Enyne metathesis approach towards the cyclopentane motif of jatrophane diterpenes

Article abstract of DOI:10.1055/s-0033-1339923

A short and efficient synthesis of the cyclopentane moiety of the jatrophane diterpene Pl-3 has been developed. The route features an enyne metathesis reaction, and a stereoselective palladium-catalyzed reductive epoxide opening as key steps. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339923

LETTER
▌2665
letter
Enyne Metathesis Approach towards the Cyclopentane Motif of Jatrophane
Diterpenes
Synthesis of Cyclopentane Motif of Jatrophane Diterpenes
Christoph Lentsch, Rita Fürst, Uwe Rinner*
Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria
Fax +43(1)42779521; E-mail: uwe.rinner@univie.ac.at
Received: 30.07.2013; Accepted after revision: 09.09.2013
AcO
AcO
Abstract: A short and efficient synthesis of the cyclopentane moi-
1
15
13
6
ety of the jatrophane diterpene Pl-3 has been developed. The route
features an enyne metathesis reaction, and a stereoselective palladi-
um-catalyzed reductive epoxide opening as key steps.
2
10
3
9
5
H
OAc
BzO
Key words: metathesis, palladium, natural products, stereoselec-
AcO
Pl-3 (1)
OAc
OH
tive synthesis, terpenoids
jatrophane skeleton
O
O
AcO
AcO
H
With more than 2000 known species, the Euphorbiaceae
family is one of the largest and most diverse of all genera.
Many species of the widely distributed spurges, as mem-
bers of this family are commonly referred to, have been
extensively used in traditional herbal folk medicine to
cure various health conditions, such as skin diseases, gon-
orrhea, migraine, intestinal parasites, and warts.1
H
OAc
O
AcO
BzO
BzO
pubescene D (2)
HO
euphoheliosnoid D (3)
Figure 1 Jatrophane diterpenes
Since the isolation of jatrophone in 1970 by Kupchan and
co-workers,2 considerable effort has been devoted to the
isolation and structure elucidation of bioactive constitu-
ents of spurges. As a result of this intensive study, a vast
number of structurally complex isoprenoid constituents
have been obtained, some of which revealed highly inter-
esting biological properties ranging from antiproliferative
to pronounced multi-drug-resistance (MDR) reversal ac-
tivity.3,4
As a result of our ongoing efforts towards Euphorbiaceae
diterpenes, we have devised a route towards Pl-3 (1).19
This bicyclic natural product was isolated from an Hun-
garian sample of the annual herbaceous plant Euphorbia
platyphyllos by Hohmann and co-workers in 2003 and has
been shown to possess remarkable MDR reversal activi-
ty.6
The synthetic strategy, outlined in Scheme 1, is based on
the late stage connection of three building blocks (5–7).
The final operation in the preparation of the jatrophane di-
terpene is a metathesis reaction to close the macrocycle.
Building block 5 becomes available from D-ribose via a
samarium diiodide mediated diastereoselective Refor-
matsky reaction as key step as recently reported.19 Ad-
vanced intermediate 6 should be accessible via selective
reductive opening of epoxide 8, followed by oxidation of
the secondary alcohol and addition of the corresponding
lithiated vinyl halide. Epoxide 8 was envisaged to be pre-
pared from the corresponding diene, the product of the
key enyne metathesis reaction of alkyne 9. As suitable
starting material for the sequence we decided to utilize
chiral carboxylic acid 10,24 available on multigram scale
via the Myers asymmetric alkylation protocol.25 Vinyl ha-
lide 7 will be prepared from commercially available
Roche ester. The route to both synthetic intermediates 5
and 6 is highly flexible and allows the preparation of
structurally related intermediates for the synthesis of other
jatrophane diterpenes.
