Four nucleophilic additions to alkenynedioic acid derivatives in tandem; Efficient one-pot synthesis of bicyclo[4.2.0]octenols

Article abstract of DOI:10.1021/ol300623j

When alkenynedioic acid derivatives were treated with a Grignard reagent, tandem cyclization and the incorporation of two molecules of the Grignard reagent occurred to give stereodefined bicyclo[4.2.0]octenols via four nucleophilic additions.

Full text of DOI:10.1021/ol300623j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Four Nucleophilic Additions to
Alkenynedioic Acid Derivatives in
Tandem; Efficient One-Pot Synthesis
of Bicyclo[4.2.0]octenols
Takeshi Hata, Haduki Imade, and Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho,
Midori-ku, Yokohama, Kanagawa 226-8501, Japan
hurabe@bio.titech.ac.jp
Received March 12, 2012
ABSTRACT
When alkenynedioic acid derivatives were treated with a Grignard reagent, tandem cyclization and the incorporation of two molecules of the
Grignard reagent occurred to give stereodefined bicyclo[4.2.0]octenols via four nucleophilic additions.
Intermolecular nucleophilic addition to R,ω-unsatu-
rated carbonyl compounds 1 (first addition in Scheme 1)
followed by spontaneous cyclization (second addition)
from 2 to 3 is a useful synthetic method to prepare cyclic
compounds 4, often in a regio- and stereoselective
manner.1,2 This transformation has found numerous ap-
plications by employing various combinations of nucleo-
philes and unsaturated carbonyl compounds.3 Although
it is likely that intermediate enolate 3 is capable of nucleo-
philic addition to the neighboring carbonyl group (third
addition) to give cyclobutanones (or cyclobutenones) 5, to
the best of our knowledge, such a route has not been
documented. Here we report this alternative path that
features the third addition and even a subsequent fourth
addition with the excess nucleophile, ultimately providing
bicyclic compound 6 in one pot. Scheme 2 summarizes the
overall reaction consisting of four consecutive nucleophilic
additions, which should satisfy current criteria for highly
efficient synthetic transformations.
(1) For reviews on the preparation of cyclic compounds by double
nucleophilic additions, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K. M.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006; pp
48À156. (b) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993,
32, 1010–1022. (c) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006,
45, 354–366. (d) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833–2891.
During our studies on the cyclization of R,ω-unsatu-
rated carbonyl compounds 1,4 we examined their reactions
with various organometallic reagents in the presence or
absence of transition metal catalysts. When enyne 7 was
(2) For general reviews on tandem reactions, see: (a) Tietze, L. F.;
Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006. (b) Shindoh, N.; Takemoto, Y.; Takasu, K.
(3) For recent examples, see: (a) Wang, X.-F.; An, J.; Zhang, X.-X.;
Tan, F.; Chen, J.-R.; Xiao, W.-J. Org. Lett. 2011, 13, 808–811. (b)
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Acc. Chem. Res. 2005, 38, 413–422. (h) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551–564. (i) Poli, G.; Giambastiani,
G.; Heumann, A. Tetrahedron 2000, 56, 5959–5989. (j) Bunce, R. A.
Tetrahedron 1995, 51, 13103–13159. (k) Parsons, P. J.; Penkett, C. S.;
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K.; Imoto, J.; Imade, H.; Urabe, H. Chem.;Eur. J. 2011, 17, 14593–
14602.
r
10.1021/ol300623j
XXXX American Chemical Society

Scheme 1. Multiple Nucleophilic Additions Leading to Differ-
ent Ring Systems
Scheme 3
Scheme 2. Efficiency in Synthesis
simply treated with excess phenylmagnesium bromide,5
the starting material disappeared and a considerable
amount of a new product was recovered (Scheme 3). The
spectroscopic properties of this product suggested it to be
bicyclic cyclobutenol 8, which corresponds to the afore-
mentioned product 6 in Scheme 1.6 No other isomeric
products including cyclobutenone 9 were observed in
1
the crude reaction mixture by H NMR spectroscopy.
Figure 1. ORTEP drawing of 10.
Although the stereochemistry at the C1 and C2 positions
of 8 could be assigned by the coupling constant between
these hydrogens (J=10.2Hz) fromthe1H NMR spectrum,
the 1,8-relationship in 8 was equivocal. The unambiguous
structure was ultimately confirmed by X-ray crystallogra-
phy of fluorene analogue 10 (Table 1, entry 9), whose
ORTEP drawing is shown in Figure 1.7
(5) The 1,4-addition of Grignard reagent to a 2-alkenoate without
copper catalyst has been precedented: Munch-Petersen, J. Org. Synth.
1961, 41, 60–64. In Organic Syntheses; Baumgarten, H. E., Ed.; John Wiley
& Sons: New York, 1973; Coll. Vol. 5, pp 762À766. When 2 equiv of
Grignard reagent was used instead, ketone 9 and product 8 could not be
isolated. Even if a copper catalyst (10 mol% to 7) was added with 4 equiv
of PhMgBr to promote the first conjugate addition, unexpectedly, the
yield of 8 decreased to 28% (CuI) or 30% (CuCN).
Additional cyclobutenols prepared by this method are
shown in Table 1. Primary alkyl Grignard reagents such as
butyl-, octyl-, phenethyl-, and 4-pentenylmagnesium bro-
mides always gave the desired products 14À17 as a single
stereoisomer (Table 1, entries 1À4). The more sterically
hindered isopropyl Grignard reagent was equally effective,
giving 18 in good yield (Table 1, entry 5). Aryl Grignard
reagents also took part in the cyclization to give 8 and 19
(Table 1, entries 6 and 7). When diester 11 was used, the
(6) Recent reports on the synthesis of bicyclo[4.2.0]octenes: (a)
€
Furstner, A.; Schlecker, A.; Lehmann, C. W. Chem. Commun. 2007,
4277–4279. (b) Bajracharya, G. B.; Nakamura, I.; Yamamoto, Y. J. Org.
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E. V.; Godovikov, I. A.; Kalinin, V. N. Tetrahedron 2008, 64, 9555–9560.
(g) Oh, C. H.; Kim, A. Synlett 2008, 777–781.
(7) The data have been deposited at the Cambridge Crystallographic
Data Centre (file no. CCDC 762549) and can be obtained free of charge
via www. ccdc.cam.ac.uk/data_request/cif.
B
Org. Lett., Vol. XX, No. XX, XXXX

