Catalytic asymmetric synthesis of enantiopure isoprenoid building blocks: Application in the synthesis of apple leafminer pheromones

Article abstract of DOI:10.1039/b419268k

The first catalytic asymmetric procedure capable of preparing all 4 diastereoisomers (ee > 99%, de > 98%) of a versatile saturated isoprenoid building block was developed and the value of this new method was demonstrated in its application to the concise total synthesis of two pheromones. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b419268k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Catalytic asymmetric synthesis of enantiopure isoprenoid building
blocks: application in the synthesis of apple leafminer pheromones{
Ruben P. van Summeren, Sven J. W. Reijmer, Ben L. Feringa* and Adriaan J. Minnaard*
Received (in Cambridge, UK) 23rd December 2004, Accepted 27th January 2005
First published as an Advance Article on the web 9th February 2005
DOI: 10.1039/b419268k
synthesis of all 4 diastereoisomers (ee . 99%, de . 98%) of a
versatile isoprenoid building block, capable of functionalization at
both terminae (Fig. 1). Furthermore, we demonstrate the synthetic
usefulness of the acquired building blocks by an application in the
total synthesis of two pheromones.
The first catalytic asymmetric procedure capable of preparing
all 4 diastereoisomers (ee . 99%, de . 98%) of a versatile
saturated isoprenoid building block was developed and the
value of this new method was demonstrated in its application to
the concise total synthesis of two pheromones.
Our method is based on the Cu-phosphoramidite catalyzed
asymmetric conjugate addition of dialkylzinc reagents to cyclic
substrates, developed in our group.10 We anticipated that this
protocol, used iteratively in the conjugate addition of Me2Zn to
cycloocta-2,7-dienone (2) followed by oxidative ring opening
(Fig. 2), would enable the rapid assembly of enantiopure syn- and
anti-isoprenoid building blocks. However, as depicted in Fig. 2,
quenching of the zinc enolate after the second conjugate addition
with a proton source would result in a meso compound in case of
the cis-adduct. To avoid a racemic product after ring opening, a
procedure was developed, involving in situ trapping of the zinc
enolate as a silyl enol ether and subsequent ring opening via
ozonolysis (Scheme 1).11
The saturated isoprenoid unit is a central theme in many natural
products including pheromones,1 vitamins,2 marine natural
products,3 and archaebacterial lipids.4 Isoprenoid based chiral
building blocks (Fig. 1) therefore constitute a major synthetic
challenge to the field of total synthesis. Current methods to
synthesize such building blocks include chiral pool strategies,1b,5
enzymatic desymmetrization protocols3b,6 and chiral auxiliary
based approaches.4b,7 However, all of these methods are inherently
multistep and either incapable of delivering all diastereoisomers or
use a stoichiometric amount of chiral material. As for asymmetric
catalytic methods, only two examples have been reported in the
literature. In 1987 Noyori employed a Ru–binap complex in the
asymmetric hydrogenation of allylic alcohols to synthesize a C15
chain containing a saturated syn-isoprenoid unit as present in the
vitamins E and K.8 More recently, Negishi developed an elegant
Zr-catalyzed enantioselective carboalumination to prepare such
compounds.9 It should be noted though, that in both cases only
the syn-isoprenoid unit has been synthesized and that one end of
the molecule is restricted to a saturated alkyl chain.
Cycloocta-2,7-dienone (2) was prepared from cyclooctanone in
one step via oxidation with IBX as described by Nicolaou et al.12
Conjugate addition of Me2Zn to 2 yielded 3 (ee . 99%) in 85%
yield using 5 mol% catalyst, 5.0 eq. Me2Zn and slow addition of
the substrate to the reaction mixture over 5 h. When standard
conditions were employed (2.5 mol% catalyst, 1.5 eq. Me2Zn),10c
a
significant amount of side product (4) was formed due to Michael
addition of the zinc-enolate to the substrate (Scheme 1). In the
second conjugate addition this side reaction was sufficiently
In order to avoid these constraints in synthetic flexibility and
stereocontrol, we have focused on a more general applicable
method towards enantiopure saturated isoprenoid units. Herein
we report a catalytic method which allows, for the first time, the
Fig. 1 General structure of the saturated isoprenoid unit and structures
of all diastereoisomers of the isoprenoid building block prepared by
asymmetric catalysis.
