Sequential Catalysis of Phosphine Oxide for Stereoselective Synthesis of Stereopentads

Article abstract of DOI:10.1021/acs.orglett.7b01719

An efficient method for accessing enantiomerically pure stereopentads via a catalytic asymmetric sequential aldol reaction has been developed for the first time. The enantioselective sequential aldol reaction produces a wide range of chiral stereopentad precursors in good yields with excellent enantioselectivities. The key to success is the use of the sequential catalytic system involving a chiral phosphine oxide catalyst and trichlorosilyl triflate.

Full text of DOI:10.1021/acs.orglett.7b01719

Letter
pubs.acs.org/OrgLett
Sequential Catalysis of Phosphine Oxide for Stereoselective
Synthesis of Stereopentads
,
†,‡
†
†
†
Shunsuke Kotani,*
Kosuke Kai, Masaharu Sugiura, and Makoto Nakajima
†
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973,
‡
Japan
*
S Supporting Information
ABSTRACT: An efficient method for accessing enantiomerically pure stereopentads via a catalytic asymmetric sequential aldol
reaction has been developed for the first time. The enantioselective sequential aldol reaction produces a wide range of chiral
stereopentad precursors in good yields with excellent enantioselectivities. The key to success is the use of the sequential catalytic
system involving a chiral phosphine oxide catalyst and trichlorosilyl triflate.
13
tereopentads, which consist of five contiguous stereogenic
BINAPO (10 mol %) in isobutylonitrile gave 3aa in a high
S
centers bearing methyl and hydroxyl functionalities, are
yield with high stereoselectivity (86% yield, 96% ee; Scheme
1).
14
important motifs in various biologically active natural
1
,2
products. Accordingly, the development of effective method-
ologies for the stereoselective synthesis of stereopentads and
their derivatives is important in synthetic chemistry. One of
Scheme 1. SiCl OTf-Mediated Enantioselective Sequential
Aldol Reaction of Ketone 1a and Aldehyde 2a
3
3
the most common approaches for the stereoselective syntheses
of stereopentads is the sequential use of asymmetric aldol
4
reactions. Stereoselective aldol reactions contiguously without
isolation manipulation, i.e., sequential aldol reactions, become
more easily feasible to extend more effective synthetic methods.
Remarkably, the first diastereoselective asymmetric sequentia5l
aldol reaction was reported in 1999 by Masamune and Abiko.
Despite recent progress in enantioselective sequential aldol
reactions, catalytic stereoselective sequential aldol reactions for
the synthesis of stereopentads remain elusive. Since the
substrate scope is limited to methyl ketones involving acetone
4
−8
or 2-alkanones,
the construction of stereopentad derivatives
9
is limited. Herein, we report that sequential catalysis with
phosphine oxide and trichlorosilyl triflate (SiCl OTf) facilitates
the efficient installation of four stereogenic centers to access
stereopentads in a highly stereoselective manner.
With the optimized reaction conditions in hand, we
examined the reaction of 3-pentanone (1a) with various
aldehydes (2a−i) (Table 1, entries 1−9). Regardless of the
substituents on the phenyl ring, high stereoselectivities were
obtained with various aldehydes (3aa−af) (entries 1−6). 2-
Naphthaldehyde (2g) gave 3ag in 79% yield and 98% ee (entry
3
We began our studies with the reaction of 3-pentanone (1a)
and benzaldehyde (2a) in the presence of phosphine oxide (S)-
BINAPO and SiCl in CH Cl , but the reaction did not afford
4
2
2
6
,7,10
7
), and 2-furfural (2h), a heteroaromatic aldehyde, afforded the
sequential aldol adduct 3ah with 98% ee (entry 8). The
reaction of cinnamaldehyde (2i), a conjugate aldehyde,
1
,5-dihydroxy-3-pentanone 3aa.
SiCl OTf, which is a more active silylating reagent than SiCl4,
However, upon applying
1
1
3
we obtained desired adduct 3aa with high stereoselectivity, but
12
in a low yield (38% yield, dr 90/10, 89% ee (major)).
