affording the desired
product in ca. 9% overall yield and 95:5 er. The strategy
presented in Scheme 5b, involving a three-step operation and
generating 13 in ca. 30% overall yield (from the aldehyde) and
96:4 er, constitutes a more efficient approach.
A key attribute of the present approach is the ease with which
the requisite chiral catalyst is prepared, the necessary reagents are
accessed, and the transformations can be performed. The
catalytic enantioselective allenyl addition illustrated in Scheme
a
See the Supporting Information for details.
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Journal of the American Chemical Society
Communication
354, 1867. (f) Meng, F.; Jung, B.; Haeffner, F.; Hoveyda, A. H. Org. Lett.
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inconsequential 50:50 mixture of E and Z alkene isomers. Direct
treatment of 14 (without purification) with 1.1 equiv of AgPF6
for 3 h15 delivered heterocyclic alkenyl iodide 15 in 76% overall
yield (1.08 g) and >98:2 diastereomeric ratio (dr). epi-
Cytoxazone was obtained after conversion of the alkenyl iodide
to the requisite primary alcohol in two steps and 75% overall
yield (Scheme 7). There are two additional noteworthy points
regarding the sequence shown in Scheme 7: (1) The synthesis
route was completed (including two chromatographic purifica-
tions) within 8 h to afford 0.52 g of epi-cytoxazone (57% overall
yield from 7f). (2) The requisite diiodide (14) would not be
easily accessible through modification of the alkene of a
homoallylamine16 or the alkyne unit of a homopropargyl
variant.17 The latter distinction also applies to the intermediates
generated in Scheme 5b en route to anisomycin.
In conclusion, we put forth the first general method for
efficient and enantioselective addition of an allenyl unit to a range
of aldimines, including the more challenging alkyl-substituted
substrates. The resulting Boc-protected amides can be readily
converted to the corresponding amines in high yield.18
Applications to enantioselective syntheses of representative N-
containing target molecules highlight the useful functionalization
possibilities, rendered feasible by the presence of an allenyl unit,
and which can be performed in a practical and reliable fashion on
a significant laboratory scale. The present investigations further
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral and analytical data for all
products, as well as crystallographic (CIF) and computational
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institutes of
Health (GM-57212). We thank D. L. Silverio, N. W. Mszar, and
Dr. S. Torker for helpful discussions, and Dr. Bo Li for assistance
with obtaining the X-ray data. We thank Boston College
Research Services for access to computational facilities.
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