α-chloro-β,γ-ethylenic esters: Enantiocontrolled synthesis and substitutions

Article abstract of DOI:10.1021/ol102142a

Chiral nonracemic γ-seleno-α,β-ethylenic esters, when treated with sulfuryl chloride and ethyl vinyl ether in hexanes, produced α-chloro-β,γ-ethylenic esters in 65 - 75% yields, with ee values of 95 - 97%, and with 1,3-syn transfer of chirality. Reaction

Full text of DOI:10.1021/ol102142a

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4694-4697
r-Chloro-ꢀ,γ-ethylenic Esters:
Enantiocontrolled Synthesis and
Substitutions
Douglas T. Genna, Christopher P. Hencken, Maxime A. Siegler, and
Gary H. Posner*
Department of Chemistry, The Johns Hopkins UniVersity, 3400 North Charles Street,
Baltimore, Maryland 21218
ghp@jhu.edu
Received September 9, 2010
ABSTRACT
Chiral nonracemic γ-seleno-r,ꢀ-ethylenic esters, when treated with sulfuryl chloride and ethyl vinyl ether in hexanes, produced r-chloro-
ꢀ,γ-ethylenic esters in 65-75% yields, with ee values of 95-97%, and with 1,3-syn transfer of chirality. Reaction of these allylic chloride
electrophiles with methylcuprate and with sodium azide nucleophiles afforded exclusively γ-substituted-r,ꢀ-ethylenic esters with faithful anti-
transfer of chirality on multigram scale.
Current literature records considerable interest in enantio-
merically pure secondary allylic chlorides1,2 and secondary
R-chloro esters.3 These useful chirons have been employed
in a variety of organic reactions including the following:
inter- and intramolecular SN2 and SN2′ reactions,4 Pd cross
couplings,5 Friedel-Crafts alkylations,6 radical reactions,7
and a wide variety of organometallic reactions (e.g., Grig-
nard).8 We describe here asymmetric, organocatalytic syn-
thesis of γ-seleno-R,ꢀ-ethylenic esters9,10,11 and, for the first
time, their enantiocontrolled conversion, in one step, into
diverse R-chloro-ꢀ,γ-ethylenic esters 2. These highly enan-
tioenriched electrophilic secondary allylic chlorides 2, which
are also R-chloro esters, undergo highly stereocontrolled
substitution reactions with carbon and nitrogen nucleophiles
yielding γ-methyl-R,ꢀ-ethylenic esters 3 and γ-amino-R,ꢀ-
ethylenic tert-butyl esters 5 in good yields and high ee values
(Scheme 1).
(1) Usami, Y.; Takaoka, I.; Ichikawa, H.; Horibe, Y.; Tomiyama, S.;
Ohtsuka, M.; Imanishi, Y.; Arimoto, M. J. Org. Chem. 2007, 72, 6127
(2) (a) Weatzig, S. R.; Tunge, J. A. Chem. Commun. 2008, 3311. (b)
Pearson, A. J.; Ray, T. Tetrahedron 1985, 41, 5765
(3) France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org. Chem. 2005,
.
.
475.
Previous reports described reactions of some racemic
γ-seleno-R,ꢀ-ethylenic esters with sulfuryl chloride to form
putative selenium dichloride intermediates followed in situ
by spontaneous allylic transpositions to produce R-chloro-
ꢀ,γ-ethylenic esters as mixtures of di- and trisubstituted olefin
geometric isomers.12 We show now for the first time that
(4) (a) Fujii, M.; Nakai, K.; Habashita, H.; Yoshizawa, H.; Ibuka, T.;
Garrido, F.; Mann, A.; Chounan, Y.; Yamamoto, Y. Tetrahedron Lett. 1993,
34, 4227. (b) Falciola, C. A.; Tissot-Croset, K.; Alexakis, A. Angew. Chem.,
Int. Ed. 2006, 45, 5995. (c) Fox, R. J.; Lalic, G.; Bergman, R. G. J. Am.
Chem. Soc. 2007, 129, 14144.
