β-Iodoallenolates as springboards for annulation reactions

Article abstract of DOI:10.1021/ol901721y

β-Iodoallenolates II, generated from alkynones I with tetra-n-butylammonlum iodide and a Lewis acid, underwent selective single or double annulation, depending on the Lewis acid promoter. Treatment with TiCl₄ gave cyclohexenyl alcohols III, whe

Full text of DOI:10.1021/ol901721y

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4374-4377
ꢀ-Iodoallenolates as Springboards for
Annulation Reactions
Jennifer Ciesielski, Daniel P. Canterbury, and Alison J. Frontier*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
frontier@chem.rochester.edu
Received July 27, 2009
ABSTRACT
ꢀ-Iodoallenolates II, generated from alkynones I with tetra-n-butylammonium iodide and a Lewis acid, underwent selective single or double
annulation, depending on the Lewis acid promoter. Treatment with TiCl4 gave cyclohexenyl alcohols III, whereas BF3·OEt2 gave oxadecalins
IV. The scope and limitations of the two annulation reactions are described.
Platelet activating factor (1-O-alkyl-2(R)-(acetylglyceryl)-
3-phosphorylcholine) is a small molecule messenger
implicated in a number of inflammatory, respiratory, and
cardiovascular diseases.1 Phomactin A and phomactin D
are potent antagonists of PAF: phomactin A inhibits
platelet aggregation induced by PAF (IC50 1.0 × 10-5 M)
and binding of PAF to its receptors (IC50 2.3 × 10-6 M),
and phomactin D was found to be roughly twice as potent
in these two assays.2 These findings inspired us to pursue
a synthetic strategy targeting the carbon skeleton of both
phomactin A and D via common ꢀ-iodoallenoate inter-
mediate A (Scheme 1).
ꢀ-Iodoallenolate intermediates generated from alkynyl
esters and ketones participate in intermolecular addition
reactions with aldehydes,3 imines,4 and epoxides5 with high
selectivity for the (Z)-iodoalkenone. Asymmetric addition of
ꢀ-iodoallenolates to aldehydes has been reported using CBS
catalysts.6 Furthermore, tandem iodide-promoted conjugate
addition/aldol cyclization has recently been used to generate
highly functionalized cyclic systems.7 Two different cycliza-
(3) (a) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27,
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P. W. Tetrahedron Lett. 2003, 44, 949–952.
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2771–2774.
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Kuwanhao, H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463–
5464. (b) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda,
K.; Hata, T. J. Org. Chem. 1994, 59, 564–569.
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Chem., Int. Ed. 2009, 48, 4398–4401.
10.1021/ol901721y CCC: $40.75
Published on Web 09/08/2009
 2009 American Chemical Society

