Sml2-promoted reformatsky-type coupling reactions in exceptionally hindered contexts

Article abstract of DOI:10.1021/ol800099a

Highly substituted, very hindered enones were synthesized using a two-step procedure that utilizes a diiodosamarium-promoted Reformatsky-type coupling and dehydration using Martin sulfurane. Both α-chloro- and α-bromoketones were coupled with a variety of carbonyl nucleophiles to form the intermediate β-hydroxyketones, occurring with excellent diastereoselectivity, favoring the syn isomer (R¹ = Me). This technique complements other methods and enables the preparation of enones outside of the scope of current olefination methodology.

Full text of DOI:10.1021/ol800099a

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1291-1294
SmI2-Promoted Reformatsky-Type
Coupling Reactions in Exceptionally
Hindered Contexts
Brian A. Sparling, Ryan M. Moslin, and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
tfj@mit.edu
Received January 22, 2008
ABSTRACT
Highly substituted, very hindered enones were synthesized using a two-step procedure that utilizes a diiodosamarium-promoted Reformatsky-
type coupling and dehydration using Martin sulfurane. Both -chloro- and -bromoketones were coupled with a variety of carbonyl nucleophiles
to form the intermediate Me). This technique
-hydroxyketones, occurring with excellent diastereoselectivity, favoring the syn isomer (R1
complements other methods and enables the preparation of enones outside of the scope of current olefination methodology.
r
r
â
)
The â-hydroxyketone and R,â-unsaturated ketone are fre-
quently used as sites of fragment couplings in target-oriented
synthesis.1,2 In numerous natural products, a quaternary alkyl-
substituted carbon exists adjacent to this functional group
(Figure 1).3 However, despite this prevalence, these highly
techniques commonly used to form similar, less sterically
hindered systems.6,7
(1) Reviews of the aldol reaction: (a) Heathcock, C. H. Science 1981,
214, 395. (b) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1. (c) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (c) Johnson, J.
S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(2) Reviews of the Horner-Wadsworth-Emmons olefination and related
methods: (a) Prunet, P. Angew. Chem., Int. Ed. 2003, 42, 2826. (b)
Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (c) Martin, S. F.
Synthesis 1979, 633.
(3) (a) Acutiphycin: Barchi, J. J., Jr.; Moore, R. E.; Patterson, F. M. L.
J. Am. Chem. Soc. 1984, 106, 8193. (b) Aurisides A-B: Sone, H.; Kigoshi,
H.; Yamada, K. J. Org. Chem. 1996, 61, 8956. (c) Chaetoglobosins A-E,
G, J-M, Q-R, and T: Jiao, W.; Feng, Y.; Blunt, J. W.; Cole, A. L. J.;
Munro, M. H. G. J. Nat. Prod. 2004, 67, 1722. (d) Chalcocaryanones
C-D: Dumontet, V.; Gaspard, C.; Hung, N. V.; Fahy, J.; Tchertanov, L.;
Se´venet, T.; Gue´ritte, F. Tetrahedron 2001, 57, 6189. (e) Epothilones
A-I: Hardt, I. H.; Steinmetz, H.; Gerth, K.; Sasse, F.; Reichenbach, H.;
Ho¨fle, G. J. Nat. Prod. 2001, 64, 847. (f) Euphoscopins A-C and E-L:
Yamamura, S.; Shizuri, Y.; Kosemura, S.; Ohtsuka, J.; Tayama, T.; Ohba,
S.; Ito, M.; Saito, Y.; Terada, Y. Phytochem. 1989, 28, 3421.
(4) For example, the syntheses of aurisides A and B do not employ this
approach, and the authors note unforeseen difficulties with an alternative
Mukaiyama aldol coupling strategy: Paterson, I.; Florence, G. J.; Heimann,
A. C.; Mackay, A. C. Angew. Chem., Int. Ed. 2005, 44, 1130.
Figure 1. Natural products containing all-carbon, R-quaternary
ketones.
(5) Syntheses of the epothilones frequently employ this strategy via
lithium enolates formed using LDA. The ketones used in these reactions
are largely unfunctionalized and are therefore compatible with the strong
base. Recent review of epothilone syntheses: Watkins, E. B.; Chittiboyina,
A. G.; Avery, M. A. Eur. J. Org. Chem. 2006, 4071.
hindered enones are rarely exploited as a site of fragment
assembly.4,5 The significant steric demand posed by these
R-quaternary carbon centers prevents the use of most
10.1021/ol800099a CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

