Catalytic enantioselective synthesis of vicinal dialkyl arrays

Article abstract of DOI:10.1021/jo8010649

(Chemical Equation Presented) With a consecutive "asymmetric allylic alkylation (AAA)/cross-metathesis (CM)/conjugate addition (CA)" protocol it is possible to synthesize either stereoisomer of compounds containing a vicinal dialkyl array with excellent stereoselectivity. The versatility of this protocol in natural product synthesis is demonstrated in the preparation of the ant pheromones faranal and lasiol.

Full text of DOI:10.1021/jo8010649

Catalytic Enantioselective Synthesis of Vicinal Dialkyl Arrays
Anthoni W. van Zijl, Wiktor Szymanski, Ferrnando Lo´pez,† Adriaan J. Minnaard,* and
Ben L. Feringa*
Stratingh Institute for Chemistry, Faculty of Mathematics and Natural Sciences, UniVersity of Groningen,
Nijenborgh 4, 9747AG, Groningen, The Netherlands
a.j.minnaard@rug.nl; b.l.feringa@rug.nl
ReceiVed May 21, 2008
With a consecutive “asymmetric allylic alkylation (AAA)/cross-metathesis (CM)/conjugate addition (CA)”
protocol it is possible to synthesize either stereoisomer of compounds containing a vicinal dialkyl array
with excellent stereoselectivity. The versatility of this protocol in natural product synthesis is demonstrated
in the preparation of the ant pheromones faranal and lasiol.
Introduction
In the synthesis of chiral natural products, it is imperative
that the stereochemistry of each of the stereogenic centers can
be controlled. Therefore, methods that allow the introduction
of each stereochemical element independently (reagent or
catalyst control), as opposed to being dependent on chirality
introduced previously (substrate control), are an invaluable
addition to the synthetic chemist’s tool box.1 The Cu-catalyzed
asymmetric allylic alkylation (AAA)2 and conjugate addition
(CA)3 are two powerful C-C bond forming reactions enabling
the formation of stereogenic centers with alkyl substituents.
Recently, we reported catalysts based on copper and diphosphine
FIGURE 1. Diphosphine ligands for asymmetric Cu-catalyzed con-
jugate addition and allylic alkylation with Grignard reagents.8
* To whom correspondence should be addressed. Fax: +31 50 363 4296.
Tel: +31 50363 4235.
ligands (Figure 1), which perform both the Cu-catalyzed allylic
alkylation4 and conjugate addition5,6 using Grignard reagents
providing the chiral products in high yields and with excellent
regioselectivity and enantiomeric excess.7
Iterative protocols based on the enantioselective Cu-catalyzed
conjugate addition for the synthesis of compounds with two or
† Current address: Departamento de Qu´ımica Orga´nica, Universidad de
Santiago de Compostela, Avda. de las Ciencias, s/n, 15782, Santiago de
Compostela, Spain.
(1) Taylor, M. S.; Jacobsen, E. N. Proc. Nat. Acad. Sci. U.S.A. 2004, 101,
5368–5373.
(2) (a) Geurts, K.; Fletcher, S. P.; van Zijl, A. W.; Minnaard, A. J.; Feringa,
B. L. Pure Appl. Chem. 2008, 80, 1025–1037. (b) Falciola, C. A.; Alexakis, A.
Eur. J. Org. Chem. 2008, 3765–3780. (c) Yorimitsu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2005, 44, 4435–4439. (d) Alexakis, A.; Malan, C.; Lea, L.; Tissot-
Croset, K.; Polet, D.; Falciola, C. Chimia 2006, 60, 124–130.
(3) (a) Christoffers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007,
1279–1300. (b) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. Copper-
Catalysed EnantioselectiVe Conjugate Addition Reactions of Organozinc Reagents
in Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
2002; Chapter 7. (c) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
3236. (d) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353.
(4) (a) van Zijl, A. W.; Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2007, 72, 2558–2563. (b) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am.
Chem. Soc. 2006, 128, 15572–15573. (c) Lo´pez, F.; van Zijl, A. W.; Minnaard,
A. J.; Feringa, B. L. Chem. Commun. 2006, 409–411.
(5) (a) Macia´ Ruiz, B.; Geurts, K.; Ferna´ndez-Iba´n˜ez, M. A.; ter Horst, B.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2007, 9, 5123–5126. (b) Harutyunyan,
S. R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.; Badorrey, R.; Meetsma,
A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103–9118.
6994 J. Org. Chem. 2008, 73, 6994–7002
10.1021/jo8010649 CCC: $40.75 2008 American Chemical Society
Published on Web 08/07/2008

Catalytic EnantioselectiVe Synthesis of Vicinal Dialkyl Arrays
SCHEME 1. Synthetic Protocol Providing Vicinal Dialkyl Compounds (LG ) Leaving Group)
more stereocenters in a 1,3-relation9 or 1,5-relation10 to each
other have been developed in our group, recently. The utility
of these protocols has been demonstrated in the total synthesis
of several natural products.11 However, these approaches do not
provide for the stereoselective synthesis of vicinal (1,2-relation)
dialkyl arrays.12
manner, adjacent stereocenters with simple alkyl substituents
are introduced with independent control over the stereochem-
istry.14 Furthermore, we applied this protocol in the synthesis
of the two ant pheromones, lasiol and faranal.
Results and Discussion
Herein we report a versatile protocol for the synthesis of such
vicinal 1,2-dialkyl arrays based on three successive modern
catalytic transformations (Scheme 1). The strategy consists of
an initial Cu-catalyzed asymmetric allylic alkylation (AAA) to
build the first stereogenic center, a subsequent cross-metathesis
(CM) reaction,13 which transforms the generated terminal alkene
moiety into an R,ꢀ-unsaturated system, and finally a Cu-
catalyzed enantioselective conjugate addition (CA) of a Grignard
reagent which delivers the desired 1,2-dialkyl motif. In this
The Cu-catalyzed allylic alkylations were performed as
reported previously, with cinnamyl bromide 1 as a model
substrate and MeMgBr or EtMgBr as Grignard reagents. The
reactions were performed in CH2Cl2 at -75 °C in the presence
of a copper catalyst, which was preformed in situ from
CuBr·SMe2 and ligand L2.4c,8 The enantioselective allylic
alkylation is high yielding and gives the chiral product with
excellent enantioselectivity (Table 1). In the AAA with meth-
ylmagnesium bromide, the regioselectivity is very high (>97:
3). However, the AAA with ethylmagnesium bromide provided
a mixture of SN2′ and SN2 products 2 and 3 in a ratio of 80:20.
Since 2 and 3 were inseparable by standard column chroma-
tography, the cross-metathesis reactions were performed on the
mixture. Consequently, the cross-metathesis reaction leads to
both products 5 and 6 from 2 and 3, respectively (Scheme 2).
(6) L4’s performance in conjugate addition was first reported by Loh and
co-workers: Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129,
276–277.
(7) For reviews on the use of Grignard reagents in asymmetric allylic
alkylation and conjugate addition, see: (a) Lo´pez, F.; Minnaard, A. J.; Feringa,
B. L. In The Chemistry of Organomagnesium Compounds; Rappoport, Z., Marek,
I., Eds.; Wiley: Chichester, 2008; Part 2, Chapter 17. (b) Harutyunyan, S. R.;
den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. ReV. 2008,
108, . in press. (c) Lo´pez, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res.
2007, 40, 179–188.
(8) The correct stereochemistry of (+)-Taniaphos L2 is (R,RFc), as depicted
in Figure 1. Based on information from the literature, our previous articles (refs
2a, 4, 5b, and 7) have erroneously depicted the ligand as its (R,SFc) diastereomer;
in ref 4b, (-)-(R,SFc)-Taniaphos should be (+)-(R,RFc)-Taniaphos. See also: (a)
Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P. Angew. Chem.,
Int. Ed. 2008, 47, 3666. (b) Fukuzawa, S.-i.; Yamamoto, M.; Hosaka, M.;
Kikuchi, S. Eur. J. Org. Chem. 2007, 5540–5545. (c) Fukuzawa, S.-i.; Yamamoto,
M.; Kikuchi, S. J. Org. Chem. 2007, 72, 1514–1517.
SCHEME 2. Formation of Distinct Products in AAA and
subsequent CM
(9) (a) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966–9967. (b) Schuppan,
J.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004, 792–793.
(10) van Summeren, R. P.; Reijmer, S. J. W.; Feringa, B. L.; Minnaard, A. J.
Chem. Commun. 2005, 1387–1389.
Our previous reports on the enantioselective Cu-catalyzed
conjugate addition have focused on three types of acyclic
substrates: R,ꢀ-unsaturated esters, ketones, and thioesters.
Therefore, three different electron-deficient olefins 4 were used
in the cross-metathesis reactions: methyl acrylate 4a, methyl
vinyl ketone 4b, and S-ethyl thioacrylate 4c. The results of the
two-step syntheses of 5a-e are summarized in Table 1.
Compounds 5a and 5b, an R,ꢀ-unsaturated ester and ketone,
respectively, with R ) Me, could be obtained readily (Table 1,
entries 1 and 2). The reactions were performed in CH2Cl2 at rt
using 5 equiv of olefin 4 and 2 mol % of the Hoveyda-Grubbs
second-generation catalyst (HG-2, Figure 2). Compound 5c was
obtained by a similar route using 2 equiv of 4c and two portions
of 5 mol % of catalyst (Table 1, entry 3).15
(11) (a) Casas-Arce, E.; ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem.
Eur. J. 2008, 14, 4157–4159. (b) ter Horst, B.; Feringa, B. L.; Minnaard, A. J.
Org. Lett. 2007, 9, 3013–3015. (c) ter Horst, B.; Feringa, B. L.; Minnaard, A. J.
