Diversity-oriented synthesis of 2,4,6-trisubstituted piperidines via Type II Anion Relay Chemistry

Article abstract of DOI:10.1021/ol2010598

An effective, general protocol for the Diversity-Oriented Synthesis (DOS) of 2,4,6-trisubstituted piperidine congeners has been designed and validated. The successful strategy entails a modular approach to all possible stereoisomers of the selected piperidine scaffold, exploiting Type II Anion Relay Chemistry (ARC), followed in turn by intramolecular S_N2 cyclization, chemoselective removal of the dithiane moieties and carbonyl reductions.

Full text of DOI:10.1021/ol2010598

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3328–3331
Diversity-Oriented Synthesis of
2,4,6-Trisubstituted Piperidines via
Type II Anion Relay Chemistry
Amos B. Smith III,* Heeoon Han, and Won-Suk Kim
Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States
smithab@sas.upenn.edu
Received April 21, 2011
ABSTRACT
An effective, general protocol for the Diversity-Oriented Synthesis (DOS) of 2,4,6-trisubstituted piperidine congeners has been designed and validated. The
successful strategy entails a modular approach to all possible stereoisomers of the selected piperidine scaffold, exploiting Type II Anion Relay Chemistry
(ARC), followed in turn by intramolecular SN2 cyclization, chemoselective removal of the dithiane moieties and carbonyl reductions.
Nature’s biosynthesis of architecturally complex molecules
often comprises iterative reaction sequences utilizing complex
molecular machines, such as polyketide synthases and the
Scheme 1. Type I and Type II ARC
ribosome, to unite activated, stereochemically pure building
blocks.1 In an attempt to mimic Nature’s iterative biosynth-
esis of complex molecules, we developed and validated Type I
and Type II Anion Relay Chemistry (ARC) (Scheme 1),2 two
closely related synthetic methods comprising multicompo-
nent union protocols. In addition to providing access to spe-
cific architectures, the ARC tactic also holds considerable
potential for Diversity-Oriented Synthesis (DOS).3 Many
DOS programs, however, suffer from the inability to provide
access to all possible stereoisomers of a selected scaffold. We
Type I Anion Relay chemistry (Scheme 1), initially as
have therefore set as a goal for our DOS programs the con-
Having achieved the development and application of
a tricomponent coupling protocol, which we employed to
struction of all stereoisomers of the selected scaffold. Such a
great advantage in a number of complex molecule syn-
thetic programs,4 we subsequently devised the Type II
goal, if widely adopted by the DOS community, will require,
and in many cases demand, the development of new, inno-
ARC tactic, also an iterative, multicomponent union strat-
vative synthetic methods to access the targeted congeners in
egy, which like the Type I ARC process exploits bifunctional
an efficient fashion, an outcome not dissimilar to one of the
core goals of natural product total synthesis.
(4) (a) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.;
McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama,
(1) Shen, B. Curr. Opin. Chem. Biol. 2003, 7, 285.
K.; Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191. (b) Smith, A. B.,
III; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.;
Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001,
40, 196. (c) Smith, A. B., III; Pitram, S. M.; Fuertes, M. J. Org. Lett.
2003, 5, 2751. (d) Smith, A. B., III; Kim, D.-S. Org. Lett. 2004, 6, 1493.
(e) Smith, A. B., III; Kim, D.-S. Org. Lett. 2005, 7, 3247. (f) Smith, A. B.,
III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547.
(2) (a) Smith, A. B., III; Wuest, W. M. Chem. Commun. 2008, 5883.
(b) Smith, A. B., III; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int. Ed.
2008, 47, 7082. (c) Smith, A. B., III; Kim, W.-S.; Tong, R. Org. Lett. 2010,
12, 588. (d) Smith, A. B., III; Tong, R. Org. Lett. 2010, 12, 1260. (e) Smith,
A. B., III; Kim, W.-S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6787.
(3) Schreiber, S. L. Science 2000, 287, 1964.
r
10.1021/ol2010598
Published on Web 06/06/2011
2011 American Chemical Society

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.
Tetrahedron 2003, 59, 2953. (c) Buffat, M. G. P. Tetrahedron 2004, 60,
1701. (d) Cossy, J. Chem. Rec. 2005, 5, 70.
Org. Lett., Vol. 13, No. 13, 2011
3329

