Transforming terpene-derived aldehydes into 1,2-epoxides via asymmetric α-chlorination: Subsequent epoxide opening with carbon nucleophiles

Article abstract of DOI:10.1039/c1cc15173h

Merging Jorgensen's and MacMillan's organocatalytic aldehyde chlorinations enables the synthesis of chiral vinylcyclopropanes and (-)-cis-aerangis lactone via terpene-derived 1,2-epoxides. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc15173h

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COMMUNICATION
Transforming terpene-derived aldehydes into 1,2-epoxides via asymmetric
a-chlorination: subsequent epoxide opening with carbon nucleophileswz
Philipp Winter, Jorg Swatschek, Matthieu Willot, Lea Radtke, Tobias Olbrisch,
Andreas Schafer and Mathias Christmann*
Received 19th August 2011, Accepted 28th September 2011
DOI: 10.1039/c1cc15173h
Merging Jørgensen’s and MacMillan’s organocatalytic aldehyde
chlorinations enables the synthesis of chiral vinylcyclopropanes
and (ꢀ)-cis-aerangis lactone via terpene-derived 1,2-epoxides.
As an inevitable consequence of the exhaustible nature of fossil
resources, an increased utilization of sustainable feedstock from
biomass will be one of the major challenges for chemists in the
21st century.1 We have initiated a research program that is
aimed at identifying larger fragments within natural products2
and fine chemicals3 that are readily available from renewable
Fig. 1 Asymmetric organocatalytic aldehyde chlorination (1), secondary
resources such as the simple bulk terpenes citronellal or
citronellene.
amine catalysts (1–2) and electrophilic chlorine sources (3–4).
this to the decomposition of radical intermediates. Other
previously reported approaches14 based on enamine activation
were also prohibitive for our intended large-scale operations
due to either costly catalysts (2) and/or chlorine sources (3).
After considerable experimentation, we were delighted to find
that N-chlorosuccinimide 4 (NCS) and imidazolidinone 1
comprise a simple yet effective reagent–catalyst combination.15
In a typical open-flask experiment, a solution of the aldehyde 5
(0.5 M) in HPLC-grade acetonitrile was treated with the catalyst
1ꢁTFA (20 mol%) and a slight excess of N-chlorosuccinimide
(4, 1.1–1.3 eq.). The terminal epoxides 7 were obtained in good
yields (Table 1) and high selectivities from the corresponding
aldehydes 5. If desired or necessary, the reaction was stopped
at the chloroalcohol 6.
The key challenge in this approach lies in finding efficient
ways to functionalize a terpene’s hydrocarbon backbone and
render these compounds suitable substrates for generally applicable
coupling reactions, e.g. metal catalyzed cross couplings,4 metathesis
reactions5 or dithiane linchpin couplings.6 Organocatalysis7 has
contributed toward this goal by enabling the stereoselective
introduction of activating groups in the a-position of carbonyl
compounds. In particular, the a-halogenation8 of aldehydes
(Fig. 1) affords valuable and flexible intermediates for follow-up
transformations. In the context of a total synthesis campaign,
we have recently converted a terpene-derived aldehyde bearing
a skipped diene motif into the corresponding terminal epoxide9
using MacMillan’s organo-SOMO methodology10 and their
ready available11 imidazolidinone 1. The practical three-step
one-pot process12 involves an enantioselective a-chlorination13
that is followed by aldehyde reduction and base-promoted
intramolecular chloride substitution. Surprisingly, attempts
to extend the otherwise successful protocol to a wider set of
terpene-derived aldehydes met with little success and led to the
decomposition of starting materials. We tentatively attribute
Accordingly, we have prepared a series of homoallylic
terminal epoxides (entries 1–6) with trisubstituted E- and
Z-configured double bonds that were subsequently rearranged
into chiral cyclopropanes (vide infra). The two diastereomeric
1,2-epoxides of citronellene (entries 8 and 10) have not yet
been described. In contrast, the 6,7-epoxide16 has been used as
chiral-pool starting material with the idea of transferring the
methyl-substituted stereocenter into a given target molecule.
The 6,7-epoxide serves as a masked carbonyl group that is
released upon periodate cleavage or by direct ozonolysis of the
alkene precursor. Starting from citronellal,17 we now have
established a route to the valuable 1,2-epoxides of citronellene
(entries 8 and 10) and the respective chloroalcohols (entries 7
and 9) under complete catalyst control.18 With this robust and
reliable route to chiral terpene-derived 1,2-epoxides in hand,
we investigated their reactivity profile as well as possible
applications in target-oriented synthesis.
TU Dortmund University, Otto-Hahn-Straße 6, D-44227 Dortmund,
Germany. E-mail: mathias.christmann@tu-dortmund.de
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc15173h
c
12200 Chem. Commun., 2011, 47, 12200–12202
This journal is The Royal Society of Chemistry 2011