Chem. Commun. 2007, 489–491. (d) van Summeren, R. P.; Moody, D. B.;
Feringa, B. L.; Minnaard, A. J. J. Am. Chem. Soc. 2006, 128, 4546–4547.
(12) For representative approaches to the asymmetric synthesis of vicinal
dialkyl arrays through asymmetric catalysis, see for example: desymmetrization:
(a) Johnson, J. B.; Bercot, E. A.; Williams, C. M.; Rovis, T. Angew. Chem., Int.
Ed. 2007, 46, 4514–4518. (b) Chen, Y.; Tian, S.-K.; Deng, L., J. Am. Chem.
Soc. 2000, 122, 9542–9543. Michael reactions: (c) Evans, D. A.; Scheidt, K. A.;
Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480–4491. For
representative approaches through chiral pool and chiral auxiliaries or reagents,
see for example: tiglylation/hydroboration: (d) Coleman, R. S.; Gurrala, S. R.;
Mitra, S.; Raao, A. J. Org. Chem. 2005, 70, 8932–8941. 1,4-addition on chiral
substrates: (e) Morita, M.; Ishiyama, S.; Koshino, H.; Nakata, T. Org. Lett. 2008,
10, 1675–1678. (f) Marshall, J. A.; Herold, M.; Eidam, H. S.; Eidam, P. Org.
Lett. 2006, 8, 5505–5508. 1,4-addition/enolate trapping: (g) Hanessian, S.; Reddy,
G. J.; Chahal, N. Org. Lett. 2006, 8, 5477–5480. (h) Reyes, E.; Vicario, J. L.;
Carrillo, L.; Bad´ıa, D.; Uria, U.; Iza, A. J. Org. Chem. 2006, 71, 7763–7772. (i)
White, J. D.; Lee, C.-S.; Xu, Q. Chem. Commun. 2003, 2012–2013. Michael
reactions: (j) Brebion, F.; Delouvrie´, B.; Na´jera, F.; Fensterbank, L.; Malacria,
M.; Vaissermann, J. Angew. Chem., Int. Ed. 2003, 42, 5342–5345. (k) Liang,
B.; Carroll, P. J.; Joullie´, M. M. Org. Lett. 2000, 2, 4157–4160. Ireland-Claisen
rearrangement: (l) Oishi, T.; Shoji, M.; Kumahara, M.; Hirama, M. Chem. Lett.
1997, 845–846, See also refs 20-28.
Despite the different reactivities of terminal and internal
olefins, under the aforementioned conditions the SN2-product 3
was transformed into the cinnamic acid derivative 6 quantita-
(14) A single example of this protocol was reported previously by our group;
see ref 4c.
(15) van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2008,
73, 5651–5653.
(13) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370. (b) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900–1923.
J. Org. Chem. Vol. 73, No. 18, 2008 6995

van Zijl et al.
TABLE 1. Synthesis of 5a-e through Allylic Alkylation Followed by Cross-Metathesisa
R
4
Ru-cat. (Figure 2)
5
yieldb (%)
(eec) (%)
5:6d
1d
2
3
4
5
Me
Me
Me
Et
Et
Et
4a
4b
4c
4a
4a
4c
(Y ) OMe) 5 equiv
(Y ) Me) 5 equiv
(Y ) SEt) 2 equiv
(Y ) OMe) 5 equiv
(Y ) OMe) 5 equiv
(Y ) SEt) 2 equiv
HG-2
HG-2
HG-2
HG-2
G-2
(2 mol %)
(2 mol %)
(10 mol %)f
(2 mol %)
(1.5 mol %)
(10 mol %)f
5a
5b
5c
5d
5d
5e
66
80
(n.d.)
(99)
(97)
(98)
(98)
(97)
>97:3
>97:3
>97:3
80:20
90:10
80:20
74
67g
49g
67g
6
HG-2
a Reaction conditions: (1) 1 (1.0 equiv), CuBr ·SMe2 (1.0 mol%), (+)-(R,RFc)-L2 (1.2 mol%), RMgBr (1.2 equiv), CH2Cl2, -75 °C, (2) 2 (1.0 equiv),
4a-c (2-5 equiv), Ru-cat. (1.5-10 mol%), CH2Cl2, rt. b Isolated yield of 5 after two steps. c Determined by chiral HPLC. d Determined by 1H NMR
spectroscopy. e Reference 4c. f Catalyst added in two portions of 5.0 mol %. g Calculated yield of 5 from 1 after two steps, based on overall yield and
ratio of 5 and 6.
TABLE 2. Conjugate Additions on r,ꢀ-unsaturated Esters 5a and 5da
entry
R
5
ligand
yieldb (%)
dr (anti:syn)c
eec (%)
1d
2d
3
Me
Me
Et
5a
5a
5d
5d
(R,S)-L3
(S,R)-L3
(R,S)-L3
(S,R)-L3
anti-7a
syn-7a
anti-7b
syn-7b
81
84
77
30e
99:1
4:96
91:9
4:96
>99.5
>99.5
>99.5
99
4
Et
a Reaction conditions: 5 (1.0 equiv), CuBr ·SMe2 (5.0 mol %), L3 (6.0 mol %), EtMgBr (5.0 equiv), CH2Cl2, -78 °C, 18 h. b Isolated yield of the
mixture of diastereomers. c Determined by chiral GC or HPLC. d Reference 4c. e Conv. ) 50%.18
TABLE 3. Conjugate Additions on r,ꢀ-Unsaturated Ketone 5ba
entry R′MgBr
ligand
yieldb (%) dr (anti:syn)c eec (%)
1
2
3
4
MeMgBr (R,S)-L1 anti-8a
MeMgBr (S,R)-L1 syn-8a
EtMgBr (R,S)-L1 anti-8b
EtMgBr (S,R)-L1 syn-8b
73
46
89
64
98:2
14:86
92:8
> 99.5
66
> 99.5
97
FIGURE 2. Ruthenium-based metathesis catalysts: Grubbs second
generation (G-2) and Hoveyda-Grubbs second generation (HG-2).
40:60
tively. This gave, in the case of 5d and 5e, where R ) Et, a
mixture of 5 and 6 (80:20) which was not separable (Table 1,
entries 4 and 6).16 The reaction with the Grubbs second-
generation catalyst (G-2, Figure 2) was more selective (90:10);
however, this decreased the total yield of 5 (Table 1, entry 5).
The results of the subsequent asymmetric 1,4-addition reac-
tions with EtMgBr on the R,ꢀ-unsaturated esters 5a and 5d are
summarized in Table 2. Stereoselective synthesis of a 1,2-
methyl,ethyl motif was accomplished readily. Thus, depending
on the enantiomer of ligand L3 used, either anti-7a or syn-7a
was obtained in good yield and diastereoselectivity from
substrate 5a (Table 2, entries 1 and 2). The synthesis of anti-
7b, which has a diethyl motif, proceeded in good yield and
diastereoselectivity from 5d (Table 2, entry 3).16 The reaction
using the ligand (S,R)-L3 was slower, however, providing syn-
7b in 30% yield, albeit with excellent diastereoselectivity (Table
2, entry 4). Introduction of a methyl substituent at the ꢀ-position
with methyl Grignard reagent was not possible with this catalyst
system, due to the insufficient reactivity of oxo esters.17
The results of the asymmetric 1,4-addition reactions on the
R,ꢀ-unsaturated ketone 5b are summarized in Table 3. Enones
are more active Michael acceptors than esters, which allows
a Reaction conditions: 5 (1.0 equiv), CuBr ·L1 (7.0 mol %), RMgBr
(1.3 equiv), t-BuOMe, -78 °C, 18 h. b Isolated yield of the mixture of
diastereomers. c Determined by chiral GC or HPLC.
for the introduction of a second methyl group through 1,4-
addition with this catalyst system. Thus, stereoselective synthesis
of a 1,2-dimethyl motif was accomplished through 1,4-addition
with MeMgBr (Table 3, entries 1 and 2). The product anti-8a
could be obtained in high yield and excellent diastereoselectivity
and enantiomeric excess, in contrast to the syn-product, which
was obtained in lower yield and with reduced diastereoselec-
tivity. Interestingly, the enantiomeric excess of the product was
(16) All conjugate additions with substrates 5d and 5e were performed on
their mixtures with 6. The conjugate addition products of 6 were separated by
column chromatography from the products of 5.
(17) During preparation of this manuscript Loh and co-workers reported that
the use of MeMgBr was possible under certain reaction conditions with their
catalyst system: (a) Wang, S.-Y.; Lum, T.-K.; Ji, S.-J.; Loh, T.-P. AdV. Synth.
Catal. 2008, 350, 673–677. (b) Lum, T.-K.; Wang, S.-Y.; Loh, T.-P. Org. Lett.
2008, 10, 761–764.
(18) Extended reaction times to allow completion of the reaction did not
improve the yield but did lead to a reduction in diastereoselectivity and
enantiomeric excess.
