Stereocontrolled synthesis of spiroketals via a remarkable methanol-induced kinetic spirocyclization reaction

Article abstract of DOI:10.1021/ja055033z

A methanol-induced kinetic spiroketalization reaction has been developed for the stereocontrolled target- and diversity-oriented synthesis of spiroketals. In contrast to existing methods for spiroketal synthesis, this reaction does not depend on thermodyn

Full text of DOI:10.1021/ja055033z

Published on Web 09/20/2005
Stereocontrolled Synthesis of Spiroketals via a Remarkable Methanol-Induced
Kinetic Spirocyclization Reaction
Justin S. Potuzak,† Sirkka B. Moilanen,‡ and Derek S. Tan*,†,‡,§
Pharmacology Program, Weill Graduate School of Medical Sciences of Cornell UniVersity,
Tri-Institutional Training Program in Chemical Biology, and Tri-Institutional Research Program and
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center,
1275 York AVenue, Box 422, New York, New York 10021
Received July 26, 2005; E-mail: tand@mskcc.org
The spiroketal motif is found in myriad natural products, and
this privileged structure can bind to multiple classes of biological
targets.1,2 Thus, spiroketals have attracted considerable attention
in both target- and diversity-oriented synthesis.1,3 In the latter
context, spiroketals present the opportunity to exploit extensive
stereochemical diversity,4 wherein these rigid scaffolds display
substituents along well-defined three-dimensional vectors.5 How-
ever, exploration of this concept has been limited by the constraints
of the existing approaches to spiroketals. In particular, there is still
no general method to synthesize systematically stereodiversified
spiroketals. We describe herein our early endeavors to develop such
a method and, toward that end, the discovery of a novel kinetic
spiroketalization reaction.
Classically, spiroketals have been synthesized using acid-
catalyzed spiroketalizations in which the stereochemical outcome
at the anomeric carbon is governed by thermodynamic product
stability.1,6 Several kinetic spirocyclization reactions have been
developed to access contrathermodynamic spiroketals, particularly
those stabilized by only one anomeric effect. However, these are
often dependent upon spirocyclization of an oxygen nucleophile
along an axial trajectory.7 As a result, these thermodynamic and
kinetic reactions are not completely stereocomplementary.
We envisioned a conceptually different approach (Figure 1), in
Figure 1. Epoxide-based approach to the stereocontrolled synthesis of
spiroketals. Potential sites of stereochemical diversity are highlighted (/).
which the stereochemical configuration at the anomeric carbon is
controlled by an initial stereoselective epoxidation reaction (2 f
3). Systematic stereodiversification is then accomplished using
kinetic spirocyclization reactions that proceed with either inversion
(4) or retention (5) of configuration at the anomeric carbon,
independent of thermodynamic considerations or cyclization trajec-
tory. We recognized that achieving epoxide opening with faithful
inversion of configuration is by no means trivial in this system.
Net trans-diequatorial opening would be required in some cases,
and oxonium-stabilized SN1-type reaction manifolds might also have
undesirable stereochemical consequences. Thus, our first attentions
have focused on addressing this challenge.
We synthesized threo-glycal 1 enantioselectively according to
literature precedents.8 The diastereomeric erythro-glycal (not shown)
was synthesized using our recently reported route.9 We next attached
C1 side chains using our B-alkyl Suzuki-Miyaura cross-coupling
methodology to form 2a-n.10 We then carried out preliminary
studies on threo-glycal 2a, which underwent efficient anti-epoxi-
dation with DMDO11 (100%, >98:2 dr; NMR, -60 °C). We were
encouraged to find that warming glycal epoxide 3a to room
temperature caused spontaneous spirocyclization to a 70:30 mixture
of spiroketals 4a and 5a.12 Equilibration of this mixture with TsOH
yielded the thermodynamically favored “retention” spiroketal 5a
(99%, >98:2 dr), benefitting from double anomeric stabilization.6
In the course of our efforts to achieve spirocyclization to the
contrathermodynamic “inversion” spiroketal 4a with greater ster-
eocontrol, we were pleasantly surprised to discover that addition
of a large excess of MeOH to the nascent epoxide 3a at -78 °C
