Stereoselective synthesis of benzannulated spiroketals: Influence of the aromatic ring on reactivity and conformation

Article abstract of DOI:10.1021/ol901437f

Image Presented A systematic stereocontrolled synthesis of benzannulated spiroketals has been developed, using kinetic spirocyclization reactions of glycal epoxides, leading to a new AcOH-induced cyclization and valuable insights into the reactivity and c

Full text of DOI:10.1021/ol901437f

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3670-3673
Stereoselective Synthesis of
Benzannulated Spiroketals: Influence of
the Aromatic Ring on Reactivity and
Conformation
Guodong Liu,† Jacqueline M. Wurst,‡ and Derek S. Tan*,†,‡
Molecular Pharmacology and Chemistry Program, Tri-Institutional
Training Program in Chemical Biology, and Tri-Institutional Research Program,
Memorial Sloan-Kettering Cancer Center, 1275 York AVenue, Box 422,
New York, New York 10065
tand@mskcc.org
Received June 24, 2009
ABSTRACT
A systematic stereocontrolled synthesis of benzannulated spiroketals has been developed, using kinetic spirocyclization reactions of glycal epoxides,
leading to a new AcOH-induced cyclization and valuable insights into the reactivity and conformations of these systems. One stereochemical series
accommodates axial positioning of the aromatic ring while another adopts an alternative 1C4 chair conformation to avoid it. Equatorial aromatic rings
also participate in nonobvious steric interactions that impact thermodynamic stability. A discovery library of 68 benzannulated spiroketals with
systematic variations in stereochemistry, ring size, and positioning of the aromatic substituent has been synthesized for broad biological evaluation.
Benzannulated spiroketals are found in a variety of natural
products with diverse, compelling biological activities. Key
examples include the rubromycin family of telomerase inhibi-
tors, the related DNA helicase inhibitor heliquinomycin, the
papulacandin family of fungal cell wall glucan synthase
inhibitors, the griseusin class of antibacterial agents, the
antimitotic paecilospirone, and the novel matrix metallopro-
teinase inhibitor berkelic acid.1 As the benzannulated spiroketal
motif has been directly implicated in the biological activity of
several of these compounds, this class is an attractive target
for the diversity-oriented synthesis of natural product-based
libraries for use in discovery screening.2 In this vein, the
aromatic ring can be expected to influence the reactivity, three-
dimensional conformation, and physicochemical properties of
these molecules relative to aliphatic spiroketals. To evaluate
the impact of the aromatic ring on the chemistry and biology
of benzannulated spiroketals, we have carried out a systematic
study of their stereocontrolled synthesis using kinetic spirocy-
clization reactions. This work has revealed unexpected reactivity
patterns and conformational preferences and paves the way to
comprehensive biological evaluation of this class.
(1) Rubromycins/heliquinomycin: (a) Brasholz, M.; Sörgel, S.; Azap, C.;
Reißig, H.-U. Eur. J. Org. Chem. 2007, 3801–3814. Papulacandins: (b)
Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. J. Antibiot. 1980, 33, 967–
978. (c) Varona, R.; Perez, P.; Duran, A. FEMS Microbiol. Lett. 1983, 20,
243–247. Griseusins: (d) Tsuji, N.; Kobayashi, M.; Wakisaka, Y.; Kawa-
mura, Y.; Mayama, M.; Matsumoto, K. J. Antibiot. 1976, 29, 7–9.
Paecilospirone: (e) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro,
S. Chem. Lett. 2000, 308–309. Berkelic acid: (f) Stierle, A. A.; Stierle,
D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357–5360.
† Molecular Pharmacology & Chemistry Program.
‡ Tri-Institutional Training Program in Chemical Biology.
(2) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74–84.
10.1021/ol901437f CCC: $40.75
Published on Web 07/27/2009
 2009 American Chemical Society

namic preferences in kinetic chromone epoxide spirocycliza-
tions, albeit with limited stereoselectivity.6 Recently, Pettus
has also advanced elegant cycloaddition-based approaches
to the stereoselective synthesis of rubromycin family mem-
bers.7 We have previously developed a stereocontrolled
approach to aliphatic spiroketals using two complementary
kinetic spirocyclization reactions of glycal epoxides that
proceed with either inversion or retention of configuration
at the anomeric carbon, independently of thermodynamic
considerations.8 We envisioned that these reactions might
also be useful for the synthesis of benzannulated spiroketals.
