An iodoetherification-dehydroiodination strategy for the synthesis of complex spiroketals from dihydroxyalkene precursors

Article abstract of DOI:10.1039/b719247a

Dihydroxyalkenes or their monoprotected alcohol derivatives are transformed to 5,5- and 5,6-spiroketals through a sequence involving an initial iodocyclization, followed by a silver triflate mediated spiroketalization step on the derived hydroxy-iodoether. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b719247a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
An iodoetherification–dehydroiodination strategy for the synthesis of complex
spiroketals from dihydroxyalkene precursors†
K. A. Tony, Xiaohua Li, Darrin Dabideen, Jialiang Li and David R. Mootoo*
Received 13th December 2007, Accepted 13th February 2008
First published as an Advance Article on the web 22nd February 2008
DOI: 10.1039/b719247a
Dihydroxyalkenes or their monoprotected alcohol deriva-
tives are transformed to 5,5- and 5,6-spiroketals through a
sequence involving an initial iodocyclization, followed by a
silver triflate mediated spiroketalization step on the derived
hydroxy-iodoether.
of complex spiroketals. We have reported a preliminary application
of this strategy to the ABCD bis-spiroketal system of azaspiracid
1.6 Herein, we describe a more detailed investigation into the scope
of this method.
Results and discussion
Introduction
Except for 29, the dihydroxyalkene derivatives were prepared via
an olefin cross-metathesis (CM) using an excess of one of the olefin
partners (Table 1).7 The metathesis reactions were performed on
various highly oxygenated alkene partners and afforded yields of
the CM product ranging from 65–85%.8 For yield optimization,
easier purification of the CM product or the requirement for
a partially protected dihydroxyalkene, it was sometimes more
practical to perform the CM with protection of the alcohol groups
in one or both of the reaction partners. The diene precursor 29
was assembled through the Wittig olefination of known aldehyde
119 and phosphonium salt 18.
Spiroketal subunits comprise the structures of several groups
of biologically interesting natural products.1 Their conforma-
tional and geometric characteristics also make them attractive as
scaffolds in diversity-oriented synthesis.2 Accordingly, spiroketal
synthesis has attracted considerable attention. Classically, spiroke-
tals have been synthesized through acid-catalyzed cyclization of
ketodiol precursors.1a,b Several elegant methodologies have been
devised to address structural complexity.3 Methods that employ
straightforward segment coupling reactions and mild conditions
for spiroketalization are particularly appealing. In this vein, we
envisaged an approach in which a dihydroxyalkene or a partially
protected derivative 1 is transformed to a spiroketal 4 (Scheme 1).
Iodoetherification of 1 could lead to iodinated cyclic ethers like
2.4 Dehydroiodination of 2 provides a highly reactive enol ether
3, which would undergo spiroketalization under mildly acidic
conditions. In essence, the alkene moiety in 1 is regioselectively
functionalized to an acetal, and acts as an alkyne synthon. The
strategy may be therefore complementary to the metal-promoted
spiroketalization of dihydroxyalkynes (e.g. 5).5 Importantly, since
precursors like 1 are obtainable via straightforward olefination re-
actions, this methodology allows for a highly convergent synthesis
Spiroketal precursors 19, 21, 23 and 24 were designed to get a
preliminary evaluation of the feasibility with respect to different
ring sizes (Table 2). Based on previous investigations10 on the
relative rates of iodoetherification of hydroxyalkenes, we argued
that dihydroxyalkenes like 19 and 21 or 23 should favor the
5-exo-trig and the 6-exo-trig pathways, respectively, over other
modes of cyclization. Therefore, it should be possible to use
substrates 19, and 21 or 23 in which the eventual alcohols
of the spiroketal are unprotected, as precursors to 5,5- and
5,6-spiroketal frameworks, respectively. Thus, treatment of 19,
21 and 23 with IDCP (iodonium dicollidine perchlorate) in
dichloromethane provided a mixture of cyclization products in
85, 85 and 70% yield respectively. However, the NMR data
for these structures did not allow for distinction between the
possible regioisomeric cyclization products. These structures were
tentatively assigned as 31, 32 and 33 based on the aforementioned
regioselectivity considerations. Exposure of the individual product
mixtures to silver triflate in dichloromethane in the presence of
collidine led to 5,5-spiroketal 43a,b in 70% yield, and the 5,6
frameworks 44a,b and 45a,b in 74 and 55% yield respectively.