{ Electronic supplementary information (ESI) available: detailed experi-
mental procedures and spectroscopic (1H and 13C NMR) and analytical
data of all compounds in Schemes 1 and 2. Chiral GC-methods for
determination of ee and de of compounds 3 and 5. See http://www.rsc.org/
suppdata/cc/b4/b419268k/
Fig. 2 General strategy for synthesizing enantiopure saturated isopre-
*B.L.Feringa@chem.rug.nl (Ben L. Feringa)
A.J.Minnaard@chem.rug.nl (Adriaan J. Minnaard)
noid building blocks; problem of formation of a meso compound.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1387–1389 | 1387

View Article Online
Scheme 2 Synthesis of apple leafminer pheromones. (a) p-TsCl, pyridine,
0 uC, 12 h; (b) DIBAH (5.0 eq.), Et2O, 278 uC, 30 min; (c) CuBr?SMe2
(1.0 eq.), n-PrMgBr (16 eq.), THF, 278 uC to 0 uC, 12 h; (d) CuBr?SMe2
(21 mol%), 6-heptenylMgBr (4.0 eq.), THF, 278 uC to 0 uC, 12 h; (e)
CuBr?SMe2 (31 mol%), n-hexylMgBr (5.7 eq.), THF, 278 uC to 0 uC, 12 h.
chains. As a first step, the primary alcohol was converted into the
tosylate 7 in 95% yield. Crude 7 was then treated with DIBAH to
give the primary alcohol 8 in 94% yield. Subsequent chain
elongation by reaction with a large excess of n-propylmagnesium
bromide (16 eq.) in the presence of a stoichiometric amount of
CuBr?SMe2 gave 9 in excellent yield (99%).19 After conversion of
the hydroxyl moiety of 9 into a tosyl group (10, 94%), the product
was applied in coupling reactions with 6-heptenylmagnesium
bromide and hexylmagnesium bromide in the presence of
CuBr?SMe2 to give 11 and 12, respectively, with full conversion.20
Further applications of this strategy are currently under investiga-
tion in our laboratory.
Scheme 1 Synthesis of enantiopure building blocks.16 (a) Cu(OTf)2
(5 mol%), L1 (10 mol%), Me2Zn (5.0 eq.), toluene, 225 uC, 12 h; (b)
Cu(OTf)2 (2.5 mol%), L1 (5 mol%), Me2Zn (1.5 eq.), CH2Cl2, 225 uC,
12 h, then Et3N (3.0 eq.), TMEDA (5.0 eq.), TMSOTf (5.0 eq.), Et2Zn
(0.42 eq.), rt, 2 h; (c) Cu(OTf)2 (2.5 mol%), ent-L1 (5 mol%), Me2Zn
(1.5 eq.), CH2Cl2, 225 uC, 12 h, then Et3N (3.0 eq.), HMPA (5.0 eq.),
TMSCl (5.0 eq.), Et2Zn (0.42 eq.), rt, 2 h; (d) O3, MeOH, CH2Cl2, 278 uC,
15 min, then NaBH4 (10 eq.), rt, 12 h; (e) MeOH, TMSCl (3.0 eq.), reflux,
12 h.
We would like to thank T.D. Tiemersma-Wegman (GC) and
A. Kiewiet (MS) for technical support. This work was supported
by the Dutch Organization for Scientific Research (NWO).
suppressed by slow addition of the substrate allowing for the use of
2.5 mol% of catalyst. In the case of the trans-adduct, quenching the
reaction with TMSOTf in the presence of Et3N and TMEDA
resulted in quantitative formation of the corresponding silyl enol
ether 5a (ee . 99%, de . 98%). The cis-adduct 5b was formed
(95% conversion as determined by 1H–NMR) with excellent
selectivity (ee . 99%, de . 98%) when HMPA and TMSCl were
used instead of TMEDA and TMSOTf, as the latter reagents
induced partial racemization.13 The silyl enol ethers (5a/5b) were
ring-opened by ozonolysis and the resulting aldehyde was reduced
upon work-up with NaBH4. The crude carboxylic acids (6a/6b)
were then heated under reflux in MeOH in the presence of TMSCl
to give the methyl esters 1a and 1b in an overall yield of 45% from
3.14 As an alternative, the conversion of 3 into carboxylic acid 6a
was performed as a one pot procedure, yielding 1a after
esterification in 40% yield.15 The enantiomers of all compounds
in Scheme 1 were prepared by using the opposite enantiomer of the
ligand, i.e. ent-L1 in place of L1 and vice versa.16
Ruben P. van Summeren, Sven J. W. Reijmer, Ben L. Feringa* and
Adriaan J. Minnaard*
Department of Organic and Molecular Inorganic Chemistry, Stratingh
Institute, University of Groningen, Nijenborgh 4, 9747 AG, Groningen,
The Netherlands. E-mail: B.L.Feringa@chem.rug.nl.,
A.J.Minnaard@chem.rug.nl
Notes and references
1 (a) K. Mori, in The Total Synthesis of Natural Products, ed. J. ApSimon,
Wiley-Interscience, New York, 1992, 9; (b) Y. Nakamura and K. Mori,
Eur. J. Org. Chem., 1999, 2175; (c) J. R. Aldrich, J. E. Oliver,
W. R. Lusby, J. P. Kochansky and M. J. Borges, J. Chem. Ecol., 1994,
20, 1103.