6996 J. Org. Chem. Vol. 73, No. 18, 2008

Catalytic EnantioselectiVe Synthesis of Vicinal Dialkyl Arrays
TABLE 4. Conjugate Additions on r,ꢀ-Unsaturated Thioesters 5c and 5ea
entry
R
R′MgBr
catalyst
yieldb (%)
dr (anti:syn)c
eec (%)
1
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
5c
5c
5c
5c
5c
5c
5e
5e
5e
5e
MeMgBr
MeMgBr
MeMgBr
MeMgBr
EtMgBr
CuBr·(R,S)-L1
CuBr·(S,R)-L1
CuI/(R)-L4
CuI/(S)-L4
CuI/(R)-L4
anti-9a
syn-9a
anti-9a
syn-9a
anti-9b
syn-9b
anti-9c
syn-9c
anti-9c
syn-9c
59
17
96
82
91
58
67
6c
99:1
61:39
99.5:0.5
5:95
98:2
64:36
98:2
45:55
nd
12:88
99
nd
99
>99.5
94%
>99.5
>99.5
nd
2d
3
4
5
6
EtMgBr
CuI/(S)-L4
7d
8d
9
MeMgBr
MeMgBr
MeMgBr
MeMgBr
CuBr·(R,S)-L1
CuBr·(S,R)-L1
CuI/(R)-L4
<5c
71
nd
>99.5
10
CuI/(S)-L4
a Reaction conditions: 5 (1.0 equiv), CuBr ·L1 (6.0 mol %) or CuI (3.0 mol %) and L4 (3.3 mol %), RMgBr (3.0-4.0 equiv), t-BuOMe, -75 °C,
18 h. b Isolated yield of the mixture of diastereomers. c Determined by chiral GC or HPLC. d Reaction time: 40 h.
SCHEME 3. Retrosynthetic Analysis of Lasiol (10) and
Faranal (11) to a Common Intermediate 12
found to be 66%, which implies that racemization of the
substrate occurs under the reaction conditions. When the reaction
was performed with EtMgBr the same trend was observed
(Table 3, entries 3 and 4), although substantial racemization
was not observed.
Compounds containing an R,ꢀ-unsaturated thioester are more
active electrophiles than their corresponding oxo esters. Nev-
ertheless, their synthetic versatility is similar. In our earlier
workers using a desymmetrization mediated by a chiral base.21
contributions, two catalysts that perform the 1,4-addition on
thioesters effectively and selectively, Cu/JosiPhos L1 and Cu/
Tol-BINAP L4, were reported. The results of the 1,4-additions
are summarized in Table 4. Conjugate addition with methyl
Grignard to the methyl-containing substrate 5c gave product
9a with a 1,2-dimethyl motif. The performance of Tol-BINAP
L4 was better in all aspects (Table 4, entries 1-4). Although
the use of L1 provided anti-9a in good yield and excellent
stereoselectivity, L4 provided the compound in higher yield and
equally excellent selectivity. The other diastereomer syn-9a
could be obtained in good yield and excellent stereoselectivity
with ligand L4, whereas a catalyst system with ligand L1 was
significantly less active and selective (entry 4 vs entry 2).
Since then, several total syntheses and formal syntheses have
followed.22
Faranal is the trail pheromone of Monomorium pharaonis,
the pharaoh’s ant, a common pest in households, food storage
facilities, and hospitals.23 The absolute configuration of natural
faranal was established through biological tests with diastere-
omeric mixtures of faranal, where one of the stereogenic centers
was set using an enzymatic condensation.23a Some stereoselec-
tive but racemic syntheses have been published.24 The first truly
asymmetric total synthesis of natural (+)-faranal (11) involved
the resolution of a racemate25 and was followed by other routes
which made use of the chiral pool,26 chiral bases,27 or enzymatic
desymmetrization.28
The anti-diastereomer of product 9b could be obtained in
excellent selectivity using ligand L4 and EtMgBr. However,
product syn-9b could not be obtained selectively by this route
(Table 4, entries 5 and 6). Curiously, stereoselective synthesis
of anti-9c, which contains a 1,2-ethyl,methyl motif, could be
accomplished with ligand L1, while the use of L4 was necessary
to obtain the other diastereomer syn-9c.16 Hence, the two ligand
systems are complementary in this case (Table 4, entries 7-10).
Importantly, in both natural products the vicinal 1,2-dimethyl
motif has an anti configuration. Retrosynthetic analysis shows
that they can be derived from a common intermediate 12, which
(21) Kasai, T.; Watanabe, H.; Mori, K. Bioorg. Med. Chem. 1993, 1, 67–70.
(22) Catalytic asymmetric desymmetrizations: (a) Vasil’ev, A. A.; Vielhauer,
O.; Engman, L.; Pietzsch, M.; Serebryakov, E. P. Russ. Chem. Bull., Int. Ed.
2002, 51, 481–487. (b) So¨dergren, M. J.; Bertilsson, S. K.; Andersson, P. G.
J. Am. Chem. Soc. 2000, 122, 6610–6618. Chiral auxiliary-based: (c) Asano, S.;
Tamai, T.; Totani, K.; Takao, K.; Tadano, K. Synlett 2003, 2252–2254. (d)
Schneider, C. Eur. J. Org. Chem. 1998, 1661–1663.
(23) (a) Kobayashi, M.; Koyama, T.; Ogura, K.; Seto, S.; Ritter, F. J.;
Bru¨ggemann-Rotgans, I. E. M. J. Am. Chem. Soc. 1980, 102, 6602–6604. (b)
Ritter, F. J.; Bru¨ggemann-Rotgans, I. E. M.; Verwiel, P. E. J.; Persoons, C. J.;
Talman, E. Tetrahedron Lett. 1977, 18, 2617–2618.
In natural products, the 1,2-dimethyl motif is the most
common of the vicinal dialkyl arrays. It is present, for example,
in the two ant pheromones lasiol (10) and faranal (11) (Scheme
3). Lasiol is a volatile compound which was isolated from the
mandibular glands of male Lasius meridionalis ants.19 Shortly
after its discovery and racemic synthesis by Lloyd et al.,19 both
enantiomers of the pheromone lasiol were synthesized by
Kuwahara et al. from the chiral pool20 and by Mori and co-
(24) (a) Vasil’ev, A. A.; Engman, L.; Serebryakov, E. P. J. Chem. Soc., Perkin
Trans. 1 2000, 2211–2216. (b) Baker, R.; Billington, D. C.; Ekanayake, N.
J. Chem. Soc., Perkin Trans. 1 1983, 1387–1393. (c) Knight, D. W.; Ojhara, B.
J. Chem. Soc., Perkin Trans. 1 1983, 955–960.
(25) Mori, K.; Ueda, H. Tetrahedron 1982, 38, 1227–1233.
(26) Wei, S.-Y.; Tomooka, K.; Nakai, T. J. Org. Chem. 1991, 56, 5973–
5974.
(19) Lloyd, H. A.; Jones, T. H.; Hefetz, A.; Tengo¨, J. Tetrahedron Lett. 1990,
(27) (a) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997, 38, 3531–
3534. (b) Mori, K.; Murata, N. Liebigs Ann. 1995, 2089–2092.
31, 5559–5562.
´
(20) Kuwahara, S.; Shibata, Y.; Hiramatsu, A. Liebigs Ann. Chem. 1992,
993–995.
(28) Poppe, L.; Nova´k, L.; Kolonits, P.; Bata, A.; Sza´ntay, C. Tetrahedron
1988, 44, 1477–1487.
J. Org. Chem. Vol. 73, No. 18, 2008 6997

van Zijl et al.
SCHEME 4. Synthesis of Common Intermediate 12
SCHEME 5. Synthesis of (-)-Lasiol (10) from Common Intermediate anti-12
SCHEME 6. Synthesis of (+)-Faranal (11) from Precursor 19
can be obtained in turn through the allylic alkylation/cross-
metathesis/conjugate addition protocol.
The synthesis of (+)-faranal (11) from compound anti-12
started with its reduction to aldehyde 19 (Scheme 5). The
aldehyde was subsequently protected as its acetal with ethylene
glycol to give dioxolane 21 (Scheme 6). The benzyl ether was
cleaved through hydrogenolysis with Pd(OH)2 to furnish alcohol
22,32 which was converted to the alkyl iodide 14 using iodine,
triphenylphosphine, and imidazole. Compound 14 was converted
in situ to the corresponding zinc bromide with t-BuLi and ZnBr2
and used in a Negishi-coupling reaction33 with alkenyl iodide
13, a known compound which was synthesized according to
the methods of Baker et al.24b and Mori et al.,27b and catalytic
[Pd(dppf)Cl2] to obtain faranal precursor 23. Hydrolysis of the
acetal in THF and water under dilute conditions completed the
synthesis of (+)-faranal (11) in nine steps and an overall yield
of 25% from the achiral precursor 15.
Allylic alkylation of compound 1529 with MeMgBr using the
preformed complex CuBr ·(R,RFc)-L2 as the catalyst gave
product 16 in excellent yield, regioselectivity, and enantiose-
lectivity (Scheme 4). Cross-metathesis with thioacrylate 4c gave
R,ꢀ-unsaturated thioester 17 in good yield together with a small
percentage of the dimer 18 (ratio ) 94:6).30 Conjugate addition
to 17 with MeMgBr and (R)-L4 as the ligand gave anti-12 in
good yield and excellent diastereoselectivity. The other dias-
tereomer syn-12 could be obtained in high diastereoselectivity
by using ligand (S)-L4 instead. In both cases the opposite
enantiomer of the major diastereomer could not be detected,
which highlights the potential of this protocol in synthesis.
(-)-Lasiol (10), which has the absolute (2S,3S)-configura-
tion,31 was synthesized from the common intermediate anti-
12. The thioester was first reduced to aldehyde 19 using
DIBAL-H (Scheme 5). A Wittig reaction with isopropyltriph-
enylphosphonium iodide was performed to obtain benzyl ether
20, followed by quantitative deprotection of the alcohol using
a dissolving metal reduction. Thus, (-)-lasiol (10) was synthe-
sized in six steps from 15 in an overall yield of 60%.
Conclusions
In summary, a new protocol for the stereoselective synthesis
of vicinal dialkyl arrays is reported. The protocol, which
combines enantioselective allylic alkylation, cross-metathesis,
and enantioselective 1,4-addition, allows for the preparation of
both of the diastereomers in enantiopure form with judicious
(29) Kottirsch, G.; Koch, G.; Feifel, R.; Neumann, U. J. Med. Chem. 2002,
45, 2289–2293.