only partial consumption of alkynone 1a (entry 7). The
cyclization was successful with both TBAI and (n-Bu)4NBr
(TBAB), which gave the bromooxadecalin (entry 8).10 The
optimal reaction temperature for the conversion of alkynone
1a to cyclohexenyl alcohol 2a and oxadecalin 3a was found to
be -78 to 0 °C and -40 to 0 °C, respectively.
Scheme 1. ꢀ-Iodoallenolate-Mediated Cyclizations: Application
to the Synthesis of Phomactins A and D
To explore the scope and limitations of the reaction, experi-
ments aimed at selective mono- and bicyclization of a series of
alkynones were performed (Tables 2 and 3). As shown in Table
2, the gem-dimethyl functionality (entry 2) was not required
for monocyclization, but it did accelerate the cyclization. In
addition, other ring sizes, such as 5- and 7-membered rings
(entries 3 and 4), could be formed in moderate yield, and finally,
tertiary alcohols (entry 6) could be formed in good yield,
although a stronger Lewis acid was required.
tion processes are reported here: the first is the intramolecular
aldol reaction of ꢀ-iodoallenolate intermediates to generate
cyclic ꢀ-iodoalkenones of type B, and the second is the
intramolecular aldol reaction followed by conjugate addition
of the hydroxyl group in a formal [4 + 2] annulation to give
oxadecalins of type C (Scheme 1). To our knowledge, these
are the first examples of cyclizations involving ꢀ-iodoalle-
nolate intermediates.8
Table 2. Intramolecular ꢀ-Iodoallenolate Aldol Cyclizationa
Alkynone 1a was subjected to Lewis acidic conditions in
the presence of iodide sources (Table 1). The optimal
conditions for obtaining cyclohexenyl alcohol 2a was found to
be the combination of TiCl4 and (n-Bu)4NI (TBAI; entry 4),
whileBF3·OEt2 and TBAI was found to be optimal for the
formation of oxadecalin 3a (entry 6). Experiments with CeCl3
as Lewis acid9 or sodium iodide as the iodide source were also
performed, but only partial consumption of alkynone 1a was
observed (entries 1, 2, and 5). A stoichiometric amount of
BF3·OEt2 was required for the complete conversion of alkynone
1a to oxadecalin 3a: catalytic amounts of BF3·OEt2 resulted in
Table 1. Lewis Acid/Iodide Source Screen for Iodocyclizationa
entry
conditions
T (°C)
ratio (2a:3a) % conversione
1
2
3
4
5
6
7
8
BF3·OEt2/NaI
TiCl4/NaIb
-40 to 0
-78 to 0
-78 to 0
-78 to 0
rt
1:1.7
6:1
5:1
∼50
∼50
100
100
∼50
100
∼40
100
TiCl4/TBAIb
TiCl4/TBAI
CeCl3/NaIc
>20:1
>20:1
<1:20
2:1
a Reaction conditions: alkynone (1.0 equiv), TiCl4 (1.3 equiv), TBAI
(1.3 equiv), CH2Cl2, at the time and temperature indicated. b Run with 1.0
equiv of TBAI. c Run with 6.5 equiv of AlCl3.
BF3·OEt2/TBAI -40 to 0
BF3·OEt2/TBAId -40 to 0
BF3·OEt2/TBAB -40 to rt
<1:20
a Reaction conditions: alkynone (1.0 equiv), Lewis acid (1.3 equiv),
halide source (1.3 equiv), CH2Cl2 at the temperature indicated. b Run with
1.2 equiv of TiCl4 and 1.1 equiv of iodide source. c Run with 1.2 equiv of
CeCl3 and 1.1 equiv of NaI in acetonitrile. d Run with 0.5 equiv of BF3·OEt2.
The results of the bicyclization experiments are sum-
marized in Table 3. As observed with the monocyclization,
the gem-dimethyl functionality was not required (entry 2).
e
1
Determined by H NMR analysis of the crude reaction mixure.
Org. Lett., Vol. 11, No. 19, 2009
4375

