Tunable and highly regio- and diastereoselective vinylogous Mannich-type reaction of dioxinone-derived silyl dienolate

Article abstract of DOI:10.1021/jo900977y

(Figure Presented) A tunable and highly regio- and diastereoselective vinylogous Mannich-type reaction of dioxinone-derived silyl dienolate (1) with chiral N-tert-butanesulfinyl imino ester (2) was developed. By appropriate choice of Lewis acid catalyst,

Full text of DOI:10.1021/jo900977y

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to the synthesis of chiral R-amino acids. Among the efficient
Tunable and Highly Regio- and Diastereoselective
Vinylogous Mannich-Type Reaction of
Dioxinone-Derived Silyl Dienolate
synthetic methods,1 the addition of nucleophiles to R-imino
esters has emerged as one of the most promising and
intensely investigated methods. Moreover, several investi-
gations on the asymmetric additions of different enolate
equivalents to R-imino esters (Mannich-type reactions) have
also been reported.2 Brassard diene and its dioxinone-
derived equivalent, which were widely used in the vinylogous
aldol reactions,3 have participated in vinylogous Mannich-
type reaction to afford multisubstituted amino acid esters.4
The vinylogous Mannich reaction of acetoacetate-derived
dienolates could take place potentially at two different
positions to give γ- and R-regioisomers (Scheme 1). Pre-
viously, exclusive γ-selectivity has always been observed in
the Lewis acid-catalyzed reactions of dioxinone-derived silyl
dienolate and Brassard diene.2b,4 However, it has been
shown that both the γ-products of vinylogous Mannich
reaction, δ-amino-β-keto esters,5 and R-product, bearing
the structural unit of β0-keto-β-amino acid, were important
intermediates to the compounds possessing potential phar-
maceutical and agrochemical activities.6 To our knowledge,
there has been no reported example of R-selective Lewis acid-
catalyzed vinylogous Mannich-type reaction. Consequently,
R-adducts of vinylogous Mannich-type reaction could be
achieved only by the corresponding coupling reaction of
Grignard reagent.7 Furthermore, to achieve asymmetric
R-selective Mannich-type reaction of dioxinone-derived die-
nolate is still a challenge. Herein, we wish to disclose the first
examples of Lewis acid-catalyzed highly R-regio- and dia-
stereoselective Mannich reactions of N-tert-butanesulfinyl
imino esters with dioxinone-derived silyl dienolate and
relative γ-regioselective reactions.
Chun-Ling Gu, Li Liu,* Dong Wang, and Yong-Jun Chen*
Beijing National Laboratory for Molecular Sciences
(BNLMS), CAS Key Laboratory of Molecular Recognition
and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
lliu@iccas.ac.cn; yjchen@iccas.ac.cn
Received May 13, 2009
(2) For selected examples, see: (a) Jacobsen, M. F.; Skrydstrup, T. J. Org.
Chem. 2003, 68, 7112–7114. (b) Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R.
G.; Jorgensen, K. A. Chem.;Eur. J. 2003, 9, 6145–6154. (c) Taggi, A. E.;
Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10–17. (d) Andreassen, T.;
Haland, T.; Hansenb, L. K.; Gautun, O. R. Tetrahedron Lett. 2007, 48, 8413–
8415.
(3) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2005, 44, 4682-4698 and references cited therein.
(4) (a) Kawecki, R. Tetrahedron 2001, 57, 8385–8390. (b) Villano, R.;
Acocella, M. R.; Massa, A.; Palombi, L.; Scettri, A. Tetrahedron 2007, 63,
12317–12323. For selected examples for vinylogous Mannich reaction of
silyl dienolates, see: (c) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed.