(30) The dimer 18 could not be separated from 17. It could be separated
from the product of the following conjugate addition, however. Pure 17 could
be obtained via cross-metathesis with methyl acrylate followed by transesteri-
fication. For this route and the separate synthesis and characterization of 18, see
the Supporting Information.
(32) Certain reaction conditions, such as extended reaction times or the use
of Pd/C as the catalyst, led to the formation of a complex mixture of products,
probably due to partial trans-acetalization. For precedents, see: (a) Andrey, O.;
Vidonne, A.; Alexakis, A. Tetrahedron Lett. 2003, 44, 7901–7904. (b) Bo¨rjesson,
L.; Cso¨regh, I.; Welch, C. J. J. Org. Chem. 1995, 60, 2989–2999.
(33) (a) Negishi, E.; Liou, S.-Y.; Xu, C.; Huo, S. Org. Lett. 2002, 4, 261–
264. (b) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298–3299.
(31) Despite selective syntheses of both enantiomers of lasiol, the absolute
configuration of the natural compound has not been established.
6998 J. Org. Chem. Vol. 73, No. 18, 2008

Catalytic EnantioselectiVe Synthesis of Vicinal Dialkyl Arrays
(-)-(S,E)-5-Phenylhex-3-en-2-one (5b). A solution of terminal
olefin 2a (0.50 mmol) in dry CH2Cl2 (2.0 mL) was stirred under a
N2 atmosphere at rt. Methyl vinyl ketone 4b (2.5 mmol) was added
via syringe in one portion, followed by Hoveyda-Grubbs second-
generation catalyst (2 mol %, 6.3 mg). The mixture was stirred
overnight. After completion of the reaction (20 h), the solvent was
evaporated, and the crude mixture was subjected to flash chroma-
tography (silica gel, pentane-pentane/ethyl acetate 99.5:0.5, v/v)
affording product 5b: 90% yield; >99.5% ee, [R]D ) -20.6 (c
choice of the ligands in the copper catalyzed reactions. The anti-
diastereomer of the products was formed more easily than the
syn-product in most cases, but on many occasions it was possible
to form either diastereomer in high diastereoselectivity and
excellent enantioselectivity.
The protocol’s utility was demonstrated through the total
syntheses of the ant pheromones (-)-lasiol and (+)-faranal in
six and nine steps, respectively, from an achiral precursor. The
products were obtained with excellent diastereomeric and
enantiomeric purity and high overall yields. This makes these
approaches the shortest, highest yielding, and most selective
catalytic asymmetric total syntheses of these pheromones
reported so far and very competitive with existing methods that
employ the chiral pool, chiral auxiliaries, or other methods based
on stoichiometric chiral reagents.
1
1.0, CHCl3); Rf ) 0.50 (pentane/EtOAc, 9:1, v/v); H NMR (400
MHz, CDCl3) δ 1.43 (d, J ) 6.8 Hz, 3H), 2.24 (s, 3H), 3.62-3.65
(m, 1H), 6.07 (dd, J ) 16.0 and 1.2 Hz, 1H), 6.92 (dd, J ) 16.0
and 6.8 Hz, 1H), 7.17-7.35 (m, 5H); 13C NMR (50 MHz, CDCl3)
δ 20.4, 27.2, 42.5, 127.1, 127.6, 129.0, 129.9, 143.5, 151.9, 199.2;
MS (EI) m/z 174 (M+, 56), 131 (100), 91 (30); HRMS calcd for
C12H14O 174.1045, found 174.1043. Enantiomeric excess was
determined by chiral HPLC analysis (Chiralcel OB-H, heptane/i-
PrOH, 98/2, v/v). Retention times (min): 36.8 (R) and 40.9 (S).
(-)-S-Ethyl (S,E)-4-Phenylpent-2-enethioate (5c). A solution
of terminal olefin 2a (0.50 mmol) in dry CH2Cl2 (2.0 mL) was
stirred under a N2 atmosphere at rt. Ethyl thioacrylate (4c) (1.0
mmol, 116 µL) was added via syringe in one portion, followed by
Hoveyda-Grubbs second-generation catalyst (5 mol %, 16.0 mg).
After 8 h, another portion of Hoveyda-Grubbs second-generation
catalyst (5 mol %, 16.0 mg) was added. Upon complete conversion
of 2a (40 h), the solvent was evaporated, and the crude mixture
was subjected to flash chromatography (silica gel, pentane-pentane/
ethyl acetate 99.5:0.5, v/v) affording the product 5c: 83% yield;
97% ee; [R]D ) -7.0 (c 1.0, CHCl3); Rf ) 0.48 (pentane/Et2O,
Experimental Section
(-)-(S,E)-Methyl 4-Phenylpent-2-enoate (5a).4c In a Schlenk
tube equipped with septum and stirring bar were dissolved
CuBr·SMe2 (15.0 µmol, 3.08 mg) and ligand L2 (18.0 µmol, 12.4
mg) in CH2Cl2 (3.0 mL), and the mixture was stirred under argon
at rt for 10 min. The mixture was cooled to -75 °C, and MeMgBr
(3.0 M solution in Et2O, 1.73 mmol, 0.575 mL) was added
dropwise. Following this, cinnamyl bromide (296 mg, 1.50 mmol)
was added dropwise over 15 min via a syringe pump. Once the
addition was complete, the resulting mixture was stirred at - 75
°C for 4 h. The reaction was quenched by addition of MeOH (0.5
mL), and the mixture was allowed to reach rt. Aqueous NH4Cl
solution (1 M, 2 mL) was added to the mixture. The organic layer
was separated, and the resulting aqueous layer was extracted with
Et2O (0.5 mL, 3×). The combined organic layers were dried and
concentrated to a yellow oil, which was dissolved in CH2Cl2 (3
mL) in a dry Schlenk tube under argon. Methyl acrylate (645 mg,
7.5 mmol) and Hoveyda-Grubbs second-generation catalyst (18
mg, 0.03 mmol) were added sequentially producing a light green
solution which was stirred for 36 h at rt. The mixture was then
concentrated in vacuo to a dark brown oil. Purification of this
residue by silica gel chromatography (SiO2, 2:98 to 5:95 Et2O/
pentane) afforded 5a as a colorless oil: 66% yield; [R]D ) -20 (c
1
95:5, v/v); H NMR (400 MHz, CDCl3) δ 1.27 (t, J ) 7.2 Hz,
3H), 1.43 (d, J ) 7.6 Hz, 3H), 2.93 (q, J ) 7.2 Hz, 2H), 3.56-3.62
(m, 1H), 6.07 (dd, J ) 15.6 and 1.6 Hz, 1H), 7.03 (dd, J ) 15.6
and 6.8 Hz, 1H), 7.20-7.33 (m, 5H); 13C NMR (50 MHz, CDCl3)
δ 14.8, 20.2, 23.1, 42.0, 126.8, 127.4, 128.7, 143.1, 148.4, 190.2;
MS (EI) m/z 220 (M+, 24), 159 (100), 115 (37); HRMS calcd for
C13H16OS 220.0922, found 220.0921. Enantiomeric excess was
determined by chiral HPLC analysis (Chiracel OD-H, heptane/i-
PrOH, 99.5:0.5, v/v). Retention times (min): 18.5 (S) and 21.2 (R).
(+)-(3S,4S)-Methyl 3-Ethyl-4-phenylpentanoate (anti-7a).4c In
a Schlenk tube were dissolved CuBr ·SMe2 (8.0 µmol, 1.62 mg)
and ligand (R,S)-L3 (9.4 µmol, 5.60 mg) in CH2Cl2 (1.5 mL), and
the mixture was stirred under argon at rt for 10 min. The mixture
was cooled to -75 °C, and EtMgBr (3.0 M in Et2O, 0.78 mmol)
was added dropwise. After the mixture was stirred for 5 min at
that temperature, a solution of 5a (30 mg, 0.16 mmol) in CH2Cl2
(0.25 mL) was added dropwise over 10 min. After the mixture was
stirred at -75 °C for 22 h, MeOH (0.25 mL) and aq NH4Cl (1 M,
2 mL) were added sequentially, and the mixture was warmed to rt.
After extraction with Et2O (0.5 mL, 3 ×), the combined organic
layers were dried and concentrated to a yellow oil which was
purified by flash chromatography (SiO2, 2:99 Et2O/pentane) to yield
anti-7a as a colorless oil: 81% yield; 98% de, >99.5% ee (major
diastereomer); [R]D ) + 25 (c 0.2, CHCl3); 1H NMR δ 7.26-7.12
(m, 5H), 3.57 (s, 3H), 2.82-2.73 (m, 1H), 2.30-2.15 (m, 2H),
2.08-1.97 (m, 1H), 1.38-1.27 (m, 1H), 1.17 (d, J ) 7.1 Hz, 3H),
1.14-1.06 (m, 1H), 0.81 (t, J ) 7.4 Hz, 3H); 13C NMR δ 174.1,
145.6, 128.2, 127.7, 126.0, 51.4, 42.8, 41.4, 35.3, 24.4, 17.1, 11.1;
MS (EI) m/z 220 (M+, 20), 189 (11), 146 (43), 105 (100) 57 (21);
HRMS calcd for C14H20O2 220.1463, found 220.1457. Diastereo-
selectivity was determined using a Chiraldex G-TA column (30 m
× 0.25 mm), 100 °C isothermic, retention times (min): 59.6 (minor:
3R,4S and 3S,4R) and 62.4 (major, 3S,4S). Alternatively, the
1
0.3, CHCl3); H NMR δ 7.29-7.25 (m, 2H), 7.21-7.14 (m, 3H),
7.07 (dd, J ) 15.7 and 6.7 Hz, 1H), 5.77 (dd, J ) 15.7 and 1.5 Hz,
1H), 3.67 (s, 3H), 3.61-3.54 (m, 1H), 1.38 (d, J ) 7.1 Hz, 3H);
13C NMR δ 167.1, 152.9, 143.2, 128.6, 127.3, 126.7, 119.6, 51.4,
42.0, 20.1; MS (EI) m/z 190 (M+, 40), 159 (18), 131 (100), 91
(22), 51 (13); HRMS calcd for C12H14O2 190.0994, found 190.0995.