The mixture 43a,b was chromatographically inseparable and this
made stereochemical assignment of the spiroketal configuration in
individual components impossible. However, mixtures 44a,b and
45a,b were separable, andtheir stereochemistry was assignedby 2D
COSY and NOESY NMR (see ESI†). It should be noted that while
the gross structures of spiroketals 43a,b, 44a,b and 45a,b support
the structures assigned to 31, 32 and 33 respectively, the possibility
that the corresponding regioisomer resulting from the 5-endo-trig
pathway could also lead to the identical spiroketal products, makes
structures 31, 32 and 33 ambiguous. In the event, the isolation of
Scheme 1 Synthetic strategy.
Department of Chemistry, Hunter College/CUNY, New York, NY, 10021,
USA. E-mail: dmootoo@hunter.cuny.edu; Fax: +1 212-772-5332; Tel: +1
212-772-4356
† Electronic supplementary information (ESI) available: Experimental
procedures, physical data and NMR spectra for selected new compounds.
See DOI: 10.1039/b719247a
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1165–1169 | 1165
©

View Article Online
Table 1 Synthesis of dihydroxyalkene derivatives and 23
Olefination precursora Olefination precursora
Dihydroxyalkene derivatives (yield)
a Except for 29, the dihydroxyalkene derivatives were prepared by CM with 10 mol% Grubbs 2nd generation catalyst in CH2Cl2 using an excess of one of
the olefin partners. For optimal yields, CM’s were in certain cases performed on protected alcohol derivatives and the CM product deprotected to give
the precursor for the iodoetherification step. The homodimer derived from the alkene that was used in excess was obtained as a side product. Compound
29 was prepared through a Wittig olefination.
a single spiroketal framework starting from dihydroxyalkenes 19
and 21 in reasonable yields suggests that for 5,5- and 5,6-spiroketal
systems, selective protection of the alcohols that constitute the
eventual acetal residue may not be necessary.
The extension of the strategy to 6,6-spiroketals was next
examined using the hydroxyalkene 24 as a test substrate. In
this case, the expectation that 5-exo-trig would be favored over
6-exo-trig or 6-endo-trig pathways meant that protection of one
of the two alcohols of the eventual spiroketal would be necessary.
Accordingly, 24 was treated with IDCP under the standard
conditions, and the product 34 was desilylated to provide 35, the
precursor for the spiroketalization step. However, treatment of 35
under the standard conditions led to adjacently linked THF-THP
47, and not the desired spiroketal 46. This result suggested
that the iodoetherification step yielded 34 as expected, but the
subsequent AgOTf-mediated reaction favored THF rather than
1166 | Org. Biomol. Chem., 2008, 6, 1165–1169
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Table 2 Synthesis of iodoethers and spiroketals
Alkene
Iodoether (yield)a
Spiroketal (yield of mixture, epimer ratio)b
19
21
23
24
25
26
28
30
a Iodocyclization reactions were performed by treatment of the dihydroxyalkenes or their mono-protected derivatives with IDCP in anhydrous CH2Cl2.
b Except for 50, spiroketals were obtained by exposure of the hydroxy-iodide precursor to a mixture of AgOTf and collidine in anhydrous CH2Cl2. For
50, the iodo-acetal 40 was treated with AgOTf in wet THF.
spiroketal formation. This result suggests that application
of this strategy to 6,6-spiroketals might in general be problematic,
and consequently we focused on evaluating the synthetic
scope for 5,5- and 5,6-frameworks.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1165–1169 | 1167
©

View Article Online
The results for carbohydrate-derived substrates 25 and 26
illustrate the compatibility in more highly functionalized settings.
The mono-acetates 25 and 26 (as opposed to their deacetylated
diol derivatives) were initially screened because these were the
direct products from the CM reaction. Thus, iodoetherification of
25 and 26, followed by acetate hydrolysis of the resulting acetoxy-
iodoethers, provided the spiroketalization precursors 37 and 39.
Treatment of the latter with AgOTf in the presence of collidine
provided the 5,5- and 5,6-spiroketals 48a,b and 49a,b in 76 and
65% yield respectively. When the deacetylated diol derivatives
of 25 and 26 were subjected to a two-step iodoetherification–
spiroketalization sequence, 48a,b and 49a,b were produced in
similar overall yield and epimer ratio to the material obtained from
the three-step iodoetherification–deacetylation–spiroketalization
sequence on 25 and 26.
