Catalytic enantioselective synthesis of naturally occurring butenolides via hetero -allylic alkylation and ring closing metathesis

Article abstract of DOI:10.1021/ol102994q

An efficient catalytic asymmetric synthesis of chiral γ-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis of (-)-whiskey lactone, (-)-cognac lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid.(Figure Presented)

Full text of DOI:10.1021/ol102994q

ORGANIC
LETTERS
2011
Vol. 13, No. 5
948–951
Catalytic Enantioselective Synthesis
of Naturally Occurring Butenolides
via Hetero-Allylic Alkylation and Ring
Closing Metathesis
~ ꢀ
Bin Mao, Koen Geurts, Martın Fananas-Mastral, Anthoni W. van Zijl,
Stephen P. Fletcher, Adriaan J. Minnaard, and Ben L. Feringa*
´
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
b.l.feringa@rug.nl
Received December 10, 2010
ABSTRACT
An efficient catalytic asymmetric synthesis of chiral γ-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA)
in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis
of (-)-whiskey lactone, (-)-cognac lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid.
The γ-butyrolactone skeleton is present in more than
13000 natural products (Figure 1).1 Due to the interesting
biological activities such as antibiotic and antitumor prop-
erties, different asymmetric synthesis approaches to access
γ-butyrolactones have been intensively investigated during
Subsequently, iminium organocatalysis with siloxy fur-
anones developed by the MacMillan group became one of
the most powerful methods to obtain enantiomerically
enriched γ-butyrolactones.5 Most recently, Trost and co-
workers reported the first direct use of 2(5H)-furanone as a
nucleophile in asymmetric Michael reactions employing a
dinuclear zinc catalyst.6
Our group has been involved in asymmetric synthesis of
butenolides over the past 20 years.7 A simple and inexpen-
sive protocol to butenolides was developed based on the
D-menthol derivatives of 5-hydroxy-2(5H) furanone.7a
Furthermore, an atom economic route was developed by
using enantioselective acylation of 5-hydroxy-2(5H) fur-
anone through lipase-catalyzed dynamic kinetic resolution
the past decades.2
3
Bruckner et al. describeda route toward the synthesis of
€
optically active butenolides through the Sharpless dihydroxy-
lation4 of β,γ-unsaturated carboxylic esters.
(1) For reviews, see: (a) Bandichhor, R.; Nosse, B.; Reiser, O. Top.
Curr. Chem. 2005, 243, 43. (b) Kitson, R. R. A.; Millemaggi, A.; Taylor,
R. J. K. Angew. Chem., Int. Ed. 2009, 48, 9426.
(2) For selective examples on the synthesis of optically active
γ-butyrolactones, see: (a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.;
Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem.
Soc. 1999, 121, 669. (b) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2006, 45, 7230. (c) Ube, H.; Shimada, N.; Terada,
M. Angew. Chem., Int. Ed. 2010, 49, 1858.
(5) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192.
€
(3) (a) Harcken, C.; Bruckner, R. Angew. Chem., Int. Ed. Engl. 1997,
€
€
36, 2750. (b) Braukmuller, S.; Bruckner, R. Eur. J. Org. Chem. 2006,
2110.
(6) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572.
(7) (a) Feringa, B. L.; de Lange, B.; de Jong, J. C. J. Org. Chem. 1989,
54, 2471. (b) van der Deen, H.; Cuiper, A. D.; Hof, R. P.; van Oeveren,
A.; Feringa, B. L.; Kellogg, R. M. J. Am. Chem. Soc. 1996, 118, 3801.
(4) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
r
10.1021/ol102994q
Published on Web 01/26/2011
2011 American Chemical Society