(+)-(S)-3-phenyl-1-butene (2a).4c To a stirred solution of
CuBr·SMe2 (15 µmol, 3.1 mg) and ligand L2 (18 µmol, 12.4 mg)
in dry CH2Cl2 (2 mL), at -75 °C, under a N2 atmosphere, was
added MeMgBr (1.73 mmol, 3.0 M solution in Et2O) dropwise via
syringe. A solution of cinnamyl bromide (1.50 mmol, 296 mg) in
CH2Cl2 (0.6 mL) was then added dropwise, and the reaction mixture
was stirred overnight at -75 °C. After 16 h, MeOH (1 mL) was
added, and the reaction was allowed to reach rt. Aqueous NH4Cl
(2 mL) was added, and the biphasic system was stirred for 10 min.
The organic layer was separated, and the aqueous layer was
extracted with Et2O (3 × 2 mL). Combined organic layers were
dried (Na2SO4), and the solvent was evaporated. Flash chromatog-
raphy (silica gel, pentane) afforded a mixture of SN2′ (2) and SN2
(3) products. Combined yield: 91%; 2/3 ratio ) 98:2; ee >99.5%;
[R]D ) +7.4 (c 1.0, CHCl3) [lit.4c [R]D ) +5.4 (c 1.2, CHCl3)]; Rf
) 0.80 (pentane); 1H NMR (300 MHz, CDCl3) δ 1.37 (d, J ) 7.0
Hz, 3H), 3.45-3.52 (m, 1H), 5.02-5.08 (m, 2H), 6.02 (ddd, J )
16.8, 10.2 and 6.6 Hz, 1H), 7.17-7.36 (m, 5H); MS (EI) m/z 132
(M+, 27), 117 (100), 91 (25). Enantiomeric excess was determined
by chiral GC 34analysis, CP-Chiralsil-Dex-CB (25 m × 0.25 mm),
initial temperature 75 °C, isothermic, retention times (min): 13.9
(R) and 14.3 (S). Retention time 3a: 26.7 min.
1
diastereoselectivity was determined by H NMR spectroscopy, by
integration of the signals at 3.5 ppm corresponding to the methyl
ester group. Enantiomeric excess was determined using a Chiraldex
(34) (a) Concello´n, J. M.; Rodríguez-Solla, H.; Concello´n, C.; Díaz, P. Synlett
2006, 837–840. (b) Ibarra, C. A.; Arias, S.; Ferna´ndez, M. J.; Sinisterra, J. V.
J. Chem. Soc., Perkin Trans. 2 1989, 503–508. (c) Heathcock, C. H.; Kiyooka,
S.; Blumenkopf, T. A. J. Org. Chem. 1984, 49, 4214–4223.
J. Org. Chem. Vol. 73, No. 18, 2008 6999

van Zijl et al.
B-PM column (30 m-0.25 mm), 85 °C isothermic. Retention times
(min): 240.5 (3S,4S), 245.5 (3R,4R).
by chiral HPLC analysis (Chiralcel OJ-H, heptane/i-PrOH, 99/1,
v/v, 40 °C). Retention times (min): 20.8 (4S,5R) and 22.4 (4R,5S).
(+)-S-Ethyl (3S,4S)-3-Methyl-4-phenylpentanethioate (anti-9a).
In a Schlenk tube CuI (3.3 µmol, 0.63 mg) and (R)-L4 (3.6 µmol,
2.46 mg) were dissolved in CH2Cl2 (0.5 mL) and stirred under a
N2 atmosphere at rt for 50 min. The solvent was evaporated, and
the residue was dissolved in t-BuOMe (1.2 mL). The mixture was
cooled to -75 °C, and MeMgBr (3.0 M in Et2O, 0.44 mmol) was
added dropwise. After the mixture was stirred for 5 min at that
temperature, a solution of 5c (0.11 mmol) in CH2Cl2 (0.4 mL) was
added dropwise over 10 min. After the mixture was stirred at -75
°C for 18 h, MeOH (0.25 mL) and NH4Cl (1 M, 2 mL) were added
sequentially, and the mixture was warmed to rt. After extraction
with Et2O (0.5 mL, 3×), the combined organic layers were dried
and concentrated to a yellow oil, which was subjected to flash
chromatography (silica gel, pentane/Et2O 99.75:0.25, v/v) to afford
syn-9a and anti-9a: 96% yield, 99% de, 99% ee (major diastere-
omer); [R]D ) + 31.4 (c 0.35, CHCl3); Rf ) 0.50 (pentane/Et2O
(+)-(3R,4S)-Methyl 3-Ethyl-4-phenylpentanoate (syn-7a).4c As
for anti-7a, but using (S,R)-L3 instead of (R,S)-L3: 84% yield; 92%
de, >99.5% ee (major diastereomer); [R]D ) + 6 (c 0.6, CHCl3);
1H NMR δ 7.24-7.20 (m, 2H), 7.14-7.11 (m, 3H), 3.53 (s, 3H),
2.71-2.67 (m, 1H), 2.16-2.01 (m, 3H), 1.44-1.29 (m, 2H), 1.19
(d, J ) 7.2 Hz, 3H), 0.83 (t, J ) 7.4 Hz, 3H); 13C NMR δ 174.0,
145.6, 128.2, 127.8, 126.1, 51.3, 42.5, 41.8, 36.3, 23.1, 18.2, 10.4;
MS (EI) m/z 220 (M+, 18), 189 (12), 146 (58), 105 (100); HRMS
calcd for C14H20O2 220.1463, found 220.1462. Diastereoselectivity
was determined using a Chiraldex G-TA column (30 m × 0.25
mm), 100 °C, retention times (min): 59.6 (major: 3R,4S), 62.4
(minor: 3S,4S) and 63.3 (minor: 3R,4R). Alternatively, the de was
determined by 1H NMR spectroscopy by integration of the signals
at 3.57 and 3.53 ppm corresponding to the methyl ester groups.
Enantiomeric excess was determined using a CP Chiralsil Dex CB
column (25m × 0.25 mm), initial T ) 70 °C, gradient: 3 °C/min
to 110 °C, 110 °C isothermic, retention times (min): 78.5 (3S,4R),
80.3 (3R,4S).
1
95:5, v/v); H NMR (400 MHz, CDCl3) δ 0.80 (d, J ) 6.8 Hz,
3H), 1.24 (t, J ) 7.2 Hz, 3H), 1.27 (d, J ) 6.4 Hz, 3H), 2.24-2.36
(m, 2H), 2.62-2.68 (m, 2H), 2.87 (q, J ) 7.6 Hz, 2H), 7.15-7.31
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 14.8, 17.2, 18.5, 23.3, 37.0,
44.5, 48.8, 126.1, 127.8, 128.1, 144.8, 199.3; MS (EI) m/z 236 (M+,
12), 175 (100), 132 (35), 105 (66), 91 (30); HRMS calcd for
C14H20OS 236.1235, found 236.1244. Diastereoisomeric ratio was
determined by chiral GC analysis, Chiralsil G-TA (25 m × 0.25
mm), initial temperature 75 °C, gradient: 3 °C/min; retention times
(min): 30.0 (syn) and 30.6 (anti). Alternatively, the dr was
determined by 1H NMR spectroscopy, by the comparison of
PhCHCH3 signal (doublet, 0.80 ppm for anti, 0.95 ppm for syn).
Enantiomeric excess was determined by chiral HPLC analysis
(Chiralcel OD-H, heptane/i-PrOH, 99/1, v/v, 40 °C). Retention times
(min): 12.3 (3S,4S) and 13.5 (3R,4R).
(+)-S-Ethyl (3R,4S)-3-Methyl-4-phenylpentanethioate (syn-9a).
The same procedure as for anti-9a however using (S)-L4 instead
of (R)-L4. The reaction afforded a mixture of syn and anti isomers:
82% yield; 90% de, >99.5% ee (major diastereomer); [R]D ) +
23.0 (c 1.0, CHCl3); Rf ) 0.50 (pentane/Et2O 95:5, v/v); 1H NMR
(400 MHz, CDCl3) δ 0.95 (d, J ) 6.8 Hz, 3H), 1.21 (t, J ) 7.2
Hz, 3H), 1.25 (d, J ) 6.4 Hz, 3H), 2.16-2.33 (m, 2H), 2.44-2.62
(m, 2H), 2.83 (q, J ) 7.6 Hz, 2H), 7.16-7.33 (m, 5H); 13C NMR
(50 MHz, CDCl3): δ 14.8, 16.6, 18.0, 23.2, 37.3, 44.7, 49.6, 126.2,
127.6, 128.3, 145.7, 199.4; MS (EI) m/z 236 (M+, 12), 175 (100),
132 (43), 105 (64), 91 (34); HRMS calcd for C14H20OS 236.1235,
found 236.1247. Diastereoisomeric ratio was determined with by
GC analysis, Chiralsil G-TA (25 m × 0.25 mm), initial temperature
75 °C, gradient: 3 °C/min; retention times (min): 30.0 (syn) and
30.6 (anti). Alternatively, the dr was determined by 1H NMR
spectroscopy, by the comparison of PhCHCH3 signal (doublet, 0.80
ppm for anti, 0.95 ppm for syn). Enantiomeric excess was
determined on a derivative of syn-9a, the tertiary alcohol (4R,5S)-
2,4-dimethyl-5-phenylhexan-2-ol: To a cooled (0 °C) solution of a
sample of syn-9a in Et2O was added MeMgBr (ca. 5 equiv), the
reaction was heated at reflux for 2 h, quenched with satd aqueous
NH4Cl and extracted with Et2O. GC analysis was performed on a
crude sample of the tertiary alcohol: CP Chiralsil Dex CB column
(25 m × 0.25 mm), initial T ) 70 °C, gradient: 3 °C/min to 150
°C, 150 °C isothermic. Retention times (min): 30.1 (4S,5R), 30.4
(4R,5S).