2008, 47, 3631–3634. (d) Wieland, L. C.; Vieira, E. M.; Snapper, M. L.;
A tunable and highly regio- and diastereoselective viny-
logous Mannich-type reaction of dioxinone-derived silyl
dienolate (1) with chiral N-tert-butanesulfinyl imino ester
(2) was developed. By appropriate choice of Lewis acid
catalyst, two diastereomers of the γ-product were ob-
tained, respectively, with dr up to 95:5. The procedure for
the Ag(I)-catalyzed vinylogous Mannich-type reaction
also provided facile access to the R-regioisomer with
excellent diastereoselectivities (up to >99:1 dr) by chan-
ging the counterion of the Ag(I) salt.
e
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Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 570–576. (e) Gonzalez, A. S.;
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5754 J. Org. Chem. 2009, 74, 5754–5757
Published on Web 06/25/2009
DOI: 10.1021/jo900977y
r
2009 American Chemical Society

Gu et al.
JOCNote
SCHEME 2. Vinylogous Mannich-Type Reaction of Dienolate 1
with (SR)-N-tert-Butanesulfinylimino Acetates 2
SCHEME 1. Vinylogous Mannich-Type Reaction of Acetoacetate-
Derived Dienolates
The chiral sulfinyl group was widely used as an efficient and
powerful auxiliary group for asymmetric induction.8 Initially,
the reaction of chiral (SR)-N-tert-butanesulfinylimino acetate
(SR)-2a with dioxinone-derived silyl dienolate 1 (Scheme 2)
was carried out in the presence of AgOTf catalyst (10 mol %)
to give the product γ-3a (γ-3aa þ γ-3ab) in 83% yield. The
1HNMR of the product mixture showed that the reaction had
both high regioselectivity (γ-3a/R-4a= 30:1) and good dia-
stereoselectivity [dr (3aa/3ab)=85:15] (Table 1, entry 1).
By using AgClO4 as a catalyst, good γ-regio- and diastereos-
electivity of γ-3a were also obtained (entry 2). With Cu(OTf)2,
CuOTf, and Zn(OTf)2 as catalyst, the reactions of 2a with 1 in
DCM at -78 °C also provided excellent γ-regioselectivities
(γ-3a/R-4a up to >50:1) and high diastereoselectivities (dr up
to 8:92) (entries 3-5). However, it was noteworthy that the
main product was γ-3ab. Although the absolute values were
similar, the observed diastereomeric ratio was opposite to the
TABLE 1. The Vinylogous Mannich Reaction of 2a with 1a
time
(h)
yield
(%)
R-4a/
γ-3ab
Dr of
γ-3ab
dr of 4a
(%)c
entry
catalyst
AgOTf
AgClO4
1
2
3
4
5
6
7
8
48
24
12
24
48
24
24
24
83
61d
85
73
86
83
84
87
1:30 85:15
1:10 83:17
1:34 21:79
<1:50 24:74
1:54
48:1
49:1
CuOTf
Cu(OTf)2
Zn(OTf)2
AgOAc
AgNO3
AgOCOCF3
8:92
98:2
94:6
98:2
>50:1
aCatalyst loading 10 mol %, reaction temperature -78 °C in DCM.
bDetermined by 1H NMR of the product mixture (dr = SR,CS:SR,CR).
cDetermined by chiral HLPC analysis. d1H NMR yield.
1
cases of AgOTf and AgClO4, which was confirmed by H
NMR and HPLC analyses of the crude products.
Interestingly, it was found that the counterion of Ag(I) salt
influenced the regioselectivity of the reaction strongly. If the
counterions of the catalyst were changed from -OTf to
-OAc, the reaction of 2a with 1 in DCM at -78 °C afforded
high R-selectivity (R-4a/γ-3a = 48:1) in high yield of R-4a
with an excellent diastereoselectivity (96:4 dr) (entry 6).
Under the same conditions, AgNO3 and AgOCOCF3 also
provided excellent R-selectivity (R/γ up to >50:1) in good
yield of R-4a and excellent diastereoselectivities (up to
98:2 dr) (entries 7 and 8).
