Expedient approach to chiral cyclobutanones: Asymmetric synthesis of cyclobut-G

Article abstract of DOI:10.1021/ol702977x

An efficient one-pot asymmetric synthesis of cyclobutanones from chiral enol ethers is described. The approach is illustrated with alkyl- and functionalized alkyl-substituted enol ethers (nine examples). A new enantioselective synthesis of cyclobut-G (Lobucavir) could thus be achieved.

Full text of DOI:10.1021/ol702977x

ORGANIC
LETTERS
2008
Vol. 10, No. 5
821-824
Expedient Approach to Chiral
Cyclobutanones: Asymmetric Synthesis
of Cyclobut-G
Benjamin Darses, Andrew E. Greene, Susannah C. Coote, and
Jean-Franc¸ois Poisson*
De´partement de Chimie Mole´culaire (SERCO) UMR-5250, ICMG FR-2607, CNRS
UniVersite´ Joseph Fourier BP 53, 38041 Grenoble Cedex 9, France
jean-francois.poisson@ujf-grenoble.fr
Received December 11, 2007
ABSTRACT
An efficient one-pot asymmetric synthesis of cyclobutanones from chiral enol ethers is described. The approach is illustrated with alkyl- and
functionalized alkyl-substituted enol ethers (nine examples). A new enantioselective synthesis of cyclobut-G (Lobucavir) could thus be achieved.
Cyclobutanes are important building blocks, primarily due
to their ring-expansion chemistry, which derives from
substantial strain energy (essentially that of cyclopropanes).1,2
The four-membered carbocycle is, furthermore, present in
numerous natural products and synthetically derived bioactive
substances.2c,3 Not surprisingly, there are many different
methods in the literature for preparing cyclobutanes, the most
useful of which involve [2 + 2] cycloaddition, intramolecular
nucleophilic substitution, and ring contraction/expansion
reactions.1b,4 However, current approaches are largely limited
in scope, and few are able to provide enantioselection.5
Herein, a flexible route to chiral, functionalized cyclobutanes
is presented.
To date, R,R-dichloro-â-alkoxycyclobutanones generated
by diastereoselective [2 + 2] thermal cycloaddition of
dichloroketene (DCK) with chiral enol ethers have been
directly used for the enantioselective synthesis of a variety
of ring expansion products.6-8 Given the interest in cyclobu-
tanes and the paucity of useful approaches to enantiomeri-
cally enriched four-membered carbocycles, the possibility
of obtaining the chiral cyclobutanones themselves through
direct dechlorination of these fragile dichlorocyclobutanones
seemed worth examining. Although dechlorination of simple
dichlorocyclobutanones can be achieved with a variety of
(1) (a) Wiberg, K. B. In The Chemistry of Cyclobutanes; Rappoport, Z.;
Liebman, J. F., Eds.; John Wiley & Sons, Ltd.: West Sussex, England,
2005; Vol. 1, Chapter 1. (b) Lee-Ruff, E.; Mladenova, G. Chem. ReV. 2003,
103, 1449-1483.
(2) (a) Fu, N.-Y.; Chan, S.-H.; Wong, H. N. C. In The Chemistry of
Cyclobutanes; Rappoport, Z.; Liebman, J. F., Eds.; John Wiley & Sons,
Ltd.: West Sussex, England, 2005; Vol. 1, Chapter 9. (b) Namyslo, J. C.;
Kaufmann, D. E. Chem. ReV. 2003, 103, 1485-1538. (c) Bellus, D.; Ernst,
B. Angew. Chem., Int. Ed. Engl. 1988, 27, 797-827.
(5) For recent approaches limited to bicyclic adducts, see: (a) Canales,
E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686-12687. (b) Luzung,
M. R.; Mauleon, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402-
12403. See also: (c) Honda, T.; Kimura, N. J. Chem. Soc., Chem. Commun.
1994, 77-78. (d) Hazelard, D.; Fadel, A. Tetrahedron: Asymmetry 2005,
16, 2067-2070.
