Catalytic SN2′- and Enantioselective Allylic Substitution with a Diborylmethane Reagent and Application in Synthesis

Article abstract of DOI:10.1002/anie.201600309

A catalytic method for the site- and enantioselective addition of commercially available di-B(pin)-methane to allylic phosphates is introduced (pin=pinacolato). Transformations may be facilitated by an NHC-Cu complex (NHC=N-heterocyclic carbene) and products obtained in 63-95 % yield, 88:12 to >98:2 S_N2′/S_N2 selectivity, and 85:15-99:1 enantiomeric ratio. The utility of the approach, entailing the involvement of different catalytic cross-coupling processes, is highlighted by its application to the formal synthesis of the cytotoxic natural product rhopaloic acid A.

Full text of DOI:10.1002/anie.201600309

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International Edition: DOI: 10.1002/anie.201600309
German Edition: DOI: 10.1002/ange.201600309
Enantioselective Catalysis Hot Paper
Catalytic S 2’- and Enantioselective Allylic Substitution with
N
a Diborylmethane Reagent and Application in Synthesis
Ying Shi and Amir H. Hoveyda*
Abstract: A catalytic method for the site- and enantioselective
addition of commercially available di-B(pin)-methane to
allylic phosphates is introduced (pin = pinacolato). Trans-
formations may be facilitated by an NHC–Cu complex
(
NHC = N-heterocyclic carbene) and products obtained in
6
9
3–95% yield, 88:12 to > 98:2 S 2’/S 2 selectivity, and 85:15–
N N
9:1 enantiomeric ratio. The utility of the approach, entailing
the involvement of different catalytic cross-coupling processes,
is highlighted by its application to the formal synthesis of the
cytotoxic natural product rhopaloic acid A.
C
atalytic enantioselective allylic substitution (EAS) gener-
ates valuable products that contain a stereogenic center
[
1]
adjacent to a transposed alkene. These processes may
involve various organometallic reagents (e.g., Zn-, Mg-, or
Al-based) and can be promoted by Cu complexes derived
from chiral O-, N-, or P-based ligands or N-heterocyclic
[
1]
Scheme 1. Problems associated with the application of catalytic enan-
carbenes (NHCs). Several applications in total synthesis
[
2]
tioselective allylic substitution (EAS) to the synthesis of rhopaloic
acid A and a possible solution. LG=leaving group, PG=protecting
group, pin=pinacolato.
have demonstrated their utility. Lately, organoboron species
have been adopted in this area because of their robustness
and tolerance towards some of the more common organic
functional groups (e.g., carboxylic esters or ketones). The
groundbreaking advance was achieved by Sawamura and co-
workers, who illustrated that trialkylboron molecules, formed
in situ by hydroboration of a-olefins, can be made to
the possibility of a catalytic EAS with commercially available
[11]
di-B(pin)-methane (1), a member of a class of compounds
[12]
conceived by Matteson and co-workers that has been the
focus of several studies following the pioneering work of
participate in efficient S 2’- and enantioselective phos-
N
[
3]
[4]
[5]
[13]
phine–Cu-catalyzed EAS. AllenylÀ, alkenylÀ, and prop-
Endo and Shibata. Such processes would not only involve
[
6]
argylÀB(pin) species (pin = pinacolato) have since been
used in related NHC–Cu-catalyzed transformations. Another
current development entails processes involving in situ gen-
erated allylcopper species that furnish modifiable boron-
an organoboron reagent, they would deliver products con-
taining a versatile CÀB(pin) bond as well. We imagined
a subsequent sequence entailing hydroboration of the EAS
product (iii), furnishing iv with differentiable CÀB bonds that
[
7]
containing products.
could then be converted chemoselectively into vi by a pair of
catalytic cross-coupling reactions (via v); the first would
chemoselectively involve the dialkylboron site, and the
second would benefit from the presence of the neighboring
Nonetheless, key shortcomings remain, one of which
revealed itself while we evaluated a possible route to the
[
8,9]
cytotoxic natural product rhopaloic acid A
(Scheme 1a).
