Stereocontrolled synthesis of spiroketals via Ti(Oi-Pr)4- mediated kinetic spirocyclization of glycal epoxides with retention of configuration

Article abstract of DOI:10.1021/ja057908f

A Ti(Oi-Pr)₄-mediated kinetic spiroketalization reaction has been developed for the stereocontrolled target- and diversity-oriented synthesis of spiroketals. In contrast to most existing methods for spiroketal synthesis, this reaction does not

Full text of DOI:10.1021/ja057908f

Published on Web 01/20/2006
Stereocontrolled Synthesis of Spiroketals via Ti(Oi-Pr)4-Mediated Kinetic
Spirocyclization of Glycal Epoxides with Retention of Configuration
Sirkka B. Moilanen,† Justin S. Potuzak,‡ and Derek S. Tan*,†,‡,§
Tri-Institutional Training Program in Chemical Biology, Pharmacology Program-Weill Graduate School of
Medical Sciences of Cornell UniVersity, and Tri-Institutional Research Program and Molecular Pharmacology &
Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York AVenue, Box 422, New York, New York
10021
Received November 21, 2005; E-mail: tand@mskcc.org
The stereocontrolled synthesis of spiroketals continues to present
a stimulating challenge in target- and diversity-oriented synthesis.1
With a view toward exploiting stereochemical diversity in spiroketal
libraries, we recently developed a synthetic approach to spiroketals
in which the stereochemical configuration at the anomeric carbon
is dictated by an initial stereoselective epoxidation of a C1-
alkylglycal 1 (Figure 1).2 The intermediate epoxide 2 can then
undergo a methanol-induced kinetic epoxide-opening spirocycliza-
tion (spirocycloisomerization) to 4 with inVersion of configuration
at the anomeric carbon. To access systematically stereochemically
diversified spiroketals, we also required a method to effect the
complementary spirocyclization to 3, in an unusual epoxide opening
with retention of configuration. We report herein our solution to
this problem, involving a new Ti(Oi-Pr)4-mediated kinetic spiro-
cyclization reaction.
We noted at the outset that access to “retention” spiroketals in
the erythro-glycal series (3a-g) is particularly challenging. The
corresponding “inversion” spiroketals (4) are thermodynamically
favored in most cases,2 owing to double anomeric stabilization.3
Further, the erythro-glycal epoxides 2a-g should be kinetically
predisposed to spirocyclization with inversion of configuration via
favorable trans-diaxial epoxide opening. However, we recognized
that the problem at hand bears a notable similarity to a key challenge
in carbohydrate synthesis, namely, the synthesis of â-mannosides.4
One effective solution has been to direct the desired â-glycosylation
reaction syn to the axial C2-hydroxyl group of mannose using a
covalent tether to the nucleophile.5 By analogy, we reasoned that,
in our spiroketal synthesis, an appropriate multidentate Lewis acid
might serve as a noncovalent tether between the epoxide oxygen
and the side chain hydroxyl of 2 (Figure 2). The Lewis acid could
then activate the epoxide electrophile (5) to form an oxonium
intermediate (6), then deliver the side chain nucleophile to the
desired â-face of the anomeric carbon (7). In this manner, the
required epoxide opening with retention of configuration might be
achieved in a kinetically controlled reaction, overriding the inherent
thermodynamic and kinetic preferences of the system.
To explore this hypothesis, we carried out initial experiments
with erythro-glycal 1a.2,6 Epoxidation with DMDO provided the
reactive glycal epoxide 2a, which began to cyclize spontaneously
even at reduced temperatures (NMR, -65 °C). Since isolation of
2a was, thus, precluded, we added various multidentate Lewis acids
directly to the nascent epoxide at -78 °C and analyzed the resulting
product ratios after warming to room temperature (Table 1).7
Despite our initial concerns that the acetone cosolvent used in the
epoxidation reaction might interfere with substrate coordination by
Figure 1. Strategy for stereocontrolled synthesis of spiroketals via epoxide-
opening spirocyclizations with retention (3) or inversion (4) of configuration
at the anomeric carbon (erythro ) 3,5-anti; threo ) 3,5-syn).
Figure 2. Proposed tethered mechanism for kinetic spirocyclization of 2.
Table 1. Epoxide-Opening Spirocyclization Reactions of 2a with
Multidentate Lewis Acidsa,b
entry
Lewis acid
3a (%)
4a (%)