Table 2. Intramolecular SN2 Cyclization
Table 3. Screening Conditions for Reduction of Ketones
A. Reduction of (R,S)-14
product ratioa
(S,R,S)-14:(R,R,S)-14
entry
condition
yieldb (%)
1
2
3
4
5
A
B
C
D
E
2:1
3:1
4:1
1:20
5:1
93
97
92
93
88
substrate
(*,*)a
product
(*,*)a
ring
substitution
yieldb
(%)
entry
R1/R2
1
2
3
4
5
6
(S,S)-4
(R,R)-4
(S,R)-4
(R,S)-4
(S,S)-5
(R,S)-10
Me/Bn
Me/Bn
Me/Bn
Me/Bn
Me/nPr
Ph/Bn
(R,S)-11
(S,R)-11
(R,R)-11
(S,S)-11
(R,S)-12
(S,S)-13
cis
cis
87
85
55
58
89
81
B. Reduction of (S,R,S)-16 (Entries 1ꢀ4) and (R,R,S)-16 (Entry 5)
trans
trans
cis
product ratioa
(S,R,S,R)-17:(S,R,S,S)-17
entry
condition
yieldb (%)
cis
1
2
3
4
5
A
B
F
G
G
5:1
20:1
2:1
1:1.5
1:1.3c
93
97
95
89
91
a Absolute stereochemistry of the chiral center. b Yield over two
steps.
Corey (R)-CBS reagent12 (Table 3A; entry 4) and Al(OiPr)3
(Table 3A; entry 5) proved optimal. The resultant diastereo-
meric alcohols (S,R,S)-15 and (R,R,S)-15, readily separable
by column chromatograpy, were then subjected to removal of
the remaining dithiane moiety under the Stork conditions13 to
provide hydroxy ketones (S,R,S)-16 and (R,R,S)-16.
a Ratio of diastereomers was determined by 1H NMR. b Combined
yield of diastereomers. c The ratio of (R,R,S,R)-17: (R,R,S,S)-17, con-
ditions: (A) NaBH4, MeOH, 0 °C; (B) L-Selectride, THF, ꢀ78ꢀ0 °C; (C)
(R)-CBS reagent, BH3 THF, THF, 0 °C; (D) (S)-CBS reagent,
3
i
BH3 THF, THF, 0 °C; (E) Al(OiPr)3, PrOH, reflux; (F) BH3 THF,
3
3
THF, ꢀ78ꢀ0 °C; (G) SmI2, H2O, THF, ꢀ78ꢀ0 °C.
energy, by ca. 16 kcal/mol than the 2,6-diequatorial chair-
like conformer D, due to pseudo A1,3-strain14 between
the substituents at the 2- and 6-positions and the tosyl
group, thus leading to hydride attack from the more
accessible R-face of C (Figure 1). In accordance
with this reasoning, an increase in the bulkiness of
the hydride reagent (L-Selectride) led to excellent
selectivity (ca. 20:1) to provide (S,R,S,R)-17 (Table 3B;
entry 4).
Scheme 3. Functional and Stereochemical Diversification of
2,6-Cis-Disubstituted Piperidine (R,S)-11
Ketones 16 were also subjected to various reduction
conditions. Regardless of steric encumberance of the hydride
reducing agent, (S,R,S)-16 led to β-hydroxy isomer (S,R,
S,R)-17 as the major diastereomer (Table 3B; entries 1ꢀ3).
Molecular mechanics calculations (MMFF94) revealed
that the 2,6-diaxial chairlike conformer C possesses a lower
Figure 1. Proposed conformational analysis for the reduction of
(S,R,S)-16 and (R,R,S)-16.
At this juncture, we presumed that the diastereoselectivity
could be reversed under dissolving metal conditions15 to
obtain diastereomer (S,R,S,S)-17. Treatment of (S,R,S)-16
with SmI2 (4.0 equiv) and H2O (6.0 equiv) in THF furnished
(12) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861.
(13) (a) Fleming, F. F.; Funk, L.; Altundas, R.; Tu, Y. J. Org. Chem.
2001, 66, 6502. (b) Stork, G.; Zhao, K. Tetrahedron 1989, 30, 287.
(14) (a) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984, 106, 1010. (b)
Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988, 110,
7445. (c) Heintzelman, G. R.; Weinreb, S. M.; Parvez, M. J. Org. Chem.
1996, 61, 4594. (d) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68,
8867. (e) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747. (f) Cariou,
C. A. M.; Snaith, J. S. Org. Biomol. Chem. 2006, 4, 51–53.
(15) (a) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc.
1987, 109, 6187. (b) Keck, G. E.; Wager, C. A.; Seel, T.; Wager, T. T. J.
Org. Chem. 1999, 64, 2172. (d) Keck, G. E.; Wager, C. A. Org. Lett. 2000,
2, 2307.
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Org. Lett., Vol. 13, No. 13, 2011

