Anion relay chemistry: An effective tactic for diversity oriented synthesis

Article abstract of DOI:10.1021/ja057059w

An effective one-flask multicomponent linchpin coupling protocol employing the concept of anion relay chemistry (ARC) was developed. This concept calls for addition of an anion (5) to an epoxide (6), bearing on a distal carbon a trialkyl silyl group and a

Full text of DOI:10.1021/ja057059w

Published on Web 12/13/2005
Anion Relay Chemistry: An Effective Tactic for Diversity Oriented Synthesis
Amos B. Smith, III* and Ming Xian
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received October 17, 2005; E-mail: smithab@sas.upenn.edu
For nearly 40 years, dithiane anions, introduced by Corey and
Seebach, have served as effective acyl anion equivalents (umpolung)
for construction of carbon-carbon bonds.1,2 Particularly attractive
is the efficient elaboration of aldol linkages with precise stereo-
control employing epoxides as the electrophile; this reaction
sequence serves as a viable alternative to the aldol reaction without
advent of the retro-aldol process. In 1997, based on the precedent
by Tietze,3 we reported that lithiation of silyl dithiane 1 with t-BuLi
in diethyl ether (Scheme 1), followed by alkylation with an epoxide,
Brook rearrangement. To avoid formation of complex reaction
mixtures, completion of the first alkylation must be achieved prior
to triggering the Brook rearrangement.
We began this study with designed anion relay linchpin (+)-10,
readily prepared on multigram scale by treatment of the lithium
anion of dithiane 1 with (-)-epichlorohydrin in diethyl ether
(Scheme 2).7 The results are summarized in Table 1.
Scheme 2
Scheme 1
In the tri-component linchpin coupling process (Scheme 1),5 Et2O
proved to be the solvent of choice for initial alkylation to suppress
premature silyl migration. However the dithiane anion derived from
11 (Table 1) was observed to form aggregates in Et2O at low tem-
Table 1. Solvent and Temperature Effects on the Coupling of
Dithiane 11 with Epoxide (+)-10
results in an intermediate oxyanion (2), which upon treatment with
HMPA triggers a solvent-controlled 1,4-Brook rearrangement,4
thereby generating a new reactive dithiane anion (3), available to
react with a second, different epoxide to furnish a differentially
protected monosilyl 1,5-diol 4.5 From the strategic sense, location
of the silyl protecting group can be orchestrated simply by the order
of the epoxide additions. The success of this linchpin process, now
a central theme in several completed and ongoing synthetic ventures
in our laboratory,6 led us to recognize the considerable utility, and
thereby the need, for additional synthetic tactics which would permit
similar rapid access to high levels of molecular diversity. In this
communication, we disclose a new multicomponent linchpin
protocol involving the concept of anion relay chemistry (ARC),
which holds great promise in the area of diversity oriented synthesis.
The ARC concept, outlined in general form in Figure 1, calls
for addition of an anion (5) to an epoxide (6), bearing on a distal
carbon a trialkyl silyl group and an anion stabilizing group (ASG),
Reaction
Entry
Solvent
temperature/time
Yield 12 (%)
Yield 13 (%)
1
2
3
4
Et2O
Et2O
THF
-78 to -20 °C
r.t./3 h
-30 °C/20 min
-30 °C/20 min
0
71
47
87
0
<5
24
THF/Et2O (1:3)
<5
perature (-78 to -20 °C), thereby precluding effective reaction
with (+)-10 (entry 1). Pleasingly, upon warming to room temper-
ature, the aggregates appear to disappear and the anion reacts with
(+)-10 to furnish the desired product (+)-12 in 71% yield, along
with a small amount of the silyl migrated product (+)-13 (<5%
yield, entry 2). This reaction, however, requires ca. 3 h to achieve
good yields and thus was deemed unsuitable for the prospective
one-flask multicomponent coupling protocol (vide infra). On the
other hand, when THF was employed, the reaction was complete
in 20 min at -30 °C, but a significant amount of Brook rearrange-
ment product (+)-13 was observed (entry 3). This result was not
unexpected since it is known that THF can trigger Brook rear-
rangements at low temperature.4,5 However, when a solvent system
composed of THF/Et2O (1:3, v/v) was employed, clean alkylation
was observed in 20 min at -30 °C to provide (+)-12 in 87% yield,
accompanied only by a small amount of (+)-13 (entry 4). These
