NHC-Cu-catalyzed addition of propargylboron reagents to phosphinoylimines. Enantioselective synthesis of trimethylsilyl-substituted homoallenylamides and application to the synthesis of S-(-)-cyclooroidin

Article abstract of DOI:10.1021/ja500373s

A catalytic method for the efficient and enantioselective addition of a 1-trimethylsilyl-substituted allene moiety to phosphinoylimines is presented. Transformations are promoted by 5.0 mol % of a copper complex of an N-heterocyclic carbene in the presenc

Full text of DOI:10.1021/ja500373s

Communication
pubs.acs.org/JACS
NHC−Cu-Catalyzed Addition of Propargylboron Reagents to
Phosphinoylimines. Enantioselective Synthesis of Trimethylsilyl-
Substituted Homoallenylamides and Application to the Synthesis of
S‑(−)-Cyclooroidin
Nicholas W. Mszar, Fredrik Haeffner, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
through catalytic transformations involving aryl-, heteroaryl-,
ABSTRACT: A catalytic method for the efficient and
enantioselective addition of a 1-trimethylsilyl-substituted
allene moiety to phosphinoylimines is presented. Trans-
formations are promoted by 5.0 mol % of a copper
complex of an N-heterocyclic carbene in the presence of a
propargylboron reagent that can be readily prepared in
multigram quantities. Within 10 min of reaction, products
are obtained in up to 91% yield, 98% allene (vs propargyl)
selectivity, and 98:2 enantiomeric ratio. An assortment of
aldimines serve as suitable substrates. The phosphinoyl
and silyl groups can be removed efficiently and
orthogonally. The silylallene moiety may be transformed
to versatile derivatives that are difficult to access via
nonsilylated allenes. The special features and utility of the
approach are highlighted through a succinct enantiose-
lective synthesis of marine alkaloid S-(−)-cyclooroidin.
alkyl-, and alkenyl-substituted imines. Transformations, pro-
moted by a catalyst generated in situ from CuCl and an
imidazolinium salt, deliver the desired products in up to 98:2
enantiomeric ratio (er). Phosphinoylimines, the chiral ligand,
and the propargylboron reagent can be synthesized in gram
quantities. Unfunctionalized allenes or unprotected amines are
accessed selectively under mild conditions, and the silyl group
can be manipulated to reveal versatile and otherwise difficult-to-
access functional groups. The utility of the approach is
demonstrated through application to a concise enantioselective
synthesis of naturally occurring S-(−)-cyclooroidin.7
Selective addition of an allene group via a propargyl−metal
intermediate (e.g., B, R = H; Scheme 1) requires identification of
Scheme 1. Selective Allene Addition through Curtin−
Hammett Kinetics
evelopment of catalytic protocols for enantioselective
Dsynthesis of N-containing organic molecules is a
compelling research objective in organic chemistry.1 An array
of strategies has been introduced for the preparation of
homoallylic amines;2 catalytic reactions that furnish homopro-
pargyl amines have been recently developed.3 Homoallenyl-
amines are another set of compounds of substantial potential
utility; such entities present unique functionalization possibil-
ities4 that generate enantiomerically enriched derivatives not
easily obtainable through manipulation of an allyl, an alkyne, or a
propargyl group. Nonetheless, catalytic enantioselective meth-
ods that deliver allene-substituted amines are scarce, and the
small number of existing protocols offers limited scope. In one
investigation propargylstannanes were added to especially
activated α-imino esters;3a in another, highly electrophilic
allenoates were employed.5 These pioneering studies were
focused on additions to aryl-substituted imines almost
exclusively; heteroaryl- or alkenyl-containing variants were not
included, and one alkyl-substituted case was shown to react with
lower efficiency and enantioselectivity.5 A later report, centered
on allyl additions promoted by an In-based salt and a Ag-based
chiral complex, included only two examples of homoallenyl-
amides generated as the major component of a 3−4:1 mixture
with the homopropargyl addition products.6
a reaction pathway that entails mainly a γ-addition process. One
challenge stems from the lower stability of entities represented by
B, which are generally less favored than the allenyl isomer (A; R =
H) and exist in minimal quantities. We have previously exploited
this stability difference, calculated to be ∼10 kcal/mol in favor of
A (vs B, R = H), toward the development of a catalytic protocol
for enantioselective synthesis of homopropargylamides.3c In
considering a route that involves B as the predominant isomer
Herein, we present an efficient and broadly applicable method
for the synthesis of silyl-substituted homoallenylamides formed
Received: January 19, 2014
Published: February 20, 2014
© 2014 American Chemical Society
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Communication
and leads to homoallenylamides selectively, we surmised that an
exclusive preference for B might not be necessary. We reasoned
that the Cu−propargyl species might well be more nucleophilic
by virtue of the higher donor ability of a Cu−Csp3 (vs Cu−Csp2 in
A)8 and that, if available in only sufficient amounts, the
transformation could proceed predominantly through the more
nucleophilic homopropargyl−Cu complex (Curtin−Hammett
kinetics; cf. Scheme 1). We were heartened by the fact that DFT
calculations reinforced the above contention, indicating that the
activation barrier for reaction via B would be lower than that
involving allenyl−Cu complex A.10
To induce the preferred shift in equilibrium favoring B, we
opted to incorporate a trimethylsilyl (TMS) group with the
organocopper complex, as illustrated in Scheme 1 (R = SiMe3);
in the presence of the sizable N-heterocyclic carbene (NHC)
ligand, the allenyl−Cu species A would then become less favored
due to steric repulsion.9 Indeed, DFT calculations pointed out
that when R = SiMe3 (Scheme 1), the preference for Cu−allene
complex A is reduced substantially such that ΔG = −0.9 kcal/mol
(vs ∼10 kcal/mol with R = H).10 Nonetheless, we remained
concerned that the presence of a silyl unit at the carbon directly
involved in C−C bond formation might diminish reaction rates
due to steric factors.
