Stereoselective approach to access 3-tert-Butyl-Dimethylsiloxy-2,6-Substituted piperidines through nucleophilic addition of N,O-acetals with organozinc reagents

Article abstract of DOI:10.1016/j.tetlet.2020.152051

An efficient approach to access chiral 3-tert-butyl-dimethylsiloxy 2,6-disubstituted 6-benzyl piperidines was developed through nucleophilic addition of N,O-acetals with organozinc reagents. A number of substituted benzyl zinc reagents could react with N,

Full text of DOI:10.1016/j.tetlet.2020.152051

Journal Pre-proofs
Stereoselective Approach to Access 3-tert-Butyl-Dimethylsiloxy-2,6-Substi‐
tuted Piperidines Through Nucleophilic Addition of N,O-acetals with Organo‐
zinc Reagents
Zhao-D-an Chen, Zhuo Chen, Qiao-E Wang, Chang-Mei Si, Bang-Guo Wei
PII:
S0040-4039(20)30497-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152051
TETL 152051
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 March 2020
12 May 2020
15 May 2020
Please cite this article as: Chen, Z-D., Chen, Z., Wang, Q-E., Si, C-M., Wei, B-G., Stereoselective Approach to
Access 3-tert-Butyl-Dimethylsiloxy-2,6-Substituted Piperidines Through Nucleophilic Addition of N,O-acetals
with Organozinc Reagents, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152051
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Stereoselective Approach to Access 3-tert-
Butyl-Dimethylsiloxy-2,6-Substituted
Leave this area blank for abstract info.
Piperidines Through Nucleophilic Addition
of N,O-acetals with Organozinc Reagents
Zhao-Dan Chen,a Zhuo Chen,a Qiao-E Wang,b Chang-Mei Sia,* and Bang-Guo Weia
OTBS
OTBS
R
TiCl4
+
FGCH2ZnX
THF,-78oC
HO
N
R
N
Boc
FG Boc
FG = Substituted Aryl, alkyl
X = Br, I
27 examples

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Stereoselective Approach to Access 3-tert-Butyl-Dimethylsiloxy-2,6-Substituted
Piperidines Through Nucleophilic Addition of N,O-acetals with Organozinc Reagents
Zhao-Dan Chen,a Zhuo Chen,a Qiao-E Wang,b Chang-Mei Sia,* and Bang-Guo Weia
aDepartment of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
bBeijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing 100048, China
———
*
ARTICLE INFO
ABSTRACT
Corresponding author. E-mail address: sicm@fudan.edu.cn
Article history:
Received
Received in revised form
Accepted
An efficient approach to access chiral 3-tert-butyl-dimethylsiloxy 2,6-disubstituted 6-benzyl
piperidines was developed through nucleophilic addition of N,O-acetals with organozinc
reagents. A number of substituted benzyl zinc reagents could react with N,O-acetals 6a-6e,
affording the desired products 7a-7j and 9a-9q in good to excellent yields and with high
diastereoselectivities.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
2-substituted 6-benzyl piperidine
N,O-acetals
Organozinc reagents
Nucleophilic addition
The development of efficient methods to access privileged
structural motifs is one of the most important tasks in
contemporary organic chemistry.1-2 As a prime instance, 3-
structures, asymmetrically synthetic approaches to these natural
products and their analogies have attracted wide attention and a
number of powerful approaches have been reported.5-9,13
Particularly, it is very difficult to selectively introduce the
substituents to C-6/C-5 position for piperidine or pyrrole
skeleton.3,6c,10-13 Although a number of powerful approaches
including one-pot successive addition- reduction process of imide
(Figure 2, eq.1)11, or nucleophilic substitution of silyl enol
ether12a or organoboron reagent12b with N,O-acetal (Figure 2, eq.2)
have been achieved in past decade, the direct method to introduce
the substituents at C-6/C-5 position of piperidine or pyrrole
skeleton is still a challenging work. For examples, the former
needs a harsh reaction condition, the latter has limited substrate
scope. Recently, our group have established approach to 3-
hydroxy-2,6-disubstituted piperidine scaffold through one–pot
Mannich process of N,O-acetal with ketone (Figure 2, eq.3)13. To
our best knowledge, there is no direct way to introduce benzyl
substituents in C-6/C-5 position for piperidine or pyrrole. In the
past decade, functionalized organozinc reagents, which are
generally prepared through insertion reaction of zinc metal into
various substituted organic halides, have demonstrated
advantages for many transformations in modern organic
synthesis.14 For example, functionalized organozinc reagents
were successfully applied in single-step reactions with N,O-
acetals by Konakahara and our group,15 carbonyl,16 nitrones,17 as
well as in cascade process like addition-elimination18 or addition-
migration.19 Encouraged by our previous work on N,O-acetals
(Fig. 2, eq. 1-2),12,13,15b we envisioned that the chiral 3-tert-butyl-
dimethylsiloxy-2-substituted 6-benzyl piperidine scaffold 7 could
be prepared through the nucleophilic substitution process of N,O-
acetal 6 with functionalized organozinc reagents (Fig.2, eq. 4).