entry
Lewis acid
3a (%)
4a (%)
1
2
3
none
Yb(OTf)3
ZnCl2
25
43
43
75
57
57
4
5
6
MgCl2
SnCl4
Ti(Oi-Pr)4
60
67
>98
40
33c
<2
a With 2 equiv of Lewis acid, 1:1 CH2Cl2/acetone, -78 °C for 1 h, then
warm to room temperature and quench with aqueous NaHCO3. Ratios of
3a:4a determined by NMR. b Treatment of 2a with TsOH yields the C3-
desilylated congener of 4a (<2:98 dr, 82%).2 c A 1:3 mixture of 4a and
its C3-desilylated congener.
these Lewis acids, we were encouraged to find that all of the
reagents tested provided an improved ratio of 3a:4a compared to
the spontaneous cyclization (entry 1). In particular, Ti(Oi-Pr)4
provided the retention spiroketal 3a as a single stereoisomer (entry
6), albeit in low purity (e55%). Further investigations revealed
that warming the reaction to 0 °C immediately after addition of
Ti(Oi-Pr)4 dramatically improved the yield of 3a by avoiding the
formation of various glycoside and overoxidation products (2 equiv
of Ti(Oi-Pr)4, -78 °C; then 0 °C, e1 h; >98:2 dr, 81% isolated
† Tri-Institutional Training Program in Chemical Biology.
‡ Weill Graduate School of Medical Sciences of Cornell University.
§ Tri-Institutional Research Program and Molecular Pharmacology & Chemistry
Program.
9
1792
J. AM. CHEM. SOC. 2006, 128, 1792-1793
10.1021/ja057908f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
spiroketalizations.9,10 In particular, our analysis revealed that
alternate nonchelated mechanisms are inconsistent with the observed
stereochemical preference for 3. Conversely, a metal-chelated early
transition state model (cf. 6) appears energetically favorable and is
consistent with formation of the retention spiroketals.
We recognized that this strategy might also provide a means to
achieve the related intermolecular glycosylations of glycal epoxides
to generate â-mannosides.11 Indeed, early investigations of this idea
have produced promising results, with â-selectivity as high as 10:1
achieved in a model system.9
In conclusion, we have developed a Ti(Oi-Pr)4-mediated ki-
netic spirocyclization for the stereocontrolled synthesis of spiro-
ketals. To our knowledge, this is the first example of a kinetic
spiroketalization that is controlled by metal chelation. This
Ti(Oi-Pr)4-mediated cyclization (C1-retention) and our previously
described MeOH-induced cyclization (C1-inversion) provide com-
prehensive access to systematically stereochemically diversified
spiroketals. Application of this strategy to the synthesis of stereo-
chemically diverse spiroketal libraries is ongoing.
Acknowledgment. We thank Dr. George Sukenick, Anna
Dudkina, Sylvi Rusli, and Hui Fang for mass spectral analyses.
D.S.T. is a NYSTAR Watson Investigator. Financial support from
the NIGMS (P41 GM076267), Mr. William H. Goodwin, and Mrs.
Alice Goodwin and the Commonwealth Foundation for Cancer
Research, the William Randolph Hearst Fund in Experimental
Therapeutics, and the MSKCC Experimental Therapeutics Center
is gratefully acknowledged.
Supporting Information Available: Additional data on threo series
spirocyclizations, transition state analysis, 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 3. Ti(Oi-Pr)4-mediated spirocyclizations. Isolated yields of retention
spiroketals 3 shown in parentheses. Indicated favored conformations
determined by NMR. Inversion spiroketals 4 were synthesized by MeOH-
induced spirocyclization for comparison.2 a: Single stereoisomer 3g
recovered; remainder isopropyl glycoside and hydrolyzed 2g.
yield). Importantly, exposure of the inversion spiroketal 4a to the
reaction conditions did not result in equilibration to 3a, establishing
that this Ti(Oi-Pr)4-mediated spirocyclization is, indeed, kinetically
controlled.8 We observed reduced stereoselectivity using sub-
stoichiometric amounts of Ti(Oi-Pr)4, suggesting that the metal may
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side chain lengths (Figure 3 and Supporting Information). We were
gratified to find that, in the erythro series, the reaction provided
contrathermodynamic five- and six-membered ring retention spiro-
ketals with complete stereocontrol and good yields (3a-f), including
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spiroketal 3g was also formed stereoselectively, but in low yield.
The reaction was similarly effective in the threo series (3h-n)9
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