The Reformatsky reaction is an excellent synthetic tool
for site-selective formation and subsequent elaboration of
an enolate.8 Many metals such as magnesium, chromium,
and zinc can be used to promote this transformation.
Nevertheless, only a few examples of such reactions involv-
ing quaternary substitution adjacent to the R-bromoketone
have been described. Dubois has reported the use of
chromium(II) chloride to promote the Reformatsky-type
coupling of pinacolone-type R-bromoketones with alde-
hydes;9 however, to date, this coupling has found limited
utility. Other metallic species, namely magnesium10 and
diethylzinc,11 have been used to promote the pinacolone-
type Reformatsky-type coupling, but the low degree of
functional group compatibility of these reagents places
significant restrictions on these methods.12
1-bromopinacolone derivatives were also effective; coupling
reactions of 3-bromo-2,2-dimethyl-3-butanone with the same
series of aldehydes proceeded in good yields and excellent
diastereoselectivities, favoring, as determined by H NMR,
the syn diastereomer (entries 5-8).16
The remarkably high reactivity observed in the aldehyde
couplings led us to also consider ketones as electrophiles
(Table 2). The intermolecular Reformatsky-type coupling of
1
Table 2. R-Bromoketone-Ketone Couplings Promoted by
a
SmI2
Since the advent of diiodosamarium as a reagent in organic
synthesis, it has been extensively employed in intramolecular
Reformatsky-type reactions.13 In contrast, this reagent has
found little use in intermolecular Reformatsky-type coupling
reactions, presumably due to the numerous side reactions
that can occur.14 Our recent total synthesis of (+)-acutiphycin
demonstrated the first use of diiodosamarium to promote a
chemoselective Reformatsky-type fragment coupling of a
pinacolone-like R-bromoketone.15 On the basis of this work,
we hypothesized that an R′-quaternary group on the R-bro-
moketone would reduce the likelihood of side reactions of
the ketone. Herein, the generality of this method is described.
The coupling of 1-bromopinacolone proved general across
a range of aldehyde electrophiles (Table 1). Aldehydes
entry
R1
R2
yield (%)
1
2
3
4
5
Me
Et
Et
t-Bu
t-Bu
Me
Me
Et
Me
Et
77
63
75
98
51
a Standard procedure: See Table 1, footnote a.
R-haloketones with ketones traditionally requires harsh Lewis
acids or elevated temperatures to obtain a serviceable yield
of the desired product.17,18 Using the diiodosamarium method,
however, simple ketones coupled efficiently (entries 1-3),
and remarkably, even pinacolone (entry 4) served as an
effective electrophile. Despite the less electrophilic nature
of ketones, the reaction proceeded efficiently at -78 °C,
without significant alterations to the procedure.
Table 1. R-Bromoketone-Aldehyde Couplings Promoted by
a
SmI2
(6) Examples involving the synthesis of R,â-unsaturated ketones derived
from 1-bromopinacolone: Oare, D. A.; Henderson, M. A.; Sanner, M. A.;
Heathcock, C. H. J. Org. Chem. 1990, 55, 132.
(7) Examples involving the synthesis of R-aryl ketones derived from
pinacolone under SRN1 conditions: (a) Carver, D. R.; Greenwood, T. D.;
Hubbard, J. S.; Komin, A. P.; Sachdeva, Y. P.; Wolfe, J. F. J. Org. Chem.
1983, 48, 1180. (b) Layman, W. J., Jr.; Greenwood, T. D.; Downey, A. L.;
Wolfe, J. M. J. Org. Chem. 2005, 70, 9147.
(8) Reviews of the Reformatsky reaction: (a) Ocampo, R.; Dolbier, W.
R., Jr. Tetrahedron 2004, 60, 9325. (b) Fu¨rstner, A. Synthesis 1989, 571.
(9) Dubois, J.-E.; Axiotis, G.; Bertounesque, E. Tetrahedron Lett. 1985,
26, 4371.
(10) Fellmann, P.; Dubois, J.-E. Tetrahedron 1978, 34, 1349.
(11) Hansen, M. M.; Bartlett, P. A.; Heathcock, C. H. Organometallics
1987, 6, 2069.
(12) The use of magnesium requires refluxing the R-bromoketone with
magnesium in benzene prior to introduction of the aldehyde, whereas the
diethylzinc reaction must be concentrated in vacuo prior to introduction of
the aldehyde substrate.
(13) Reviews: (a) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96,
307. (b) Kagan, H. B. Tetrahedron 2003, 59, 10351. (c) Edmonds, D. J.;
Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371.
(14) R-Bromoesters often “self-couple” to form products of reductive
dimerization, among others. Moreover, SmI2 promotes numerous reactions
of aldehydes themselves. For further examples see ref 13 and Krief, A.;
Laval, A.-M. Chem. ReV. 1999, 99, 745.
(15) (a) Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128,
15106. (b) Moslin, R. M.; Jamison, T. F. J. Org. Chem. 2007, 72, 9736.
(16) (a) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066. (b) Ando, A.;
Shioiri, T. Tetrahedron 1989, 45, 4969.
entry
R1
R2
yield (%)
syn:anti
1
2
3
4
5
6
7
8
H
H
H
H
Me
Me
Me
Me
n-Bu
Cy
t-Bu
Ph
n-Bu
Cy
t-Bu
Ph
60b
94b
85
72
85
80
84
70
na
na
na
na
95:5
93:7
>98:2
94:6
a
Standard procedure: A THF solution of the R-bromoketone (1 equiv)
and the aldehyde (1 equiv) was prepared and added dropwise over 25 min
to a THF solution of SmI2 (5 equiv) at -78 °C, and the reaction was stirred
1 h. Air was bubbled through the solution for 5 min before a sodium
thiosulfate workup. Compounds were isolated using standard column
chromatography. See Supporting Information for details. b A minor product
was also isolated and is tentatively assigned as an Evans-Tischenko-type18
monoprotected diol, formed from the addition a second equivalent of the
aldehyde to the Reformatsky-type coupling product.
(17) Aoyagi, Y.; Yoshimura, M.; Tsuda, M.; Tsuchibuchi, T.; Kawamata,
S.; Tateno, H.; Asano, K.; Nakamura, H.; Obokata, M.; Ohta, A.; Kodama,
Y. J. Chem. Soc., Perkin Trans. 1 1995, 689.
containing secondary (entry 1), tertiary (entry 2), quaternary
(entry 3), and aromatic (entry 4) R-substitution performed
well in the coupling reaction. More sterically demanding
(18) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
1292
Org. Lett., Vol. 10, No. 6, 2008