hydroxy
2,6-disubstituted
piperidines/3-hydroxy
2,5-
disubstituted pyrrole exist as subunits for many natural products3
and biologically active molecules in life-science industry.4 Some
representative pyrrolidine and piperidine alkaloids are shown in
Figure 1, which include hyacinthacine B5 (1),5 (-)-morusimic
acid D (2),6 (-)-sedacryptine (3),7 (-)-azimine (4)8 and (-)-
carpaine (5).9 Due to the divergent activities and attractive
OH
HO
OH
H
N
O
OH
OH
HO
N
H
OH
2
(-)-morusimic acid D
1
hyacinthacine B5
OH
O
O
NH
O
n(H2C)
OH
(CH2)n
O
N
CH3
HN
O
4
n=5, (-)-azimine
3
(-)-sedacryptine
5
n=7, (-)-carpaine
Figure 1. Representative 2,6-disubstituted piperidine/2,5-
disubstituted pyrrole alkaloids.

2
Tetrahedron Letters
One-pot addition- reduction process of imide11
screened, and the results were summarized in Table 1. Several
Lewis acids except SnCl4 could afford the desired product (Table
1, entries 2-6), and TiCl4 turned out to be the best one, producing
7a not only in extremely high yield (up to 99%), but also with
excellent diastereoselectivity (Table 1, entry 6). Decreasing the
use of TiCl4 to 1 eq. resulted in significant drop for the reaction
yield although high diastereoselectivity of 7a was maintained
(Table 1, entry 7). Lanthanide salts like Tm(OTf)3, Pr(OTf)3,
Nd(OTf)3 and Ce(OTf)3 proved to be ineffective for this
transformation, instead an olefin by-product 8 was generated
(Table 1, entries 8-11).
OBn
OBn
.
Et3SiH
+
(1)
RCH2MgBr
O
N
N
BF3 Et2O
R
Ph
-78 ~-40 oC
Ph
Boc
Boc
Nucleophilic substitution process of N,O-acetal12
OTBS
OTBS
R'
n
n
AllylSi or AllylB
(2)
(3)
HO
N
R'
N
Lewis Acid
Next, we turned to investigate the scope and limitation of the
nucleophilic addition of N,O-acetal 6a by organozinc reagents
(Table 2). Different substituted (methyl, fluoro, trifluoromethyl
and chloro) benzylzinc bromides were surveyed under the
optimal conditions, as summarized in Scheme 1. In general, the
reactions of N,O-acetal 6a with ortho-, meta- and para-
substituted benzylzinc reagents underwent smoothly, affording
Boc
Boc
One-pot Mannich process of N,O-acetal13
OTBS
O
OTBS
O
Lewis Acid
+
Ar
HO
N
R
Ar
N
Boc
R'
Boc
the
desired
3-tert-butyl-dimethylsiloxy-2,6-disubstituted
This Work
piperidines 7b-7j in moderate to excellent yields and with high
diastereoselectivities. It is worth mentioning that cyano
substitution was tolerated and the corresponding product 7h was
obtained in 72% yield (dr > 99:1). When chloro substituted zinc
reagent was used, the desired product 7g was also produced in
excellent yield and with high diastereoselectivity. Notably, allyl
zinc bromide and α-naphthalene methyl zinc bromide also
showed good reactivities in this transformation, though affording
the desired products 7i and 7j with slightly lower
diastereoselectivities.