transformation performed with 0.3 g of 2a resulted in >98%
conv in 10 min, delivering 4a in 98:2 allene:propargyl selectivity,
80% yield, and 95:5 er after purification. The mechanistic
scenario depicted in Scheme 1 was further substantiated by the
strong preference for the formation of homopropargylamide 5a
with the Cu catalyst lacking an NHC ligand (98% 5a, entry 4), or
with 3b, which does not carry a TMS group, serving as the
reagent (R = H; entry 5; 98% 5b).
The transformations in Scheme 2, resulting in the efficient and
selective formation of desilylated allene 4b (92% yield)12 or silyl-
Scheme 2. Representative Functionalization of
a
Homoallenyamides
Based on the above considerations, we examined the NHC−
Cu-catalyzed transformations between phosphinoylimine 2a and
silyl-substituted propargyl−B(pin) reagent 3a, which is acces-
sible in multigram quantities through a one-step operation
(Table 1).11 With the complex derived from bis-adamantyl
a
Table 1. Initial Examination of Catalysts and Reagents
a
Yields are for purified products. See the Supporting Information for
details.
substituted amine 6 (93% yield), underscore a notable feature of
the present strategy: The TMS group may be deleted, and the
phosphinoyl unit, orthogonally removed. Another attribute of
the approach is that the silylallene moiety can be manipulated to
allow access to enantiomerically enriched products that cannot
be prepared through homoallenylamides or synthesized easily by
alternative pathways. A noteworthy example is illustrated in
Scheme 2: Treatment of homoallenylamide 4a with KBr in acetic
acid and peracetic acid at ambient temperature for 10 min
generated propargyl bromide 7.13 In all the cases shown in
Scheme 2, there was neither loss of enantiomeric purity nor
formation of the homopropargyl isomer. The X-ray structures for
4b and 7 allowed us to establish the stereochemical identity of
the products.
Syntheses of the enantiomerically enriched aryl-substituted
homoallenylamides delineate the scope of the method. Additions
to o-substituted arylimines are facile (Scheme 3). The preference
for allene transfer is diminished as the size of the substituent is
increased: 4c−4e were formed with 95:5, 75:25, and 57:43
allene:propargyl addition selectivity, respectively. Product
mixtures were further enriched by routine silica gel chromatog-
raphy, as revealed by the ratios indicated in the parentheses
(Scheme 3), to deliver samples of 96−98% allene in 46−84%
yield and 92:8−95:5 er. Control experiments show that the
diminution in allene addition selectivity with a larger ortho
substituent in a sluggish NHC−Cu-catalyzed addition originates
from competitive non-Cu-catalyzed processes that engender
exclusive transfer of a propargyl unit.14 When the aryl substituent
b
c
reagent (R);
catalyst
conv (%);
allene:
yield (%);
allene:
er (of allenyl
b
d
e
entry
1
precursor
propargyl
propargyl
isomer)
3a; 1a
3a; 1b
3a; 1c
83; 8:92
75; 8:92
76; 96:4
80; 98:2
81; 2:98
na
f
2
>98; 83:17
>98; 95:5
95; 2:98
na
g
3
95:5
na
4
5
3a; none
3b; 1c
70; 2:98
44; 2:98
b
92:8
a
Reactions performed under N2 atmosphere. By analysis of 1H NMR
spectra of unpurified mixtures ( 2%). Yields of purified products
( 5%). Allenyl/propargyl ratios after purification. By HPLC
analysis. Performed on 0.5 g of 2a. Reaction performed on 0.3 g
of 2a; 95% allenylamide before purification. See the Supporting
Information for details. Ad = adamantyl; Mes = 2,4,6-Me3-C6H2;
B(pin) = (pinacolato)boron; na = not applicable.