Optimization of the reaction conditions revealed that SiCl OTf
Received: June 7, 2017
3
(3.0 equiv), N,N-diisopropylethylamine (10.0 equiv), and (S)-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01719
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Letter
Table 1. Enantioselective Sequential Aldol Reaction of
Based on the obtained results, we propose a possible reaction
pathway, which is shown in Figure 2. First, trichlorosilyl enol
Various Ketones (1a−d) and Aldehydes (2a−i) Catalyzed by
a
(S)-BINAPO
Figure 2. Assumable reaction pathway for the sequential aldol
reaction.
ether (Z)-4, converted from ketone 1a upon treatment with
b
c
d
entry
1x
2y
temp (°C)
3xy
dr
yield (%) ee (%)
16,17
SiCl OTf,
reacts with aldehyde 2a via a chairlike six-
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
2a
2b
2c
2d
2e
2f
−40
−40
−30
−20
−20
−20
−40
−40
−30
−30
−20
−30
−20
3aa
3ab
3ac
3ad
3ae
3af
95/5
96/4
95/5
90/10
85/15
88/12
98/2
97/3
94/6
92/8
93/7
93/7
88/12
86
79
86
79
80
80
79
68
66
71
64
72
50
96
97
98
97
93
93
98
98
98
98
99
99
99
membered transition state involving a hypervalent silicon
11
complex to preferably give 1,2-syn-5, which is rapidly
18
converted into silyl enol ether 1,2-syn-(Z)-6. Since the
transformation required more than 2 equiv of SiCl OTf, two
3
silicon centers might be involved in the transition state.
Furthermore, the observed enantioselectivity in double aldol
adduct 3 was higher than that in a single aldol adduct. Based on
these observation, the phosphine oxide catalyzed sequential
aldol reaction appeared to occur via 1,5-anti remote stereo-
2g
2h
2i
3ag
3ah
3ai
0
1
2
3
2a
2a
2a
2d
3ba
3ca
3da
3dd
induction with a bicyclic transition state, resulting in 1,2-syn-
19
4
,5-syn-1,5-anti-3aa.
The highly stereoselective production of 1,2-syn-4,5-syn-1,5-
anti adducts implied that even if unsymmetrical ketones
produced different silyl aldolate intermediates 7A and 7B
after the first aldol reaction, they could be transformed into
identical products (Scheme 2). Next, we examined the reaction
of unsymmetrical ketones 1e−g, which can lead to more
a
All reactions were carried out in the presence of ketone 1x (0.2
mmol), aldehyde 2y (0.6 mmol), SiCl OTf (0.6 mmol), Pr NEt (2.0
mmol), and (S)-BINAPO (10 mol %) in PrCN (2.0 mL) at the
indicated temperature for 16 h. The ratio of major/minor isomer was
estimated from the isolated product yields and H NMR. Isolated
yield of major isomer. Ee of major isomer was determined by HPLC.
i
3
2
i
b
1
c
d
Scheme 2. Enantioselective Sequential Aldol Reaction of
a
Unsymmetrical Ketones 1e−g
proceeded with 98% ee at −30 °C (entry 9). Next, reactions
between various symmetrical ketones (1b−d) and aldehydes
were carried out (entries 10−13). Although the reaction with 4-
heptanone (1c) required −30 °C, high enantioselectivity (99%
ee) was obtained. The reaction of ketone 1d and aldehyde 2d
furnished 3dd in the crystal form, and the X-ray crystal
structure revealed that the absolute configuration of the major
15
isomer was 1R,2R,4R,5R with C -symmetry (Figure 1).
2
a
The reaction was carried out in the presence of ketone 1e−g (0.2
i
Figure 1. Determination of absolute configuration of (1R,2R,4R,5R)-
dd by X-ray structure. Thermal ellipsoids are shown at 10%
probability.
mmol), aldehyde 2a (0.6 mmol), SiCl OTf (0.6 mmol), Pr NEt (2.0
mmol), and (S)-BINAPO (10 mol %) in PrCN (2.0 mL). At −30
°C. At −20 °C.
3
2
i
b
3
c
B
DOI: 10.1021/acs.orglett.7b01719
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complicated molecules with four stereogenic centers. In the
reaction of 3-hexanone (1e), adduct 3ea was isolated as a single
isomer in 71% yield with 97% ee. Other ketones such as 1f and
REFERENCES
■
(
1) (a) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
b) Paterson, I.; Cowden, C. J.; Wallace, D. J. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000: p 249.
(c) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; p 403. (d) Yeung, K. S.;
Paterson, I. Chem. Rev. 2005, 105, 4237.
2) (a) Omura, S., Ed. Macrolide Antibiotics, Chemistry, Biology, and
Practice, 2nd ed.; Academic Press: New York, 2002. (b) Newman, D.