(3) (a) Hansen, T. V.; Stenstrøm, Y. Naturally Occurring Cyclobutanes.
In Organic Synthesis Theory and Applications; Hudlicky, T., Ed.; Elsevier
Science Ltd.: New York, 2001; Vol. 5, pp 1-38. (b) Taber, D. F.;
Frankowski, K. J. J. Org. Chem. 2005, 70, 6417-6421 and references
therein.
(4) Lee-Ruff, E. In The Chemistry of Cyclobutanes; Rappoport, Z.;
Liebman, J. F., Eds.; John Wiley & Sons, Ltd.: West Sussex, England,
2005; Vol. 1, Chapter 8.
(6) Cyclopentanones: (a) Greene, A. E.; Charbonnier, F.; Luche, M.-J.;
Moyano, A. J. Am. Chem. Soc. 1987, 109, 4752-4753. (b) Kanazawa, A.;
Delair, P.; Pourashraf, M.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1
1997, 1911-1912.
(7) Lactones: (a) B. M. de Azevedo, M.; Murta, M. M.; Greene, A. E.
J. Org. Chem. 1992, 57, 4567-4569. (b) Murta, M. M.; De Azevedo, M.
B. M.; Greene, A. E. J. Org. Chem. 1993, 58, 7537-7541. (c) De Azevedo,
M. B. M.; Greene, A. E. J. Org. Chem. 1995, 60, 4940-4942.
10.1021/ol702977x CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/13/2008

reagents (Bu3SnH, Zn/AcOH, Zn/NH4Cl/MeOH, Al/Hg,...),9
the presence of an epimerizable substituent and an elimina-
tion-prone and possibly acid-sensitive alkoxyl group in these
R,R-dichlorocyclobutanones made success far from certain.
To study the [2 + 2] cycloaddition/dechlorination se-
quence, the prototypical cis-enol ether 1a was prepared10
from (S)-Stericol.11 Cycloaddition of dichloroketene occurred
rapidly at room temperature with this reactive ketenophile
to provide the rather unstable crude dichlorocyclobutanone
2a as a 92:8 mixture of diastereomers (see Table 1).
product was partially isomerized and, furthermore, the use
of this toxic reagent was to be avoided, if at all possible
(Table 1, entry 1). Encouragingly, zinc-copper couple in
warm acetic acid produced in moderate yield only the cis-
cyclobutanone 3a, along with some Stericol-containing
products from degradation (entry 2). On replacing the acetic
acid with a methanolic ammonium chloride solution, an
improved yield of the dechlorinated cyclobutanone could be
obtained after 12 h at reflux, however now as a 45:55 cis-
trans mixture (entry 3). Brief exposure of the dichloride to
the same reagents at -20 °C successfully eliminated the
problem of isomerization, but at this temperature the
monochlorocyclobutanone was the unique product (entry 4);
at reflux temperature for only 10 min, however, the desired
cis-cyclobutanone 3a was cleanly produced in a respectable
63% overall yield (entry 5). Even better, this [2 + 2]
cycloaddition/dechlorination sequence could be conveniently
compressed into a one-pot procedure, which obviated the
need to handle the sensitive dichlorocyclobutanone: after
cycloaddition, a methanolic solution of NH4Cl was merely
added to the reaction mixture (containing residual zinc-
copper couple), which was then refluxed for 10 min. The
diastereomerically enriched (92:8) cis-cyclobutanone 3a
could thus be obtained in 91% overall yield (entry 6).
These optimized conditions were next applied to a variety
of cis-enol ethers (Table 2).12,13 The cyclobutanones were
obtained in good to excellent overall yields and, in most
cases, in stereopure form after simple flash chromatography.