Reformatsky-type coupling was also achieved with the
R-chloroketones, that is, 1-chloropinacolone and 3-chloro-
2,2-dimethyl-3-butanone. Using the same aldehyde electro-
philes and reactions conditions as above, â-hydroxyketones
were formed in yields comparable to or higher than the
analogous R-bromoketone coupling reactions (Table 3). A
coupling of R-chloroketones with ketones and nonaromatic
aldehydes.19
Dehydration to form the E-disubstituted enones proceeded
smoothly using a half-molar excess of the Martin sulfurane
reagent at room temperature (Table 5).20 This method was
Table 5. Dehydration of â-Hydroxyketones with Martin
Sulfuranea
Table 3. R-Chloroketone-Aldehyde Couplings Promoted by
SmI2
a
entry
R1
R2
R3
yield (%)
E:Z ratio
entry
R1
R2
yield (%)
syn:anti
1
2
3
4
5
6
7
H
H
H
H
H
H
Me
n-Bu
Cy
t-Bu
Ph
Et
t-Bu
n-Bu
H
H
H
H
Me
Me
H
89
>99
68
89
92
>98:2
>98:2
>98:2
>98:2
72:28
77:23
>98:2
1
2
3
4
5
6
7
8
H
H
H
H
Me
Me
Me
Me
n-Bu
Cy
t-Bu
Ph
n-Bu
Cy
t-Bu
Ph
77b
>99
>99
72
90
94
na
na
na
na
95:5
93:7
>98:2
94:6
37
94
90
71
a
Standard procedure: A solution of Martin sulfurane (1.5 equiv, CH2Cl2)
was added to the â-hydroxyketone in CH2Cl2, and the reaction was stirred
for 30 min. The reaction was quenched with sat. aq NaHCO3, extracted
with Et2O, and washed (4 × 1 M NaOH) prior to purification via column
chromatography.
a Standard procedure: See Table 1, footnote a. b See Table 1, footnote
b.
quantitative yield was observed in cases where the aldehyde
contained tertiary and quaternary (entries 2-3) substitution
at the R-position. Excellent diastereoselectivity was also
observed in the reactions of 3-chloro-2,2-dimethyl-3-bu-
tanone (entries 5-8).
highly successful for secondary (entry 1), tertiary (entry 2),
and quaternary (entry 3) aliphatic substitution adjacent to
the alcohol. The product of entry 3 cannot be accessed using
a Wittig olefination approach.6 Benzylic alcohols were also
dehydrated efficiently (entry 4).
The coupling of 1-chloropinacolone with hindered ketones
also proceeded in good yield (Table 4). The increased yields
The observed E/Z selectivity can be explained using
Newman projection models (Figure 2). The lower selectivity
Table 4. R-Chloroketone-Ketone Couplings Promoted by
a
SmI2
entry
R1
R2
yield (%)
1
2
3
4
5
Me
Et
Et
t-Bu
t-Bu
Me
Me
Et
Me
Et
81
84
77
93
65
Figure 2. Stereoselectivity model for Martin sulfurane dehydration.
a Standard procedure: See Table 1, footnote a.
with tertiary alcohols (entries 5 and 6) may be due to
increasing E1-type elimination character, which is com-
observed in these cases may be a result of the higher
reduction potential of the C-Cl bond compared to that of
the C-Br bond in R-haloketones; a smaller concentration
of the samarium enolate in the case of R-chloroketones
precludes the formation of possible side products, such as
the Evans-Tischenko-type monoprotected diol. These condi-
tions are the first reported to effect the Reformatsky-type
(19) Prior examples of R-choroketones in couplings that afford â-hy-
droxyketones: (a) Ishihara, T.; Yamanaka, T.; Ando, T. Chem. Lett. 1984,
1165. (b) Kagayama, A.; Igarashi, K.; Shiina, I.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 2000, 73, 2579. (c) Yanagisawa, A.; Takahashi, H.; Arai, T. Chem.
Commun. 2004, 580. (d) Shibata, I.; Suwa, T.; Sakakibara, H.; Baba, A.
Org. Lett. 2002, 4, 301.
Org. Lett., Vol. 10, No. 6, 2008
1293