OTBS
OTBS
R
TiCl4
-78oC
+
FGCH2ZnX
FG
HO
N
R
(4)
N
Boc
FG = Substituted Aryl, alkyl
X = Br, I
Boc
6a-6e
7a-7j, 9a-9q
Figure 2. Our strategy to access chiral 3-tert-butyl-dimethylsiloxy-2-
substituted 6-benzyl piperidine scaffold.
The substrate, chiral N,O-acetal (5R,6S)-6a, was readily
prepared according to our previous intramolecular tandem
sequence of the α-chiral aldimine with Grignard reagents20 and
the known reduction procedure.21 When 6a was treated with
benzylzinc bromide in the presence of BF3 OEt2 at -78 °C for 12
h, the desired product 7a was obtained in 44% yield, albeit with
Table 2. The scope of this method to 3-tert-butyl-dimethylsiloxy-
2,6-disubstituted piperidines 7a-7ja-c.
.
R2CH2ZnX
TiCl4, THF
OTBS
OTBS
R2
HO
N
Bn
N
Bn
-78oC,12h
Table 1. Optimization of reaction conditions.
Boc
6a
Boc
OTBS
Bn
OTBS
Bn
OTBS
7a-7j
PhCH2ZnBr
LA, THF
+
Bn
HO
N
N
Bn
N
OTBS
Bn
Boc
Boc
8
Boc
7a
R
OTBS
Bn
6a
N
Boc
Entriesa
LA (equiv.)
Y% (7a)b
Y% (8)b
dr (7a)c
N
7a
7b
7c
7d
7e
, R = H, 99%, dr > 99:1
Boc
, R = 2-CF3, 96%, dr > 99:1
, R = 3-CF3, 87%, dr > 99:1
, R = 4-Me, 97%, dr > 99:1
, R = 4-CF3, 80%, dr > 99:1
, R = 3-Me, 69%, dr > 99:1
BF3·Et2O (2.0)
SnCl4 (2.0)
44
-
-
64:36
7i
, 71%, dr = 90:10
1
2
-
-
OTBS
AlCl3 (2.0)
34
84
96
99
76
-
-
94:6
3
N
Bn
TMSOTf (2.0)
TMSCl (2.0)
TiCl4 (2.0)
-
-
>99:1
7f
4
Boc
7g
, R = 3-Cl, 90%, dr > 99:1
, R = 4-CN, 72%, dr > 99:1
>99:1
5
7j
, 70%, dr = 85:15
7h
-
>99:1
6
aThe reactions were performed with 6a (100 mg), FGCH2ZnX (4 eq.) and
TiCl4 (2 eq.) in THF (1 mL) at -78 °C for 12 h. The reaction was quenched
with saturated NaHCO3 solution and diluted with EtOAc.
TiCl4 (1.0)
-
>99:1
7
Tm(OTf)3 (0.2)
Pr(OTf)3 (0.2)
Nd(OTf)3 (0.2)
Ce(OTf)3 (0.2)
75%
70%
60%
78%
-
-
-
-
8
b Isolated yield.
-
9
c dr was determined by 1H NMR.
-
10
11
Then, the scope and limitation of different N,O-acetals 6b-6e
were explored and the results are summarized in Table 3.
Different N,O-acetals 6b-6e were surveyed under the optimal
conditions, all of them reacted smoothly with various benzyl zinc
reagents, affording the desired 3-tert-butyl-dimethylsiloxy-2,6-
disubstituted piperidines 9a-9p in moderate to excellent yields
and with high diastereoselectivities. Consistent with previous
research, when allyl zinc reagent was used, the desired product
9q was also produced with lower diastereoselectivities (dr =
65:35).