[14]
Preparation of enantiomerically enriched i called for an
organoboron reagent that requires site-selective hydrobora-
tion of a somewhat sensitive dienyl aldehyde (or ester
derivative). The alternative pathway via diene ii, accessible
hydroxy group that would then be deployed to form the
pyran ring. Herein, we describe the realization of these plans.
We favor allylic phosphates as substrates because the
Lewis basic phosphate may bind to a chiral Cu complex, an
[10]
by previously reported EAS methods, would demand the
differentiation of two terminal olefins, likely to generate
difficult-to-separate isomeric mixtures. We thus envisioned
association that is often pivotal to achieving high S 2’ and/or
N
[
4–6,7]
enantioselectivity.
We first found that EAS with only
CuCl (no ligand) proceeds to 45% conversion, affording the
linear isomer (4a) exclusively (Table 1, entry 1). A chiral
ligand would have to bind efficiently to the transition metal
and/or the derived Cu complex to promote CÀC bond
[
*] Y. Shi, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College
formation considerably faster than a free Cu complex. We
then determined that catalysts containing bisphosphines 5 and
6 generate the linear isomer (4a) selectively (entries 2 and 3).
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
[15]
With imidazolinium salts 7–9 (entries 4–6), 4a was again
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201600309.
favored. Matters improved with the NHC–Cu species derived
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[
a]
Table 1: Examination of different types of Cu complexes.
products from the formation of a benzylic CÀC bond
could be detected (12n). Allylsilane 12o may be
utilized in stereoselective synthesis.
[17]
A distinct feature of the sulfonate-containing
chiral NHC ligands (compare 8 and 9) is that the Cu
complexes promote highly S 2’-selective reactions
N
(see Table 1 and Scheme 2). This is congruent with
the most recent mechanistic and computational
[6]
studies, revealing that the active species is likely
a monodentate system wherein the sulfonate group,
without the geometric constraints of chelation with
[18]
the Cu center, is oriented anti to the nearby phenyl
substituent (I, Figure 1). Formation of an alkali
metal bridge between the anionic tether of the
chiral catalyst and the Lewis basic phosphate unit
can engender a well-defined transition structure with
the CuÀC bond disposed for S 2’ addition. There is
N
indeed measurable dependence of branch selectivity
on the identity of the base used (Figure 1). With the
[
b]
[c]
[b]
[d]
Entry Ligand (mol%) Conv. [%] Yield [%] S 2’/S 2 (3a/4a) e.r.
N
N
more Lewis acidic lithium salt, there was > 98% S 2’
N
1
2
3
4
5
6
7
8
–
45
80
65
>98
>98
>98
>98
>98
21
76
41
73
54
69
77
83
<2:>98
2:98
NA
NA
selectivity, albeit at lower yield owing to solubility
issues. More of the achiral isomer was generated with
the less Lewis acidic and larger potassium meth-
oxide.
5 (11)
6 (11)
7 (11)
8 (11)
9 (11)
10 (11)
11 (5.5)
7:93
5:95
20:80
<2:>98
76:24
95:5
ND
ND
ND
NA
97:3
97:3
We then probed the feasibility of the application
[
8,9]
of this process to the synthesis of rhopaloic acid A
Scheme 3). Organoboron compound 12p was puri-
(
[
a] Performed under N atmosphere; ꢀ5% of the linear methoxy addition products fied by column chromatography on silica gel and
2
observed in all cases. [b] Conversions and S 2’/S 2 ratios determined by analysis of isolated in 89% yield, > 98:2 S 2’/S 2 selectivity, and
N
N
N
N
1
H NMR spectra of the unpurified mixtures; conv. (Æ2%) refers to the disappear-
ance of 2a. [c] Yields of isolated and purified products but as a mixture of 3a and 4a
Æ5%). [d] e.r. values determined by HPLC (Æ1%). See the Supporting Information
for details. Mes=2,4,6-(Me) C H , NA=not applicable, ND=not determined.