(+)-(4S,5S)-4-Methyl-5-phenylhexan-2-one (anti-8a). In a
Schlenk tube, (R,S)-L1 (7.5 µmol, 5.54 mg) was dissolved in
t-BuOMe (1.0 mL) and stirred under a N2-atmosphere at rt for 10
min. The mixture was cooled to -75 °C, and MeMgBr (0.15 mmol,
3.0 M solution in Et2O) was added dropwise. After the mixture
was stirred for 5 min at that temperature, a solution of 5b (0.11
mmol, 20 mg) in dry t-BuOMe (0.5 mL) was added dropwise over
10 min. After 16 h, methanol (0.5 mL) was added, and the mixture
was allowed to reach rt. Aqueous NH4Cl (2 mL) was added, and
the biphasic system was stirred for 10 min. The organic layer was
separated, and the aqueous layer was extracted with Et2O (2 × 3
mL). Combined organic layers were dried (MgSO4), and the solvent
was evaporated. Flash chromatography (silica gel, pentane-pentane/
Et2O, 99.5:0.5, v/v) afforded a mixure of syn-8a and anti-8a: 73%
yield, 96% de, >99.5% ee (major diastereomer); [R]D ) +12.5 (c
1
1.0, CHCl3); Rf ) 0.52 (pentane/EtOAc, 9:1, v/v); H NMR (300
MHz, CDCl3) δ 0.79 (d, J ) 6.3 Hz, 3H) 1.27 (d, J ) 6.9 Hz, 3H),
2.13 (s, 3H), 2.09-2.34 (m, 2H), 2.47-2.53 (m, 1H), 2.60-2.70
(m, 1H), 7.15-7.32 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 17.6,
18.1, 30.5, 35.2, 44.5, 48.2, 126.0, 127.9, 128.1, 145.1, 208.9; MS
(EI) m/z 190 (M+, 8), 132 (100), 105 (86); HRMS calcd for C13H18O
190.1358, found 190.1352. Diastereoisomeric ratio and enantiomeric
excess were determined by chiral GC analysis, CP Chiralsil Dex
CB (25 m × 0.25 mm), initial temperature 75 °C, gradient: 3 °C/
min; retention times (min): 26.4 (syn) and 25.8 (4S,5S), 26.1
(4R,5R). Alternatively, the dr was determined by 1H NMR
spectroscopy by comparison of COCH3 signal (2.13 ppm for anti,
2.00 ppm for syn).
(+)-(4R,5S)-4-Methyl-5-phenylhexan-2-one (syn-8a). The same
procedure as for anti-8a but using (S,R)-L1 instead of (R,S)-L1.
Reaction time: 18 h. The reaction afforded a mixture of syn and
anti isomers: 46% yield, 72% de, 66% ee (major diastereomer);
[R]D ) +4.7 (c 0.3, CHCl3, 84% ee, 92% de);35 Rf ) 0.58 (pentane/
EtOAc, 9:1, v/v); 1H NMR (300 MHz, CDCl3) δ 0.94 (d, J ) 6.3
Hz, 3H), 1.25 (d, J ) 6.9 Hz, 3H), 2.00 (s, 3H), 2.09-2.34 (m,
3H), 2.45-2.58 (m, 1H), 7.15-7.32 (m, 5H); 13C NMR (50 MHz,
CDCl3): δ 17.4, 18.5, 30.4, 35.5, 45.1, 49.4, 126.1, 127.6, 128.3,
146.2, 209.0; MS (EI) m/z 190 (M+, 8), 149 (35), 132 (100), 105
(75); HRMS calcd for C13H18O 190.1358, found 190.1349. Dias-
tereoisomeric ratio was determined by chiral GC analysis, CP
Chiralsil Dex CB (25 m × 0.25 mm), initial temperature 75 °C,
gradient: 3 °C/min; retention times (min): 26.4 (syn) and 25.8
(4S,5S), 26.1 (4R,5R). Alternatively, the dr was determined by 1H
NMR spectroscopy, by the comparison of COCH3 signal (2.13 ppm
for anti, 2.00 ppm for syn). Enantiomeric excess was determined
(-)-S-Ethyl (E,4S)-(2)-5-(Benzyloxy)-4-methyl-2-pentenethio-
ate (17).36 In a dry Schlenk tube, under a N2 atmosphere,
Hoveyda-Grubbs second-generation catalyst (50 µmol, 31.3 mg)
was added to a solution of S-ethyl thioacrylate 4c (2.0 mmol, 229
µL) and 16 (1.0 mmol, 176 mg) in CH2Cl2 (2.5 mL). The resulting
green solution was heated for 6 h at reflux temperature. The mixture
was allowed to cool, a second portion of the catalyst was added
(35) Optical rotation measured of the product of a reaction with reaction
time 3 h, which had lower conversion and yield.
(36) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50, 709–
710.
7000 J. Org. Chem. Vol. 73, No. 18, 2008

Catalytic EnantioselectiVe Synthesis of Vicinal Dialkyl Arrays
(50 µmol, 31.3 mg), and the mixture was heated for another 18 h
at reflux temperature. The mixture was then concentrated in vacuo
and purified by flash chromatography (SiO2, 5:95 Et2O/pentane, Rf
) 0.5), which afforded an inseparable mixture of 17 and the side
product 18 (236 mg, ratio 17:18 ) 20:1, 83% corrected yield 17)
as a colorless oil: 94% ee; [R]D ) - 17.6 (c 1.9, CHCl3); 1H NMR
δ 7.37-7.26 (m, 5H), 6.88 (dd, J ) 7.0 and 15.7 Hz, 1H), 6.14
(dd, J ) 1.4 and 15.7 Hz, 1H), 4.52 (s, 2H), 3.44-3.37 (m, 2H),
2.95 (q, J ) 7.4 Hz, 2H), 2.69-2.61 (m, 1H), 1.28 (t, J ) 7.4 Hz,
3H), 1.10 (d, J ) 6.8 Hz, 3H); 13C NMR δ 190.1, 146.9, 138.1,
128.3, 128.2, 127.6, 127.5, 73.7, 73.1, 36.7, 23.1, 16.0, 14.8; MS
(EI) m/z 264 (M+, 0.2), 235 (2), 203 (4), 174 (11), 145 (9), 117
(12), 92 (8), 91 (100), 83 (6), 82 (14), 65 (6); HRMS calcd for
C15H20SO2 264.1187, found 264.1184. Enantiomeric excess was
determined by chiral HPLC analysis, Chiralcel OB-H (98% heptane/
i-PrOH), 40 °C. Retention times (min): 20.7 (S-enantiomer) and
26.3 (R-enantiomer).
(+)-S-Ethyl (3S,4S)-5-(Benzyloxy)-3,4-dimethylpentanethioate
(anti-12). A dry Schlenk tube equipped with septum and stirring
bar was charged with CuI (42 µmol, 8.0 mg), (R)-Tol-BINAP (46
µmol, 31.2 mg), and t-BuOMe (11.0 mL) and stirred under a N2
atmosphere at rt until a yellow color appeared. The mixture was
cooled to -70 °C, methyl Grignard reagent (5.6 mmol, 3 M solution
in Et2O, 1.85 mL) was added dropwise, and the mixture was stirred
for 10 min. Unsaturated thioester 17 (contaminated with 18) (1.39
mmol, 94 wt %, 391 mg) was added dropwise as a solution in 3.5
mL of CH2Cl2 at that temperature. The resulting mixture was stirred
at -70 °C for 16 h. The reaction was quenched by addition of
MeOH (2 mL) and satd aqueous NH4Cl solution (10 mL), and the
mixture was removed from the cooling bath and allowed to reach
rt. Subsequently, enough H2O to dissolve all salts and 15 mL of
Et2O were added, the organic layer was separated, and the resulting
aqueous layer was extracted with Et2O (2 × 10 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo to yield a yellow oil, which was purified by flash chroma-
tography (SiO2, 5:95 Et2O/pentane, Rf ) 0.35), affording anti-12
as a colorless oil (352 mg): 91% yield; 98:2 dr, >99.5% ee (major
diastereomer); [R]D ) +5.1 (c 2.4, CHCl3); 1H NMR δ 7.35-7.26
(m, 5H), 4.50 (s, 2H), 3.39 (dd, J ) 6.5 and 9.3 Hz, 1H), 3.29 (dd,
J ) 6.4 and 9.3 Hz, 1H), 2.88 (q, J ) 7.4 Hz, 2H), 2.62 (dd, J )
4.3 and 14.4 Hz, 1H), 2.35 (dd, J ) 9.7 and 14.4 Hz, 1H),
2.28-2.18 (m, 1H), 1.87-1.76 (m, 1H), 1.25 (t, J ) 7.4 Hz, 3H),
0.93 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 7.0 Hz, 3H); 13C NMR δ
199.6, 138.6, 128.3, 127.5, 127.4, 73.2, 73.0, 47.8, 37.8, 32.9, 23.3,
16.8, 14.8, 13.9; MS (EI) m/z 280 (M+, 0.3), 219 (14), 92 (9), 91
(100); HRMS calcd for C16H24SO2 280.1497, found 280.1498.
