Total synthesis of (+)-virgatusin via AlCl3-catalyzed [3+2] cycloaddition

Article abstract of DOI:10.1039/b911765b

The AlCl₃-catalyzed cycloaddition of a donor-acceptor (don-acc) cyclopropane and piperonal succinctly provides the core of virgatusin in a selective, high-yielding manner. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b911765b

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Total synthesis of (+)-virgatusin via AlCl3-catalyzed [3+2]
cycloadditionwz
Shanina D. Sanders, Andrea Ruiz-Olalla and Jeffrey S. Johnson*
Received (in College Park, MD, USA) 16th June 2009, Accepted 13th July 2009
First published as an Advance Article on the web 27th July 2009
DOI: 10.1039/b911765b
The AlCl3-catalyzed cycloaddition of
a
donor–acceptor
The concise synthesis of 2,5-cis-substituted tetrahydrofurans may
be realized via the formal [3+2] cycloaddition of donor–acceptor
(don–acc) cyclopropanes and aldehydes (eqn (2)). Such reactions
are stereospecific at the donor site via a substitution reaction that
proceeds with inversion and the subsequent ring closure proceeds
with high diastereoselectivity.11–14 We believed this strategy would
be applicable to the virgatusin core in a highly selective fashion.
This communication reports the results of our studies.
(don–acc) cyclopropane and piperonal succinctly provides the
core of virgatusin in a selective, high-yielding manner.
The furanolignan virgatusin was first isolated in 1996 by Chen
and co-workers from Phyllanthus virgatus.1 Members of this
lignan subgroup display a 2,5-diaryl-3,4-disubstituted tetra-
hydrofuran skeleton. Virgatusin belongs to the cis, trans, trans
diastereoisomeric class of furanolignans which is the largest
target for which total syntheses have been reported (Fig. 1).
Recent studies have revealed antibacterial and antifungal
activity for virgatusin and its derivatives.2–5
ð2Þ
Scheme 1 details a diastereoselective route to (ꢁ)-virgatusin
(Scheme 1). The trans cyclopropane (ꢁ)-1 was synthesized in
two steps from veratraldehyde via
a
Knoevenagel–
Corey–Chaykovsky sequence (73% yield).z The formal
[3+2] cycloaddition of the cyclopropane with piperonal (2)
was conducted to yield the tetrahydrofuran
3 as one
diastereomer in 80% yield. AlCl3 and Hf(OTf)4 were the only
Lewis acids in our screen to yield the tetrahydrofuran 3
selectively and in high yield. After the cycloaddition, a
Krapcho decarboxylation15 was attempted, but the diastereo-
selectivity was low under a variety of conditions. Hydrogenolysis
of the benzyl ester followed by decarboxylation furnished the
virgatusin core (4) in 420 : 1 diastereoselectivity, presumably
via directed protonation by the carboxylic acid. Subsequent
LiAlH4 reduction gave the diol and methylation produced
(ꢁ)-virgatusin in five steps from 1. Every stereochemical issue
was addressed with 495% selectivity. The strategic application
of the benzyl ester was helpful at several stages. First,
it simplified the preparation of the cyclopropane. The
Fig. 1 Representative cis, trans, trans furanolignans.
The challenge of constructing the virgatusin core containing
four contiguous stereocenters has been met by several groups.
Yoda et al. completed the first synthesis of (ꢀ)-virgatusin.6 The
key step of Yoda’s synthesis delivered the substituted tetra-
hydrofuran core via diastereoselective reduction of a cyclic hemi-
acetal intermediate (eqn (1)). Later syntheses by Yamauchi et al.7
and Ghosh and Matcha8 proceed through selective hydrogenolysis
of a similar hemiacetal. Marsden et al. took a different approach
accessing the tetrahydrofuran core from a condensation of
allylsiloxanes with aldehydes.9 The Brun synthesis is dependent
on their Mn(III)-based radical synthesis of 2,3-dihydrofurans.10
A
diastereoselective hydrogenation of the dihydrofuran reveals the
virgatusin core and also allows access to (+)-urinaligran.
ð1Þ
Department of Chemistry, University of North Carolina at Chapel
Hill, Chapel Hill, NC 27500-3290, USA. E-mail: jsj@unc.edu
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details and characterization data for all new compounds. See
DOI: 10.1039/b911765b
Scheme 1 Diastereoselective synthesis of (ꢁ)-virgatusin.
Chem. Commun., 2009, 5135–5137 | 5135
ꢂc
This journal is The Royal Society of Chemistry 2009