(5) (a) Ma, S.; Yu, F.; Gao, W. J. Org. Chem. 2003, 68, 5943. (b) Shing,
T.; Kwong, K. M.; Cheung, C. S. K.; Cheung, A. W. C.; Kok, S. H. L.;
Yu, Z.; Li, J.; Cheng, C. H. K. J. Am. Chem. Soc. 2004, 126, 15990. (c)
Trost, B. M.; Schroeder, G. M. Chem.sEur. J. 2005, 11, 174.
(6) (a) Kodomari, M.; Nawa, S.; Miyoshi, T. Chem. Soc. Commun. 1995,
1895. (b) Min, J.; Lee, J.; Yang, J.; Koo, S. J. Org. Chem. 2003, 68, 7925.
(c) Hayashi, R.; Cook, G. H. Org. Lett. 2007, 9, 1311.
(8) Idrissi, M. E.; Santelli, M. J. Org. Chem. 1988, 53, 1010.
(9) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 757
.
(7) (a) Huval, C. C.; Singleton, D. A. Tetrahedron Lett. 1993, 19, 3041.
(b) Heinrich, M. R.; Blank, O.; Ullrich, D.; Kirchstein, M. J. Org. Chem.
2007, 72, 9609.
(10) Tiecco, M.; Carlone, A.; Sternativo, S.; Marini, F.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46, 6882
(11) Hess, L. C.; Posner, G. H. Org. Lett. 2010, 12, 2120
.
.
10.1021/ol102142a  2010 American Chemical Society
Published on Web 09/20/2010

Scheme 1
Scheme 2
2 were chemically and stereochemically stable for at least 3
days at room temperature when dissolved in methanol,
tetrahydrofuran, acetonitrile, chloroform, acetone, or hexanes;
however, after only a few hours at room temperature in N,N-
dimethylformamide, considerable racemization was observed
by chiral HPLC analysis. Disappointingly, the corresponding
R-chloro-ꢀ,γ-ethylenic nitriles, produced in good yields and
high ee values, partially racemized in such solvents as
chloroform, tetrahydrofuran, and especially acetonitrile at 40
°C for 48 h. We report here successful use of carbon and
nitrogen nucleophiles to effect substitutions of the chloride
in allylic chlorides 2.
Asymmetric organocopper SN2′ substitution reactions on
R-hydroxy-ꢀ,γ-ethylenic esters in which the hydroxy group
has been esterified into a phosphate leaving group have been
reported.14 However, asymmetric organocopper substitution
reactions on R-chloro-ꢀ,γ-ethylenic esters have not been
reported probably due to the previous inaccessibility of these
chirons. Pursuing our long interest in organocopper chem-
istry,15 we treated allylic chlorides 2a,d-f,h with
Me2CuMgBr (derived from 1 equiv of CuCN and 2 equiv
of MeMgBr) in THF (Scheme 1, Table 2) to yield γ-methyl-
this protocol, when applied to chiral nonracemic γ-seleno-
R,ꢀ-ethylenic esters 1, proceeded with faithful 1,3-syn
transfer of chirality to form diverse R-chloro-ꢀ,γ-ethylenic
chlorides 2 in good yields, with exclusive (E)-olefin geom-
etry, and, especially significant, in at least 95% ee as
determined by chiral HPLC (Scheme 1, Table 1). The
Table 2. Methylations of Allyic Chlorides 2
Table 1. Selenide 1 to Chloride 2 Transformations
product
R
R′
yield of 3 (%) ee of 3 (%)
yield
yield of ee of
product
R
R′
of 1 (%)
2 (%)
2 (%)
3a
3d
3e
3f
PhCH2
PhCH2
CH3(CH2)4
CH2dCH(CH2)7 t-Bu
PhCH2O(CH2)4 t-Bu
t-Bu
PhCH2
Me
88
57
70
57
80
95
93
96
97
96
a
b
c
d
e
f
PhCH2
PhCH2
PhCH2
PhCH2
t-Bu
Me
Et
PhCH2
Me
91
72
79
80
75
54
75
72
75
75
72
78
71
69
65
68
97
95
95
95
97
97
96
97
3h
CH3(CH2)4
CH2dCH(CH2)7 t-Bu
cyclohexyl
PhCH2O(CH2)4
g
h
t-Bu
t-Bu
R,ꢀ-ethylenic esters 3 via an SN2′ mechanism in good yields