J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022.
c) Baerson, S. R., Ed. Polyketides, Biosynthesis, Biological Activity and
Genetic Engineering; American Chemical Society: Washington DC,
006; p 296.
3) For selected papers on stereoselective synthesis of stereotetrads
and stereopentads, see: (a) Chemler, S. R.; Roush, W. R. J. Org. Chem.
003, 68, 1319. (b) Torres, E.; Chen, Y.; Kim, I. C.; Fuchs, P. L.
(
1
g also reacted with aldehyde 2a to furnish unsymmetrical
stereopentad-type derivatives 3fa and 3ga with high stereo-
selectivities (3fa: 97% ee, 3ga: 99% ee).
Next, we highlighted the synthetic potential of this sequential
aldol reaction in an efficient derivatization of 3aa to
stereopentad 8 (Figure 3). Obtained adduct 3aa was treated
(
with NaBH in MeOH, resulting in stereopentad 8 bearing five
4
(
contiguous stereogenic centers in 91% yield.
2
(
2
Angew. Chem., Int. Ed. 2003, 42, 3124. (c) Brazeau, J.-F.; Mochirian, P.;
Prevost, M.; Guindon, Y. J. Org. Chem. 2009, 74, 64. (d) Rohr, K.;
Herre, R.; Mahrwald, R. J. Org. Chem. 2009, 74, 3744. (e) Gao, X.;
Han, H.; Krische, M. J. Am. Chem. Soc. 2011, 133, 12795. (f) Chen,
M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 3925. (g) Ruiz, j.; Karre,
N.; Roisnel, T.; Chandrasekhar, S.; Gree, R. Eur. J. Org. Chem. 2016,
Figure 3. Derivatization of 3aa to stereopentad 8.
2
(
016, 773.
4) For selected papers on sequential aldol reactions, see: (a) Boxer,
In conclusion, we have demonstrated a sequential aldol
reaction catalyzed by chiral phosphine oxide to form four
stereogenic centers in a single operation. The use of
trichlorosilyl triflate was critical to the installation of the four
M.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48. (b) Albert, B. J.;
Yamamoto, H. Angew. Chem., Int. Ed. 2010, 49, 2747. (c) Brady, P. B.;
Yamaoka, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2012, 51, 1942.
(d) Brady, P. B.; Albert, B. J.; Akakura, M.; Yamamoto, H. Chem. Sci.
2
(
reactions, see: (a) Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama, S.;
Masamune, S. J. Am. Chem. Soc. 1999, 121, 7168. (b) Abiko, A.; Inoue,
T.; Masamune, S. J. Am. Chem. Soc. 2002, 124, 10759.
stereogenic centers. Symmetrical ketones produced C -sym-
2
013, 4, 3223.
5) For selected examples of diastereoselective sequential aldol
metrical derivatives with a high degree of stereoselectivity, while
unsymmetrical ketones produced more complicated molecules
bearing four stereogenic centers with high enantioselectivities.
The enantioselective sequential aldol reaction is highly effective
in the construction of 1,3,5-polyketides and 1,3,5-polyols with
(
6) For papers on Lewis base catalyzed enantioselective sequential
1,2-syn-4,5-syn-1,5-anti configurations. The synthesis of bio-
aldol reactions, see: (a) Shimoda, Y.; Kubo, T.; Sugiura, M.; Kotani, S.;
Nakajima, M. Angew. Chem., Int. Ed. 2013, 52, 3461. (b) Zhang, P.;
Han, Z.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2013, 52, 11054.
(c) Maier, F.; Trapp, O. Angew. Chem., Int. Ed. 2014, 53, 8756.
logically active stereopentad derivatives via this reaction is being
investigated in our laboratory and will be reported in due
course.
(
7) For application of the enantioselective sequential aldol reaction to
ASSOCIATED CONTENT
Supporting Information
the total synthesis of (−)-ericanone, see: Kotani, S.; Kai, K.; Shimoda,
■
Y.; Sugiura, M.; Nakajima, M. Chem. - Asian J. 2016, 11, 376.
*
S
(8) For examples of prolinamide-catalyzed enantioselective asym-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01719.
metric sequential aldol reactions, see: (a) Ramachary, D. B.; Mondal,
R.; Madhavachary, R. Org. Biomol. Chem. 2012, 10, 5094. (b) Valero,
G.; Ribo, J. M.; Moyano, A. Chem. - Eur. J. 2014, 20, 17395.