Table
1,2-epoxides (7)
1
Synthesis of terpene-derived chloroalcohols (6) and
Table 2 Transformation of epoxides (7) into cyclopropanes (8–10)
Entry
1
Substrate
Product
1
6
2
3
4
2
3
7
8
4
9
5
10
5
a
Isolated yields. Enantiomeric excess and diastereomeric ratio were
b
determined by GC or HPLC. Acetate ester of the primary alcohol
a
1
Isolated yields. Diastereomeric ratio was determined by H-NMR.
c
was used as starting material. From the corresponding chloroalcohol.
d
Catalyst ent-1ꢁTFA was used.
atom to the epoxide oxygen during the deprotonation of
the methylene group. In our mechanistic rationale shown
in Scheme 1, a possibly diastereoselective deprotonation is
followed by a rapid intramolecular epoxide opening in which
the lithium atom activates the epoxide and accepts the evolving
negative charge on oxygen. Further experiments will be necessary
to narrow down the complex mechanistic possibilities and the
stereochemical details of this reaction.
There are two major strategies for the transformation of
epoxyalkenes into cyclopropanes. While Hodgson et al.19
have devised an efficient protocol for the intramolecular
cyclopropanation20 via epoxide lithiation featuring a carbenoid–
alkene-addition, an alternative pathway involves allylic deproto-
nation and intramolecular SN2-epoxide opening.21 The latter
route has been largely neglected due to a lack of diastereo-
control in the absence of functional groups.22 In line with
previous observations, the cyclization of 7c afforded cyclo-
propane 8 bearing a quaternary stereocenter23 as a 1 : 1-mixture
of cis–trans-isomers (Table 2, entry 1). However, when we
changed the configuration of the trisubstituted double bond
from E to Z, the cyclization of 7d gave 8 with an improved 10 : 1
trans-selectivity (entry 2). In the optimized protocol, treatment
of epoxides 7c–f and 7i24 with t-BuLi in the presence of a
disaggregating additive (DMPU) at low temperature (ꢀ78 1C)
furnishes the chiral vinylcyclopropanes25 8–10 in good to
excellent yields. The relative configuration of the vinylcyclo-
propanes was established using 1D-NOE experiments and the
absolute configuration was deduced from the epoxide (assuming
an intramolecular SN2 opening) or by comparison of the optical
rotation (10) to that reported in the literature.26
Terminal epoxides are extremely useful intermediates in
total synthesis. Classical synthetic applications were dominated
by dithiane or cuprate openings, but nowadays metal catalyzed
reductive openings27 are quickly advancing. Following our
interest in semiochemicals,28 we were excited to showcase the
utility of 1,2-epoxycitronellene 7h as a chiral building block in a
short synthesis of volatile constituent responsible for the lovely
scent of Aerangis kirkii.29 As shown in Scheme 2, a copper(I)-
catalyzed nucleophilic epoxide opening of 7h with n-butyl
lithium afforded alcohol 11 in 72% yield. Subsequent ozono-
lysis (71%) and in situ oxidation of the somewhat labile lactol
with IBX (57%) provided the fragrant (ꢀ)-cis-aerangis lactone
12 in three steps from 7h.30
In conclusion, we have developed a practical protocol for
the conversion of aldehydes into terminal epoxides via an
organocatalytic asymmetric enamine chlorination. The required
MacMillan catalyst (1) is easily available on the multigram scale
rendering this approach viable for total synthesis. In addition,
We speculate that the Z-configuration of the shifting double
bond allows for a concomitant coordination of the lithium
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12200–12202 12201