From (S)- and (R)-Stericol, the 3R and 3S configurations,
respectively, were assigned in 3a-i based on considerable
antecedent.6-8 Pleasingly, benzyl, allyl, and phenylpropyl
substituents (entries 2-4), as well as even hydrolysis-
susceptible benzoyl- and TBDMS-protected hydroxybutyl
groups (entries 5,6), were compatible with the conditions of
the sequence. The outcomes with the TIPS-, benzyl-, and
benzoyl-protected hydroxymethyl substituents proved par-
ticularly interesting in several respects (entries 7-9).14
Acyclic enol ethers bearing a protected hydroxyl function
in the allylic position have not, to the best of our knowledge,
previously been subjected to dichloroketene cycloaddition.
These molecules in the presence of dichloroketene can
potentially undergo, in addition to cycloaddition, a [3,3]-
sigmatropic (Bellus-Claisen) rearrangement (Figure 1),
which is well precedented with allylic alcohol and thiol
derivatives.15
Table 1. Dechlorination of Cyclobutanone 2a
entry
1
dechlorination conditions
yield (%)a,b
68 (62:38)
Bu3SnH, ACCN, toluene,
90 °C, 1 h
2
3
4
5
6
Zn/Cu, AcOH,
50 °C, 1 h
Zn/Cu, MeOH/NH4Cl,
reflux,12 h
Zn/Cu, MeOH/NH4Cl,
-20 °C, 10 min
Zn/Cu, MeOH/NH4Cl,
reflux, 10 min
Zn/Cu, MeOH/NH4Cl,
reflux, 10 min (one-pot)
37 (100:0)
59 (45:55)
99c
63 (100:0)
91 (100:0)d
a Overall yield from 1a after chromatography (without separation of
diastereomers). b cis/trans cyclobutanone ratio in parentheses. c Crude
monochlorocyclobutanone (single isomer, â-Cl). d dr ) 92:8. SStOH ) (S)-
(-)-1-(2,4,6-triisopropylphenyl)ethanol ((S)-(-)-Stericol). ACCN ) 1,1′-
azobis(cyclohexanecarbonitrile).
Although a large excess of Bu3SnH in hot toluene did
effect the desired transformation in acceptable yield, the
(8) Pyrrolidinones: (a) Nebois, P.; Greene, A. E. J. Org. Chem. 1996,
61, 5210-5211. (b) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J.
Org. Chem. 1998, 63, 4660-4663. (c) Delair, P.; Brot, E.; Kanazawa, A.;
Greene, A. E. J. Org. Chem. 1999, 64, 1383-1386. (d) Pourashraf, M.;
Delair, P.; Rasmussen, M. O.; Greene, A. E. J. Org. Chem. 2000, 65, 6966-
6972. (e) Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org. Chem. 2001,
66, 5438-5443. (f) Roche, C.; Delair, P.; Greene, A. E. Org. Lett. 2003, 5,
1741-1744. (g) Muniz, M. N.; Kanazawa, A.; Greene, A. E. Synlett 2005,
1328-1330. (h) Ceccon, J.; Poisson, J. F.; Greene, A. E. Synlett 2005,
1413-1416. (i) Roche, C.; Kadlecikova, K.; Veyron, A.; Delair, P.;
Philouze, C.; Greene, A. E.; Flot, D.; Burghammer, M. J. Org. Chem. 2005,
70, 8352-8363. (j) Ceccon, J.; Greene, A. E.; Poisson, J. F. Org. Lett.
2006, 8, 4739-4742.
(9) For selected references, see: (a) Jeffs, P. W.; Molina, G.; Cass, M.
W.; Cortese, N. A. J. Org. Chem. 1982, 47, 3871-3875. (b) Johnston, B.
D.; Slessor, K. N.; Oehlschlager, A. C. J. Org. Chem. 1985, 50, 114-117.
(c) Redlich, H.; Lenfers, J. B.; Kopf, J. Angew. Chem., Int. Ed. Engl. 1989,
28, 777-778. (d) Hanna, I.; Pan, J.; Lallemand, J.-Y. Synlett 1991, 511-
512. (e) Paquette, L. A.; Heidelbaugh, T. M. Synthesis 1998, 495-508.
(10) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74, 13-
22.