(
c) Kucherenko, A. S.; Gerasimchuk, V. V.; Lisnyak, V. G.; Nelyubina,
Y. V.; Zlotin, S. G. Eur. J. Org. Chem. 2015, 2015, 5649.
9) For enantioselective sequential asymmetric aldol-type reactions
Tables for reaction condition studies, Experimental
1
13
procedure, H and NMR spectra, HPLC trace, X-ray
crystal structures (PDF)
(
via isomerization of allyloxyboronates, see: Lin, L.; Yamamoto, K.;
Mitsunuma, H.; Kanzaki, Y.; Matsunaga, S.; Kanai, M. J. Am. Chem.
Soc. 2015, 137, 15418.
Crystallographic data (CIF, CIF)
(
10) For reviews on Lewis base catalysis, see: (a) Orito, Y.; Nakajima,
AUTHOR INFORMATION
Corresponding Author
E-mail: skotani@gpo.kumamoto-u.ac.jp.
■
*
M. Synthesis 2006, 2006, 1391. (b) Malkov, A. V.; Kocovsky, P. Eur. J.
Org. Chem. 2007, 2007, 29. (c) Denmark, S. E.; Beutner, G. L. Angew.
Chem., Int. Ed. 2008, 47, 1560. (d) Benaglia, M.; Guizzetti, S.;
Pignataro, L. Coord. Chem. Rev. 2008, 252, 492. (e) Benaglia, M.;
Rossi, S. Org. Biomol. Chem. 2010, 8, 3824.
ORCID
(
11) (a) Kotani, S.; Aoki, S.; Sugiura, M.; Nakajima, M. Tetrahedron
Shunsuke Kotani: 0000-0003-4801-8341
Notes
Lett. 2011, 52, 2834. (b) Aoki, S.; Kotani, S.; Sugiura, M.; Nakajima,
M. Chem. Commun. 2012, 48, 5524.
The authors declare no competing financial interest.
(12) Formation of only two stereoisomers was observed. The major
was the C -symmetrical, 1,2-syn-4,5-syn-1,5-anti isomer as mentioned
2
later. The major and minor diastereomers are easily separable by
column chromatography on silica gel.
ACKNOWLEDGMENTS
■
This work was partially supported by the Naito Foundation and
JSPS KAKENHI Grant Number 16K08168, a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
(13) Propionitrile could react with aldehyde 2a to produce 3-
hydroxy-2-methyl-3-phenylpropionitrile as a side product, which was
difficult to separate from desired adduct 3aa.
(14) The detailed results of solvent, amine, and catalyst screening are
described in the Supporting Information (SI).
C
DOI: 10.1021/acs.orglett.7b01719
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
15) CCDC 1533052 (major isomer) and 1533053 (minor isomer)
of 3dd contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Center via https://www.ccdc.cam.ac.uk.
(
(
16) Denmark, S. E.; Pham, S. M. J. Org. Chem. 2003, 68, 5045.
17) Upon investigating the Z/E ratio of trichlorosilyl enol ethers
derived from ketone 1a in isobutyronitrile, we estimated the Z/E ratio
of 4 to be 94/6. The detailed procedures and results of NMR
experiments are provided in the SI.
(
18) No-D NMR and NOESY analyses of the reaction mixture of
i
intermediate syn-5 treated with SiCl OTf/ Pr NEt (Figure 2) also
3
2
confirmed the nearly perfect formation of 1,2-syn-(Z)-6 (Z/E = >97/
), suggesting predominant formation of the Z-form due to allylic
strain of both alkyl substituents in the E-isomer.
19) For remote 1,5-anti stereoinduction in the aldol reaction of β-
3
(
oxygenated ketones, see: (a) Paterson, I.; Oballa, R. M.; Norcross, R.
D. Tetrahedron Lett. 1996, 37, 8581. (b) Paterson, I.; Gibson, K. R.;
Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585. (c) Evans, D. A.;
Coleman, P. J.; Cote, B. J. Org. Chem. 1997, 62, 788. (d) Paterson, I.;
Collett, L. A. Tetrahedron Lett. 2001, 42, 1187. (e) Denmark, S. E.;
Fujimori, S. Org. Lett. 2002, 4, 3477.
D
DOI: 10.1021/acs.orglett.7b01719
Org. Lett. XXXX, XXX, XXX−XXX