Copper(I)-Catalyzed Enantioselective 1,6-Borylation of α,β,γ,δ-Unsaturated Phosphonates

Article abstract of DOI:10.1021/acs.orglett.8b03532

Copper(I)-catalyzed asymmetric 1,6-borylation of 1,3-dienylphosphonates was achieved using (S,S)-Ph-BPE as a chiral ligand. Regio-, stereo-, and enantioselective borylation successfully proceeded to afford phosphonate-containing allylboronates, with high enantioselectivity up to 97% ee. Further applications of the resulting products generated a valuable phosphonate analogue of γ-butyrolactone.

Full text of DOI:10.1021/acs.orglett.8b03532

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(I)-Catalyzed Enantioselective 1,6-Borylation of α,β,γ,δ-
Unsaturated Phosphonates
Hyesu Lee and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 16419, Korea
S
* Supporting Information
ABSTRACT: Copper(I)-catalyzed asymmetric 1,6-borylation
of 1,3-dienylphosphonates was achieved using (S,S)-Ph-BPE
as a chiral ligand. Regio-, stereo-, and enantioselective
borylation successfully proceeded to afford phosphonate-
containing allylboronates, with high enantioselectivity up to
97% ee. Further applications of the resulting products
generated a valuable phosphonate analogue of γ-butyrolactone.
borylations of acyclic α,β,γ,δ-unsaturated carbonyl compounds
ptically active phosphonate derivatives play an important
Orole as a bioisostere of a carboxylic acid in drug with a small amount of copper catalyst were reported by Lam
synthesis1 and a probe for designing antibodies.2 In particular,
chiral allyl phosphonate derivatives are observed in pharmaco-
and co-workers, which afforded (E) or (Z)-allylboronates with
high enantioselectivity up to 96% ee.11b,c
In recent years, our laboratory has been engaged in the
development of copper-catalyzed 1,4-borylation of α,β-
unsaturated acceptors.7a−d Despite the promising reactivity of
unsaturated phosphonates to access interesting compounds,
regio- and enantioselective borylation of these compounds
with copper catalysts has not been achieved.13 Herein, we
report a copper-catalyzed enantioselective 1,6-borylation of
dienylphosphonates.
logically interesting compounds, such as antibiotics rhizocticin
(1) and plumbemycin (2) and an analogue of cidoforvir (3)
(Figure 1).3
We initiated our investigation by examining the reaction of
(1E,3E)-pentadienylphosphonate (1a) with bis(pinacolato)
diboron (B2pin2), in the presence of a catalytic amount of
copper and racemic ligand and MeOH as a protic additive
(Table 1). Racemic DPEphos ligand (Figure 2) displayed
excellent regio- and stereoselectivity affording only (E)-2a in
good yield (entry 1). When the IMes−CuCl complex was
used, a mixture of (Z)-2a and (E)-2a was obtained, with (Z)-
2a formed as the major product (entry 2). Based on these
racemic results, we screened various chiral bisphosphine
ligands. (R,S)-Josiphos, the representative ligand in our
previous copper catalyzed asymmetric conjugate borylation
of various electron-deficient alkenes7a−c afforded (E)-2a in
good enantioselectivity, but with moderate regioselectivity
(entry 3). Mandyphos ligand displayed a poor E/Z ratio and
enantioselectivity (entry 4). Changing the ligand to Me-
Duphos or MeO-BIPHEP allowed better regioselectivity, but
the enantiomeric excess was disappointing (entries 5 and 6).
Finally, (S,S)-Ph-BPE predominantly produced (E)-allylic
boronate 2a in 72% good yield with high 90% ee (entry 7).
With the optimized reaction conditions in hand, we next
investigated the 1,6-borylation of various 1,3-dienylphospho-
nates (Scheme 1). Products were isolated after oxidation, due
Figure 1. Examples of biologically active chiral allyl phosphonate
derivatives.
Asymmetric conjugate addition to Michael acceptors is a
powerful method for construction of optically active building
blocks.4 Among them, enantioselective 1,4-borylation of α,β-
unsaturated acceptors is one of the most well-established areas
in organic chemistry5 due to the applicability of C−B bonds to
various functional groups such as C−O, C−N, and C−C
bonds.6 Successful examples of asymmetric 1,4-borylation of
electron-deficient alkenes have been reported with transition
metals7,8 and organocatalysts9 in past years. On the other hand,
enantioselective 1,6-borylation of extended Michael acceptors
has been underdeveloped, due to difficulty in controlling
regio-, stereo-, and enantioselectivity.10 For that reason, to the
best of our knowledge, limited examples were reported using a
copper catalyst.11,12 In 2013, Kobayashi and co-workers
succeeded in Cu(II)-catalyzed asymmetric 1,6-borylation of
cyclic dienones in water, with good enantioselectivity up to
89% ee.11a However, acyclic dienones and dienoates
predominantly afforded β-borylated products via 1,4-addition,
and δ-selective borylation was possible only with β,β-
disubstituted cyclic substrates. In 2014 and 2018, 1,6-