Scheme 2. Chiral γ-Butenolides via h-AAA Followed by RCM
Figure 1. Natural products with γ-butyrolactone rings.
Scheme 1. Cu-Catalyzed Hetero-Allylic Asymmetric
Scheme 3. Retrosynthesis of (-)-Whiskey Lactone, (-)-Cognac
Lactone, (-)-Nephrosteranic Acid, and (-)-Roccellaric Acid
Alkylation8b
(DKR), which offered the complete conversion of racemic
furanone into the single enantiomer of γ-butyrolactone.7b
Although a number of powerful methods have been de-
scribed,2 there is still a major incentive to develop efficient
catalytic asymmetric protocols toward butenolides. Recently
we reported an efficient catalyst system to accomplish
highly enantioselective Cu-catalyzed allylic alkylations
with Grignard reagents.8a Novel prospects were offered
by discovering that the transformation can also be per-
formed with allylic esters through hetero-allylic asym-
metric alkylation (h-AAA) with excellent enantiomeric
control (Scheme 1).8b,9 As shown in Scheme 2, the reaction
with cinnamyl ester 1 gives rise to compound 2 bearing two
olefinic moieties. The olefinic substrates will directly lead
to γ-butenolides by ring closing metathesis (RCM).10,11
Such a route could be a valuable alternative to current
methods.1a
Whiskey and cognac lactones12 are well-known perfume
compounds with a distinct aroma, bearing the γ-butyro-
lactone ring as the main structure. (-)-Nephrosteranic
acid and (-)-roccellaric acid13 are also naturally occurring
γ-butyrolactones, containing a carboxylic acid group in
the three position as their characteristic functionality.
Despite extensive synthetic efforts toward their total synthe-
sis using either chiral pool13a or chiral auxiliaries,13e there
are limited reports on efficient catalytic enantioselective
routes of these natural products.12,13
ꢀ
(8) (a) Lopez, F.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L.
Chem. Commun. 2006, 409. (b) Geurts, K.; Fletcher, S. P.; Feringa, B. L.
J. Am. Chem. Soc. 2006, 118, 3801.
(9) For reviews, see: (a) Harutyunyan, S. R.; den Hartog, T.; Geurts,
K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824.
Here we present a catalytic enantioselective synthesis
of γ-butenolides via an h-AAA/RCM strategy. To further
demonstrate the utility of this protocol, we report the
concise total synthesis of (-)-whiskey lactone, (-)-cognac
lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid.
Asshowninthe retrosyntheticroute(Scheme 3), starting
from the inexpensive commercially available cinnamic acid
and acrolein,14 the allylic ester is readily obtained. The key
intermediate γ-butenolides could be prepared through the
h-AAA-RCM protocol.15 Thus the desired natural prod-
ucts (-)-nephrosteranic acid and (-)-roccellaric acid
would be possible to obtain after the conjugate addition
€
(b) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
Chem. Rev. 2008, 108, 2796. (c) Teichert, J. F.; Feringa, B. L. Angew.
Chem., Int. Ed. 2010, 49, 2486.
(10) For reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18. (b) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109,
3783.
(11) (a) Bassetti, M.; D’Annibale, A.; Fanfoni, A.; Minissi, F. Org.
Lett. 2005, 7, 1805. (b) Fujii, M.; Fukumura, M.; Hori, Y.; Akita, H.;
Nakamura, K.; Toriizuka, K.; Ida, Y. Tetrahedron Lett. 2006, 17, 2292.
(12) (a) Takahata, H.; Uchida, Y.; Momose, T. Tetrahedron Lett.
1994, 35, 4123. (b) Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem.
1995, 60, 5628. (c) Ito, K.; Yoshitake, M.; Katsuki, T. Tetrahedron 1996,
52, 3905. (d) Nishikori, H.; Ito, K.; Katsuki, T. Tetrahedron: Asymmetry
1998, 9, 1165. (e) Tsuboi, S.; Sakamoto, J.; Yamashita, H.; Sakai, T.;
Utaka, M. J. Org. Chem. 1998, 63, 1102.
(13) For selected examples of syntheses toward (-)-nephrosteranic
acid and (-)-roccellaric acid, see: (a) Mulzer, J.; Salimi, N.; Hartl, H.
Tetrahedron: Asymmetry 1993, 4, 457. (b) Bella, M.; Margarita, R.;
Orlando, C.; Orsini, M.; Parlanti, L.; Piancatelli, G. Tetrahedron Lett.
(14) (a) Lombardo, M.; Morganti, S.; Trombini, C. J. Org. Chem.
2003, 68, 997. (b) Lombardo, M.; Girotti, R.; Morganti, S.; Trombini, C.
Chem. Commun. 2001, 2310.
(15) For some consecutive AAA-RCM reactions, see: (a) Giacomina,
F.; Riat, D.; Alexakis, A. Org. Lett. 2010, 12, 1156. (b) Teichert, J. F.;
Zhang, S.; van Zijl, A. W.; Slaa, J. W.; Minnaard, A. J.; Feringa, B. L.
Org. Lett. 2010, 12, 4658.
€
2000, 41, 561. (c) Bohm, C.; Reiser, O. Org. Lett. 2001, 3, 1315.
(d) Jacobi, P.; Herradura, P. Can. J. Chem. 2001, 79, 1727. (e) Sibi,
M. P.; Liu, P.; Ji, J. G.; Hajra, S.; Chen, J. X. J. Org. Chem. 2002, 67,
1738. (f) Barros, M. T.; Maycock, C. D.; Ventura, M. R. Org. Lett. 2003,
€
€
5, 4097. (g) Chhor, R. B.; Nosse, B.; Sorgel, S.; Bohm, C.; Seitz, M.;
Reiser, O. Chem. Eur. J. 2003, 9, 260.
;
Org. Lett., Vol. 13, No. 5, 2011
949