While it is well established that most macrocyclic diterpe-
noids are biosynthesized from an isomer of geranylgera-
nyl diphosphate,5 the exact process leading to the different
core frameworks of jatrophane diterpenes and related nat-
ural products remains unknown. Despite the differences in
the twelve-membered macrocycle of jatrophane diter-
penes (oxygenation pattern, double bond geometry, ste-
reochemistry of substituents), structural features in the
cyclopentane moiety are essentially identical in many of
these fascinating natural products. Some examples of re-
cently isolated biologically interesting jatrophane diter-
penes are shown in Figure 1.6–8
We have been interested in the active ingredients of the
Euphorbiaceae family for some time, partly due to their
intriguing biological properties but also because of the
fascinating synthetic challenge presented by this class of
natural products. Additionally, only a few routes to jatro-
phane diterpenes have been reported so far.9–23
SYNLETT 2013, 24, 2665–2670
Advanced online publication: 28.10.2013
DOI: 10.1055/s-0033-1339923; Art ID: ST-2013-B0718-L
© Georg Thieme Verlag Stuttgart · New York
As outlined in Scheme 2, the sequence started with the
preparation of chiral carboxylic acid 10.24 Thus, reaction
of pseudoephedrine (11) with propionyl chloride afforded
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2666
C. Lentsch et al.
LETTER
OR
X*
RCM
RO
RO
OR OR
O
AcO
AcO
OR
X*
5
O
Reformatsky
reaction
H
H
OR
OAc
RO
BzO
+
RO
RO
cross-
metathesis
OR
OAc
RO
4
AcO
Pl-3 (1)
OR
H
vinyl halide
addition
Myers
alkylation
RO
enyne
metathesis
Weinreb amide
synthesis
6
TMS
O
O
X
HO
8
OH
OH
RO
7
10
9
Scheme 1 Retrosynthetic analysis of Pl-3.
the precursor for the diastereoselective Myers alkylation accessed in a two-step procedure via initial acid hydroly-
with allyl iodide and amide 12 was obtained in excellent sis of 12 and subsequent exposure of the carboxylic acid
yield as single diastereomer.25
(10) to N-methlyhydroxylamine hydrochloride, DCC,
Et3N, and a catalytic amount of DMAP. Reaction of
Weinreb amide 13 with deprotonated ethynyltrimethyl-
silane then afforded enynone 14 in high yield.
Next, amide 12 had to be converted to the corresponding
Weinreb amide to facilitate the nucleophilic attack of de-
protonated ethynyl trimethylsilane (16). Unfortunately,
the trimethyl aluminum catalyzed reaction of amide 12 With 14 in hand, the stereoselective reduction of the car-
with N-methylhydroxylamine hydrochloride did not af- bonyl moiety could be attempted. Initial experiments with
ford the desired product26 and Weinreb amide 13 had to be the CBS reagent27 or Alpine borane28 delivered the de-
1. Et3N, propionyl
chloride, r.t.
2. LiCl, DIPEA, n-BuLi,
allyl iodide, –78 °C to r.t.
OH Me
NH
OH Me
N
O
92%
12
11
H2SO4,
Me3Al, (MeO)MeNH⋅HCl, r.t.
dioxane,
H2O, reflux
X
85%
Me
N
DCC, DMAP, Et3N,
(MeO)MeNH⋅HCl, 0 °C to r.t.
Me
O
O
70%
O
13
OH
10
16, n-BuLi,
THF, –78 °C
TMS
83%
16
17 (0.65 mol%),
i-PrOH, 40 °C
TMS
TMS
95%; dr 10:1
OH
O
14
9
imidazole,
TBSCl, r.t.