the desired R-hydroxy isomer as the major product, albeit
with poor selectivity (Table 3B; entry 4). The lack of dias-
tereoselectivity in the dissolving metal reductions presumably
arises from competition of the two possible chelated inter-
mediates (Figure 1; E and F). The structures and the relative
configurations of (S,R,S,R)-17 and (R,R,S,R)-17 were con-
firmed by X-ray crystallographic analysis. Under the same
reduction conditions, (R,R,S,R)-17 and (R,R,S,S)-17 were
obtained from (R,R,S)-16 (Table 3B; entry 5).
Reduction of the remaining side chain ketone employing
BH3 THF furnished mixtures (ca. 1:1) of diastereomeric
3
diols [(S,R,R,R)-17/(R,R,R,R)-17 and (S,R,R,S)-17/(R,R,R,
S)-17], which were separated by SFC, thereby providing
access to all possible stereoisomers obtainable from (R,R)-11.
Identical synthetic steps were followed with (S,R)-11 and (S,
S)-11 to prepare the enantiomeric library ent-A.
On the basis of the successful elaboration of the 2,6-cis-
piperidine congeners from (R,S)-11, the 2,6-trans congener
(R,R)-11 was subjected to the same procedure.16 Following
selective removal of the less-hindered dithiane moiety of
(R,R)-11, all attempts to arrive at a single diastereomeric
alcohol employing a wide variety of reducing agents proved
unsuccessful. Equally disappointing, separations of the two
diastereomeric alcohols (S,R,R)-15/(R,R,R)-15 as well as the
hydroxy ketones (S,R,S)-16/(R,R,S)-16 could not be achieved.
Scheme 4. Functional and Stereochemical Diversification of
2,6-Trans-Disubstituted Piperidine (R,R)-11
Figure 2. Complete piperidne library.
In summary, an effective DOS strategy has been de-
signed and validated to access the complete matrix of
stereoisomers of the targeted 2,4,6-trisubsituted piperidine
scaffold, exploiting our modular Type II ARC protocol,
followed in turn by intramolecular SN2 cyclization
(Figure 2). Regioselective dithiane removal and reduction
conditions were then examined and optimized. In the
context of complex molecule synthesis, the reported non-
selective reductions would be viewed as a shortcoming.
However for Diversity Oriented Synthesis (DOS) directed
at the construction of a complete matrix of congeners,
nonselective reactions in conjunction with effective
chromatographic separation has considerable advantage.
Nonetheless, the lack of observed selectivity serves to
reveal a continuing need to develop new, selective reactivity
to enhance the synthetic arsenal.
To solve this issue, we explored the regioselective reduc-
tion of dione (R,R)-18 (Scheme 4), which was generated by
removal of the both dithiane moieties in (R,R)-11 employing
the CoreyꢀErickson protocol.17 Pleasingly, the internal
ketone of (R,R)-18 was reduced regioselectively upon treat-
ment with 1.0 equiv of the bulky reducing agent [LiAlH-
(OCEt3)3] to provide a mixture of (S,R,R)-19 and (S,R,S)-
19, readily separable by flash column chromatography.
Acknowledgment. Financial support was provided by
the NIH through Grant No. GM-29028. We thank Drs. G.
Furst, P. J. Carroll and R. Kohli at the University of
Pennsylvania for assistance in obtaining the NMR, X-ray
diffraction, and high-resolution mass spectra, respectively.
(16) See the Supporting Information for details.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
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