Table 1. h-AAA/RCM of Cinnamyl Substratea
Scheme 5. Synthesis of (-)-Nephrosteranic Acid and
(-)-Roccellaric Acid
yieldd
(%)
time yieldd eef, g
entry
1
R
2
γ/Rc
3
(h)
(%)
(%)
C4H9
2a >99:1
91
3a
24
83
(74)e
82
97
2
C5H11
2b >99:1
89
84
78
3b
3c
3d
24
40
40
98
98
97
3b
4b
C11H23 2c >99:1
C13H27 2d >99:1
84
82
a General conditions for h-AAA: 3 mol % of CuBr SMe2, 3.6 mol %
3
of (R,R)-(þ)-Taniaphos, 2 equiv of RMgBr in CH2Cl2 at -75 °C.
b 3 equiv of RMgBr were employed at -55 °C. c Regioselectivity was
1
determined by H NMR spectroscopy. d Isolated yield. e Reaction was
performed with a solution 4.6 mM of 2a. f Ee was determined after
converting compounds 2 to γ-butenolides 3. g Determined by chiral
HPLC analysis.
With the isolated products 2 in hand, we turned our
attention to the study of the ring closing metathesis (RCM)
for diolefinic esters.11 When a solution of 2a (4.6 mM) was
refluxed in CH2Cl2 with Hoveyda-Grubbs II catalyst
(6 mol %), the desired furanone 3a was obtained in 74%
yield. However, a more concentratedsolution of2a(0.2 M)
allowed use of a lower catalyst loading (3 mol %), and
provided compound 3a in 83% yield with excellent enantio-
meric excess (97% ee). Noteworthy, the reaction time was
significantly reduced from 7 d to 24 h (entry 1). The same pro-
cedure was followed for substrates 2b-2d (entries 2-4).
It should be pointed out that good isolated yields (up to
84%) and excellent ee (up to 98%) were found in all cases
under the optimized conditions. The yield of the RCM step
was still good despite the reaction time being extended for
2c and 2d with a longer alkyl substituent at the γ-position
(entries 3, 4).
As shown in Scheme 4, chiral γ-butenolides 3a and 3b
were used for the synthesis of (-)-whiskey and (-)-cognac
lactone. The conjugate addtion of dimethylcopper lithium
(in situ formed from methyllithium and copper iodide in
ether at -20 °C)12b to butenolide 3a provided 4a in 93%
yield with complete diastereoselectivity. The homologous
lactone 4b was prepared with 96% yield by performing the
same reaction sequence. Their spectroscopic data and
optical rotation were in agreement with those previously
reported.12
Scheme 4. Synthesis of (-)-Whiskey and (-)-Cognac Lactones
and subsequent enolate trapping to the corresponding
γ-butenolides, followed by hydrolysis. The stereochemis-
try is anticipated to occur in a double anti fashion due to
the directing influence of the alkyl substituent at γ-position.
Analogously, the appropriate γ-butenolides could be con-
verted to (-)-whiskey lactone and (-)-cognac lactone by
straightforward 1,4-addition.
Our initial approach focused on the copper-catalyzed
h-AAA reaction of cinnamyl substrate 1 with the corre-
sponding Grignard reagents. Under the optimized con-
ditions,8b using 3 mol % CuBr SMe2 and 3.6 mol % (R,R)-
3
(þ)-Taniaphos, the desired products 2a and 2b were
obtained in high yields with excellent regio- (>99:1) and
enantioselectivities (97-98% ee) (Table 1, entries 1, 2). In
accordance with our previous findings8b no competing
conjugate addition to the cinnamyl moiety was observed.
To avoid the precipitation of the Grignard reagents, the tem-
perature was increased to -55 °C when Grignard reagents
with long alkyl chains were introduced (entries 3, 4).
As presented in Table 1, the regio- and enantioselectiv-
ities during formation of 2c and 2d were not affected by
increasing the temperature. In addition, good yields were
still obtained when the Grignard reagents bearing long
alkyl chains (3 equiv) were added (entries 3, 4).
Next we turned our attention to the synthesis of (-)-
nephrosteranic acid and (-)-roccellaric acid (Scheme 5).13
We treated 3c with lithiated tris(methylthio)methane at
-78 °C,12b followed by quenching the resulting enolate
with methyl iodide (10 equiv) in the presence of HMPA.16a
The trisubstituted product 5c was obtained in 46% yield,
and the intermediate lactone 4c was recovered in 42% yield.
Unfortunately the use of DMPU16b instead of HMPA
did not improve the double alkylation and a mixture of 4c
and trisubstituted γ-butyrolactone 5c was obtained as well.
(16) (a) HMPA = Hexamethylphosphoramide. (b) DMPU = 1,3-
Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
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Org. Lett., Vol. 13, No. 5, 2011

