1,3-Dithianes as Acyl Anion Equivalents in Pd-Catalyzed Asymmetric Allylic Substitution

Article abstract of DOI:10.1021/acs.orglett.6b03161

A Pd-catalyzed asymmetric allylic substitution with 1,3-dithianes as acyl anion equivalents has been developed in high yields and excellent enantioselectivities. The reaction was performed on a gram scale, and the corresponding alkylated products were con

Full text of DOI:10.1021/acs.orglett.6b03161

Letter
pubs.acs.org/OrgLett
1,3-Dithianes as Acyl Anion Equivalents in Pd-Catalyzed Asymmetric
Allylic Substitution
Kun Yao,† Delong Liu,*,† Qianjia Yuan,‡ Tsuneo Imamoto,‡,§ Yangang Liu,† and Wanbin Zhang*,†,‡
‡
†School of Pharmacy and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed asymmetric allylic substitution with 1,3-dithianes as acyl anion equivalents has been developed in
high yields and excellent enantioselectivities. The reaction was performed on a gram scale, and the corresponding alkylated
products were conveniently converted into several biologically active products. This work provides an alternative strategy
utilizing electrophilic carbonyl compounds as nucleophilic species in a Pd-catalyzed allylic substitution.
he 1,3-dithiane unit (Figure 1, A), a masked carbonyl
group, is often used as an acyl anion synthon I due to its
Scheme 1. 1,3-Dithianes as Acyl Anion Equivalents
T
Figure 1. 1,3-Dithiane and its derivatives.
metal catalyzed asymmetric reactions has not yet been
reported.8
reversed-polarity or can alternatively act as a carbanion II via a
final reductive desulfurization (sulfur−hydrogen exchange).1
Therefore, 1,3-dithiane A is useful for the construction of many
important organic compounds. Such examples include the key
intermediates, B and C, for the synthesis of an antibiotic2 and
an antitumor compound,3 respectively. Additionally, it is known
that the introduction of a dithiane species can also significantly
improve the catalytic efficiency of chiral ligands D4 and catalysts
E.5
Since the seminal work reported by Corey and Seebach
(Scheme 1, eq 1),6 numerous reactions of 1,3-dithianes have
been reported. For example, 1,3-dithianes were allowed to react
with many electrophiles, such as alkyl halides,7a−e carbonyl
compounds,7f,g and epoxides.7h−l Despite these significant
achievements, to the best of our knowledge, the use of 1,3-
dithianes as acyl anion and carbanion equivalents in transition-
Transition-metal-catalyzed allylic substitution is a powerful
synthetic tool for the formation of C−C and C−X bonds (X =
N, O, S, etc.).9 Recently, we have developed several metal-
catalyzed asymmetric allylic alkylations for the construction of
biologically active chiral molecules with excellent catalytic
behavior.10 To further develop novel asymmetric allylic
substitutions, we envisioned that 1,3-dithianes would be
suitable nucleophiles as acyl anion equivalents for use in the
above reaction. Recent studies have revealed several examples
adopting different acyl anion equivalents in asymmetric allylic
substitutions. Trost reported the use of the sodium salt of 1-
phenylsulfonyl-1-nitroethane as an acetyl equivalent in a Pd-
Received: October 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03161
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalyzed asymmetric allylic substitution for the total synthesis
of hygromycin A.11 Evans developed a regio- and stereospecific
Rh-catalyzed allylic substitution with trialkylsilyl-protected
alkenyl cyanohydrins as acyl anion equivalents, which permits
the construction of acyclic quaternary-substituted α,β-unsatu-
rated ketones.12 Carreira disclosed the use of formaldehyde
N,N-dialkylhydrazones as neutral C1-nucleophiles in an Ir-
catalyzed substitution of allylic carbonates.13 To complement
these interesting discoveries, we herein report a Pd-catalyzed
asymmetric allylic substitution using 1,3-dithianes as acyl anion
equivalents. To our delight, the reaction proceeded smoothly
and the resulting chiral products could be conveniently
transformed into several biologically active compounds via
either oxidative or reductive desulfurization (Scheme 1, eq 2).
Our initial experiment was conducted with the reaction of
1,3-diphenylallyl pivalate (1a) and 2-phenyl-1,3-dithiane (2a).