-
a
The reactions were performed with 6a (100 mg), PhCH2ZnBr (4 eq.) and
LA in THF (1 mL) at -78 °C for 12 h. The reaction was quenched with
saturated NaHCO3 solution and diluted with EtOAc.
b Isolated yield.
c dr was determined by 1H NMR.
low diastereoselectivity (Table 1, entry 1). To improve the
reaction yield and diastereoselectivity, various Lewis acids were

3
Table 3. The scope of this method to 3-tert-butyl-dimethylsiloxy-
2,6-disubstituted piperidines 9a-9qa-c.
Br
OH
(COCl)2
OTBS
R1
9p
OTBS
R2CH2ZnX
R2
DCM, 100%
N
H
HO
N
R1
N
TiCl4, THF
-78oC,12h
10
Boc
9a-9q
Boc
6b-6e
OTBS
OTBS
N
N
Boc
Boc
CF3
9b
, 88%, dr > 99:1
9a
, 72%, dr > 99:1
OTBS
OTBS
10
(COOH)2
N
N
Boc
Boc
Scheme 1. Synthesis of 10.
9c
, 92%, dr > 99:1
9d
, 73%, dr > 99:1
OTBS
A possible mechanism for this nucleophilic addition was
illustrated in Figure 3. When N,O-acetal 6a reacted with organic
zinc, imide onium was first generated under Lewis acid
conditions. Conformation a is more stable than b due to the
smaller steric hindrance between OTBS and Bn. Then, the
organic zinc would take place from the less steric side of form c
to generate cis-product 7a.
F3C
OTBS
F3C
N
N
Boc
Boc
9g,
77%, dr > 99:1
9e
, 75%, dr > 99:1
F3C
OTBS
OTBS
F3C
OTBS
TiCl4
HO
N
R1
N
N
Boc
Boc
Boc
CF3
OTBS
R1
9f
, 97%, dr > 99:1
OTBS
9h
, 75%, dr > 99:1
Cl
OTBS
R1
FGH2C
N
NC
OTBS
Boc
H
O
N
N
N
R'
Boc
C Ti
l4
Boc
Boc
9j
, R'=Ph, 73%, dr > 99:1
9k
9l
9m
, R'=4-CF3Ph, 98%, dr > 99:1
, R'=C2H5, 74%, dr = 85:15
OTBS
R1
9i
, 99%, dr > 99:1
, R'=n-Bu, 73%, dr > 99:1
TiCl4
N
FGCH2ZnX
H
CF3
Boc
CF3
OTBS
OTBS
Bn
LA
N
OTBS
Bn
N
H
N
H
N
6a
Boc
Boc
Boc
OTBS
Boc
H
9n
9o
, 80%, dr > 99:1
, 90%, dr > 99:1
steric hindrance disfavored
steric hindrance favored
a
b
Br
BnZnBr
OTBS
OTBS
N
u
Bn
N
n-C4H9
N
Bn
N
N
Boc
Boc
H
H
Boc
H
H
9q
, 50%, dr = 65:35
Boc
9p
N
, 98%, dr > 99:1
OTBS
u
OTBS
c
d
favored attack
disfavored attack
aThe reactions were performed with 6b-6e (100 mg), FGCH2ZnX (4 eq.) and
TiCl4 (2 eq.) in THF (1 mL) at -78 °C for 12 h. The reaction was quenched
with saturated NaHCO3 solution and diluted with EtOAc.
OTBS
Bn
OTBS
Bn
b Isolated yield.
c dr was determined by 1H NMR.
Bn
N
Bn
N
Boc
Boc
7a
The attempts to obtain single crystal for 9p were unsuccessful,
fortunately the oxalic acid salt of deprotected compound 10 could
afford good co-crystal (Scheme 1), from which the
stereochemistry of 9p was unambiguously assigned as 2,6-cis-
form based on its X-ray crystallography22 (see Supporting
Information).
7a
cis-
trans-
Figure 3. Proposed mechanism of the nucleophilic addition.