Our overall synthetic strategy is outlined in Figure 1.9 The
threo- and erythro-glycal stannanes 18a,10 were functionalized
at C1, either by direct Stille cross-couplings of aryl and
benzyl bromides,11 or via conversion to the corresponding
glycal iodides followed by B-alkyl Suzuki-Miyaura cross-
couplings with styrenes and allylbenzenes.12 Stille couplings
of benzyl bromide substrates required copper iodide to
suppress glycal dimer formation, and yields were further
increased by protection from light.13 Deacetylation then
provided all nine precursors to five-, six-, and seven-
membered rings with the aromatic ring systematically
positioned along the side chain (2a-r).
Figure 1. Overall approach to stereocontrolled synthesis of
benzannulated spiroketals using kinetic spirocyclization reac-
tions. * ) site of stereochemical diversity.
Stereoselective anti-epoxidation at low temperature af-
forded glycal epoxide intermediates 3a-r, which were
subjected in situ to various spirocyclization conditions
(Figures 2 and 3). Warming the glycal epoxides (-78 °C f
rt) resulted in spontaneous cyclization with variable selectiv-
ity for retention of configuration (4a-r). Acid-catalyzed
spirocyclization with TsOH (-78 °C f rt) led to 4a-r
exclusively, although these reactions were often compro-
mised by side reactions.14 In contrast, our Ti(Oi-Pr)4-
mediated spirocyclization (-78 °C f 0 °C)8b afforded 4a-r
in high yields and with complete stereocontrol for all
substrates.9 Notably, the conformational constraint provided
by the aromatic ring allowed highly efficient formation of
seven-membered rings (4c,e,f,i,l,n,o,r), which was not the
case for the corresponding aliphatic systems.8b
The synthesis of benzannulated spiroketals has depended
largely upon thermodynamically controlled transketalization
reactions of glycoside or ketoalcohol precursors.3,4 Several
kinetically controlled approaches have also been developed
but still generally do not provide selective access to con-
trathermodynamic products. Fully stereocontrolled access to
either diastereomer at the anomeric carbon is preferable both
for total synthesis applications and to leverage stereochemical
diversity in spiroketal libraries.5 Early work by Wallace
suggested the feasibility of overcoming inherent thermody-
(3) For examples from natural product total synthesis, see the following.
Rubromycins: (a) Reviewed in ref 1a. (b) Akai, S.; Kakiguchi, K.;
Nakamura, Y.; Kuriwaki, I.; Dohi, T.; Harada, S.; Kubo, O.; Morita, N.;
Kita, Y. Angew. Chem., Int. Ed. 2007, 46, 7458–7461. Heliquinomycinone:
(c) Siu, T.; Qin, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4713–4716. Papulacandins: (d) Denmark, S. E.; Regens, C. S.; Kobayashi,
T. J. Am. Chem. Soc. 2007, 129, 2774–2776. Griseusins: (e) Kometani, T.;
Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983, 48, 2311–2314. Berkelic acid:
(f) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem., Int. Ed. 2009, 48, 1283–
1286. (g) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard,
Conversely, our MeOH-induced spirocyclization (-63 °C)8a
provided stereocontrol for the inherently thermodynamically
and kinetically disfavored inversion products in several cases
(6) Cremins, P. J.; Wallace, T. W. J. Chem. Soc., Chem. Commun. 1986,
1602–1603.
(7) (a) Wu, K.-L.; Wilkinson, S.; Reich, N. O.; Pettus, T. R. R. Org.
Lett. 2007, 9, 5537–5540. (b) Marsini, M. A.; Huang, Y.; Lindsey, C. C.;
Wu, K.-L.; Pettus, T. R. R. Org. Lett. 2008, 10, 1477–1480.
(8) (a) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc.
2005, 127, 13796–13797. (b) Moilanen, S. B.; Potuzak, J. S.; Tan, D. S.
J. Am. Chem. Soc. 2006, 128, 1792–1793.
R.; Fürstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450–8454
.
(4) For other approaches to benzannulated spiroketals, see the following.
Alkoxyselenation: (a) Elsley, D. A.; MacLeod, D.; Miller, J. A.; Quayle,
P.; Davies, G. M. Tetrahedron Lett. 1992, 33, 409–412. Alkyne cyclotri-
merization: (b) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am.
Chem. Soc. 1995, 117, 6605–6606. Glycoside rearrangement: (c) Kumazawa,
T.; Asahi, N.; Matsuba, S.; Sato, S.; Furuhata, K.; Onodera, J.-I. Carbohydr.