The reaction was carried out using a catalytic system consisting
of [Pd(η3-C3H5)Cl]2 and a chiral ligand with LiHMDS as a
base under a nitrogen atmosphere in THF at room temperature
for 12 h. The effect of the ligand on the reaction was examined
first, and chiral diphosphine ligands provided the most
promising results.14 BenzP* was found to be the best ligand
with the desired product being obtained in 41% yield and with
78% ee (Table 1, entry 1). LiF, LiCl, LiBr, and LiI were then
7), and no reaction occurred at −40 °C (Table 1, entry 8).
Finally, allylic substrates bearing OBoc (1b) and OAc (1c)
leaving groups were examined at −20 °C (Table 1, entries 9
and 10). Compound 1b bearing OBoc as a leaving group
provided the best result (95% yield and 96% ee) (Table 1, entry
9). The effect of different bases, such as NaHMDS, KHMDS,
and LDA, on the reaction was studied, and LiHMDS was found
to be the most effective base.14
With the optimized reaction conditions in hand (Table 1,
entry 9), nucleophiles 2 with different aryl substituents were
explored (Scheme 2). 2-Aryl-1,3-dithianes bearing a Me group
a
Scheme 2. Scope of Substrates
a
Table 1. Optimization of Reaction Conditions
b
c
entry
additive
temp (°C)
LG
yield (%)
ee (%)
1
2
−
20
20
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OBoc
OAc
41
78
68
72
90
92
92
95
−
LiF
LiCl
LiBr
LiI
LiI
LiI
LiI
LiI
LiI
42
3
20
trace
34
a
Unless otherwise noted, the reaction of 1 (0.1 mmol) with 2 (0.2
4
20
mmol) was carried out using a catalytic system consisting of [Pd(η3-
C3H5)Cl]2 (2.5 mol %) and BenzP* (5.5 mol %) under a N2
atmosphere in the presence of LiHMDS (1.5−5 mmol) and LiI (0.1
mmol) in THF (3 mL) at −20 °C for 12 h; Isolated products; Ee
5
20
52
6
0
74
7
−20
−40
−20
−20
30
8
N.R.
95
b
values were determined by HPLC using chiral Daicel columns. The
9
96
reaction was conducted at 0 °C.
10
51
80
a
Unless otherwise noted, the reaction of 1 (0.1 mmol) with 2a (0.2
at the 3- or 4-position of the phenyl ring were examined first,
with both reactions affording excellent enantioselectivities (3b
and 3c). 2-Aryl-1,3-dithianes with electron-withdrawing groups
on the phenyl ring were next considered. Substrates bearing a F
atom at the 2- or 4-position of the phenyl ring provided higher
enantioselectivity than that of 2-(3-fluorophenyl)-1,3-dithiane
(3d and 3f vs 3e). Compound 3f was obtained in only
moderate yield. We also carried out the reaction with a 2-aryl-
1,3-dithiane bearing a Me group at the 2-position; however, no
desired product was observed. Substrates 3g and 3h with Cl
and Br atoms at the 4-position of the phenyl ring were then
used, providing the corresponding products with excellent
yields and good enantioselectivities. When the phenyl ring was
replaced by a 2-naphthyl or thienyl group, the reaction
proceeded smoothly with the desired products being obtained
with excellent yields and enantioselectivities (3i and 3j).
Finally, an allyl substrate with Me at para-positions of the
phenyl rings was used and the corresponding 3k was obtained
mmol) was carried out using a catalytic system consisting of [Pd(η3-
C3H5)Cl]2 (2.5 mol %) and BenzP* (5.5 mol %) under a N2
atmosphere in the presence of LiHMDS (0.15 mmol) and an additive
(0.1 mmol) in THF (3 mL) at the indicated temperature for 12 h.
b
c
Isolated yields. Determined by HPLC using a chiral Daicel OD-H
column.
used as additives to improve the yield and enantioselectivity of
the alkylated product (Table 1, entries 2−5).15 The use of LiI
gave 3a in 92% ee but still with only a moderate isolated yield
owing to the formation of a byproduct (Table 1, entry 5).14
Therefore, we lowered the reaction temperature in order to
suppress side reactions and improve product yield (Table 1,
entries 6−8). To our delight, the desired product was obtained
in up to 74% yield at 0 °C without any negative effect on the
enantioselectivity (Table 1, entry 6). Further lowering of the
reaction temperature to −20 °C led to an increase in
enantioselectivity but a sharp decline in yield (Table 1, entry
B
DOI: 10.1021/acs.orglett.6b03161
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
in 93% yield and 94% ee. In addition, we applied an alkyl
substituted dithiane (R = i-Pr) in the above asymmetric
catalytic reaction. However, the reaction could not occur at all.