91%
O
H
O
S
N
TMS
Ru
Cl
H
N
OTBS
15
(S,S)-RuCl[TsDPEN]p-cymene (17)
Scheme 2 Preparation of metathesis precursors 15
Synlett 2013, 24, 2665–2670
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Cyclopentane Motif of Jatrophane Diterpenes
2667
sired secondary alcohol in disappointingly low yield as a to exclusively address the endocyclic double bond. As
nearly racemic mixture. Finally, reduction of the ketone in shown in Table 1, several methods were investigated to
14 was achieved in highly diastereoselective manner fol- achieve the cleavage of the TMS group. Reaction of 19
lowing the Noyori asymmetric hydrogenation protocol. with TBAF (1.0 M in THF) resulted in low and irrepro-
When allowed to react with significantly dried isopropyl ducible yields of the desired product, along with decom-
alcohol as transfer reducing agent at elevated tempera- position of the starting material. The use of DMSO instead
tures (40 °C) in the presence of ruthenium catalyst 17, of THF did not improve the outcome of the reaction.
ynol 9 was obtained in excellent yield and stereoselectiv- When TBAF trihydrate was employed, 21 was isolated in
ity.29,30 The synthesis of the enyne metathesis precursor 12% yield along with unreacted starting material.
was completed after silylation of the newly installed
Table 1 Conditions for the Cleavage of the TMS Group in 19
hydroxyl moiety (15).
The key enyne metathesis reaction proved to be more
challenging than anticipated (Scheme 3). Extensive ex-
perimentation with silyl ether 15 with either the 1st or 2nd
generation Grubbs metathesis catalyst in CH2Cl2 or tolu-
ene at different concentrations only led to isolation of the
starting material. Only when alcohol 9 was allowed to re-
act with Grubbs 2nd generation catalyst in carefully de-
gassed and ethene-purged toluene, small amounts of 19
could be isolated. Careful optimization of the reaction
conditions and slow addition of the metathesis catalyst
over six hours via a syringe pump increased the yield of
the desired material to 90%.31
Entry Reagents and conditions
Yield
1
2
3
4
5
6
7
8
9
TBAF (1.0 M, THF), THF, r.t.
no reaction
no reaction
10%; decomposition
TBAF (1.0 M, THF), DMSO, 50 °C
TBAF (1.0 M, THF), DMSO, 80 °C
TBAF (1.0 M, THF), DMSO, 100 °C 10%; decomposition
TBAF trihydrate, THF
KHMDS, THF
12%
unidentified products
unidentified products
15%
LHMDS, THD
NaH, THF
conditions
TMS
NaH–HMPA, THF
82%
R = TBS
TBSO
OR
TMS
We then turned our attention to the cleavage of the silyl
group via a Brook rearrangement,32,33 taking advantage of
the adjacent hydroxyl moiety. Initial experiments with
NaH, LHMDS, or KHMDS proved unsuccessful, but
when HMPA was added to the reaction mixture, 21 could
be isolated in an excellent yield of 84% after subsequent
cleavage of the silyl ether during acidic workup.34
9 R = H
15 R = TBS
R = H
18
Grubbs II (5 mol%),
toluene, 80 °C
93%
NaH, HMPA, r.t.
HO
TMSO
TMS
With desilylated alkene 21 in hand, the vanadium-cata-
lyzed directed epoxidation with tert-butyl hydroperoxide
as oxidant delivered the desired oxirane 8 as the sole isol-
able product. Next, the secondary hydroxyl moiety was
protected as TIPS ether and oxirane 22 was obtained as
substrate for the key reductive epoxide opening reaction.
20
82%
19
HCl
VO(acac)2 (10 mol%),
t-BuOOH, CH2Cl2,
–20 °C to 0 °C to r.t.
(from 19)
O
80%; de > 98%
HO
HO
Palladium-catalyzed reductive epoxide openings were de-
scribed by Tsuji and Shimizu in 1986.35 A few years later,
Shimizu reported the influence of the double bond geom-
etry on the stereochemical outcome of this highly useful
protocol. Shimizu further demonstrated that in the case of
terminal alkenes 1:1 mixtures of stereoisomers were ob-
tained because of the π-σ-π interconversion of the π-allyl-
palladium complex.36
21
8
TIPSOTf,
lutidine,
0 °C to r.t.