differentiation from the malonate permitted selective acid
formation at C40 in the triester 3. Ultimately, reduction of
the derived C40 acid could take place concurrently with the
C30 ester in 4, maximizing overall step efficiency.
Mechanistic studies for the [3+2] cycloaddition have
provided evidence for a stereospecific nucleophilic substitution
mechanism wherein the aldehyde acts as a nucleophile toward
a configurationally stable intimate ion pair in a process that
proceeds with inversion at the cyclopropane donor site;13
however, the conversion of 1 - 3 in the present study
proceeds with retention at C3 of the cyclopropane. How
then does 3 arise? To answer this question, we examined
the chemistry of tetrahydrofuran 5 which arises from a
moderate-yielding [3+2] cycloaddition of 1 and 2 using SnCl4
as the Lewis acid. The substituents at C40 and C50 of this
diastereomer possess the cis relationship that would be
expected from the nucleophilic substitution mechanism. Upon
exposure to AlCl3 in CH2Cl2, tetrahydrofuran 5 was converted
to 3 (C40/C50-trans) along with piperonal and cyclopropane-
derived decomposition products (Scheme 2). If 5 is formed
initially in the AlCl3-catalyzed cycloaddition it is conceivable
that further association with the AlCl3 isomerizes the product
to the observed diastereomer. A possible mechanism involves
AlCl3 binding with the ether of the tetrahydrofuran ring
causing reversible ring cleavage at both C20 and C50. The
resultant carbenium ions 6 and 7 are stabilized by the strongly
electron releasing aryl groups (Scheme 2) and isomerization of
this type is precedented.9,13,16–19 The appearance of piperonal
(2) but not veratraldehyde in the reaction of 5 and AlCl3
may be understood in terms of the relative facility of retro-
aldolization of intermediates 6 and 7. It is apparent that C40 is
the only non-epimerizable stereocenter and acts as the
keystone that regulates the C20/C50 stereochemical outcome
via what is apparently thermodynamic control. Our data do
not exclude pre-cycloaddition isomerization of trans-1 to cis-1
and subsequent stereospecific cycloaddition via the established
nucleophilic substitution pathway; however, efforts to induce
such an isomerization have yielded no evidence of cis-1.
The stability of the C40 stereocenter was confirmed in a
subsequent asymmetric synthesis of (+)-virgatusin. The
Scheme 3 (+)-Virgatusin synthesis.
requisite preparation of enantioenriched cyclopropane 1 is
detailed in Scheme 3. An organocatalytic Michael addition–
intramolecular alkylation20 between enal 8 and bromomalonate
9 gave the formyl cyclopropane 10 (er 90 : 10). Oxidation20
and nucleophilic esterification gave (2R,3S)-1. Cycloaddition
with 2 was performed as with the racemate and a single
recrystallization gave (2S,4S,5S)-3 with an er of 99 : 1.
The synthesis was completed as detailed for the racemate in
Scheme 1 to give (+)-virgatusin.
In conclusion, we have shown that the [3+2] cyclopropane–
aldehyde cycloaddition previously developed in our laboratory
can be used to synthesize more complex tetrahydrofuran
derivatives such as virgatusin. This synthesis is straight-
forward and should be amenable to other members of the
furanolignan family of natural products.
Funding for this work was provided by the NSF (CHE-
0749691) and Novartis (Early Career Award to J.S.J.). S.D.S.
acknowledges
a National Physical Science Consortium
Fellowship. The authors thank Professor Stephen Marsden
for providing an authentic synthetic sample of (+)-virgatusin.
Notes and references
1 C.-C. Chen, Y-L Huang, F-L Hsu and C-F Chen, J. Nat. Prod.,
1996, 59, 520–521.
2 K. Akiyama, S. Yamauchi, T. Nakato, M. Maruyama,
T. Sugahara and T. Kishida, Biosci., Biotechnol., Biochem., 2007,
71, 1028–1035.
3 M. Maruyama, S. Yamauchi, K. Akiyama, T. Sugahara,
T. Kishida and Y. Koba, Biosci., Biotechnol., Biochem., 2007, 71,
677–680.
4 T. Nakato, R. Tago, K. Akiyama, M. Maruyama, T. Sugahara,
T. Kishida and S. Yamauchi, Biosci., Biotechnol., Biochem., 2008,
72, 197–203.
5 S. Yamauchi, T. Nakato, M. Tsuchiya, K. Akiyama,
M. Maruyama, T. Sugahara and T. Kishida, Biosci., Biotechnol.,
Biochem., 2007, 71, 2248–2255.
6 H. Yoda, M. Mizutani and K. Takabe, Tetrahedron Lett., 1999, 40,
4701–4702.
7 S. Yamauchi, M. Okazaki, K. Akiyama, T. Sugahara, T. Kishida
and T. Kashiwagi, Org. Biomol. Chem., 2005, 3, 1670–1675.
8 K. Matcha and S. Ghosh, Tetrahedron Lett., 2008, 49, 3433–3436.
9 T. Akindele, S. P. Marsden and J. G. Cumming, Org. Lett., 2005,
7, 3685–3688.
´
10 S. Martinet, A. Meou and P. Brun, Eur. J. Org. Chem., 2009,
2306–2311.
11 P. D. Pohlhaus and J. S. Johnson, J. Org. Chem., 2005, 70,
1057–1059.
12 P. D. Pohlhaus and J. S. Johnson, J. Am. Chem. Soc., 2005, 127,
16014–16015.
Scheme 2 Isomerization mechanism.
ꢂc
This journal is The Royal Society of Chemistry 2009
5136 | Chem. Commun., 2009, 5135–5137

13 P. D. Pohlhaus, S. D. Sanders, A. T. Parsons, W. Li and
J. S. Johnson, J. Am. Chem. Soc., 2008, 130, 8642–8650.
14 A. T. Parsons and J. S. Johnson, J. Am. Chem. Soc., 2009, 131,
3122–3123.
17 H. Kim, C. M. Wooten, Y. Park and J. Hong, Org. Lett., 2007, 9,
3965–3968.
18 D. J. Aldous, A. J. Dalenc¸ on and P. G. Steel, J. Org. Chem., 2003,
68, 9159–9161.
15 A. P. Krapcho, Synthesis, 1982, 805–822.
16 P. Andrew, W. R. S. C. Peter and V. Revuru, J. Chem. Soc., Perkin
Trans. 1, 1985, 587–594.
19 Y. L. Jiang and J. T. Stivers, Tetrahedron Lett., 2003, 44, 85–88.
20 H. Xie, L. Zu, H. Li, J. Wang and W. Wang, J. Am. Chem. Soc.,
2007, 129, 10886–10894.
ꢂc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5135–5137 | 5137