With the most promising results being obtained in the Pd-
catalyzed asymmetric substitution with 2-aryl-1,3-dithianes 2 as
acyl anion equivalents, 2-aroyl-1,3-dithianes 4 containing an
additional carbonyl group were then used in place of 2 in the
above reaction. After examining the effects of the ligand and
base, we found that a catalytic system consisting of [Pd(η3-
C3H5)Cl]2 and BenzP* was also effective in this case and the
reaction proceeded smoothly in the presence of NaH and 15-
crown-5 in THF at room temperature.14 Under the optimum
reaction conditions, a series of 2-aroyl-1,3-dithianes 4 were
allowed to react with 1b (Scheme 3). We were pleased to find
that almost all alkylated products could be obtained with
excellent yields and enantioselectivities regardless of the
electronic nature of the aryl ring (5a−5o). Only product 5f
was obtained in a somewhat lower yield. Furthermore, allyl
substrates with both Me and Cl groups at para-positions of the
phenyl rings were screened with 5p and 5q being obtained in
excellent catalytic behaviors.
To prove the usefulness of this new synthetic methodology,
the reaction of 1b with 2a was performed on a gram scale with
the above optimized reaction conditions (Scheme 4). The
Scheme 4. Gram Scale Synthesis of 3a and Its
Transformation
a
Scheme 3. Scope of Substrates
desired product 3a was obtained in high yield (1.48 g, 95%)
with excellent enantioselectivity (96% ee). The derivatization of
3a, including the conversion of the 1,3-dithiane moiety into a
carbonyl group using oxidative desulfurization and a methylene
group via reductive desulfurization, was examined. Thus,
compound 6 was obtained in high yield via the desulfurization
of product 3a using N-iodosuccinimide (NIS) as an oxidizing
agent in a mixed solvent system of MeCN and H2O. The
enantioselectivity remained unaltered (Scheme 2).8a Alter-
natively, 3a could also be converted to the reductive
desulfurization product 7 by sulfur−hydrogen exchange in the
presence of Raney-Ni in ethanol.16
2,4,6-Triphenyl-1-hexene (9), isolated from the starfish
Pteraster militaris,17a metabolites of Phellinus pini, a fungus
pathogenic to conifer trees,17b and rhizomes of Begonia
nantoensis,17c could be synthesized from 5a via compound 8
as an intermediate with ease (Scheme 5). Thus, by treating 5a
a
Scheme 5. Derivatization of 5a
a
Reaction conditions: (a) Raney-Ni , EtOH; (b) Ph3PMeBr, n-BuLi,
THF, −40 °C to rt.
with Raney-Ni in ethanol, compound 8 was prepared in 86%
yield and 93% ee. Subsequently, compound 8 could be further
converted to (R)-2,4,6-triphenyl-1-hexene (9) via the Wittig
reaction in 94% yield and 90% ee. To the best of our
knowledge, this is the first asymmetric synthesis of compound
9.
In summary, we have developed a Pd-catalyzed asymmetric
allylic substitution with 1,3-dithianes as acyl anion equivalents.
Under the optimal reaction conditions, the desired products
can be obtained in high yields and with up to 96% ee. A gram
scale synthesis has been achieved, and the corresponding
alkylated products can be easily converted into several
biologically active products. Our current work provides an
alternative strategy that utilizes electrophilic carbonyl com-
a
Unless otherwise noted, the reaction of 1 (0.15 mmol) with 4 (0.1
mmol) was carried out using a catalytic system consisting of [Pd(η3-
C3H5)Cl]2 (2.5 mol %) and BenzP* (5.5 mol %) under a N2
atmosphere in the presence of NaH (0.15 mmol) and 15-crown-5
(0.12 mmol) in THF (4 mL) at room temperature for 12 h. Isolated
products; ee values were determined by HPLC using chiral Daicel
b
columns. t-BuONa (0.15 mmol) was used in place of NaH.