In summary, we have established a novel and practical
approach for the synthesis of chiral 3-tert-butyl-dimethylsiloxy-

4
Tetrahedron Letters
2-substituted 6-benzyl piperidines 7a-7j, 9a-9q through
Acknowledgments
nucleophilic addition of N,O-acetals 6a-6e with organozinc
reagents. TiCl4 was found to be the most effective lewis acid for
We thank the National Natural Science Foundation of China
(21702032 to C.-M. Si and 21772027 to B.-G. Wei) and the
Open Research Fund Program of Beijing Key Lab of Plant
Resource Research and Development, BTBU (No. PRRD-2019-
YB2) for financial support. The authors also thank Dr. Han-Qing
Dong (Arvinas, Inc.) for helpful suggestions.
this transformation, and
dimethylsiloxy-2-substituted
a
variety of chiral 3-tert-butyl-
6-benzyl piperidines were
successfully synthesized in moderate to excellent yields and with
high diastereoselectivities. To the best of our knowledge, the
present process is the first direct method for the preparation of
chiral
3-tert-butyl-dimethylsiloxy-2-substituted
6-benzyl
piperidines.
1996, 100-102; (e) Plehiers, M.; Hootelé, C. Can. J. Chem. 1996,
74, 2444-2453; (f) Wee, A. G. H.; Fan, G.-J. Org. Lett. 2008, 10,
3869-3872.
References and notes
8.
9.
For the isolation of (-)-azimine, see: (a) Rall, G. J. H.; Smalberger,
T. M.; de Waal, H. L.; Arndt, R. R. Tetrahedron Lett. 1967, 8,
3465-3469; (b) Kurogome, Y.; Kogiso, M.; Looi, K. K.; Hattori,
Y.; Konno, H.; Hirota, M.; Makabe, H. Tetrahedron 2013, 69,
8349-8352.
For the isolation of (-)-carpaine, see: (a) Rapoport, H.; Baldridge,
H. D., Jr. J. Am. Chem. Soc. 1951, 73, 343-346; (b) Govindachari,
T. R.; Pai, B. R.; Narasimhan, N. S. J. Chem. Soc. 1954, 1847-
1849; For syntheses of carpaine, azimine, see: (c) Corey, E. J.;
Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614-5616; (d) Sato,
T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839-3842.
1.
(a) Ojima, I. Catalytic Asymmetric Synthesis, Wiley-VCH:
Weinheim, 2000; (b) Tsuji, J. Transition Metal Reagents and
Catalysts: Innovations in Organic Synthesis, Wiley: Chichester,
2000.
2.
For selected recent examples, see: (a) Stempel, E.; Gaich, T. Acc.
Chem. Res. 2016, 49, 2390-2402; (b) Jamison, C. R.; Badillo, J. J.;
Lipshultz, J. M.; Comito, R. J.; MacMillan, D. W. C. Nat. Chem.
2017, 9, 1165-1169; (c) Wang, X.; Xia, D.; Qin, W.; Zhou, R.;
Zhou, X.; Zhou, Q.; Liu, W.; Dai, X.; Wang, H.; Wang, S.; Tan,
L.; Zhang, D.; Song, H.; Liu, X.-Y.; Qin, Y. Chem. 2017, 2, 803-
816. (d) Macha, L.; Ha, H.-J. J. Org. Chem. 2019, 84, 94-103; (e)
Tan, P. W.; Seayad, J. Tetrahedron Lett. 2019, 60, 151338; (f)
Yazaki, R.; Ohshima, T. Tetrahedron Lett. 2019, 60, 151225; (g)
Sui, J.-J.; Xiong, D.-C.; Ye, X.-S. Chin. Chem. Lett. 2019, 30,
1533-1537.
For selective recent works of natural products based on a 3-
hydroxy-2, 6-disubstituted piperidine scaffold: the reviews and
book, see: (a) Huang, P.-Q. Synlett 2006, 1133-1149; (b)
Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J. Org.
Chem. 2010, 2831-2844; the papers for see: (c) Shu, C.; Alcudia,
A.; Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123, 12477-
12487; (d) Noël, R.; Vanucci-Bacqué, C.; Fargeau-Bellassoued,
M.-C.; Lhommet, G. Eur. J. Org. Chem. 2007, 476-486; (e)
Arena, G.; Zill, N.; Salvadori, J.; Girard, N.; Mann, A.; Taddei, M.