2 (a) C. Mercier and P. Chabardes, Pure Appl. Chem., 1994, 66, 1509; (b)
P. Dowd, R. Hershline, S. W. Ham and S. Naganathan, Nat. Prod.
Rep., 1994, 11, 251.
3 (a) L. Minale, in Marine Natural Products, ed. P. J. Scheuer, Academic
Press, 1978, vol. 1, ch. 4; (b) S. Sankaranarayanan, A. Sharma and
S. Chattopadhyay, Tetrahedron: Asymmetry, 2002, 13, 1373.
4 (a) D. Zhang and C. D. Poulter, J. Am. Chem. Soc., 1993, 115, 1270; (b)
W. F. Berkowitz and Y. Wu, J. Org. Chem., 1997, 62, 1536.
5 (a) T. Eguchi, K. Arakawa, T. Terachi and K. Kakinuma, J. Org.
Chem., 1997, 62, 1924; (b) S. Hanessian, P. J. Murray and S. P. Sahoo,
Tetrahedron Lett., 1985, 26, 5623.
6 R. Cheˆnevert and M. Desjardins, J. Org. Chem., 1996, 61, 1219.
7 (a) C. H. Heathcock, B. L. Finkelstein, E. T. Jarvi, P. A. Radel and
C. R. Hadley, J. Org. Chem., 1988, 53, 1922; (b) J. Fujiwara,
Y. Fukutani, M. Hasegawa, K. Maruoka and H. Yamamoto, J. Am.
Chem. Soc., 1984, 106, 5004; (c) A. Gambacorta, D. Tofani, P. Lupattelli
and A. Tafi, Tetrahedron Lett., 2002, 43, 2195.
In summary, all 4 diastereoisomers of 1 were synthesized in
excellent ee (.99%) and de (.98%) from 2 in 4 steps with an
overall yield of 38%. It should be emphasized, that the resulting
chiral building blocks, can be used in subsequent coupling
reactions to prepare oligoprenoids of any desired length and
stereochemistry. This novel approach should, therefore, show
broad application in the total synthesis of a range of natural
products and analogues thereof.
To demonstrate the synthetic versatility of this catalytic
approach, it was employed in the total synthesis (Scheme 2) of
two—female-produced—pheromones 11 and 12 of the apple
leafminer (Lyonetia prunifoliella), a pest endemic to the eastern
regions of North America.17,18 The total synthesis required, that
both ends of the anti-building block (1a) are elongated with alkyl
8 H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa,
S. Inoue, I. Kasahara and R. Noyori, J. Am. Chem. Soc., 1987, 109,
1596.
9 S. Huo, J. Shi and E. Negishi, Angew. Chem. Int. Ed., 2002, 41, 2141.
1388 | Chem. Commun., 2005, 1387–1389
This journal is ß The Royal Society of Chemistry 2005

View Article Online
10 (a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos and A. H. M.
De Vries, Angew. Chem. Int. Ed., 1997, 36, 2620; (b) B. L. Feringa, Acc.
Chem. Res., 2000, 33, 346; (c) R. B. C. Jagt, R. Imbos, R. Naasz,
A. J. Minnaard and B. L. Feringa, Isr. J. Chem., 2001, 41, 221.
11 O. Knopff and A. Alexakis, Org. Lett., 2002, 4, 3835.
15 In this case the prime loss of product was due to oxidation of the
aldehyde in the ozonolysis step.
16 (7S)-3, (3S,7S)-1a and (3S,7R)-1b were isolated in comparable yield, ee
and de as compared to their enantiomers.
17 For earlier synthesis of these pheromones see: Y. Nakamura and
K. Mori, Eur. J. Org. Chem., 2000, 2745.
18 R. Gries, G. Gries, G. G. S. King and C. T. Maier, J. Chem. Ecol., 1997,
23, 1119.
19 The use of catalytic amounts of CuBr?SMe2 or Li2CuCl4 and a
smaller excess of Grignard reagent (5 eq.) was less successful, with
incomplete reaction after 12 h and partial exchange of the tosyl group by
bromide.
20 12 was not separated from dodecane, which resulted from homocou-
pling of the Grignard. The estimated yield (GC) of 12 was 70%.
12 K. C. Nicolaou, T. Montagnon, P. S. Baran and Y.-L. Zhong, J. Am.
Chem. Soc., 2002, 124, 2245.
13 Partial racemization of the cis-adduct 5b upon use of TMSOTf is
probably due to the fact that TMSOTf is reactive enough to convert
small quantities of (meso) ketone into racemic 5b while TMSCl is not.
14 The main loss of product occurred in the purification of 5a/5b due to
volatility of the silyl enol ethers. Therefore, CH2Cl2 was the solvent of
choice in the second 1,4-addition, even though toluene gave similar
conversions and equally high ee’s and de’s.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1387–1389 | 1389