C
DOI: 10.1021/acs.orglett.6b03161
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Soc. 2015, 137, 15426. (l) Farrell, M.; Melillo, B.; Smith, A. B.,
III Angew. Chem., Int. Ed. 2016, 55, 232.
pounds as nucleophilic species in Pd-catalyzed allylic
substitution reactions.
(8) Selected examples for organocatalyzed asymmetric synthesis:
(a) Kondoh, A.; Oishi, M.; Takeda, T.; Terada, M. Angew. Chem., Int.
Ed. 2015, 54, 15836. (b) Massolo, E.; Benaglia, M.; Genoni, A.;
Annunziata, R.; Celentano, G.; Gaggero, N. Org. Biomol. Chem. 2015,
13, 5591. Selected examples for metal-catalyzed achiral synthesis:
(c) Yucel, B.; Walsh, P. J. Adv. Synth. Catal. 2014, 356, 3659. (d) Du,
W.; Tian, L.; Lai, J.; Huo, X.; Xie, X.; She, X.; Tang, S. Org. Lett. 2014,
16, 2470. (e) Dockrey, S. A. B.; Makepeace, A. K.; Schmink, J. R. Org.
Lett. 2014, 16, 4730. (f) Unoh, Y.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2015, 17, 704.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03161.
■
S
Experimental procedures, characterization details, and
additional data (PDF)
(9) Selected reviews of transition-metal-catalyzed allylic substitutions:
(a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (c) Trost,
B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (d) Dai, L.-X.; Tu,
T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 36, 659.
(e) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258. (f) Trost, B.
M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427. (g) Tosatti, P.;
Nelson, A.; Marsden, S. P. Org. Biomol. Chem. 2012, 10, 3147.
(h) Trost, B. M. Org. Process Res. Dev. 2012, 16, 185. (i) Lumbroso, A.;
Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 1890. (j) Butt,
N. A.; Liu, D.; Zhang, W. Synlett 2014, 25, 615. (k) Zhuo, C.-X.;
Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558. (l) Butt, N. A.;
Zhang, W. Chem. Soc. Rev. 2015, 44, 7929. (m) Butt, N.; Yang, G.;
Zhang, W. Chem. Rec. 2016, 16, DOI: 10.1002/tcr.201600071.
(10) (a) Liu, D.; Xie, F.; Zhang, W. J. Org. Chem. 2007, 72, 6992.
(b) Liu, D.; Xie, F.; Zhang, W. Tetrahedron Lett. 2007, 48, 585. (c) Xie,
F.; Liu, D.; Zhang, W. Tetrahedron Lett. 2008, 49, 1012. (d) Zhao, X.;
Liu, D.; Xie, F.; Zhang, W. Tetrahedron 2009, 65, 512. (e) Zhao, X.;
Liu, D.; Liu, Y.; Zhang, W. Org. Biomol. Chem. 2011, 9, 1871. (f) Zhao,
X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133,
19354. (g) Quan, M.; Butt, N. A.; Shen, J.; Shen, K.; Liu, D.; Zhang,
W. Org. Biomol. Chem. 2013, 11, 7412. (h) Huo, X.; Quan, M.; Yang,
G.; Zhao, X.; Liu, D.; Liu, Y.; Zhang, W. Org. Lett. 2014, 16, 1570.
(i) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W.
Angew. Chem., Int. Ed. 2014, 53, 6776. (j) Wei, X.; Liu, D.; An, Q.;
Zhang, W. Org. Lett. 2015, 17, 5768. (k) Huo, X.; He, R.; Zhang, X.;
Zhang, W. J. Am. Chem. Soc. 2016, 138, 11093.
(11) Trost, B. M.; Dirat, O.; Dudash, J., Jr.; Hembre, E. J. Angew.
Chem., Int. Ed. 2001, 40, 3658.
(12) Turnbull, B. W. H.; Oliver, S.; Evans, P. A. J. Am. Chem. Soc.
2015, 137, 15374.
(13) Breitler, S.; Carreira, E. M. J. Am. Chem. Soc. 2015, 137, 5296.