optimized conditions proved equally successful with 2-substituted
dithianes 14, 15, and 16 (Scheme 3). In general, best results were
obtained with n-BuLi; however, t-BuLi can be employed in many
cases.
Figure 1. Anion Relay Chemistry (ARC).
to furnish upon epoxide ring opening oxyanion 7. Addition of
HMPA or other polar solvents to trigger a solvent-controlled 1,4-
Brook rearrangement then leads to a new distal anion (8), which
in turn is available to react with a variety of second electrophiles.
Critical to the success of this tactic is the precise timing of the
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J. AM. CHEM. SOC. 2006, 128, 66-67
10.1021/ja057059w CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
halides serve as excellent electrophiles in this reaction sequence.
Particularly interesting is the example illustrated in entry 6, which
leads to (+)-25, possessing a new electrophilic epoxide site for
further diversity.
The anion relay protocol was next applied to a series of 2-sub-
stituted dithiane substrates (Table 3). Again, the desired products
were obtained in good yield. Importantly, the dithiane moieties can
be removed without loss of the silyl moiety,9 thereby providing a
diverse series of 1,3,5-oxygenated systems.
With alcohol (+)-12 in hand, we next explored the Brook rear-
rangement (Scheme 4). Deprotonation of the hydroxyl of (+)-12
with t- or n-BuLi in THF followed by addition of HMPA furnished
silylether(+)-13ingoodyield.Furthermore,whenallylbromidewasadd-
ed with the HMPA, coupling product (-)-20 was obtained in 86%
yield.
Table 3. Three-Component Couplings of Different Dithianes
Scheme 4
Encouraged by these results, we turned to the development of a
one-flask three-component coupling protocol, employing anion relay
linchpin (+)-10, 2-methyl dithiane 11, and a series of second
electrophiles (Table 2). Optimal conditions entail deprotonation of
11 in THF at room temperature for 5 min,8 followed by cannula
addition of the resulting anion to a solution of the linchpin (+)-10
in Et2O, such that the resultant solvent system becomes 1:3 (v/v)
in THF and Et2O, respectively. Completion of the first alkylation
is achieved in ca. 20 min at -30 °C (TLC).
In summary, an effective one-flask multicomponent linchpin
coupling protocol employing the concept of anion relay chemistry
(ARC) has been developed (Figure 1). Given the potential to extend
the anion relay tactic both to non-dithiane nucleophiles and linchpin
electrophiles, this method holds considerable promise in diversity
oriented synthesis to access complex molecular architecture in a
concise fashion.
Table 2. Three-Component Linchpin Couplings of Dithiane 11
Acknowledgment. Financial support was provided by the
National Institutes of Health through Grant GM-29028 and by a
Postdoctoral Fellowship from the U.S. Department of Defense (PC-
030136) to M.X.
Supporting Information Available: Spectroscopic and analytical
data and selected experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075.
(b) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(2) Reviews: (a) Seebach, D. Synthesis 1969, 1, 17. (b) Page, P. C. B.; Van
Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643. (c) Yus, M.;
Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147.
(3) (a) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994,
511. Also see: (b) Fischer, M. P.; Kirschning, A.; Michel, T.; Schaumann,
E. Angew. Chem., Int. Ed. Engl. 1994, 33, 217.
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(6) (a) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001. (b) Smith,
A. B., III; Pitram, S. M.; Fuertes, M. J. Org. Lett. 2003, 5, 2751. (c)
Smith, A. B., III; Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.;
Koyanagi, J.; Takeuchi, M. Org. Lett. 2002, 4, 783. (d) Smith, A. B., III;
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(7) If the reaction of the lithium anion of dithiane 1 with epichlorohydrin
was stopped at -25 °C, the corresponding 1-chloro-2-hydroxy derivative
was obtained exclusively (>95% yield).
Addition of the second electrophile, premixed with HMPA (10%
v/v in Et2O), completes the reaction sequence. In general, the yields of
anion relay products (20-25) are good. Terminal epoxides and alkyl
(8) Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491.
(9) See Supporting Information.
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