monly observed for Martin sulfurane dehydrations of tertiary
alcohols.20 E-Trisubstituted enones can also be formed from
the R-methyl-â-hydroxy coupling products (entry 7).
Acknowledgment. This work was supported by the
NIGMS (GM-063755). B.A.S. thanks the MIT Undergradu-
ate Research Opportunities Program (UROP) for funding,
including the Thomas A. Spencer Endowed UROP Fund and
the Paul E. Gray Endowed Fund for UROP. We are grateful
to Ms. Li Li for obtaining mass spectrometric data for all
new compounds (MIT Department of Chemistry Instrumen-
tation Factility, which is supported in part by the NSF (CHE-
9809061 and DBI-9729592) and the NIH (1S10RR13886-
01)).
Overall, this method represents a mild and efficient two-
step synthesis of a class of challenging R,â-unsaturated
enones and is complementary to the standard olefination
procedures. Diiodosamarium-promoted Reformatsky-type
couplings of R-haloketones with various aldehyde and ketone
electrophiles yielded â-hydroxyketones in good to excellent
yield and diastereoselectivity. These hindered â-hydroxyke-
tones were dehydrated using Martin sulfurane to yield R,â-
unsaturated enones with excellent yields and diastereoselec-
tivity, in most cases. Currently, extensions of this methodology
are being explored, including Reformatsky-type couplings
catalytic in diiodosamarium.
Supporting Information Available: General experimen-
tal procedures and spectral and analytical data for all new
1
compounds, including H and 13C NMR data. This mat-
erial is available free of charge via the Internet at
http://pubs.acs.org.
(20) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
OL800099A
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