c
d
e
f
g
imidazolium salt 1a and CuCl, 83% conv was observed within 10
min, but it was homopropargyl amide 5a that was obtained with
92% selectivity (entry 1). With the catalyst derived from 1b
(entry 2), carrying two wider spanning mesityl units, reaction
with 0.5 g of 2a afforded 4a as the major product (83:17
allene:propargyl, 96% allene after purification; 76% yield). Use of
the larger chiral imidazolinium salt 1c (entry 3) in a
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Scheme 3. Enantioselective Synthesis to Aryl and Heteroaryl
Homoallenylamides
Scheme 4. Enantioselective Additions to Alkyl and Alkenyl
Imines
a
a
a
For conditions, see Table 1 (entry 3). Yields refer to purified
products. See the Supporting Information for details.
Scheme 5. Application to Enantioselective Synthesis of
Cyclooroidin
a
For conditions, see Table 1 (entry 3). Yields refer to purified
a
products. See the Supporting Information for details.
is at the meta (4f) or para position (4g−h), the preference for
allene addition remains strong (≥90:10); after chromatography,
4f−h were isolated in 67−87% yield and 91:9−98:2 er along with
≤3% of the homopropargyl derivative. The lower conversion
observed with 4h suggests that an electron-donating substituent
can diminish the rate of addition. Heteroaryl-substituted
products were prepared efficiently and with excellent group
selectivity and enantioselectivity: pyridyl 4i, furyl 4j, and thienyl
4k, containing 84−98% of the allene product, in 76−85% yield
and 96:4−98:2 er. The X-ray structure for 4f was obtained,
supporting the absolute stereochemical assignment that is
consistent with the stereochemical model formerly pro-
posed.15,16
A significant feature of the Cu-catalyzed protocol is that
reactions of alkyl-substituted phosphinoylimines proceed with
excellent group transfer and enantioselectivity; amides 8a−b
were isolated in 72−90% yield, 95−97% allene:propargyl
selectivity, and 97:3−98:2 er (Scheme 4). Formation of the
sterically encumbered cyclohexyl-substituted 8c proceeded less
readily (85% conv), delivering the desired amide in 55% yield
and 96:4 er (98% allene). The applicability of the approach can
be extended to reactions involving imines derived from α,β-
unsaturated aldehydes that possess different electronic attributes;
homoallenylamides 9a−c (Scheme 4) were isolated in 86−91%
yield and 96:4 er (93−96% allene). The transformation leading
to sterically hindered 10 proceeded to 62% conv, affording the
desired product in 56% yield and 91:9 er (93% allene).
a
See the Supporting Information for details. Ts = p-toluenesulfonyl;
Enantioselective synthesis of cyclooroidin,17 outlined in
Scheme 5, highlights some of the attractive features of the
NHC−Cu-catalyzed approach. Treatment of 11, prepared in
three steps from readily available materials (52% overall yield),18
with NaHCO3 generated the requisite phosphinoylimine; direct
subjection of the latter compound to the enantioselective
addition conditions led to the formation of homoallenylamide
12 in 62% overall yield and 97:3 er (98:2 allene:propargyl); the
sequence (11→12) was complete within a total of 70 min. The
phosphinoyl group was then selectively removed under the mild
acidic conditions mentioned previously (Scheme 2) without
Fmoc = fluorenylmethyloxycarbonyl.
unmasking of the silyl unit, which is needed at a later key step, or
deprotection to afford the primary amine, the exposure of which
would also have to be implemented at a later stage. Subsequent
conversion of the enantiomerically enriched amine to 2-
carboxylic ester substituted pyrrole 14 was effected through
reaction with ethyl 2,5-dioxopentanoate (13);19 the silyl-
substituted allene thus remained intact after two processes
carried out in acidic media. Next, simultaneous with the
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Communication
8766. (c) Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074. (d) Zbieg,
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2009, 131, 6105. For enantioselective additions of trisubstituted
allenoates to N-tosylimines, see: (b) Hashimoto, T.; Sakata, K.;
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(6) Huang, Y.-Y.; Chakrabarti, A.; Morita, N.; Schneider, U.;
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(7) (a) Ferretti, C.; Marengo, B.; De Ciucis, C.; Nitti, M.; Pronzato, M.
A.; Marinari, U. M.; Pronzato, R.; Manconi, R.; Domenicotti, C. Int. J.