13 For recent reviews including a-halogenations see: (a) M. Ueda,
T. Kano and K. Maruoka, Org. Biomol. Chem., 2009, 7, 2005;
(b) M. Nielsen, D. Worgull, T. Zweifel, B. Gschwend, S. Bertelsen
and K. A. Jørgensen, Chem. Commun., 2011, 47, 632; (c) S. Bertelsen
and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178.
14 (a) N. Halland, A. Braunton, S. Bachmann, M. Marigo and K. A.
Jørgensen, J. Am. Chem. Soc., 2004, 126, 4790; (b) N. Halland,
M. A. Lie, A. Kjærsgaard, M. Marigo, B. Schiøtt and K. A.
Jørgensen, Chem.–Eur. J., 2005, 11, 7083; (c) M. Marigo,
S. Bachmann, N. Halland, A. Braunton and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2004, 43, 5507; (d) M. P. Brochu,
S. P. Brown and D. W. C. MacMillan, J. Am. Chem. Soc., 2004,
126, 4108; For a theoretical study see: (e) X.-H. Duan and
H. Mayr, Org. Lett., 2010, 12, 2238.
Scheme 1 Proposed mechanism of the vinylcyclopropane formation.
15 The combination of commercially available (S)-proline amide and
NCS as reported in ref. 14a resulted in significantly lower ee’s.
16 For example, see: (a) L. Petit and S. Z. Zard, Chem. Commun.,
2010, 46, 5148; (b) F. Bouazza, B. Renoux, C. Bachmann and
J.-P. Gesson, Org. Lett., 2003, 5, 4049.
17 For
a kinetic resolution of a-chlorinated citronellal, see:
A. Quintard and A. Alexakis, Chem. Commun., 2010, 46, 4085.
18 For a pertinent discussion, see: M. S. Taylor and E. N. Jacobsen,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5368.
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Soc., 2004, 126, 8664; (b) D. M. Hodgson, Y. K. Chung, I. Nuzzo,
G. Freixas, K. K. Kulikiewicz, E. Cleator and J.-M. Paris, J. Am.
Chem. Soc., 2007, 129, 4456 and references therein.
20 For the first report, see: K. Crandall and L.-H. Lin, J. Am. Chem.
Soc., 1967, 89, 4526.
21 (a) F. Narjes, O. Bolte, D. Icheln, W. A. Konig and E. Schaumann,
J. Org. Chem., 1993, 58, 626; (b) A. Mordini, P. Peruzzi, F. Russo,
M. Valacchi, G. Reginato and A. Brandi, Tetrahedron, 2005,
61, 3349.
Scheme 2 Synthesis of (ꢀ)-trans-aerangis lactone 12.
we found a useful stereoselective rearrangement of 1,2-epoxy-4Z-
alkenes into cyclopropanes and we used 1,2-epoxycitronellene in
a short synthesis of (ꢀ)-aerangis lactone.
We thank the Fonds der Chemischen Industrie (fellowships
to M.C. and P.W.) and the Humboldt-Foundation (fellowship
to M.W.) and Takasago International Corporation for a generous
donation of (+)-citronellal. We thank Prof. D. W. C. MacMillan
for sharing an unpublished preparation of 1.
22 For an elegant application of a related deprotonation–cyclization
the context of a total synthesis, see: A. Robinson and V. K.
Aggarwal, Angew. Chem., Int. Ed., 2010, 49, 6673.
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c
12202 Chem. Commun., 2011, 47, 12200–12202
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