9
6:4 e.r.; in this case, the Cu complex derived from
1
1
1b gave higher enantioselectivity (84:16 e.r. with
(
[19]
1a). Hydroboration afforded diboron product 13,
3
6
2
[20]
which was coupled in situ with E-alkenyl iodide 14
by a phosphine–Pd-catalyzed process, affording 15
(> 98% chemoselectivity, 87% yield). Removal of
[21]
from sulfonate-containing 10 (entry 7), which afforded 3a
with 76% S 2’ selectivity and 97:3 enantiomeric ratio (e.r.).
Based on the finding that 4a is produced by a ligand-free Cu
the silyl ether and NHC–Cu-catalyzed cross-coupling involv-
ing the alkylÀB(pin) moiety and commercially available allyl
N
catalyst (entry 1), we used the crystalline and air-stable
[
6]
dimeric Ag complex 11a, one of a set of complexes found
[16]
to exchange ligands with exceptional efficiency;
the
branched isomer 3a was thus formed in 95:5 S 2’/S 2
N
N
selectivity and 97:3 e.r. (entry 8).
The method has considerable range (Scheme 2). Various
aryl-substituted substrates, including those with an electron-
donating or -withdrawing substituent, whether it is at the
ortho, meta, or para position (12a–12j), were converted into
the corresponding primary alcohols in 61–95% yield (after
oxidation), 88:12 to > 98:2 S 2’/S 2 selectivity, and 85:15–
N
N
9
9:1 e.r. There were no complications due to the aryl ketone
substituent in 12i, a functional unit not typically tolerated by
the more nucleophilic organometallic species and, notably, in
NHC–Cu-catalyzed transformations with a propargylÀB(pin)
[
6]
reagent. The Cu catalyst remained operative in the presence
of Lewis basic and potentially catalyst-deactivating N- and S-
containing heterocyclic moieties: Pyridyl- and thienyl-sub-
stituted 12k and 12l were obtained with similar efficiency and
selectivity. Alkyl-substituted allylic phosphates (e.g., 12m)
were suitable. The reaction with a 1,3-dienyl substrate was
somewhat less site- and enantioselective but none of the side
Figure 1. Mechanistic model to account for the origin of stereoselectiv-
ity and evidence pointing to the significance of the counterion of the
basic reagent used. See the Supporting Information for details.
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phosphate delivered tet-
raene 16 in 67% overall
yield. As noted earlier,
this
latter
process
strongly benefits from
the proximal hydroxy
[
14]
group:
2% CÀC bond forma-
tion with silyl ether
there was
<
[22]
1
5.
Cross-metathesis
with Ru complex 17
and acrolein led to enal
1
8 (71% overall yield).
Intramolecular conju-
[23]
gate addition
deliv-
ered pyran 19, which
has previously been con-
verted into rhopaloic
acid A in 85% yield
and 89:11 diastereo-
[
9f]
meric ratio (d.r.).
To conclude, we
have introduced an
EAS method involving
commercially available
and functional-group-
tolerant di-B(pin)-meth-
Scheme 2. Scope of the method. Conversions refer to the consumption of allylic phosphate and were determined
1
by analysis of the H NMR spectra of the unpurified reaction mixtures (the same for the S 2’/S 2 ratios); ꢀ5% of
N
N
the linear methoxy addition products observed in all cases. For 12h–12k, the mixture was treated with NaIO /
4
NH OAc at 228C for 1 h (acetone/H O, 1:1). Yields refer to the isolated and pure S 2’ isomers, except for 12k
4
2
N
(5% linear product isomer), 12l (3% boryl addition side product), and 12n (3% product from the Z isomer of the
substrate). Enantioselectivities were determined by HPLC analysis. See the Supporting Information for details.
Scheme 3. Application to the enantioselective synthesis of rhopaloic acid A. d.r.=diastereomeric ratio. See the Supporting Information for details.
-BBN=9-borabicyclo[3.3.1]nonane, dppf=1,1’-bis(diphenylphosphanyl)ferrocene, pTsOH=para-toluenesulfonic acid, TBS=tert-butyldimethyl-
9
silyl.
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Keywords: allylic substitution · boron · copper ·
enantioselective synthesis · N-heterocyclic carbenes
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3455–3458
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Published online: February 4, 2016
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