76%
Pd2(dba)3⋅CHCl3 (2.5 mol%),
CHOOH, Et3N, Bu3P, THF
OH
O
89%; 23a/23b = 1:1
TIPSO
23a,b
TIPSO
22
Taking these observations into consideration, we were not
surprised to also isolate a 1:1 mixture of stereoisomers
(23a and 23b) in 89% yield when epoxy alkene 22 was al-
lowed to react with Pd(dba)3·CHCl3 with Bu3P as ligand,
Et3N, and formic acid as reductant.
Scheme 3 Synthesis of cyclopentane 23a,b
Next, we intended to functionalize the endocyclic double
bond in cyclopentene 19. All attempts to directly access
the desired oxirane resulted in a homoallylic epoxidation
of the exocyclic double bond because of the electron-
donating properties of the TMS moiety. Thus, the silyl
group had to be cleaved prior to the epoxidation in order
The mechanistic similarity of the palladium-catalyzed re-
ductive epoxide opening and the Tsuji–Trost allylation
motivated us to further investigate this interesting reac-
tion. The asymmetric version of the Tsuji–Trost allylation
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2665–2670

2668
C. Lentsch et al.
LETTER
Pd2(dba)3⋅CHCl3 (0.025 equiv), THF
CHOOH, Et3N, (R,R)-DACH (24)
OH
H
O
85%; de > 98%
TIPSO
TIPSO
22
23a
OH
O
Pd0Ln
H
TIPSO
TIPSO
22
23a
OH
H
H
O
TIPSO
L
L
N
N
Pd
P
P
(R)
O
(R)
O
Pd L
L
TIPSO
H
(R,R)-DACH phenyl Trost ligand
(24)
OH
TIPSO
CO2
HCO2H•NEt3
Pd
L
H
L
O
O
Scheme 4 Mechanistic rationale for the selective epoxide opening and formation of alcohol 23a
has many beautiful applications in natural product synthe- ly confirmed by correlation NMR experiments (see Sup-
sis.37,38 Trost also described the palladium-catalyzed reac- porting Information).
tion of vinylic epoxides and reported the asymmetric
To our knowledge, this is the first application of the
alkylation of vinylglycidols.39,40 This protocol has been
DACH-phenyl Trost ligand in a reductive allylic epoxide
successfully employed in the asymmetric synthesis of
opening reaction and constitutes an extension to the pro-
(–)-malyngolide.41 Although the palladium-catalyzed re-
tocol described by Shimizu and co-workers for the stere-
action has only been applied to carbon or oxygen nucleo-
oselective conversion of terminal epoxy alkenes.36
philes, we reasoned that the DACH phenyl Trost ligand
Summarizing, we were able to design a short and concise
synthesis of the cyclopentane motif present in Pl-3 (1).
The route can also be utilized for the preparation of other
(24) might also be suitable for the intended reductive ep-
oxide opening. The reaction, along with the mechanistic
rationale, which shows the attack of the hydride from the
structurally related jatrophanes as the five-membered
bottom face, is outlined in Scheme 4. Trost developed a
rings show very similar or identical substitution patterns
working model which allows the prediction of the stereo-
in many jatrophane diterpenes. Furthermore, the novel ap-
chemical outcome of the palladium-catalyzed allylation
plication of the DACH-phenyl Trost ligand in the stereo-
selective palladium-catalyzed reductive epoxide opening
is a valuable extension of Shimizu’s protocol and should
be of interest for the preparation of complex natural prod-
ucts.
reaction.42 Among others, Lloyd-Jones contributed to this
area with some interesting studies indicating that depend-
ing on concentration, temperature, and solvents, the cata-
lytically active species might exist as monomer or
oligomer.43,44 Thus, a general prediction of the exact na-
ture of the intermediary palladium species seems extreme-
ly challenging.
