linchpins. The Type II ARC protocol holds, we believe, even
more potential for the design and synthesis of complex
molecular structures. The development of the Type II ARC
process, however, required the design, synthesis, and valida-
tion of a series of effective bifunctional linchpins.2
To illustrate the utility of the Type II ARC tactic in the
area of DOS, we report here the synthesis of all possible
stereoisomers of a family of 2,4,6-trisubstituted piperidines
(Scheme 2: VI), utilizing this union tactic, followed in turn
by an intramolecular SN2 cyclization and further elaboration.
aziridines III [(þ)-3a, (þ)-3b, and (ꢀ)-3a, (ꢀ)-3c)],
the latter readily accessible from enantiomerically
pure amino acids.8
With these components in hand, reaction conditions for
the Type II ARC protocol were optimized based on our
earlier studies.4 Conditions employing the modified
Schlosser base9 proved highly effective without the use of
cosolvents such as HMPA or DMPU to enhance the
nucleophilicity of dithiane anion.10 The initial multicom-
ponent adducts were subjected to removal of the TBS
group with TBAF (Table 1).
Scheme 2. General Synthetic Route To Access Diverse Piper-
idine Analogues via Type II ARC
Table 1. Multicomponent Reaction (Type II ARC)
entry
dithiane
linchpin
aziridine
config (*,*)a
yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1d
1d
(þ)-2
(þ)-2
(ꢀ)-2
(ꢀ)-2
(þ)-2
(þ)-2
(þ)-2
(ꢀ)-2
(þ)-2
(þ)-2
(þ)-2
(ꢀ)-2
(þ)-3a
(ꢀ)-3a
(þ)-3a
(ꢀ)-3a
(þ)-3b
(ꢀ)-3c
(þ)-3a
(þ)-3a
(þ)-3b
(þ)-3a
(þ)-3a
(þ)-3a
(S,S)-4
(S,R)-4
(R,S)-4
(R,R)-4
(S,S)-5
(S,S)-6
(S,S)-7
(R,S)-7
(S,S)-8
(R,S)-9
(R,S)-10
(S,S)-10
74
69
69
74
61
41
65
59
55
56
52
55
From the medicinal perspective, the piperidine scaf-
fold has attracted considerable interest in the synthetic5
and biological6 communities. However, notwithstanding
the availability of numerous methods to access individual
members of the 2,4,6-trisubstituted piperidine family in a
stereocontrolled fashion, there are few general methods
that can provide access to all stereoisomers.7
10
11
12
a Absolute configuration of the corresponding stereocenters. b Iso-
lated yield for ARC.
Mesylation of the hydroxy group then furnished the
substrates for the subsequent intramolecular SN2 cycliza-
tions. Examination of a variety of conditions, including
solvents, bases, and leaving groups to suppress potential
elimination reactions,11 revealed that treatment of the mesy-
lates in dilute THF solution with NaH effectively provided
both 2,6-cis- and 2,6-trans-piperidines, again in preparatively
useful yields (Table 2).
Next, the utility of the two dithiane groups was explored
(Scheme 3). Treatment of (R,S)-11 with Hg(ClO4)2 and
2,6-lutidine in wet THF led to regioselective removal of the
more accessible side chain dithiane moiety to furnish
ketone (R,S)-14, which in turn was subjected to various
reduction conditions (Table 3A; entries 1ꢀ5). Use of the
The Type II ARC tactic, as illustrated in Scheme 2,
not only would provide a convergent route to 2,4,6-
trisubstituted piperidines, but also enables chemical
and stereochemical diversification at the C(2) and C(6)
stereogenic centers, depending on the components
IꢀIII employed. In addition, the two dithiane groups
provide synthetic handles for further chemoselective
diversification. To initiate this program, the three
requisite components for the Type II ARC reaction
were prepared: initiating nucleophiles I (dithianes
1aꢀd), bifunctional linchpins II [(þ)-2, (ꢀ)-2], and
(5) Recent examples, see: (a) Krishna, P. R.; Sreeshailam, A. Tetra-
hedron Lett. 2007, 48, 6924. (b) Chandraskhar, S.; Babu, G. S. K.;
Reddy, Ch. R. Tetrahedron: Asymmetry 2009, 20, 2216. (c) Gnamm, C.;
€
Krauter, C. M.; Brodner, K.; Helmchen, G. Chem.;Eur. J. 2009, 15,
2050. (d) Kumar, R. S. C.; Reddy, G. V.; Shankaraiah, G.; Babu, K. S.;
Rao, J. M. Tetrahedron Lett. 2010, 51, 1114. (e) Cui, L.; Li, C.; Zhang, L.
Angew. Chem., Int. Ed. 2010, 49, 9178.
(8) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455.
(9) Schlosser, M.; Strunk, S. Tetrahedron Lett. 1984, 25, 741.
(10) Reich, H. J.; Sanders, A. W.; Fielder, A. T.; Bevan, M. J. J. Am.
Chem. Soc. 2002, 124, 13386.
(11) Elimination reaction: see the Supporting Information for
details.
(6) (a) Daly, J. J. Nat. Prod. 1998, 61, 162. (b) Kuznetsov, V. V.
Khim.-Farm. Zh. 1991, 25, 61. Chem. Abstr. 1991, 115, 158846. J.
Enzym. Inhib. Med. Chem. 2005, 20, 551. (c) Li, H.; Asberom, T.; Bara,
T. A.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Mcbriar, M. D.;
Nomeir, A.; Pissarnitski, D. A.; Rajagopalan, M.; Xu, R.; Zhao, Z.;
Song, L.; Zhang, L. Bioorg. Med. Chem. Lett. 2007, 17, 6290.
(7) Recent reviews:(a) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(b) Weintraub, J. S.; Sabol, P. M.; Kane, J. M.; Borcherding, D. R.
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