Gratifyingly, the TIPS-, benzyl-, and benzoyl-protected
γ-hydroxy enol ethers 1g-i, on exposure to dichloroketene,
(12) The cis-enol ethers were prepared from Stericol (52-71% yields)
by the procedure described in ref 10.
(13) General procedure for cycloaddition-dechlorination: To enol ether
1 (0.5 mmol) in degassed Et2O (10 mL) at 20 °C was added Zn-Cu (480
mg, 7.3 mmol), followed by trichloroacetyl chloride (0.11 mL, 1.0 mmol)
dropwise over 30 min. A saturated solution of ammonium chloride in
methanol (20 mL) was then added, and the resulting mixture was refluxed
for 10 min. The crude product was isolated in the usual way and purified
by flash chromatography on silica gel to afford cyclobutanone 3.
(14) Except for the cycloadditions of the benzyl- and allyl-substituted
enol ethers 1b and 1c, these cycloadditions have not been previously
reported.
(11) Delair, P.; Kanazawa, A. M.; de Azevedo, M. B. M.; Greene, A. E.
Tetrahedron: Asymmetry 1996, 7, 2707-2710. (R)- and (S)-Stericol
[1-(2,4,6-triisopropylphenyl)ethanol] are now commercially available from
Sigma-Aldrich.
(15) (a) Malherbe, R.; Bellus, D. HelV. Chim. Acta 1978, 61, 3096-
3099. (b) For a minireview, see: Gonda, J. Angew. Chem., Int. Ed. 2004,
43, 3516-3524.
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Org. Lett., Vol. 10, No. 5, 2008

Table 2. One-Pot cis-Disubstituted Cyclobutanones Synthesis
Figure 1. Potential Bellus-Claisen pathway.
tanone 3g in 78% overall yield (entry 7). Curiously, the crude
benzyloxymethyl cyclobutanone suffered epimerization on
silica gel, alumina, or Florisil chromatography, which
produced a mixture of the cis- and trans-isomers 3h (entry
8). In contrast, the crude benzoyloxymethyl derivative
underwent facile elimination on simple silica gel filtration
to afford in 65% overall yield the novel methylenecyclobu-
tanone 3i (entry 9), a synthetically attractive intermediate
that is the formal product of an unprecedented chiral allenol
ether-ketene cycloaddition. The ready cycloaddition/dechlo-
rination of these hydroxy-substituted enol ether derivatives
is significant in that it allows a useful functional group to
be easily introduced into the cyclobutanones in a key position
(see below).
To demonstrate some of the considerable potential of this
asymmetric approach to cyclobutanones, a synthesis of
cyclobut-G (Lobucavir)16 was undertaken. This cyclobutyl
guanine nucleoside analogue, which was developed by
Bristol-Myers-Squibb in 1997, derives from oxetanocin A,
an unusually potent anti-HIV oxetan.17 Our approach began
by methoxy olefination of cyclobutanone 3g, which was
followed by hydrolysis of the enol ether and isomerization
of the resulting formyl group (13:1, trans:cis), to afford
aldehyde 4 in 65% yield for the three steps (Scheme 1).
Dibenzoate 5 was next produced from 4 by sequential
carbonyl reduction, TIPS cleavage, and benzoylation of the
two free hydroxyl groups (80%, three steps), and then treated
with trifluoroacetic acid to generate cleanly the corresponding
cyclobutanol (92%).16a-c,18 The last step of this sequence
illustrates the efficiency of Stericol cleavage to prepare the
corresponding cyclobutanols. Triflation of the free hydroxyl
function in this derivative was followed by nucleophilic
(16) (a) Bisacchi, G. S.; Braitman, A.; Cianci, C. W.; Clark, J. M.; Field,
A. K.; Hagen, M. E.; Hockstein, D. R.; Malley, M. F.; Mitt, T.; Slusarchyk,
W. A.; Sundeen, J. E.; Terry, B. J.; Tuomari, A. V.; Weaver, E. R.; Young,
M. G.; Zahler, R. J. Med. Chem. 1991, 34, 1415-1421. (b) Bisacchi, G.
S.; Singh, J.; Godfrey, J. D., Jr.; Kissick, T. P.; Mitt, T.; Malley, M. F.; Di
Marco, J. D.; Gougoutas, J. Z.; Mueller, R. H.; Zahler, R. J. Org. Chem.