Both the reactivity and diastereoselectivity of the R-regio-
selective reactions were much higher (dr up to >99:1) than
that of the triflates-catalyzed γ-selective reactions. In the case
of 2d, the reaction took a relatively longer time to complete,
with a low yield and regioselectivity (entry 11). Interestingly,
when methanol (2 equiv) was added into the AgOTf-catalyzed
reaction system, the γ-selectivity switched to R-selectivity
with a high diastereoselectivity (97:3 dr) (entry 13).9 However,
the reaction of 1 with 2c catalyzed by AgOAc was sluggish
to give a complicated mixture. When (SS)-2a was employed
in the reaction with 1 in the presence of AgOCOCF3, R-4a was
obtained as the main product (R:γ=20:1) with high diastereo-
selectivity (97:3 dr) (entry 9); however, the configuration of
the newly formed chiral carbon center was opposite to that
obtained from the reaction of (SR)-2a (entry 8) based on the
analysis of HPLC.
The vinylogous Mannich product could be transformed into
piperidinediones. According to the reference procedure,10
γ-3db (R = Bn), which was produced from the Zn(OTf)2-
catalyzed reaction of 1 with 2d, was converted into optically
active (-)-6d through the removal of chiral sulfinyl group (5db,
98% ee after crystallization) and subsequent cyclization
(Scheme 3). The product (-)-6d was an efficient precursor
of chiral natural amino acid, 4-hydroxypipecolic acid.11
To further demonstrate that the regio- and diastereoselec-
tivity of the vinylogous Mannich-type reactions can be
regulated by Lewis acid catalysts, several chiral imino esters
(2a-d) were tested (Scheme 2). The results were summarized
in Table 2. For Zn(OTf)2-catalyzed reactions of 1 with 2,
excellent γ-selectivity was achieved (R:γ < 1:50) and γ-3ab-
3db were obtained in moderate to good yields, but the
diastereoselectivities increased slightly with bulky group of
the iminoester (2c, R=tert-butyl) (entries 4-7). On the other
hand, despite the slight decrease of both the reactivities and
regioselectivities, AgOTf-catalyzed reactions maintained the
γ-selectivity and provided a reversal of the stereoselectivity
and high diastereoselectivities (entries 1-3). For less reactive
imines such as N-tert-butanesulfinylbenzaldimine (2e), the
reaction of 2e with 1 could not proceed at -78 °C.
The AgOCOCF3- or AgOAc-catalyzed reactions selec-
tively occurred at the R-position (Table 2, entries 8-12).
(9) Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem., Int. Ed. 2005, 44,
1546–1548.
(10) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006,
128, 6304–6305.
(8) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984–995. (b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–8905.
(c) Gragg, R.; McCaffrey, S.; Sridharan, V.; Fishwick, C. W. G.; Kilner, C.;
Korn, S.; Bailey, K.; Blacker, J. Tertrahedron 2006, 62, 12159–12171. (d) Dai,
H.-X.; Lu, X.- Y. Org. Lett. 2007, 9, 3077–3080. (e) Andreassen, T.; Hansen,
L.-K.; Gauntun, O. R. Eur. J. Org. Chem. 2008, 4871–4876. (f) Lin, G.-Q.;
Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res., 2008, 41, 831-840
and references cited therein.
(11) (a) De Lucca, G. V. Bioorg. Med. Chem. Lett. 1997, 7, 501–504. (b)
Chung, J. Y. L.; Hughes, D. L.; Zhao, D.; Song, Z.; Mathre, D. J.; Ho, G.-J.;
McNamara, J. M.; Douglas, A. W.; Reamer, R. A.; Tsay, F.-R.; Varsolona,
R.; McCauley, J.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1996, 61,
215–222. (c) MacKenzie, A. R.; Marchington, A. P.; Middleton, D. S.;
Newman, S. D.; Jones, B. C. J. Med. Chem. 2002, 45, 5365–5377. (d)
Schafmeister, C. E.; Brown, Z. Z.; Gupta, S. Acc. Chem. Res. 2008, 41,
1387–1398.