Res. 1998, 308, 213–216. Michael addition: (d) Carretero, J. C.; De Diego,
J. E.; Hamdouchi, C. Tetrahedron 1999, 55, 15159–15166. (e) Choi, P. J.;
Rathwell, D. C. K.; Brimble, M. A. Tetrahedron Lett. 2009, 50, 3245–
3248. Ring-closing metathesis: (f) Van Hooft, P. A. V.; Van Swieten, P. F.;
Van der Marel, G. A.; Van Boeckel, C. A. A.; Van Boom, J. H. Synlett
2001, 269–271. o-Quinone methide hetero-Diels-Alder: (g) Zhou, G.;
Zheng, D.; Da, S.; Xie, Z.; Li, Y. Tetrahedron Lett. 2006, 47, 3349–3352.
(h) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett. 2006, 8, 2365–
2367. Alkyne hydroalkoxylation: (i) Messerle, B. A.; Vuong, K. Q.
Organometallics 2007, 26, 3031–3040. (j) Zhang, Y.; Xue, J.; Xin, Z.; Xie,
Z.; Li, Y. Synlett 2008, 940–944. Radical cyclization: (k) Liu, Y.-C.; Sperry,
(9) See Supporting Information for full details.
(10) Moilanen, S. B.; Tan, D. S. Org. Biomol. Chem. 2005, 3, 798–
803
.
(11) (a) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 2572–
2574. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992–
4998. (c) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J. Org. Chem. 1994, 59, 5905–5911.
(12) Potuzak, J. S.; Tan, D. S. Tetrahedron Lett. 2004, 45, 1797–1801.
(13) Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Kapdi, A. R.;
Taylor, R. J. K.; Whitwood, A. C. Tetrahedron 2005, 61, 9736–9751.
(14) In particular, for erythro series substrates (3j-r), loss of the C3-
OTIPS group with concomitant oxidation of the C2-OH group was observed.
This may occur via enolization (C2-deprotonation) of the intermediate cyclic
oxocarbenium species, followed by Ferrier type elimination of the C3-
substituent, tautomerization of the resulting C2 enol to a ketone, and ring
reclosure at C1.
J.; Rathwell, D. C. K.; Brimble, M. A. Synlett 2009, 793–797
.
(5) For a recent review of non-anomeric spiroketal synthesis, see: Aho,
J. E.; Pihko, P. M.; Rissa, T. K. Chem. ReV. 2005, 105, 4406–4440.
Org. Lett., Vol. 11, No. 16, 2009
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Figure 2
.
Diastereomeric ratios of benzannulated spiroketals
Figure 3. Diastereomeric ratios of benzannulated spiroketals
formed from D-erythro-glycal epoxides 3j-r. Isolated yields of
4 (Ti[Oi-Pr]4) and 5 (MeOH or AcOH) shown in parenthe-
ses. Notes: a Spontaneous spirocyclization (-78 °C f rt).
b Remainder methyl glycoside 6. c Inseparable mixture of 4 and
5 (separable after desilylation).
formed from D-threo-glycal epoxides 3a-i. Isolated yields of 4
(Ti[Oi-Pr]4) and 5 (MeOH or AcOH) shown in parenthe-
ses. Notes: a Spontaneous spirocyclization (-78 °C f rt).
b Remainder methyl glycoside 6. c Inseparable mixture of 4 and
5 (separable after desilylation).
To achieve more efficient access to the inversion products,
we explored alternative Brønsted acids and were gratified
to find that AcOH (10 equiv, -63 °C f -44 °C) provided
increased yields for both the problematic seven-membered
ring and phenolic systems (5e-i,n-r).15,16 Treatment of the
isolated products with AcOH confirmed that this reaction
remains under kinetic control. The increased yields could
be attributed largely to the absence of competing intermo-
lecular glycosylation. AcOH may also provide increased
epoxide reactivity for less-reactive phenol nucleophiles,
(5a,b,d-f,j,m,n). The aromatic ring constraint provided
reduced competing intermolecular formation of methyl glyco-
side side products (6) compared to the corresponding aliphatic
systems8a and again allowed several seven-membered rings to
be formed (5e,f,n). Two additional reactivity trends were noted
in these MeOH-induced spirocyclizations. C1-Aryl substrates
yielded decreased selectivity for inversion of configuration (5b
vs 5d; 5c vs 5e,f; 5k vs 5m; 5l vs 5n), which we attributed to
stabilization of a cyclic oxocarbenium intermediate leading to
the retention products. Phenolic substrates also afforded de-
creased stereoselectivity (5 g-i,p-r) and increased methyl
glycoside formation, presumably due to the lower nucleophi-
licity of the phenol side chains.