cyclobutenols in Table 1 was assigned on the basis of that
determined for 10.
Table 1. Synthesis of Various Bicyclic Cyclobutenols According
to Scheme 3
The proposed stereochemical course of the reaction is
shown in Scheme 4. Conjugate addition of the Grignard
reagent to the olefinic ester in 7 leads to enolate 22, wherein
the small olefinic hydrogen and the large Ph group occupy
the axial and equatorial positions, respectively, in a chair-
like alignment. From this conformation, the ring closure
occurs to generate allenolate 23, which undergoes an
intramolecular addition to the ester carbonyl group to give
cyclobutenone 24. Finally, stereoselective 1,2-addition of
the Grignard reagent to 24 from its convex face furnishes
cyclobutenol8 withthe specified stereochemistry. Itshould
be emphasized that overall, this reaction creates four new
carbonÀcarbon bonds in a stereoselective manner, incor-
porating three components in one pot.11
Scheme 4. Proposed Stereochemical Course to Bicyclo-
[4.2.0]octenols
a Grignard reagent(3.6equiv) was used. b Grignard reagent (6.2 equiv)
was used.
The bicyclic cyclobutenols described above appear to
be susceptible to a retro-aldol reaction, as evidenced by
the fact that 8 collapsed to cyclohexane 25 upon treatment
with t-BuOK in THF even at À78 °C (Scheme 5).12 Thus,
this transformation offers a stereoselective route to synthe-
size polysubstituted cyclohexane derivatives.
first intermolecular addition of the Grignard reagent
occurred exclusively at the olefinic bond to give similar
product 20 as above.8 Thus, discrimination between ole-
finic and acetylenic esters is possible in the conjugate
addition of Grignard reagents. In Table 1, entries 9 and
10 show substrates having different tether substituents
including dithiane.9,10 The stereochemistry of bicyclic
Scheme 5
(8) The reaction of the corresponding diethyl ester instead of 11
failed, affording a complex mixture of products.
(9) For reviews on dithianes, see: (a) Seebach, D. Synthesis 1969, 17–
€
36. (b) Grobel, B.-T.; Seebach, D. Synthesis 1977, 357–402. (c) Seebach,
D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239–258. (d) Page, P. C. B.; van
Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643–7677. (e) Kolb,
M. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; John Wiley & Sons: Chichester, 1995; Vol. 5, pp 2983À2989. (f) Yus,
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recent example of conversion of dithianes, see: (g) Kim, H.; Park, Y.;
Hong, J. Angew. Chem., Int. Ed. 2009, 48, 7577–7581.
This sequence turned out to be the major pathway when
alkadienediester was used instead of alkenynediester as a
substrate, as shown in Scheme 6. Following the addition of
the Grignard reagent to alkadienedioate 26, a diolefinic
counterpart of 11, the expected cyclobutanol resulting
from the hydrolytic workup of 29 was not isolated.13,14
Instead, 29 apparently suffered the retro-aldol reaction as
(10) As the cyclization of some substrates having a non- or mono-
substituted tether was unsuccessful, the geminal disubstitution to the
tether portion appears essential in this reaction. For a review on the
geminal-disubstituent effect, see: (a) Jung, M. E.; Piizzi, G. Chem. Rev.
2005, 105, 1735–1766. For the same effect by dithiane, see: (b) Kim, H.;
Park, Y.; Hong, J. Angew. Chem., Int. Ed. 2009, 48, 7577–7581. In
addition, similar substrates with a gem-disubstituted ethylene tether did
not give the corresponding bicyclo[3.2.0]heptenols.
Org. Lett., Vol. XX, No. XX, XXXX
C

stereochemistry of major isomer 30 was deduced on the
basis of the 1H NMR coupling constant for the hydrogen
at the 4-position (triplet, J = 10.8 Hz).
In conclusion, four consecutive nucleophilic additions
to alkenynedioic acid derivatives, incorporating two mo-
lecules of Grignard reagent, proceeded in one pot to give
stereodefined bicyclo[4.2.0]octenols. Further investigations
into this new type of tandem cyclization as well as synthetic
applications of the products are now in progress.
Scheme 6. Cyclohexanes Prepared from Alkadienedioate and
Grignard Reagent
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (B) (No. 21350027)
from JSPS and a Grant-in-Aid for Young Scientists (B)
(No. 20750071, to T.H.) from MEXT, Japan. The authors
are grateful to Professor Kohtaro Osakada and Dr.
Makoto Tanabe of this institute for X-ray crystallography
of 10.
Supporting Information Available. Experimental pro-
cedures and spectroscopic properties for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
demonstrated in Scheme 5, giving ketoester 30 directly
with good diastereoselectivity. The depicted relative
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The authors declare no competing financial interest.
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