(14) See details in Supporting Information.
(15) Halide additives might provide different catalytic behaviors in
Pd-asymmetric allylic substitution: (a) Burckhardt, U.; Baumann, M.;
Togni, A. Tetrahedron: Asymmetry 1997, 8, 155. (b) Trost, B. M.;
Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(16) Panek, J. S.; Yang, M.; Solomon, J. Tetrahedron Lett. 1995, 36,
1003.
(17) (a) Yayli, N. Indian J. Chem. B 1994, 33, 556. (b) Ayer, W. A.;
Muir, D. J.; Chakravarty, P. Phytochemistry 1996, 42, 1321. (c) Wu, P.-
L.; Lin, F.-W.; Wu, T.-S.; Kuoh, C.-S.; Lee, K.-H.; Lee, S.-J. Chem.
Pharm. Bull. 2004, 52, 345.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dlliu@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
Wanbin Zhang: 0000-0002-4788-4195
Notes
The authors declare no competing financial interest.
§Visiting professor of Shanghai Jiao Tong University from
Chiba University (Japan).
ACKNOWLEDGMENTS
■
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21232004, 21372152,
21402117, and 21472123), Program of Shanghai Subject Chief
Scientists (No. 14XD1402300), and the Instrumental Analysis
Center of SJTU for characterization. We also thank Dr. Masashi
Sugiya of Nippon Chemical Industrial Co., Ltd. for helpful
discussions.
REFERENCES
■
(1) For recent reviews, see: (a) Seebach, D. Synthesis 1969, 1969, 17.
(b) Grobel, B.-T.; Seebach, D. Synthesis 1977, 1977, 357. (c) Page, P.
̈
C. B.; van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643.
́
(d) Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147.
(2) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001.
(3) Hale, K. J.; Hummersone, M. G.; Bhatia, G. S. Org. Lett. 2000, 2,
2189.
(4) Bao, D.-H.; Wu, H.-L.; Liu, C.-L.; Xie, J.-H.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2015, 54, 8791.
(5) Rohde, V. H. G.; Pommerening, P.; Klare, H. F. T.; Oestreich, M.
Organometallics 2014, 33, 3618.
(6) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075. (b) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1077.
(7) Representative examples with alkyl halides: (a) Hayashi, Y.;
Gotoh, H.; Honma, M.; Sankar, K.; Kumar, I.; Ishikawa, H.; Konno,
K.; Yui, H.; Tsuzuki, S.; Uchimaru, T. J. Am. Chem. Soc. 2011, 133,
20175. (b) Larson, R. T.; Clift, M. D.; Thomson, R. J. Angew. Chem.,
Int. Ed. 2012, 51, 2481. (c) Lee, K.; Kim, H.; Hong, J. Angew. Chem.,
Int. Ed. 2012, 51, 5735. (d) Wang, Y.; Zheng, Z.; Zhang, L. Angew.
Chem., Int. Ed. 2014, 53, 9572. (e) Yoneda, N.; Fukata, Y.; Asano, K.;
Matsubara, S. Angew. Chem., Int. Ed. 2015, 54, 15497. Representative
examples with carbonyl compounds: (f) Shimada, N.; Stewart, C.;
Bow, W. F.; Jolit, A.; Wong, K.; Zhou, Z.; Tius, M. A. Angew. Chem.,
Int. Ed. 2012, 51, 5727. (g) Chen, M. Z.; Micalizio, G. C. J. Am. Chem.
Soc. 2012, 134, 1352. Representative examples with epoxides:
(h) Winter, P.; Hiller, W.; Christmann, M. Angew. Chem., Int. Ed.
2012, 51, 3396. (i) Zou, Y.; Wu, Y. Angew. Chem., Int. Ed. 2012, 51,
4968. (j) Kim, H. J.; Choi, S.-H.; Jeon, B.-S.; Kim, N.; Pongdee, R.;
Wu, Q.; Liu, H.-W. Angew. Chem., Int. Ed. 2014, 53, 13553. (k) Ai, Y.;
Kozytska, M. V.; Zou, Y.; Khartulyari, A. S.; Smith, A. B., III J. Am.
D
DOI: 10.1021/acs.orglett.6b03161
Org. Lett. XXXX, XXX, XXX−XXX