J. Org. Chem. Vol. 74, No. 15, 2009 5755

Gu et al.
JOCNote
TABLE 2. The (Vinylogous) Mannich Reactions of 2 with 1a
aCatalyst loading 10 mol %, reaction temperature -78 °C. bDetermined by 1HNMR of the product mixture. cDetermined by HPLC analysis of the
crude products (3: dr=SR,CS:SR,CR). d(SS)-2a was used. eDetermined by HPLC analysis of its derivative 8b. f20% Zn(OTf)2 was used . g2 equiv of MeOH
was added. h1HNMR yield.
By comparing the optical rotation of 6d ([R]20 -76.0) with
D
for removal of the chiral sulfinyl group under the same
conditions to give optically active 5aa and 5ab, respectively.
In terms of the signs of optical rotation, the chiral center of
(þ)-5aa ([R] þ28) and (-)-5ab ([R] -36.5) should have oppo-
site configurations.
On the basis of the above results, the configuration of
γ-3aa from the AgOTf-catalyzed reaction can be deduced
to be (SR,CS), while the configuration of γ-3ab from the
Zn(OTf)2-catalyzed ones should be (SR,CR).
the literature value of the (S)-isomer12 ([R]20 Dþ 76.1), the
configuration of 6d was deduced as (R), which meant
the configuration of the newly formed chiral center of the
γ-product was (R). Meanwhile, γ-3aa (R = Et, dr = 87:13)
and γ-3ab (R=Et, dr=8:92) were employed in the reactions
(12) Marin, J.; Didierjean, C.; Aubry, A.; Casimir, J.-R.; Briand, J.-P. G.;
Guichard, J. J. Org. Chem. 2004, 69, 130–141.
5756 J. Org. Chem. Vol. 74, No. 15, 2009

Gu et al.
JOCNote
SCHEME 3. Derivation of the Vinylogous Mannich Products
inhibited the approach of OTMS to Agþ and resulted in the
γ-selectivity (Figure 1, T.S.B. vs. T.S.C).13 When Zn(OAc)2
and Cu(OAc)2 were used in the reaction of 2a with 1, no
product was detected during the reaction. It could be sug-
gested that a proper Ag(I) salt catalyst14 plays an essential
role for the R-selective Mannich-type reaction of 1 and 2.
In conclusion, a highly R-regio- and diastereoselective
vinylogous Mannich-type reaction of dioxinone-derived silyl
dienolate catalyzed by Ag(I) salts was developed. Agþ and its
counterions played a crucial role in controlling the R- and
γ-selectivities, and achieving high diastereoselectivities. The
regioselectivity could be tuned by the appropriate choice of
Lewis acid catalysts used in the reaction. The method also
provided a feasible route to synthesize multisubstituted
chiral amino acids.
Experimental Section
General Procedure for the Regio- and Diastereoselective
Vinylogous Mannich Reaction of Silyl Dienolate 1 and R-Imino
Ester 2. Lewis acid (0.02 mmol) and R-imino ester 2a-d
(0.2 mmol) were charged in a dried 5 mL flask under argon,
followed by addition of CH2Cl2 (0.9 mL). The solution was
cooled to -78 °C, then after 30 min silyl dienolate 1 (0.3 mmol)
was added. After stirring for the indicated time, brine (10 mL)
was added, followed by extraction with CH2Cl2. The combined
organic phases were dried with Na2SO4 and the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent: petroleum ether/
ethyl acetate=1/1 to 1/2) to afford product 3a-d and 4a,b,d.
Ethyl 2-(tert-butoxycarbonylamino)-3-(2,2-dimethyl-4-oxo-4-
The product R-4a was readily converted into 7a under the
same conditions and to 8a through the m-CPBA oxidation
in excellent yields without the racemization (Scheme 3). The
absolute configuration of the chiral carbon center in 8a was
deduced as (R) according to X-ray structural analysis of
a single crystal (see the Supporting Information). Conse-
quently, the absolute configuration of R-4a was determined
as (SR,CR).