and with faithful transfer of chirality from the starting allylic
chloride. Since both syn and anti SN2′ pathways are possible
during organocopper allylic substitutions,16 the anti-SN2′
pathway of this transformation was established by stereo-
chemical correlation of ester 3e with the same intermediate
reported in a total synthesis of the mealworm sex pheromone
(R)-4-methyl-1-nonanol (7) (Scheme 3). This new 4-step
synthesis of alcohol 7, in 22% overall yield and in 97% ee,
important role of ethyl vinyl ether is likely to trap any PhSeCl
produced during the conversions of allylic selenides 1 into
allylic chlorides 2. This protocol tolerated a diverse range
of R and R′ groups. X-ray crystallographic analysis of the
diol 6, the major diol diastereomer formed via osmium
tetroxide catalyzed syn-dihydroxylation of allylic chloride
2a (Scheme 2), led to the unambiguous assignment of the
three contiguous stereocenters as 2S, 3S, 4R. Therefore, the
conversion of allylic selenide 1 into allylically transposed
chloride 2 proceeded reliably with syn stereochemistry.2 The
chemically and stereochemically rich diol 6 is itself a
synthetically versatile chiron.13 Secondary allylic chlorides
(13) Albrecht, L.; Jiang, H.; Dickmeiss, G.; Gschwend, B.; Hansen,
S. G.; Jorgensen, K. A. J. Am. Chem. Soc. 2010, 132, 9188.
(14) Baeza, A.; Najera, C.; Sansano, J. M. Eur. J. Org. Chem. 2007,
1101.
(15) (a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911.
(b) Posner, G. H.; Whitten, C. E.; McFarland, P. E. J. Am. Chem. Soc.
1972, 94, 5106.
(12) (a) Duclos, J.; Outurquin, F.; Paulmier, C. Tetrahedron Lett. 1993,
Org. Lett., Vol. 12, No. 20, 2010
(16) Magid, R. M. Tetrahedron 1980, 36, 1901.
4695

Scheme 3
Table 3. Synthesis of Vinylogous N-Boc R-Amino Esters 5
product
R
yield of 5 (%)
ee of 5 (%)
5a
5f
5h
PhCH2
CH2dCH(CH2)7
PhCH2O(CH2)4
76
51
52
95
93
97
allylic azide 4r to the thermodynamically favored27 conju-
gated ester azide 4γ; subsequent azide reduction and protec-
tion yielded the known26 γ-amino conjugated ester 5a(Fmoc)
in 60% yield (Scheme 4).
(21) Experimental Details for γ-Seleno-r,ꢀ-ethylenic Ester (S)-1a.
To a 500 mL round-bottomed flask with stirbar under argon was added
3-phenylpropanal (2.68 g, 20.00 mmol, 1.00 equiv) in toluene (50 mL).
(S)-R,R-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimeth-
ylsilyl ether (2.39 g, 4.00 mmol, 0.20 equiv) was added and the reaction
was allowed to cool to -20°C and stirred for 5 min at that temperature.
N-(Phenylseleno)phthalimide (7.85 g, 26.00 mmol, 1.30 equiv) was added
in one portion and the reaction was allowed to stir for 2 h at -20°C. At
this time TLC analysis indicated complete reaction, and the flask was further
cooled to -40 °C and anhydrous THF (150 mL) was added dropwise via
pressure equalizing addition funnel. A solution of (tert-butoxycarbonylm-
ethylene)triphenylphosphorane (10.15 g, 27.00 mmol, 1.35 equiv) in
anhydrous THF (100 mL) was added dropwise via pressure equalizing
addition funnel. After addition was completed the reaction was warmed to
-20°C and the reaction was allowed to stir overnight. At this time TLC
analysis indicated complete reaction. The reaction was quenched with sat.