Taking this into account, we considered the possibility
of completing the formation of 5c in two steps. After the
addition of lithiated tris(methylthio)methane to 3c was
completed, the reaction was quenched with sat. aq. NH4Cl
solution. Then the crude product was treated with Na-
HMDS17 and excess MeI at -78 °C. To our delight, the
desired all trans product was obtained with 86% yield over
two steps in a fully diastereoselective manner.
Efficient hydrolysis of 5c afforded the final product (-)-
nephrosteranic acid 6c with excellent yield (97%). Analo-
gously, γ-butenolide 3d was converted to (-)-roccellaric
acid 6d in an overall yield of 79%. The trans configuration
of the substituents at the γ-butyrolactones 6c and 6d was
determined by comparison of the 1H NMR spectroscopy
data and optical rotation with those in literature.13c,d
In summary, we have developed a novel enantioselective
method toward the synthesis of chiral γ-butenolides based
on h-AAA in combination with an RCM strategy. The
synthetic potential of this protocol is illustrated with the
facile synthesis of (-)-whiskey and (-)-cognac lactone.
Moreover, the biologically active γ-butyrolactones, (-)-
nephrosteranic acid and (-)-roccellaric acid, were prepared
efficiently with this catalytic enantioselective synthetic route.
Acknowledgment. Financial support from TheNetherlands
Organization for Scientific Research (NWO-CW) is acknow-
ledged. B.M. thanks the China Scholarship Council for
financial support (No. 2008618001). M.F.-M. thanks the
Spanish Ministry of Science and Innovation (MICINN)
for a postdoctoral fellowship. We thank M. Smith (GC
and HPLC) and T. D. Tiemersma-Wegman (HRMS) for
technical assistance.
Supporting Information Available. Detailed experimen-
tal procedures and full compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Schleth, F.; Vogler, T.; Harms, K.; Studer, A. Chem. Eur. J.
;
2004, 10, 4171. (b) Schleth, F.; Studer, A. Angew. Chem., Int. Ed. 2004,
43, 313.
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