In order to determine whether the stereochemistry in the
iodoether impacts on the stereoselectivity of the AgOTf-mediated
spiroketalization reaction, the latter was performed on individual
diastereomers of THP-iodide 33 and THF-iodide 37. In both cases
the ratio of spiroketals produced from the individual iodoether
diastereomers was very similar to that obtained from the corre-
sponding mixture (that is, ca. 2 : 1 for 45a:45b and 1 : 1 for 48a:48b
respectively). These results suggested that the stereochemistry of
the iodoether precursor is not directly transferred to the spiroketal
product.
The conversion of hydroxy-acetal-alkene substrate 27 to the bis-
spiroketal 50 was next investigated. However, iodoetherification
of 27 produced a complex mixture, in part due to unwanted 5-
endo-trig cyclization involving the OH group of the lactol. The
methyl acetal 28 was therefore subjected to the iodocyclization
procedure and the crude product exposed to AgOTf in wet THF
(without added collidine). This sequence afforded a mixture of
bis-spiroketals 50a,b in 52% overall yield from 28.
The transformation of 30 to 51a,b illustrates that the chemos-
elective elaboration of diene substrates may be possible. Thus,
IDCP cyclization on 30 followed by removal of the PMB protecting
group provided the hydroxy-iodo-dihydropyran 42, which led to
the spiroketal mixture 51a,b.
the crude reaction mixture, even though spiroketalization occurs
in the presence of excess collidine, supports the direct formation of
55 from 53. However, the possibility that 54 is formed then rapidly
converted to product under the reaction conditions cannot be
excluded.
Conclusion
In conclusion, the transformation of dihydroxyalkenes or their
partially protected derivatives to highly substituted 5,5- and 5,6-
spiroketal frameworks has been explored. The compatibility of
this strategy with a wide variety of functional groups and the
availability of the dihydroxyalkene precursors through straight-
forward olefination procedures, of which the olefin metathesis
is a prominent example, makes this an attractive methodology
for the convergent assembly of complex targets. More extensive
mechanistic and synthetic investigations are underway and will be
reported in due course.
Acknowledgements
This investigation was supported by grants R01 GM57865 from
the National Institute of General Medical Sciences of the National
Institutes of Health (NIH). A “Research Centers in Minority Insti-
tutions” award RR-03037 from the National Center for Research
Resources of the NIH, which supports the infrastructure and
instrumentation of the Chemistry Department at Hunter College,
and MBRS-RISE award GM60665, are also acknowledged.
Notes and references
1 (a) F. Perron and K. F. Albizati, Chem. Rev., 1989, 89, 1617–1661; (b) J.
Pietruszka, Angew. Chem., Int. Ed, 1998, 37, 2629–2636; (c) W. Francke
and W. Kitching, Curr. Org. Chem., 2001, 5, 233–251; (d) M. A. Brimble
and D. P. Furkert, Curr. Org. Chem., 2003, 7, 1461–1484; (e) K. T. Mead
and B. N. Brewer, Curr. Org. Chem., 2003, 7, 227–225; J. E. Aho, P. M.
Pihko and T. K. Rissa, Chem. Rev., 2005, 105, 4406–4440.
2 (a) R. Haag, A. G. Leach, S. V. Ley, M. Nettekoven and J. Schnaubelt,
Synth. Commun., 2001, 31, 2965–2977; (b) B. A. Kulkarni, G. P. Roth,
E. Lobkovsky and J. A. Porco, Jr., J. Comb. Chem., 2002, 4, 56–72;
(c) O. Barun, S. Sommer and H. Waldeman, Angew. Chem., Int. Ed.,
2004, 43, 3195–3199; (d) G. Zinzalla, L.-G. Milroy and S. V. Ley, Org.
Biomol. Chem., 2006, 4, 1977–2002.
3 Selected recent synthesis of complex spiroketals: (a) J. Hao and C. J.
Forsyth, Tetrahedron Lett., 2002, 43, 1–2; (b) M. T. Crimmins, J. D.
Katz, D. G. Washburn, S. P. Allwein and L. F. McAtee, J. Am.