Enantiomeric excess and diastereomeric ratio were determined by
chiral HPLC analysis, Chiralcel OB-H (99.7% heptane/i-PrOH),
40 °C. Retention times (min): 25.4 (3R,4S), 29.0 (3S,4S [major]),
33.5 (3R,4R) and 38.1 (3S,4R).
) 7.0 Hz, 3H); 13C NMR δ 203.0, 138.4, 128.3, 127.5, 127.5, 73.1,
73.0, 47.3, 37.8, 29.5, 17.6, 13.5; MS (EI) m/z 220 (M+, 5), 177
(6), 129 (7), 113 (22), 111 (6), 108 (27), 107 (32), 96 (7), 95 (6),
92 (35), 91 (100), 83 (12), 81 (11), 79 (6), 77 (7), 71 (20), 70 (8),
69 (15), 65 (13); HRMS calcd for C14H20O2 220.1463, found
220.1455.
(+)-Benzyl (2S,3S)-2,3,6-Trimethyl-5-heptenyl Ether (20). In a
dry Schlenk tube equipped with septum and stirring bar was
suspended isopropyltriphenylphosphonium iodide (1.33 mmol, 577
mg) in THF (8.5 mL) under a N2 atmosphere and the mixture cooled
to 0 °C. A solution of n-BuLi (1.33 mmol, 1.6 M in hexanes, 0.83
mL) was added dropwise, and the mixture was stirred at 0 °C for
15 min. The resulting red mixture was cooled to -78 °C and stirred
for 15 min at this temperature, after which time a solution of
aldehyde 19 (0.43 mmol, 94.9 mg) in THF (4.5 mL) was added
dropwise. The reaction mixture was stirred at -78 °C for 60 min
and then at 0 °C for 1.5 h, and then a satd aqueous solution of
NH4Cl (1 mL) was added. The mixture was diluted with EtOAc
(20 mL) and washed with a satd aqueous solution of NH4Cl (2 ×
5 mL). The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography (SiO2, 1:99 Et2O/pentane, Rf ) 0.55), which afforded 20
as a colorless oil (95 mg): 90% yield; [R]D ) +8.4 (c 2.1, CHCl3);
1H NMR δ 7.36-7.25 (m, 5H), 5.12 (t, J ) 7.2 Hz, 1H), 4.50 (s,
2H), 3.46 (dd, J ) 5.7 and 9.1 Hz, 1H), 3.29 (dd, J ) 7.3 and 9.1
Hz, 1H), 2.06-1.99 (m, 1H), 1.86-1.74 (m, 2H), 1.70 (s, 3H),
1.59 (s, 3H), 1.63-1.54 (m, 1H), 0.94 (d, J ) 6.9 Hz, 3H), 0.86
(d, J ) 6.9 Hz, 3H); 13C NMR δ 138.8, 131.8, 128.3, 127.5, 127.4,
123.8, 73.8, 73.0, 37.8, 35.8, 31.5, 25.8, 17.8, 16.9, 14.4; MS (EI)
m/z 247 (7), 246 (M+, 38), 175 (14), 155 (9), 138 (8), 137 (42), 97
(23), 96 (11), 95 (20), 92 (12), 91 (100), 83 (10), 81 (17), 71 (6),
70 (6), 69 (53), 65 (7), 57 (10), 55 (16); HRMS calcd for C17H26O
246.1984, found 246.1979.
(-)-Lasiol [(2S,3S)-2,3,6-Trimethyl-5-hepten-1-ol] (10).19-22 Liq-
uid NH3 was condensed in a dry Schlenk flask under a N2
atmosphere at -78 °C. A second dry Schlenk flask under N2 was
equipped with septum and stirring bar, charged with pieces of Li
(5.8 mmol, 40 mg) and THF (3.0 mL), and cooled to -78 °C. The
flasks were connected via cannula, and the flask with NH3 was
removed from the cooling bath allowing the NH3 (ca. 10 mL) to
distill into the second flask. After the dark blue solution was stirred
at -78 °C for 30 min, a solution of 20 (0.34 mmol, 84.3 mg) in
THF (2.0 mL) was added dropwise. After 20 min, solid NH4Cl
(1.5 g) was added carefully, and the NH3 was allowed to evaporate
using a waterbath at rt. A satd aqueous solution of NaCl (10 mL)
was added, followed by just enough H2O to dissolve all of the salts.
The organic layer was separated, and the resulting water layer was
extracted with Et2O (3×, 15 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (SiO2, 20:80 Et2O/
pentane, Rf ) 0.4) to afford (-)-lasiol 10 as a colorless liquid (52
(+)-(3S,4S)-5-(Benzyloxy)-3,4-dimethylpentanal (19). Thioester
anti-12 (0.36 mmol, 101 mg) was dissolved in CH2Cl2 (3.5 mL)
under a N2 atmosphere in a dry Schlenk tube equipped with stirring
bar and septum. The solution was cooled to -55 °C, and a solution
of diisobutylaluminum hydride (0.55 mmol, 1.0 M in CH2Cl2, 0.55
mL) was added dropwise. After the mixture was stirred at -55 °C
for 2 h, a satd aqueous solution of Rochelle salt (5 mL) was added
and the resulting mixture was stirred vigorously at rt for 1 h. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 5 mL). The combined organic layers were washed
with brine (1 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by flash chromatography (SiO2, 10:90 Et2O/
pentane, Rf ) 0.35), which afforded 19 as a colorless oil (76 mg):
mg): 99% yield; [R]D ) -10.2 (c 1.9, n-hexane) [lit.22c [R]D
)
1
-12.1 (c 0.995, n-hexane)]; H NMR δ 5.12 (br t, J ) 7.2 Hz,
1H), 3.65 (dd, J ) 5.4 and 10.6 Hz, 1H), 3.46 (dd, J ) 7.1 and
10.6 Hz, 1H), 2.00-2.07 (m, 1H), 1.84-1.51 (m, 10H, containing
two singlets of each 3H: 1.70 and 1.60 ppm), 0.93 (d, J ) 6.8 Hz,
3H), 0.87 (d, J ) 6.8 Hz, 1H); 13C NMR δ 132.0, 123.5, 66.0,
40.2, 35.4, 31.3, 25.8, 17.7, 16.9, 13.7; spectroscopic data were in
good agreement with those reported in literature;19 MS (EI) m/z
156 (M+, 38), 139 (7), 138 (10), 137 (9), 125 (6), 123 (33), 109
(19), 97 (21), 96 (34), 95 (25), 86 (6), 85 (32), 83 (13), 82 (24), 81
(21), 71 (16), 70 (55), 69 (100), 68 (12), 67 (16), 59 (10), 58 (7),
57 (19), 56 (17), 55 (46), 53 (11); HRMS calcd for C10H20O
156.1514, found 156.1519.
1
96% yield; [R]D ) + 14.7 (c 1.4, CHCl3); H NMR δ 9.72 (dd, J
) 1.6 and 2.9 Hz, 1H), 7.37-7.26 (m, 5H), 4.50 (d, J ) 12.0 Hz,
1H), 4.46 (d, J ) 12.0 Hz, 1H), 3.36 (dd, J ) 7.0 and 9.3 Hz, 1H),
3.32 (dd, J ) 6.0 and 9.4 Hz, 1H), 2.46 (ddd, J ) 1.4, 4.3 and
15.9 Hz, 1H), 2.35-2.25 (m, 1H), 2.17 (ddd, J ) 2.9, 9.2 and 15.8
Hz, 1H), 1.89-1.78 (m, 1H), 0.95 (d, J ) 6.9 Hz, 3H), 0.89 (d, J
(+)-2-((2S,3S)-4-(Benzyloxy)-2,3-dimethylbutyl)-1,3-dioxolane (21).
A catalytic amount of p-TsOH·H2O (0.26 mmol, 50 mg) was added
to a stirred suspension of aldehyde 19 (4.7 mmol, 1.04 g), ethylene
glycol (30 mmol, 1.5 mL), and 5.0 g of MgSO4 in 60 mL of
benzene. The mixture was heated at reflux temperature for 14 h,
J. Org. Chem. Vol. 73, No. 18, 2008 7001

van Zijl et al.
after which it was diluted with 50 mL of Et2O and filtered. The
filtrate was washed with satd aq NaHCO3 (40 mL) and brine (20
mL), dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (SiO2, 10:90 Et2O/
pentane, Rf ) 0.25) to afford 21 as a colorless oil (1.19 g): 95%
yield; [R]D ) +3.0 (c 5.2, CHCl3); 1H NMR δ 7.36-7.25 (m, 5H),
4.89 (dd, J ) 4.4 and 5.9 Hz, 1H), 4.49 (s, 2H), 3.99-3.91 (m,
2H), 3.89-8.80 (m, 2H), 3.42 (dd, J ) 6.0 and 9.2 Hz, 1H), 3.27
(dd, J ) 7.0 and 9.2 Hz, 1H), 1.90-1.76 (m, 2H), 1.69 (ddd, J )
3.8, 5.9 and 13.8 Hz, 1H), 1.47 (ddd, J ) 4.4, 9.8 and 14.0 Hz,
1H), 0.96 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H); 13C NMR
δ 138.7, 128.2, 127.4, 127.3, 104.1, 73.4, 72.9, 64.7, 64.5, 38.3,
36.9, 31.0, 17.1, 13.6; MS (EI) m/z 264 (M+, 0.8), 173 (6), 157
(10), 115 (11), 113 (14), 107 (7), 97 (6), 96 (6), 92 (7), 91 (54), 73
(100), 65 (6); HRMS calcd for C16H24O3 264.1726, found 264.1735.