Acknowledgment
We were delighted to see that the palladium-catalyzed re-
action of epoxy alkene 22 in the presence of the chiral
The authors thank Dr. Hanspeter Kählig (University of Vienna) for
assistance with NMR spectroscopy. The Fonds zur Förderung der
Trost ligand 24 afforded the desired stereoisomer of the wissenschaftlichen Forschung (Austrian Science Fund, FWF) is
gratefully acknowledged for financial support (Project FWF-
P20697-N19).
cyclopentane building block as the only isolable product
in excellent 85% yield.45 Reaction of 22 in the presence of
the enantiomer of ligand 24 resulted in low yield of the de-
sired product, along with mainly decomposed material.
The absolute configuration of 23a has been unambiguous-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Synlett 2013, 24, 2665–2670
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Cyclopentane Motif of Jatrophane Diterpenes
2669
CDCl3): δ = 5.77–5.87 (m, 1 H), 5.02–5.10 (m, 2 H), 4.28
(dd, J = 5.44, 5.44 Hz, 1 H), 2.33–2.40 (m, 1 H), 1.97–2.04
(m, 1 H), 1.78–1.86 (m, 2 H), 1.00 (s, 3 H), 0.18 (br s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 137.17 (CH), 116.65
(CH2), 105.76 (C), 90.65 (C), 66.98 (CH), 39.40 (CH), 36.86
(CH2), 15.08 (Me), 0.03 (Me). HRMS (ESI): m/z [M – Me]+
calcd for C10H17OSi: 181.1049; found: 181.1044 ±5 ppm.
[α]D20 +3.8° (c = 1.630, CHCl3). IR (ATR): 3351, 2960,
2352, 2171, 1640, 1376, 1249, 983, 947, 911, 838, 759, 698,
638 cm–1.
References and Notes
(1) Graham, J. G.; Quinn, M. L.; Fabricant, D. S.; Farnsworth,
N. R. J. Ethnopharmacol. 2000, 73, 347.
(2) Kupchan, S. M.; Sigel, C. W.; Matz, M. J.; Renauld, J. A. S.;
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4476.
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Chemother. Pharmacol. 2003, 51, 67.
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Helv. Chim. Acta 2003, 86, 3386.
(7) Valente, C.; Ferreira, M. J. U.; Abreu, P. M.; Gyemant, N.;
Ugocsai, K.; Hohmann, J.; Molnar, J. Planta Med. 2004, 70,
81.
(8) Zhang, W.; Guo, Y. W. Chem. Pharm. Bull. 2006, 54, 1037.
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Soc. 1989, 111, 6648.
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1993, 1503.
(13) Mulzer, J.; Giester, G.; Gilbert, M. Helv. Chim. Acta 2005,
88, 1560.
(14) Gilbert, M.; Galkina, A.; Mulzer, J. Synlett 2005, 2558.
(15) Helmboldt, H.; Rehbein, J.; Hiersemann, M. Tetrahedron
Lett. 2004, 45, 289.
(16) Helmboldt, H.; Köhler, D.; Hiersemann, M. Org. Lett. 2006,
8, 1573.