Org. Lett. 2011, 13, 2294-2297; (f) Annadi, K.; Wee, A. G. H. J.
Org. Chem. 2015, 80, 5236-5251; (g) Huang, W.; Yi, X.; Feng, J.;
Wang, Y.; He, X. Phytochemistry 2017, 143, 81-86; (h) Chen, W.;
Ma, L.; Paul, A.; Seidel, D. Nat. Chem. 2018, 10, 165-169; (i) Ou,
W.; Lu, G.-S.; An, D.; Han, F.; Huang, P.-Q. Eur. J. Org. Chem.
2020, 2020, 52-56.
For selective biological activities of 3-hydroxy-2,6-substituted
piperidine scaffold: the reviews and book, see: (a) Strunz, G. M.;
Findlay, J. A. in: A. Brossi (Ed.), The Alkaloids, vol. 26,
Academic Press, San Diego, 1986, 89; (b) Butler, M. S. J. Nat.
Prod. 2004, 67, 2141-2153; the papers, see: (c) Taylor, R. D.;
MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845-
5859; (d) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med.
Chem. 2014, 57, 10257-10274; (e) de Castro, A. T.; Castro, A. P.;
Silva, M. S.; de Souza, I. M. M.; Martins-Souza, R. L.; Chagas-
Paula, D. A.; Coelho, L. F. L.; da Silva Bolzani, V.; Pivatto, M.;
Viegas, C.; Marques, M. J. Bioorg. Med. Chem. Lett. 2016, 26,
4197-4204.
For the isolation of hyacinthacine B5, see: (a) Yamashita, T.;
Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.;
Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002, 65, 1875-1881; For
selected syntheses of hyacinthacine B5, see: (b) Savaspun, K.; Au,
C. W. G.; Pyne, S. G. J. Org. Chem. 2014, 79, 4569-4581.
For the isolation of (-)-morusimic acid D, see: Kusano,
10. A review in the synthesis of 2,6-disubstituted hydroxypiperidine
alkaloids: (a) Makabe, H. Stud. Nat. Prod. Chem. 2014, 42, 353-
371; other methods to synthesis 2,6-disubstituted piperidine: (b)
Szcześniak, P.; Stecko, S.; Maziarz, E.; Staszewska-Krajewska,
O.; Furman, B. J. Org. Chem. 2014, 79, 10487-10503.
11. Yoda, H.; Yamazaki, H.; Takabe, K. Tetrahedron: Asymmetry
1996, 7, 373-374.
12. (a) Han, P.; Si, C.-M.; Mao, Z.-Y.; Li, H.-T.; Wei, B.-G.; Du, Z.-T.
Tetrahedron 2016, 72, 862-867; (b) Si, C.-M.; Mao, Z.-Y.; Ren, R.-
G.; Du, Z.-T.; Wei, B.-G. Tetrahedron 2014, 70, 7936-7941.
13. Liu, Y.-W.; Ma, R.-J.; Yan, J.-H.; Zhou, Z.; Wei, B.-G. Org.
Biomol. Chem. 2018, 16, 771-779.
3.
14. (a) Bhanu Prasad, A. S.; Stevenson, T. M.; Citineni, J. R.; Nyzam,
V.; Knochel, P. Tetrahedron 1997, 53, 7237-7254; (b) Picotin, G.;
Miginiac, P. J. Org. Chem. 1987, 52, 4796-4798; (c) Erdik, E.
Tetrahedron 1987, 43, 2203-2212.
15. (a) Sakai, N.; Asano, J.; Kawada, Y.; Konakahara, T. Eur. J. Org.
Chem. 2009, 2009, 917-922; (b) Wang, X.-M.; Liu, Y.-W.; Ma,
R.-J.; Si, C.-M.; Wei, B.-G. J. Org. Chem. 2019, 84, 11261-11267.