NH4Cl solution, then the aqueous layer was separated and extracted with
Et2O (3×). The combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The resulting crude oil was purified
via column chromatography (1% EtOAc in hexanes) to yield the desired
ester 1a (7.00 g, 18.00 mmol) as a pale yellow oil in 91% yield.
Experimental Details for r-Chloro-ꢀ,γ-ethylenic Ester (S)-2a. To a 500
mL round-bottomed flask with a stirbar under argon was added ester 1a
(7.0 g, 18.0 mmol, 1.0 equiv) in hexanes (67 mL). Ethyl vinyl ether (21.0
mL, 220.0 mmol, 12.0 equiv) was added followed by the dropwise addition
of a solution of sulfuryl chloride (2.9 mL, 36.0 mmol, 2.0 equiv) in hexanes
(140 mL) via pressure equalizing addition funnel. After 10 min TLC analysis
indicated complete reaction. The volatiles were removed by rotary evapora-
tion and the resulting crude oil was immediately purified via column
chromatography (1% EtOAc in hexanes). The chloride 2a was isolated as
a yellow oil (3.5 g, 13.0 mmol) in 75% yield and 97% ee as determined by
chiral HPLC. Experimental Details for γ-Methyl-r,ꢀ-ethylenic Ester (R)-
3a. To a 250 mL three-necked round-bottomed flask with a stir bar under
argon was added CuCN (1.24 g, 13.80 mmol, 1.05 equiv) in anhydrous
THF (85 mL). The suspension was cooled to -78 °C and a solution of 3
M MeMgBr in Et2O (9.20 mL, 27.60 mmol, 2.10 equiv) was added
dropwise via syringe over 5 min and the resulting solution was allowed to
stir for 30 min at -78 °C. At this time a solution of chloride 2a (3.50 g,
13.15 mmol, 1.00 equiv) in anhydrous THF (50 mL) was added dropwise
via pressure equalizing addition funnel over 15 min. After addition was
completed the reaction was allowed to stir for an additional 30 min after
which TLC analysis indicated complete reaction. The reaction was quenched
with sat. NH4Cl. The aqueous layer was separated and extracted with Et2O
(3×). The combined organic layers were dried over anhydrous MgSO4, the
solids were filtered, and the filtrate was concentrated in vacuo. The resulting
crude oil was purified via column chromatography to yield the ester 3a
(2.80 g, 11.30 mmol) as a colorless oil in 88% yield and in 95% ee as
determined by chiral HPLC.
has distinct advantages over previously reported asymmetric
syntheses of this pheromone in terms of stereochemical
purity,14 number of steps, and total yield.17 Furthermore, the
chiral γ-methyl-R,ꢀ-enoate structural unit is present in many
natural products, including steroids,18 macrolides,19 and
squalestatins.20 The scalability of this short protocol was
confirmed when 2.8 g of γ-methyl ester 3a was synthesized
in 60% overall yield and 95% ee starting with commercial
3-phenylpropanal.21 Lithium dimethylcuprate (Me2CuLi) also
gave exclusive SN2′ methylation but in much lower yield
than the magnesiocuprate used in Table 2. Attempts to
synthesize other γ-alkyl-R,ꢀ-ethylenic esters with this mag-
nesiocuprate allylic substitution procedure yielded mixtures
of inseparable R- and γ-substitution products. We do not
yet understand fully the critical factors that determine R- vs
γ-substitution.
Syntheses of non-natural γ-amino-R,ꢀ-ethylenic esters
(vinylogous R-amino esters)22 5 (Scheme 1) are appealing
due to these amino esters having diverse chemical properties
ranging from induction of a non-natural secondary structure
in polypeptides23 to inhibition of enzyme function.24 To this
end, we treated allylic chlorides 2 with sodium azide,
followed by in situ stannous chloride reduction to the amine,
which was then treated with di-tert-butyl dicarbonate af-
fording the N-Boc-γ-amino-R,ꢀ-ethylenic tert-butyl esters 5
(Scheme 1, Table 3) in good yields and with faithful 1,3-
anti-transfer of chirality. Anti-SN2′ substitutions with nitrogen
nucleophiles are well documented.25 The stereochemical
course of this transformation was confirmed to be 1,3-anti
by comparing the [R]D +14.4 optical rotation of the Fmoc-
γ-amino-R,ꢀ-ethylenic tert-butyl ester 5a (Fmoc) with that
of the known standard.26 We cannot rule out the possibility
that this substitution proceeded via an initial direct SN2
mechanism with stereochemical inversion followed by a
spontaneous syn-3,3-sigmatropic rearrangement of the initial
(22) Soto-Cairoli, B.; Justo de Pomar, J. J.; Soderquist, J. A. Org. Lett.