(15) p-NO2PhOH provided comparable 4i:5i selectivity, whereas weaker
(PhOH) and stronger acids (HCO2H, p-NO2PhCO2H, TFA) led to decreased
amounts of the desired inversion product 5i. Larger amounts of AcOH
(100-1000 equiv) led to increased formation of the retention products 4,
presumably due to increased competing oxocarbenium formation.
3672
Org. Lett., Vol. 11, No. 16, 2009

interactions involving C1-O, the thermodynamic preference
for 4j can be rationalized by an additional, nonobvious steric
interaction between the ortho-proton of the aromatic ring
and C2-OH in 5j. Strikingly, after desilylation (R′ ) H),
the thermodynamic preference is reversed, with 8 stabilized
by an intramolecular hydrogen bond. These results highlight
the profound impact of the aromatic ring upon both the
conformational and thermodynamic preferences of benzan-
nulated spiroketals and the increased conformational diversity
in this class compared to that of the corresponding aliphatic
spiroketals.
Desilylation of all products provided a discovery library
of 68 out of the 72 possible benzannulated spiroketals (both
enantiomeric series), having all combinations of five-, six-,
and seven-membered rings and aromatic ring positions, with
nearly comprehensive stereochemical diversity. These com-
pounds have been deposited in the NIH Molecular Libraries
Small Molecule Repository19 and are undergoing biological
evaluation to assess the effectiveness of this structural class
against a wide range of targets. Analysis of those results will
be reported in due course.
In conclusion, we have carried out a systematic analysis
of kinetic and thermodynamic spirocyclization reactions to
form benzannulated spiroketals, leading to the development
of a new AcOH-induced kinetic spirocyclization. Notably,
the systematic nature of this study, mandated by our interest
in diversity-oriented synthesis applications, has revealed
significant reactivity changes and conformational effects
imparted by the aromatic ring, which may be useful in the
design and synthesis of a broad range of molecules with
related structural motifs. Finally, this work sets the stage for
further biological investigation of this compelling class of
molecules.
Figure 4. Alternative conformations of benzannulated spiroketals
4a, 5a, 4j, 5j and desilylated congeners 7, 8. NOESY interactions
are indicated in blue; steric interactions are indicated in red. A
nonobvious steric interaction in 5j between the ortho-proton of the
aromatic ring and C2-OH is highlighted in bold red.
consistent with our previous proposal that the MeOH-induced
spirocyclization proceeds via activation of the epoxide by
MeOH hydrogen bonding.8a,17
To evaluate the impact of the aromatic ring upon the
conformation of benzannulated spiroketals, we carried out
detailed structural analyses of several products (Figure 4).9
Analyses of NOESY spectra and J values18 indicated that
both threo series products 4a and 5a adopt standard 4C1 chair
conformations. Notably, this is despite the axial orientation
of the aromatic ring in 5a, due to unfavorable 1,3,5-triaxial
Acknowledgment. We thank Prof. Ian Fairlamb (Univer-
sity of York) for helpful discussions and Dr. George
Sukenick, Dr. Hui Liu, Hui Fang, and Dr. Silvia Rusli for
expert mass spectral analyses. DST is an Alfred P. Sloan
Research Fellow. Financial support from the NIH (P41
GM076267), NYSTAR Watson Investigator Program, Wil-
liam H. Goodwin and Alice Goodwin and the Com-
monwealth Foundation for Cancer Research, and MSKCC
Experimental Therapeutics Center is gratefully acknow-
ledged.
1
interactions in the alternative C4 conformation (5a′). In
contrast, the corresponding erythro series product 4j adopts
the alternative 1C4 conformation, due to the additional steric
impact of the C3-OTIPS group (4j′). While both 4j and 5j
have anomeric stabilization and comparable 1,3-diaxial
Supporting Information Available: Detailed experimen-
tal procedures and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) For related reactions of glycals and glycosides, see: (a) Pothier,
N.; Goldstein, S.; Deslongchamps, P. HelV. Chim. Acta 1992, 75, 604–
620. (b) Castagnolo, D.; Breuer, I.; Pihko, P. M. J. Org. Chem. 2007, 72,
10081–10087.
(17) Related effects have been proposed in epoxide-opening cascades
leading to ladder polyethers: (a) Vilotijevic, I.; Jamison, T. F. Science 2007,
317, 1189–1192. (b) Byers, J. A.; Jamison, T. F. J. Am. Chem. Soc. 2009,
131, 6383–6385.
OL901437F
(19) PubChem Substance Identifiers (SID): “DST_SK2_*”; http://
pubchem.ncbi.nlm.nih.gov/.
(18) Karplus, M. J. Chem. Phys. 1959, 30, 11–15.
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