16. Tsujiyama, H.; Ono, N.; Yoshino, T.; Okamoto, S.; Sato, F.
Tetrahedron Lett. 1990, 31, 4481-4484; (b) Hu, Y.; Yu, J.; Yang,
S.; Wang, J.-X.; Yin, Y. Synth. Commun. 1998, 28, 2793-2800; (c)
Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549-
2551; (d) Zhou, W.; Yan, W.; Wang, J.-X.; Wang, K. Synlett,
2008, 2008, 137-141; (e) Fan, X.; Walsh, P. J. Acc. Chem. Res.
2017, 50, 2389-2400.
17. Fu, Y.; Liu, Y.; Chen, Y.; Hügel, H. M.; Wang, M.; Huang, D.;
Hu, Y. Org. Biomol. Chem. 2012, 10, 7669-7672.
18. Wang, J.-X.; Fu, Y.; Hu, Y. Angew. Chem., Int. Ed. 2002, 41,
2757-2760.
19. Huang, W.; Ye, J.-L.; Zheng, W.; Dong, H.-Q.; Wei, B.-G. J. Org.
Chem. 2013, 78, 11229-11237.
20. Si, C.-M.; Huang, W.; Du, Z.-T.; Wei, B.-G.; Lin, G.-Q. Org. Lett.
2014, 16, 4328-4331.
4.
5.
6.
21. Thomas, E. W.; Rynbrandt, R. H.; Zimmermann, D. C.; Bell, L.
T.; Muchmore, C. R.; Yankee, E. W. J. Org. Chem., 1989, 54,
4535-4543.
22. CCDC 1990470 contains the supplementary crystallographic data
for this paper.
G.; Orihara,
S.; Tsukamoto,
D.; Shibano,
M.; Coskun,
M.; Guvenc, A.; Erdurak, C. S. Chem. Pharm. Bull. 2002, 50, 185-
192; For selected syntheses of morusimic acid D, see: (b) Yu, D.-
S.; Xu, W.-X.; Liu, L.-X.; Huang, P.-Q. Synlett 2008, 1189-1192;
(c) Xiao, K.-J.; Wang, Y.; Huang, Y.-H.; Wang, X.-G.; Huang, P.-
Q. J. Org. Chem. 2013, 78, 8305-8311;
Supplementary Material
Supplementary material that may be helpful in the review process
should be prepared and provided as a separate electronicfile. That
file can then be transformed into PDF format and submitted
along with the manuscript and graphic files to the appropriate
7.
For the isolation of (−)-sedacryptine, see: (a) Hootelé, C.; Colau,
B.; Halin, F.; Declercq, J. P.; Germain, G.; Van Meerssche, M.
Tetrahedron Lett. 1980, 21, 5061-5062; (b) Colau, B.; Hootelé, C.
Can. J. Chem. 1983, 61, 470-472; For selected syntheses of
sedacryptine, see: (c) Natsume, M.; Ogawa, M. Heterocycles
1983, 20, 601-605; (d) Akiyama, E.; Hirama, M. Synlett 1996,
editorial
office.
☒ The authors declare that they have no known
competing financial interests or personal
Declaration of interests

5
relationships that could have appeared to influence
the work reported in this paper.

An efficient approach to access chiral
3-tert-butyl-dimethylsiloxy 2,6-
disubstituted 6-benzyl piperidines
Nucleophilic addition of N,O-acetals
with organozinc reagents
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:


TiCl4 was found to be the most effective
lewis acid for this transformation
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Highlights
Stereoselective Approach to Access 3-tert-
Butyl-Dimethylsiloxy-2,6-Substituted
Leave this area blank for abstract info.
Piperidines Through Nucleophilic Addition
of N,O-acetals with Organozinc Reagents
Zhao-Dan Chen,a Zhuo Chen,a Qiao-E Wang,b Chang-Mei Sia,* and Bang-Guo Weia
OTBS
OTBS
R
TiCl4
+
FGCH2ZnX
THF,-78oC
HO
N
R
N
Boc
FG Boc
FG = Substituted Aryl, alkyl
X = Br, I
27 examples