Chem. Soc., 2002, 124, 5661–5663; (c) E. B. Holson and W. R. Roush,
Org. Lett., 2002, 4, 3719–3723; (d) K. I. Tsang, M. A. Brimble and
J. B. Bremner, Org. Lett., 2003, 5, 4425–4427; (e) L. Wang and P. E.
Floreancig, Org. Lett., 2004, 6, 569–572; (f) J. Liu and R. P. Hsung, Org.
Lett., 2005, 7, 2273–2276; (g) A. V. Statsuk, D. Liu and S. Kozmin,
J. Am. Chem. Soc., 2004, 126, 9546–9547; (h) L. R. Takaoka, A. J.
Buskmelter, T. E. LaCruz and S. D. Rychnovsky, J. Am. Chem. Soc.,
2005, 127, 528–529; (i) J. S. Potuzaz, S. B. Moilanen and D. S. Tan,
J. Am. Chem. Soc., 2005, 127, 13796–13797; (j) K. C. Nicolaou, M. O.
Frederick, G. Petrovic, K. P. Cole and E. Z. Loizidou, Angew. Chem.,
Int. Ed., 2006, 45, 2609–2615; (k) X.-T. Zhou and R. G. Carter, Angew.
Chem., Int. Ed., 2006, 45, 1787–1790; (l) Y. Li, F. Zhou and C. J. Forsyth,
Angew. Chem. Int. Ed., 2007, 46, 279–282; (m) D. A. Evans, T. B. Dunn,
L. Kvrnø, A. Beauchemin, B. Raymer, E. J. Olhava, J. A. Mulder, M.
Juhl, K. Kagechika and D. A. Favor, Angew. Chem., Int. Ed., 2007, 46,
4698–4703.
The observation that the stereoselectivity of the spiroketaliza-
tion step is not affected by the stereochemistry of the iodoether
precursor is consistent with a mechanism involving the cyclic
oxocarbenium ion 55. However, the pathway leading to 55 is more
conjectural (Scheme 2). Intermediate 55 could arise from proto-
nation of an initially formed exocyclic enol ether 54, or via iodide
activation in 53 and cation formation, followed by hydride transfer.
That enol ether 54 (or its endocyclic isomer) was not observed in
4 G. Cardilo and M. Orena, Tetrahedron, 1990, 46, 3321–3408.
5 For a recent example of Au(I) alkyne spiroketalization, see: B. Liu and
J. K. De Brabander, Org. Lett., 2006, 8, 4907–4910.
Scheme 2 Mechanistic analysis.
6 X. Li, J. Li and D. R. Mootoo, Org. Lett., 2007, 4303–4306.
1168 | Org. Biomol. Chem., 2008, 6, 1165–1169
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
7 A. K. Chatterjee, T.-L. Choi, D. P. Sanders and R. M. Grubbs, J. Am.
Chem. Soc., 2003, 125, 11360–11370; S. J. Connon and S. Blechert,
Angew. Chem., Int. Ed., 2003, 42, 1900–1923.
8 (a) Alkenes 7, 8, 14, 17 and 18, were obtained through known
procedures on (S)-malic acid: R. Zemribo and K. T. Mead, Tetrahedron
Lett., 1998, 39, 3895–3898; J. A. Marshall and J. J. Sabatini, Org.
Lett., 2005, 7, 4819–4822; (b) Alkenes 15 and 16 were prepared
from the homoallylic alcohol derived from the Keck allylation of
5-benzyloxypentanal: G. E. Keck, K. H. Tarbet and L. S. Geraci,
J. Am. Chem. Soc., 1993, 115, 8467–8468; (c) Alkene 11: S. J.
Danishefsky, M. P. DeNinno, G. B. Phillips, R. E. Zelle and P. A.
Lartey, Tetrahedron, 1986, 42, 2809–2819; (d) Alkene 12 was prepared
via modification of the synthesis of a related sugar derivative: M.
Terauchi, H. Abe, A. Matsuda and S. Shuto, Org. Lett., 2004, 6, 3751–
3754.
9 C. R. Schmid, J. D. Bryant, M. Dowlatzedan, J. L. Philllips, D. E.
Prather, R. D. Schantz, N. L. Sear and C. S. Vianco, J. Org. Chem.,
1991, 56, 4056–4058.
10 S. B. Bedford, K. E. Bell, F. Bennet, C. J. Haynes, D. W. Knight and
D. E. Shaw, J. Chem. Soc., Perkin Trans. 1, 1999, 2142–2153.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1165–1169 | 1169
©