1
H-1,3-dioxin-6-yl)propanoate (3a): colorless oil, 86% yield; H
NMR (300 MHz, CDCl3) δ 5.20 (s, 1H), 5.13-5.10 (m, 1H),
4.27-3.88 (m, 3H), 2.84 (m, 2H), 2.72 (d, J=5.6 Hz, 2H), 1.66
(s, 6H), 1.32-1.18 (m, 12H); 13C NMR (75 MHz, CDCl3)
δ 199.9, 167.0, 165.1, 151.3, 84.8, 62.6, 53.9, 50.5, 40.6, 27.9,
14.0; IR (film) νmax 3278, 1732, 1639 cm-1; HRMS (ESI) m/z
calcd for C15H26N1O6S1 [M]þ 348.1475, found 348.1485.
Ethyl 2-((R)-1,1-dimethylethylsulfinamido)-2-(2,2,6-trimethyl-
4-oxo-4H-1,3-dioxin-5-yl)acetate (4a): white solid, 87% yield;
1H NMR (300 MHz, CDCl3) δ 4.78 (d, J=3.1 Hz, 1H), 4.71
(br, 1H), 4.30-4.16 (m, 2H), 2.18 (s, 3H), 1.70 (s, 3H), 1.68 (s,
3H), 1.23 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.1, 167.3,
160.0, 105.8, 104.3, 62.4, 56.0, 52.6, 25.1, 25.0, 22.5, 17.6, 14.0;
IR (film) ν 2249, 1743, 1684, 1597, 1580, 1515, 1448, 1252, 1209
cm-1; HRMS (EI) m/z calcd for C15H25N1O6S1 [M]þ 347.1403,
found 347.1400.
FIGURE 1. Proposed transition states for the vinylogous Mannich-
type reaction of silyl dienolate 1 with imino ester 2.
In terms of the triflate salt-catalyzed reaction, the
γ-selectivity is a rational outcome through the normal path-
way of chiral sulfinylimines catalyzed by Lewis acid.4,8 For
the Zn(OTf)2-catalyzed vinylogous Mannich reaction, the
transition state should adopt the T.S.A mode (Figure 1) in
which Zn2þ could coordinate to the carbonyl oxygen and the
imine nitrogen,8e and Re-attack leads to the R-configuration
of the newly formed chiral carbon center. In contrast, it
could be proposed that Agþ (AgOTf or AgClO4) coordinates
to the sulfinyl oxygen atom, the carbonyl oxygen atom, and
the sulfinyl nitrogen atom (T.S.B),8c,8d affording the isomer
due to Si-attack.
Acknowledgment. We thank the National Natural Science
Foundation of China, the Chinese Academy of Sciences, and
Ministry of Science and Technology (No. 2009ZX09501-
066) for financial support.
Supporting Information Available: Experimental procedure
characterization data of the products, chiral HPLC separa-
tions for ee determination, and X-ray structural data of 8a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In the cases of AgOAc, AgOCOCF3, and AgNO3, the
counterion may play an important role in the R-regioselec-
tivity by interacting with the TMS to enhance the coordina-
tion between Agþ and the oxygen of silyl dienolate (Figure 1,
T.S.C),4d which leads to Re-attack to give R-product with
(13) Ion radius: CH3COO- < CF3COO- (0.156 nm) < NO3 (0.189
-
nm) < ClO4- (0.240 nm) < CF3SO3- (0.256 nm): Sunderrajan, S.; Freeman,
B. D.; Hall, C. K. Ind. Eng. Chem. Res. 1999, 38, 4051–4059.
(14) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132–3148.
(SR,CR)-configurations. However, under the catalysis of
-
AgOTf or AgClO4, the larger anions, -OTf- and ClO4
,
J. Org. Chem. Vol. 74, No. 15, 2009 5757