(-)-(2S,3S)-4-(1,3-Dioxolan-2-yl)-2,3-dimethylbutan-1-ol (22). A
suspension of benzyl ether 21 (0.3 mmol, 79 mg) and Pd(OH)2/C
(15 µmol, 60 wt % (moist), dry: 20 wt % Pd(OH)2, 26 mg) in
EtOAc (3.0 mL) was stirred vigorously at rt under a H2 atmosphere
for 30 min. Celite was added, and the suspension was filtered over
Celite. The filtercake was washed with EtOAc, and the combined
filtrates were concentrated. The residue was purified by flash
chromatography (SiO2, 20:80 to 100:0 Et2O/pentane gradient, Rf
(70:30) ) 0.35), to afford 22 as a colorless oil (52 mg): 99% yield;
1-iodo-2,6-dimethylocta-1,5-diene 13 (0.35 mmol, 92 mg) and
[Pd(dppf)Cl2]·CH2Cl2 (11.6 µmol, 9.5 mg) in a mixture of THF/
DMF (0.8 mL, 1:1) was added via syringe, and the resulting green
suspension was stirred at rt for 16 h. H2O (5 mL) was added to the
mixture, which was extracted with Et2O (3 × 5 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (SiO2,
1:99-2:98 Et2O/pentane gradient, Rf (1:99) ) 0.1), affording 23
as a colorless oil (48 mg): 71% yield; [R]D ) -3.8 (c 0.9, CHCl3);
1H NMR δ 5.12 (br t, J ) 6.7 Hz, 1H), 5.06 (br t, J ) 6.5 Hz, 1H),
4.88 (dd, J ) 4.4 and 5.8 Hz, 1H), 4.00-3.91 (m, 2H), 3.89-3.80
(m, 2H), 2.10-1.95 (m, 7H), 1.83-1.75 (m, 1H), 1.74-1.67 (m,
2H), 1.66 (dd, J ) 1.2 and 2.4 Hz, 3H), 1.58 (s, 3H), 1.40-1.42
(m, 2H), 0.96 (t, J ) 7.2 Hz, 3H), 0.93 (d, J ) 6.1 Hz, 3H), 0.82
(d, J ) 6.8 Hz, 3H); 13C NMR δ 136.9, 135.3, 123.9, 123.7, 104.3,
64.7, 64.5, 40.1, 38.8, 37.1, 33.5, 31.3, 26.2, 24.7, 22.8, 16.8, 16.0,
15.9, 12.8; MS (EI) m/z 294 (M+, 4), 149 (6), 123 (7), 121 (5),
115 (7), 114 (6), 113 (100), 107 (16), 95 (15), 93 (6), 83 (21), 81
(16), 73 (66), 69 (10), 67 (10), 55 (44); HRMS calcd for C19H34O2
294.2559, found 294.2550.
(+)-Faranal [(3S,4R,6E,10Z)-3,4,7,11-Tetramethyl-trideca-6,10-
dienal] (11).23-28 In a Schlenk flask under a N2 atmosphere was
dissolved dioxolane 23 (63 µmol, 18.5 mg) in a mixture of THF
and water (24 mL, 5:1). p-TsOH·H2O (1.26 mmol, 240 mg) was
added, and the solution was heated at reflux temperature for 1 h.
The mixture was poured into satd aqueous NaHCO3 (20 mL) and
extracted with 40 mL of Et2O. The organic layer was subsequently
washed with satd aqueous NaHCO3 (10 mL) and brine (10 mL),
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (SiO2, 2:98 Et2O/pentane,
Rf ) 0.2), affording 11 as a colorless oil (9.7 mg): 62% yield; [R]D
) +19.2 (c 1.0, CHCl3) [lit.28 [R]D ) +17.4 (c 4.12, CHCl3); lit.27b
1
[R]D ) -20.3 (c 2.4, CHCl3); H NMR δ 4.86 (dd, J ) 3.6 and
6.2 Hz, 1H), 3.97-3.88 (m, 2H), 3.86-3.78 (m, 2H), 3.49 (dd, J
) 7.4 and 11.0 Hz, 1H), 3.39 (dd, J ) 6.5 and 11.0 Hz, 1H), 2.38
(br s, 1H), 1.89-1.79 (m, 1H), 1.69-1.59 (m, 2H), 1.45-1.38 (m,
1H), 0.94 (d, J ) 6.9 Hz, 3H), 0.79 (d, J ) 6.9 Hz, 3H); 13C NMR
δ 103.9, 65.1, 64.5, 64.4, 40.2, 35.7, 29.5, 17.7, 12.2; MS (EI) m/z
173 ([M - H]+, 4), 115 (8), 113 (7), 102 (10), 88 (13), 85 (5), 74
(12), 73 (100), 71 (8), 69 (7), 55 (8); MS (CI) m/z 193 (11), 192
([M + NH4]+, 100), 175 ([M + H]+, 6), 147 (12), 131 (6), 130
(62), 113 (16); HRMS calcd for [M - H]+ C9H17O3 173.1178,
found 173.1185.
(+)-2-((2S,3S)-4-Iodo-2,3-dimethylbutyl)-1,3-dioxolane (14). To
a stirred solution of alcohol 22 (0.27 mmol, 46 mg), PPh3 (0.4
mmol, 105 mg), and imidazole (0.5 mmol, 34 mg) in benzene (2.0
mL) and DMF (0.1 mL) was added I2 (0.45 mmol, 114 mg) in one
portion. The resulting mixture was stirred at rt for 45 min, after
which it was poured into 5 mL of satd aq Na2S2O3 solution and
extracted with Et2O (5 mL, 2×). The combined organic layers were
dried (MgSO4), filtered, and concentrated. The residue was purified
by flash chromatography (SiO2, 5:95 Et2O/pentane, Rf ) 0.25) to
afford 14 as a colorless oil (69 mg): 91% yield; [R]D ) +1.3 (c
3.2, CHCl3); 1H NMR δ 4.89 (dd, J ) 4.3 and 5.8 Hz, 1H),
4.00-3.92 (m, 2H), 3.89-3.81 (m, 2H), 3.27 (dd, J ) 4.7 and 9.7
Hz, 1H), 3.10 (dd, J ) 7.9 and 9.7 Hz, 1H), 1.85-1.76 (m, 1H),
1.68 (ddd, J ) 3.8, 5.7 and 13.7 Hz, 1H), 1.64-1.56 (m, 1H), 1.48
(ddd, J ) 4.3, 9.6 and 13.9 Hz, 1H), 1.00 (d, J ) 6.7 Hz, 3H),
0.96 (d, J ) 6.9 Hz, 3H); 13C NMR δ 103.6, 64.7, 64.5, 40.5, 36.5,
33.5, 17.1, 17.1, 14.2; MS (EI) m/z 283 (7), 157, (8), 95 (7), 73
(100); MS (CI) m/z 302 ([M + NH4]+, 17), 69 (100); HRMS calcd
for [M - H]+ C9H16O2I 283.0195, found 283.0248.
1
[R]D ) +17.5 (c 0.52, n-hexane)]; H NMR δ 9.74 (dd, J ) 1.7
and 2.6 Hz, 1H), 5.11 (br t, J ) 6.7 Hz, 1H), 5.05 (br t, J ) 6.6
Hz, 1H), 2.47-2.41 (m, 1H), 2.21-1.95 (m, 9H), 1.87-1.78 (m,
1H), 1.66 (s, 3H), 1.58 (s, 3H), 1.52-1.42 (m, 1H), 0.96 (t, J )
7.6 Hz, 3H), 0.94 (d, J ) 6.6 Hz, 3H), 0.84 (d, J ) 6.8 Hz, 3H);
13C NMR δ 203.3, 137.1, 135.9, 123.8, 123.0, 47.4, 40.1, 38.4,
32.0, 31.8, 26.2, 24.7, 22.8, 17.5, 16.1, 15.9, 12.8; spectroscopic
data were in good agreement with those reported in literature.28
MS (EI) m/z 250 (M+, 6), 203 (5), 194 (7), 193 (44), 177 (5), 175
(12), 149 (9), 138 (6), 137 (23), 136 (6), 124 (5), 123 (29), 122
(7), 121 (9), 111 (8), 109 (13), 107 (17), 99 (6), 97 (9), 96 (7), 95
(20), 93 (9), 84 (8), 83 (100), 82 (23), 81 (27), 79 (6), 69 (20), 68
(7), 67 (17), 57 (5), 55 (87), 53 (7); HRMS calcd for C17H30O
250.2297, found 250.2307.
Acknowledgment. We thank the NRSC-Catalysis, the Eu-
ropean Community’s 6th Framework Programme (Marie Curie
Intra-European Fellowship to F.L.), and Pharmaceutical Analysis
(Prof. E. Verpoorte), Department of Pharmacy, University of
Groningen, for financial support. W.S. was on leave from
Politechnika Warszawska in an Erasmus EC program. T. D.
Tiemersma-Wegman and A. Kiewiet are thanked for technical
assistance and Dr. W. R. Browne for valuable suggestions.
(-)-2-((2S,3R,5E,9Z)-2,3,6,10-Tetramethyldodeca-5,9-dienyl)-1,3-
dioxolane (23). A dry Schlenk tube equipped with septum and
stirring bar was charged with alkyl iodide 14 (232 µmol, 66 mg)
and Et2O (1.2 mL) under a N2 atmosphere and cooled to -78 °C.
t-BuLi (0.51 mmol, 1.9 M solution in pentane, 0.27 mL) was added
dropwise via syringe, and the solution was stirred at -78 °C for
20 min. A solution of dried ZnBr2 (0.29 mmol, 65 mg) in THF
(0.7 mL) was added dropwise via syringe, and the resulting mixture
was allowed to warm to 0 °C in 1 h. At 0 °C, a solution of (1E,5Z)-
Supporting Information Available: Experimental proce-
dures and full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8010649
7002 J. Org. Chem. Vol. 73, No. 18, 2008