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(8) For recent studies that address the issue of propargyl- to allenyl-
metal complex isomerization and its attendant consequences, see:
transformation of silyl-substituted allene to the derived bromo-
propargyl derivative, the heterocyclic moiety was outfitted with
two halogen atoms to afford tribromide 15 in 63% yield.
Subsequent treatment with bis-Boc-guanidine (16) and K2CO3
in dimethylformamide (22 °C, 8.0 h) furnished 17 in 62% yield
as a result of three operations: alkylation of the propargyl
bromide,20 removal of the Fmoc unit, and cyclization to the six-
membered ring amide. Intramolecular Ag-catalyzed hydro-
amination of the alkyne21 proceeded with >98% preference for
the five-membered ring heterocycle. The ensuing removal of the
remaining Boc group21b allowed for the generation of the
heterocyclic aromatic ring, delivering the target molecule in 90%
overall yield (for the last two-step sequence; 97:3 er). The route
depicted in Scheme 5 (11 steps, including a three-step synthesis
of 11) is shorter than the two previously disclosed
enantioselective syntheses (17−18 steps).17
We present the first general catalytic protocol for the
enantioselective synthesis of silyl-substituted homoallenylamides
and their various derivatives (including amines; cf. 14). The
approach is applicable to readily accessible aldimines. The
versatility of the approach is underscored by efficient removal of
the phosphinoyl unit while the C−Si bond is retained, and
selective reaction of the silyl-substituted allene with Br2/HOAc
without adversely impacting an Fmoc-protected amine. Another
key aspect is the possibility of converting a silyl-substituted
homoallenylamide or amine to a propargyl bromide, a versatile
electrophilic moiety that offers the possibility of a variety of
functionalization options.
(a) Lambert, C.; Schleyer, P. v. R.; Wurthwein, E. U. J. Org. Chem. 1993,
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(9) Similar trends in allene vs propargyl addition to ketones
(nonenantioselective) have been recently reported to be the result of
the size of Cu−bisphosphine complexes involved. See: (a) Fandrick, K.
R.; Ogikubo, J.; Fandrick, D. R.; Patel, N. D.; Saha, J.; Lee, H.; Ma, S.;
Grinberg, N.; Busacca, C. A.; Senanayake, C. H. Org. Lett. 2013, 15,
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ASSOCIATED CONTENT
* Supporting Information
■
(10) See the Supporting Information for details of the DFT
calculations.
(11) Fandrick, D. R.; Roschangar, F.; Kim, C.; Hahm, B. J.; Cha, M. H.;
Kim, H. Y.; Yoo, G.; Kim, T.; Reeves, J. T.; Song, J. J.; Tan, Z.; Qu, B.;
Haddad, N.; Shen, S.; Grinberg, N.; Lee, H.; Yee, N.; Senanayake, C. H.
Org. Process Res. Dev. 2012, 16, 1131.
S
Experimental procedures, spectral and analytical data for all
products, and crystallographic (CIF) and computational data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(12) Reddy, L. R. Chem. Commun. 2012, 48, 9189.
AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
(13) Hernandez, E.; Burgos, C. H.; Alicea, E.; Soderquist, J. A. Org. Lett.
2006, 8, 4089.
(14) As an example, subjection of 2a to 1.5 equiv of 3a and 2.0 equiv of
i-PrOH in thf at 22 °C leads to 66% conv to 5a in 1 h (4a:5a = 2:98).
(15) Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2011, 133, 3332.
■
Notes
The authors declare no competing financial interest.
(16) For DFT calculations in connection with reactions involving
imidazolinium salt 1c, see the Supporting Information.
(17) (a) Patel, J.; Pelloux-Leon, N.; Minassian, F.; Vallee, Y.
́ ́
Tetrahedron Lett. 2006, 47, 5561. (b) Mukherjee, S.; Sivappa, R.;
Yousufuddin, M.; Lovely, C. J. Org. Lett. 2010, 12, 4940.
(18) See the Supporting Information for experimental details.
(19) Hughes, C. C.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Org.
Chem. 2010, 75, 3240.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH (GM-57212). We are
grateful to Dr. Bo Li for his assistance with obtaining X-ray data
as well as to D. L. Silverio, E. M. Vieira, and H. Wu for helpful
discussions. We thank Boston College Research Services for
access to computational facilities.
(20) Yamaguchi, J.; Seiple, I. B.; Young, I. S.; O’Malley, D. P.; Maue,
M.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3578.
(21) (a) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers, H. P. L.; De
Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew. Chem., Int. Ed.
2010, 49, 9465. (b) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.; Looper,
R. E. Angew. Chem., Int. Ed. 2011, 50, 684.
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