4), even with excess Lewis acid, stronger Lewis acids, longer
reaction times, and higher temperatures. The use of TBAB
resulted in the formation of bromooxadecalin 3g (entry 5)
but required both a higher temperature and a longer reaction
time than the TBAI cyclization (entry 1).
Table 3. Bicyclization via Stepwise [4 + 2] Annulationa
The use of a disubstituted olefin demonstrated that the
cyclization was diastereoselective (entry 6). The relative ster-
eochemistry of oxadecalin 3e was confirmed by NOE experi-
ments.11 Ketone 1f, however, did not cyclize to give the
corresponding oxadecalin (entry 7). The intramolecular aldol
reaction gave 2f, but the second cyclization did not occur,
presumably because the tertiary hydroxyl group is too sterically
hindered to undergo cyclization. Extended reaction times and
higher temperatures resulted in elimination of the tertiary
alcohol. When intermediate alcohol 2f was subjected to basic
conditions, formation of the original ketone 1f was observed.
The proposed mechanistic pathway for the two cyclization
processes is shown in Scheme 2. Activation of the alkynone
carbonyl group by the Lewis acid followed by addition of
the iodide to the alkyne in a conjugate fashion gives
ꢀ-iodoallenolate 4. This intermediate then undergoes an
intramolecular aldol reaction to give cyclohexenyl alcohol
5, stabilized as its titanium chelate. Protonation of cyclo-
hexenyl alcohol 5 upon workup would then generate cyclo-
hexenyl alcohol 2a.
Scheme 2. Proposed Mechanistic Pathway
a Reaction conditions: alkynone (1.0 equiv), BF3•OEt2 (1.3 equiv), TBAI
(1.3 equiv), CH2Cl2, at the time and temperature indicated. b See text.
c Monocyclization products only. d TBAB was used instead of TBAI.
Cyclization to give the [5,6] bicycle was successful (entry
3); but formation of the [7,6] system did not occur (entry
(7) (a) Yagi, K.; Turitani, T.; Shinokubo, H.; Oshima, K. Org. Lett.
2002, 4, 3111–3114. (b) Douelle, F.; Capes, A. S.; Greaney, M. F. Org.
Lett. 2007, 9, 1931–1934. (c) Koseki, Y.; Fujino, K.; Takeshita, A.; Sato,
H.; Nagasaka, T. Tetrahedron: Asymmetry 2007, 18, 1533–1539.
(8) For examples of intramolecular Morita-Baylis-Hillman reactions,
see: (a) Roth, F.; Gygax, P.; Fra´ter, G. Tetrahedron Lett. 1992, 33, 1045–
1048. (b) Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687–3690. (c)
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237. (d) Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.; Nielsen, M.;
Williams, H. L.; Walshe, N. D. A. Tetrahedron Lett. 1997, 38, 8561–8564.
(e) Chen, S.-H.; Hong, B. C.; Su, C. F.; Sarshar, S. Tetrahedron Lett. 2005,
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Chem. 2004, 69, 6467–6469. (g) Basavaiah, D.; Rao, A. J.; Satyanarayana,
T. Chem. ReV. 2003, 103, 811–892. (h) Wang, L.-C.; Luis, A. L.; Agapiou,
K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402–2403.
(i) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002,
124, 2404–2405. (j) Teng, W.-D.; Huang, R.; Kwong, C. K.-W.; Shi, M.;
Toy, P. H. J. Org. Chem. 2005, 71, 368–371, and references therein.
Subjection of cyclohexenyl alcohol 2a to BF3·OEt2 pro-
duced oxadecalin 3a, indication of a stepwise [4 + 2]
cyclization process. In contrast to the first step of the
(9) For the use of CeCl3 as a Lewis acid to generate ꢀ-iodoallenolate
intermediates, see: (a) Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.;
Eeshwaraiah, B. Synthesis 2005, 57–60. (b) Fujisawa, T.; Tanaka, A.; Ukaji,
Y. Chem. Lett. 1989, 7, 1255–1256.
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M.; Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi, Y. Tetrahedron Lett.
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4376
Org. Lett., Vol. 11, No. 19, 2009

cyclization sequence (ꢀ-iodoallenolate aldol reaction), which
required stoichiometric amounts of Lewis acid (Table 1,
entries 4 and 6), the second step of the bicyclization
(conjugate addition) was effective using as little as 30 mol
% BF3·OEt2.
The different reactivity and selectivity observed with the
two Lewis acids studied can be attributed to differences in
their coordination properties. The selectivity is likely due to
the fact that TiCl4, unlike BF3·Et2O, can engage in bidentate
chelation.12 Thus, the TiCl4-promoted intramolecular aldol
reaction is expected to proceed through intermediate 5, and
the rigid geometry of the Ti(IV) chelate is likely to disfavor
formation of oxadecalin 3a (Scheme 2). In contrast, BF3·Et2O-
induced cyclization would involve intermediate 6, which is
appropriately poised to undergo conjugate addition and
generate oxadecalin 3a.
tions, enabling conversion of alkynones into either mono-
cyclic or bicyclic (oxadecalin) products containing ꢀ-io-
doalkenone functionality. In most cases, selective formation
of either product was possible, depending on the choice of
Lewis acid. Application of this method to the synthesis of
natural product targets is underway in the laboratory and will
be reported in due course.
Acknowledgment. We are grateful to the Petroleum
Research Fund (47919-AC1), the US Department of Educa-
tion (GAANN No. P200A060048; graduate fellowship
support for J.C.), and the University of Rochester for
generous financial support. We are also grateful to Dr. Alice
Bergmann (University of Buffalo) for carrying out high-
resolution mass spectroscopy.
Note Added after ASAP Publication. The structure of
compound 2c in Table 2, entry 3 was incorrect in the version
published ASAP September 8, 2009; the correct version was
published on the web September 24, 2009.
In summary, we have demonstrated that ꢀ-iodoallenolate
intermediates can participate in intramolecular aldol reac-
(11) The NOE spectrum (500 MHz, CDCl3) showed a correlation
between the methyl at C-1 and the proton at C-2, as shown. A correlation
between the protons at C-1 and C-2 was not observed.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Santelli, M.; Pons, J. Lewis Acids and SelectiVity in Organic
Synthesis; CRC Press, Inc.: New York, 1996; pp 1-16.
OL901721Y
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