1995, 60, 2902-2905. (c) Singh, J.; Bisacchi, G. S.; Ahmad, S.; Godfrey,
J. D., Jr.; Kissick, T. P.; Mitt, T.; Kocy, O.; Vu, T.; Papaioannou, C. G.;
Wong, M. K.; Heikes, J. E.; Zahler, R.; Mueller, R. H. Org. Process Res.
DeV. 1998, 2, 393-399. (d) Genovesi, E. V.; Lamb, L.; Medina, I.; Taylor,
D.; Seifer, M.; Innaimo, S.; Colonno, R. J.; Clark, J. M. AntiViral Res.
2000, 48, 197-203. (e) Hanson, R. L.; Shi, Z.; Brzozowski, D. B.; Banerjee,
A.; Kissick, T. P.; Singh, J.; Pullockaran, A. J.; North, J. T.; Fan, J.; Howell,
J.; Durand, S. C.; Montana, M. A.; Kronenthal, D. R.; Mueller, R. H.; Patel,
R. N. Bioorg. Med. Chem. 2000, 8, 2681-2687.
a
SStOH ) (S)-(-)-1-(2,4,6-triisopropylphenyl)ethanol ((S)-(-)-Stericol);
RStOH ) (R)-(+)-1-(2,4,6-triisopropylphenyl)ethanol ((R)-(+)-Stericol).
b Cl3CCOCl, Zn/Cu, Et2O, 20 °C, then MeOH/NH4Clsat, reflux, 10 min.
c After flash chromatography; dr measured by NMR and/or HPLC (dr of
crude mixtures 91:9 to 93:7). d 10-mmol scale. e 33:67 cis:trans mixture.
experienced predominantly (or exclusively) cycloaddition,
as only the dechlorinated cyclobutanones could be detected
in the crude reaction mixtures. Purification of the crude
silyloxymethyl derivative afforded the stereopure cyclobu-
(17) (a) Hoshino, H.; Shimizu, N.; Shimada, N.; Takita, T.; Takeuchi,
T. J. Antibiot. 1987, 40, 1077-1078. For additional references to this and
related compounds, see: (b) Rustullet, A.; Alibe´s, R.; de March, P.;
Figueredo, M.; Font, J. Org. Lett. 2007, 9, 2827-2830.
Org. Lett., Vol. 10, No. 5, 2008
823

reported in the literature ([R]20D -24.7; lit.16b [R]22D -24.4).16a,b
This approach should permit novel structural modification
at several points.
Scheme 1. Cyclobut-G Synthesis
In summary, a simple, efficient, and stereoselective one-
pot transformation of readily available enol ethers to func-
tionalized chiral cyclobutanes has been developed. Given the
dearth of generally useful approaches to chiral cyclobutane
derivatives, we expect that this new approach will find
additional application. Further work in this area is planned.
Acknowledgment. We thank the French Ministry of
Research for a fellowship (to B.D.) and Prof. P. Dumy (UJF)
for his interest in our work.
Supporting Information Available: Complete charac-
1
terization data and H and 13C NMR spectra for cyclobu-
tanones 3a-g, 3i and intermediates for the synthesis of
Cyclobut-G. This material is available free of charge via the
Internet at http://pubs.acs.org.
b
a (Ph3PCH2OMe,Cl), KHMDS. 2-Amino-6-iodopurine tetra-
butylammonium salt.
OL702977X
substitution with a purine salt and hydrolysis.16b,c to afford
cyclobut-G, which provided spectral data identical to those
(18) Er ) 98.3:1.7, by HPLC: Chiracel AD-H, 5 mm, hexane/
isopropanol, 9:1, 1.0 mL/min. tR ) 16.0 min; tR (enantiomer) ) 18.0 min.
824
Org. Lett., Vol. 10, No. 5, 2008