(31) Preparation of Cyclopentene 19: Toluene (1.5 L) was
degassed by an argon purge of approximately 1 h. Enyne 9
(3.00 g, 15.28 mmol, 1 equiv) was added and the solution
was purged with argon for 10 min and with ethene for 10
min. Grubbs 2nd generation catalyst (0.649 g, 0.764 mmol,
0.005 equiv) was added in one portion and the solution was
purged with ethene for 15 min. The mixture was heated to 80
°C for 16 h at positive pressure of ethene. After total
consumption of the starting material, the mixture was
reduced in vacuo (40 °C, 60 mbar) to a volume of
approximately 70 mL. This volume was applied on a column
and eluted with hexane (300 mL). After purification by flash
column chromatography (hexane–EtOAc, 19:1), 19 (2.80 g,
93%) was isolated as a slightly brownish fluid. 1H NMR
(400 MHz, CDCl3): δ = 5.92 (d, J = 2.80 Hz, 1 H), 5.79 (dd,
J = 2.69, 2.69 Hz, 1 H), 5.52 (d, J = 2.69 Hz, 1 H), 4.54 (br
s, 1 H), 2.72–2.79 (m, 1 H), 2.11–2.20 (m, 1 H), 1.90–1.96
(m, 1 H), 1.51 (br s, 1 H), 1.09 (d, J = 7.12 Hz, 3 H), 0.17 (s,
9 H). 13C NMR (100 MHz, CDCl3): δ = 146.23 (C), 145.72
(C), 130.73 (CH), 125.82 (CH2), 84.31 (CH), 41.47 (CH),
38.97 (CH2), 19.71 (Me), –0.59 (Me). HRMS (ESI): m/z [M
+ Na]+ calcd for C11H20NaOSi: 219.1181; found: 219.1183
±5 ppm. [α]D20 −89.1° (c = 1.030, CHCl3).
(17) Shimokawa, K.; Takamura, H.; Uemura, D. Tetrahedron
Lett. 2007, 48, 5623.
(32) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886.
(33) Preparation of 21: NaH (60% dispersion in mineral oil,
0.224 g, 5.60 mmol, 2.2 equiv) was added to HMPA (1.66
mL, 9.57 mmol, 3.75 equiv) in one portion. After 5 min, a
solution of 19 (0.500 g, 2.55 mmol, 1 equiv) in THF (1.66
mL) was added. After consumption of the starting material
as indicated by TLC analysis (60 min) the reaction was
quenched via addition of a sat. aqueous solution of NH4Cl.
The solution was acidified to pH 2 by addition of HCl (1 M)
and stirred for approximately 20 min. The aqueous solution
was extracted with CH2Cl2 (3 × 20 mL) and dried over
MgSO4. Silica was added and the solvent was reduced in
vacuo. The crude product was purified by flash column
chromatography (dry loading; pentane–Et2O, 10:1). The
solvent was carefully reduced under reduced pressure (700
mbar, 35 °C) to yield 21 (260 mg, 82%) as a colorless liquid.
Note: The product is highly volatile; thus, yields vary
between 40% and 82%. 1H NMR (400 MHz, CDCl3): δ =
6.45 (dd, J = 17.73, 11.00 Hz, 1 H), 5.82 (dd, J = 2.63, 2.63
Hz, 1 H), 5.41–5.46 (m, 1 H), 5.14 (dd, J = 10.89, 0.84 Hz,
1 H), 4.52 (br s, 1 H), 2.71–2.78 (m, 1 H), 2.14–2.23 (m, 1
H), 1.87–1.94 (m, 1 H), 1.51 (br s, 1 H), 1.10 (d, J = 7.16 Hz,
3 H). 13C NMR (100 MHz, CDCl3): δ = 143.58 (C), 133.11
(CH), 131.87 (CH), 115.01 (CH2), 83.20 (CH), 42.56 (CH),
38.60 (CH2), 19.67 (Me). HRMS (ESI): m/z [M + Na]+ calcd
(18) Lentsch, C.; Rinner, U. Org. Lett. 2009, 11, 5326.
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2293.
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1698.
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Hiersemann, M. J. Org. Chem. 2011, 76, 512.
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2012, 53, 2730.
(23) Fürst, R.; Rinner, U. J. Org. Chem. 2013, 78, 8748.
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Asymmetry 2008, 19, 838.
(25) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119,
6496.
(26) White, J. D.; Blakemore, P. R.; Green, N. J.; Hauser, E. B.;
Holoboski, M. A.; Keown, L. E.; Nylund Kolz, C. S.;
Phillips, B. W. J. Org. Chem. 2002, 67, 7750.
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53, 2861.
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(29) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 7562.