resulted in stereospecific spirocyclization to 4a (Table 1, entry 1).
Meanwhile, the expected methyl glycosides 6a were formed as
minor products. In keeping with entropic considerations, the
intermolecular glycosylation was less competitive at higher tem-
peratures, although the stereoselectivity of the intramolecular
spirocyclization was also decreased (entries 3 and 4). Reactions
using other alcohols or lower alcohol concentrations proved to be
less selective (entries 5-12). Our best results were achieved with
MeOH at -63 °C, where 4a was formed with complete stereo-
control, along with only a small amount of readily separable 6a
(entry 2). Notably, this reaction allows equatorial installation of
the oxygen nucleophile, in contrast to most existing kinetic
spiroketalization reactions.7
We carried out several experiments to probe the mechanism of
this intriguing reaction. Exposure of the retention spiroketal 5a to
the same conditions (DMDO, -78 °C; then MeOH, -63 °C) did
not produce any inversion spiroketal 4a, confirming that the MeOH-
induced spirocyclization is kinetically controlled. Likewise, the
isolated methyl glycosides 6a were unchanged under these condi-
tions, thus eliminating them as possible intermediates in mechanisms
† Weill Graduate School of Medical Sciences of Cornell University.
‡ Tri-Institutional Training Program in Chemical Biology.
§ Tri-Institutional Research Program and Molecular Pharmacology and Chemistry
Program.
9
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J. AM. CHEM. SOC. 2005, 127, 13796-13797
10.1021/ja055033z CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Alcohol-Induced Spirocyclizations of Glycal Epoxide 3aa
five-membered rings (4d-f). Notably, the resulting spiroketals have
diverse three-dimensional structures. In the corresponding erythro-
glycal series, TsOH-catalyzed equilibration generally led to inver-
sion spiroketals (4h,i,k-m) having two anomeric stabilizations,
albeit with concomitant desilylation of the C3-hydroxyl group
(Figure 2 and Supporting Information). In contrast, MeOH-induced
spirocyclization provided 4h-m without compromising the C3-
OTIPS group.8 Attempted spirocyclizations of 3g,n to form seven-
membered rings produced only the methyl glycosides 6g,n.
In conclusion, we have developed a novel MeOH-induced kinetic
spiroketalization that provides stereocontrolled access to spiroketals
based solely upon stereoinduction provided by a preceding epoxi-
dation reaction. This epoxide-opening spirocyclization proceeds with
inversion of configuration and appears to result from hydrogen-
bonding catalysis. Efforts to develop stereocomplementary spiro-
cyclizations that proceed with retention of configuration, but do
not rely upon thermodynamic product stability, and to apply this
route to the synthesis of systematically stereodiversified spiroketal
libraries are progressing and will be reported in due course.
temp
C)
time
(h)
4a
(%)
5a
(%)
6ac
(%)
entry
ROH
volb
(
°
1
2
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
CH3OD
EtOH
i-PrOH
MeOH
5
5
5
5
5
5
5
0.5
0.5
0.5
0.5
0.5
-78
-63
-44
0
-63
-63
-63
-63
-63
-63
-63
-63
1
1
1
1
1
2
2
1
2
2
2
2
80
92
92
71
87
77
72
50
59
69
70
70
0
0
3
21
0
0
4
8
6
8
20
8
5
8
13
23
24
42
35
23
16
0
EtOH
10
11
12
i-PrOH
CF3CH2OH
(CF3)2CHOH
14
30
a Product ratios determined by NMR. b Volume of alcohol added to 3a
relative to the initial volume of 1:1 acetone/CH2Cl2 used in the preceding
epoxidation reaction. c Formed as a ≈1:1 mixture of R- and â-anomers.
Acknowledgment. We thank Profs. Chulbom Lee and Don
Coltart for helpful discussions, and Dr. George Sukenick, Anna
Dudkina, Sylvi Rusli, and Hui Fang for expert mass spectral
analyses. Generous financial support has been provided by Mr.
William H. Goodwin and Mrs. Alice Goodwin and the Com-
monwealth Foundation for Cancer Research, the William Randolph
Hearst Fund in Experimental Therapeutics, and the Experimental
Therapeutics Center of MSKCC.
Supporting Information Available: Complete ref 2, additional data
on erythro series spirocyclizations, and experimental procedures and
analytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Figure 2. Spirocyclization product ratios. Isolated yields of major products
are shown in parentheses. Indicated favored conformations were determined
by NMR or predicted based on conformational analysis. a Inseparable
b
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