Received: November 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Scope in Asymmetric 1,6-Borylation
NMR yield
ee
a
b
c
entry
ligand
DPEphos
IMes-CuCl
(E)-2a:(Z)-2a
(%)
(%)
1
2
3
4
5
6
7
>99:<1
20:80
77:23
41:59
91:9
87
−
−
86
8
55
13
90
17
63
34
86
87
(R,S)-Josiphos
(R,R,S,S)-Mandyphos
(S,S)-Me-Duphos
(R)-MeO-BIPHEP
(S,S)-Ph-BPE
>99:<1
96:4
d
83 (72)
a
b
Determined by 1H NMR analysis. NMR yield of (E)-2a,
1
determined by H NMR analysis using DMF as an internal standard.
c
Ee of (E)-2a, determined by chiral HPLC analysis. See the
d
Supporting Information for details. Isolated yield.
a
b
c
20 mol % NaOt-Bu was used. (1E,3Z)-1b was used. (1E,3Z)-1f
was used.
Figure 2. Ligand structure.
Scheme 2. Limitation of 1,6-Borylation
to instability of phosphonate-containing allylboronates to silica
gel chromatography. Corresponding allylic alcohol products
bearing methyl (3a), n-propyl (3b), isobutyl (3c), and
CH2CH2Ph (3d) at the δ carbon were obtained with high
enantioselectivities. The absolute configuration of 3a was
confirmed by comparing its optical rotation value with the
value of 3a synthesized from (L)-ethyl lactate.14,15 The chloro
group was compatible with the catalytic system as well,
affording the desired product (3e) in 67% yield with 97% ee.
Conversely, moderate ee was observed for silyl ether and ester
containing products 3f and 3g. β,β-Disubstituted dienyl-
phosphonate (1h) provided a δ-addition product (3h) in
moderate yield with high enantiomeric excess. However,
changing the substituent of phosphonates from ethyl to
other groups, such as isopropyl (3i) and methyl (3j), did
not improve the enantioselectivity. In addition, standard
catalytic conditions were not effective for dienyl-diphenylphos-
phine oxide, as the desired product (3k) was afforded in poor
yield and enantioselectivity. Changing the geometry of 1b and
1f from (E) to (Z) resulted in formation of the final products
(3b and 3f), with exact opposite absolute configuration and
similar enantioselectivities.16
(Scheme 2, eq 2). Adding steric hindrance to the δ-position led
to the 1,4-addition product (3n) in moderate yield, but with
good enantioselectivity with a small amount of deborylated
product 6 (Scheme 2, eq 3).
To demonstrate the synthetic utility of the phosphonate-
containing allyl boronic ester, we performed its allylation with
diverse aldehydes (Scheme 3). We screened various Lewis acid
catalysts, and ZnBr2 was the most effective Lewis acid catalyst
among them, generating corresponding product 7a with good
regioselectivity.17 Reaction of (E)-2a with isovaleraldehyde, 3-
phenylpropionaldehyde, hexanal, and cyclohexanecarbox-
aldehyde allowed the desired product 7b−7e with excellent
regioselectivities. Also, the enantioselectivity was maintained
without erosion during the reaction. As a further application to
The catalytic system was also sensitive to the substituent at
the δ position (Scheme 2). The dienylphosphonate bearing a
cyclohexyl substituent at the δ-carbon (1l) did not produce
either the 1,6-borylated product under the optimized reaction
conditions or 1,4-borylated product, as was the case in the
borylation of α,β,γ,δ-unsaturated carbonyl compounds by the
Lam group11b (Scheme 2, eq 1). Deborylated products (4 and
5) were observed with a phenyl-containing substrate (1m)
B
DOI: 10.1021/acs.orglett.8b03532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we have developed a copper-catalyzed
asymmetric 1,6-borylation of 1,3-dienylphosphonates with
B2pin2. We found that the (S,S)-Ph-BPE ligand is efficient in
producing δ-borylated allylphosphonates with high regio- and
enantioselectivity. Also, further transformation of the resulting
product provides a synthetic method for cyclic phosphonate
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03532.
Experimental procedures, characterization of products,
and NMR spectra (PDF)
́
V.; Geier, M. J.; Westcott, S. A.; Fernandez, E. Org. Biomol. Chem.
2009, 7, 4674−4676.
AUTHOR INFORMATION
■
(9) For asymmetric 1,4-borylations with organocatalysts, see:
(a) Lee, K.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
Corresponding Author
*E-mail: jaesook@skku.edu.
ORCID
́
́
2009, 131, 7253−7255. (b) Bonet, A.; Gulyas, H.; Fernandez, E.
Angew. Chem., Int. Ed. 2010, 49, 5130−5134. (c) Wu, H.; Radomkit,
S.; O’Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 8277−
Jaesook Yun: 0000-0003-4380-7878
Notes
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The authors declare no competing financial interest.
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H.; Garcia, J. M.; Haeffner, F.; Radomkit, S.; Zhugralin, A. R.;
ACKNOWLEDGMENTS
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Hoveyda, A. H. J. Am. Chem. Soc. 2015, 137, 10585−10602.
This research was supported by National Research Foundation
of Korea (NRF) grants (Nos. 2016R1A2B4011719 and
2016R1A4A1011451), funded by the Korea government
(MEST).
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