(30) Preparation of Alcohol 9: Acetylene 14 (1.0 g, 5.15 mmol,
1.0 equiv) was dissolved in freshly distilled 2-propanol (45
mL; degassed by three pump-freeze-thaw cycles prior to
use). The solution was stirred at 40 °C and catalyst 17 (20
mg, 0.003 mmol, 0.0065 equiv; for preparation see
Supporting Information), dissolved in 2-propanol (1 mL),
was added via a syringe pump over 6 h. After consumption
of the starting material the reaction was reduced in vacuo (30
°C, 40 mbar) and the residue (ca. 3 mL) was purified by flash
column chromatography (hexane–EtOAc, 9:1) to afford 9
(950 mg, 95%) as a colorless oil. 1H NMR (400 MHz,
20
for C8H12NaO: 147.0786; found: 147.0788 ±5 ppm. [α]D
−70° (c = 0.2250, CHCl3). IR (ATR): 3316, 2954, 2924,
2868, 1641, 1454, 1374, 1260, 1021, 988, 905, 813 cm–1.
(34) Hadimani, M. B.; Hua, J. Y.; Jonklaas, M. D.; Kessler, R. J.;
Sheng, Y. Z.; Olivares, A.; Tanpure, R. P.; Weiser, A.;
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LETTER
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(45) Preparation of 23a: The reaction was carried out in Schlenk
flasks using degassed solvents. A Schlenk flask containing
Pd2(dba)3·CHCl3 (4.4 mg, 2.5 mol%) and (R,R)-DACH
([138517-61-0], 8.7 mg, 7.5 mol%) was purged with argon
five times before CH2Cl2 (0.6 mL) was added. After 5 min a
mixture of Et3N (117 μL, 0.844 mmol, 5.0 equiv) and formic
acid (32 μL, 0.844 mmol, 5.0 equiv) in CH2Cl2 (0.6 mL) was
added and stirring was continued for additional 5 min before
epoxide 22 (50 mg, 0.169 mmol, 1.0 equiv) was added neat
followed by CH2Cl2 (0.1 mL). The reaction was stirred until
TLC analysis showed total consumption of the starting
material (3 h). A sat. aqueous solution of NH4Cl was added
and the mixture was extracted with CH2Cl2 (3 × 20 mL), the
organic extracts were dried over MgSO4, filtered and
reduced in vacuo. The crude product was purified by flash
column chromatography (hexane–EtOAc, 40:1) delivering
the desired product 23a (43 mg, 86%) as a colorless oil as
sole isolable product. 1H NMR (400 MHz, CDCl3): δ = 6.20–
6.26 (m, 1 H), 5.22–5.24 (m, 1 H), 5.20 (d, J = 0.78 Hz, 1 H),
4.07–4.11 (m, 1 H), 3.98 (br d, J = 3.90 Hz, 1 H), 3.25 (d, J
= 11.16 Hz, 1 H), 2.36–2.40 (m, 1 H), 2.32–2.36 (m, 1 H),
2.25 (ddd, J = 14.42, 8.99, 0.95 Hz, 1 H), 1.51 (ddd, J =
14.37, 5.37, 5.37 Hz, 1 H), 1.05–1.13 (m, 21 H), 0.97 (d, J =
7.32 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 135.16
(CH), 117.43 (CH2), 85.48 (CH), 78.18 (CH), 52.81 (CH),
43.47 (CH2), 41.40 (CH), 20.87 (Me), 18.21 (Me), 18.16
(Me), 12.37 (CH). HRMS (ESI): m/z [M + Na]+ calcd for
20
C17H34NaO2Si: 321.2226; found: 321.2223 ±5 ppm. [α]D
−5° (c = 1.0900, CHCl3). IR (ATR): 3531, 2943, 2866, 2359,
2342, 1636, 1463, 1419, 1383, 1119, 1060, 1014, 997, 912,
881, 847, 823, 729, 678 cm–1.
Synlett 2013, 24, 2665–2670
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