2008, 10, 333.
(23) (a) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber,
S. L. J. Am. Chem. Soc. 1992, 114, 6568. (b) Baldauf, C.; Gunther, R.;
Hofmann, H. HelV. Chim. Acta 2003, 86, 2573. (c) Grison, C.; Coutrot, P.;
Geneve, S.; Didierjean, C.; Marraud, M. J. Org. Chem. 2005, 70, 10753.
(24) (a) Hanzlik, R. P.; Thompson, S. A. J. Med. Chem. 1984, 27, 711.
(b) Dragovich, P. S.; Prins, T. J.; Zhou, R.; Fuhrman, S. A.; Patick, A. K.;
Mathews, D. A.; Ford, C. E.; Meador, J. W., III; Ferre, R. A.; Worland,
S. T. J. Med. Chem. 1999, 42, 1203. (c) Powers, J. C.; Asgian, J. L.; Ekici,
O. D.; James, K. E. Chem. ReV. 2002, 102, 4639.
(17) Lu, C.; Li, D.; Wang, Q.; Yang, G.; Chen, Z. Eur. J. Org. Chem.
2009, 1078.
(18) Vanderah, D. J.; Djerassi, C. J. Org. Chem. 1978, 43, 1442.
(19) Dai, W.; Chen, Y.; Jin, J.; Wu, J.; Lou, J.; He, Q. Synlett 2008, 11,
1737.
(25) Mulzer, J.; Funk, G. Synthesis 1995, 101.
(20) Nicolaou, K. C.; Yue, E. W.; Naniwa, Y.; De Riccardis, F.; Nadin,
A.; Leresche, J. E.; La Greca, S.; Yang, Z. Angew. Chem., Int. Ed. 1994,
33, 2184.
(26) Concellon, J. M.; Mejica, C. Eur. J. Org. Chem. 2007, 5250.
(27) (a) Gagnon, D.; Lauzon, S.; Godbout, C.; Spino, C. Org. Lett. 2005,
7, 4769. (b) Trost, B. M.; Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737.
4696
Org. Lett., Vol. 12, No. 20, 2010

stitutions into highly enantioenriched γ-methyl-R,ꢀ-ethylenic
esters 3 (Scheme 1, 2 f 3), with 3e being a known precursor
to the natural pheromone (R)-4-methyl-1-nonanol (7). Ad-
ditionally, we report here enantiocontrolled syntheses of
functionality-rich non-natural vinylogous R-amino esters 5
via 1,3-anti allylic substitutions (Scheme 1, 2 f 4 f 5).
The chiral, nonracemic allylic chlorides 2 are versatile and
stereochemically stable electrophilic chirons which are
expected to undergo various other useful nucleophilic
substitution reactions as well as olefin addition reactions with
excellent control of chirality.
Scheme 4
Acknowledgment. We dedicate this paper to Professor
Carmen Najera, University of Alicante, Spain, on the happy
occasion of her special birthday. We thank The Johns
Hopkins University for financial support and Ms. Sara
Milrad, a summer 2010 undergraduate researcher at The
Johns Hopkins University, for some experimental help.
In conclusion, starting from simple achiral aldehydes,
R-chloro-ꢀ,γ-ethylenic esters 2a-h were synthesized for the
first time in good yields and with ee values greater than or
equal to 95% via 1,3-syn allylic replacements of selenide
by chloride (Scheme 1, 1 f 2). These secondary allylic
chlorides 2 were converted via organocopper 1,3-anti sub-
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102142A
Org. Lett., Vol. 12, No. 20, 2010
4697