Application of the B-alkyl Suzuki-Miyaura cross-coupling reaction to the stereoselective synthesis of analogues of (3S)-oxidosqualene

Article abstract of DOI:10.1021/ol061962z

(Chemical Equation Presented) A general method is described for the direct and stereoselective synthesis of epoxypolyenes via Suzuki-Miyaura cross-coupling reaction of 1-iodoalkenes with B-alkylboron compounds. It allows for the straightforward and conver

Full text of DOI:10.1021/ol061962z

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4815-4818
Application of the B-Alkyl
Suzuki Miyaura Cross-Coupling
−
Reaction to the Stereoselective
Synthesis of Analogues of
(3S)-Oxidosqualene
Johan M. Winne, Bing Guang, Jo D’herde, and Pierre J. De Clercq*
Department of Organic Chemistry, Ghent UniVersity, Krijgslaan 281/S4,
B-9000 Ghent, Belgium
pierre.declercq@ugent.be
Received August 8, 2006
ABSTRACT
A general method is described for the direct and stereoselective synthesis of epoxypolyenes via Suzuki−Miyaura cross-coupling reaction of
1-iodoalkenes with B-alkylboron compounds. It allows for the straightforward and convergent assembly of compounds that are structurally
similar to (3S)-oxidosqualene, an important intermediate in steroid biosynthesis.
The reported study is part of a project that investigates the
cyclization behavior of several analogues of (3S)-oxido-
squalene,1 the natural substrate for the intriguing enzymatic
polycyclization reaction in the steroid biosynthesis.2,3
Initial attempts to assemble analogues such as 1 or 2
(Figure 1) from advanced intermediates 3, 5, 8, and 11 (see
Schemes 1 and 2) using recently established coupling
reactions in this field4,5 were frustrated by the failure to
prepare any suitable organometallic reagents from both
iodoalkenes 3 and 5 or from derivatives of 11.
We were, however, able to achieve the sp2-sp3 C-C bond
applying the B-alkyl Suzuki-Miyaura cross-coupling reac-
tion.6,7
The electrophiles 5 and 6, respectively, bearing a protected
(R)-diol and the required (S)-epoxide (of which the acetonide
is a latent form), were efficiently obtained starting from the
known iodoalkene 38 via a highly regio- and enantioselective
Scheme 1
Figure 1. Analogues of (3S)-oxidosqualene.
10.1021/ol061962z CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/26/2006

Grieco-Sharpless elimination protocol.13 Hydroboration
reactions with 9-borabicyclo[3.3.1]nonane were found to be
very sluggish even under the harsh conditions used, espe-
cially in the case of the neopentyl vinyl substrates derived
from 11. In contrast, reactions with dicyclohexylborane
proceeded very smoothly under mild conditions.
Scheme 2
A first successful coupling of iodoalkene 5 with model
alkene substrate 13 showed the feasibility of the approach
via Suzuki reaction (Scheme 3).
Scheme 3
We then proceeded to investigate the cross-coupling of
B-alkylboron substrates 9a,b and 12a,b. The results of the
coupling experiments with iododiene 3 and these alkylborane
species are outlined in Table 1.
Sharpless asymmetric dihydroxylation reaction (Scheme
1).9,10
Table 1. Cross-Coupling Reactions of Some B-Alkylboron
Compounds with 3 under Various Conditions
The central part of target structure 1 was easily derived
from the readily available diacid 7 (Scheme 2). For target
polyene 2, the advanced key intermediate 11 was synthesized
from the known (S)-methyloctalone 10 (Scheme 2).11,12 The
corresponding B-alkylboron species 9a,b and 12a,b could
be conveniently prepared in situ via hydroboration of the
alkenes derived from intermediates 8 and 11, using the
temp
time
(h)
yieldb
(%)
entry substrate product procedurea (°C)
1
2
3
4
5
6
9a
15
17
17
17
17
15
A
A
B
B
Bd
Bd
60
60
60
rt
rt
rt
3
3
3
64
(1) (a) Berckmoes, K.; De Clercq, P. J. J. Am. Chem. Soc. 1995, 117,
5857. (b) Zhou, S.; Sey, M.; De Clercq, P. J.; Milanesio, M.; Viterbo, D.
Angew. Chem., Int. Ed. 2000, 16, 2861.
(2) For a review, see: (a) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem.
ReV. 1993, 93, 2189. (b) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D.
R. Angew. Chem., Int. Ed. 2000, 39, 2812.
(3) For reviews of some elegant syntheses in which this enzymatic
reaction is mimicked, see: (a) Yoder, R. A.; Johnston, J. N. Chem. ReV.
2005, 105, 4730. (b) Barrero, A. F.; Qu´ılez del Moral, J. F.; Sa´nchez, E.
M.; Arteaga, J. F. Eur. J Org. Chem. 2006, 1627.
(4) Pd-catalyzed Negishi reaction of alkylzinc reagents with 1-halo-
alkenes: Negishi, E.; Liou, S. Y.; Xu, C.; Huo, S. Org. Lett. 2002, 4, 261.
(5) Cu-catalyzed reaction of alkenyl Grignard reagents with primary alkyl
halides: Cahiez, G.; Chaboch, C.; Je´ze´quel, M. Tetrahedron 2000, 56, 2733.
(6) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Org. Chem. 1989, 111, 314.
12b
12b
12b
12b
9b
trace
10c
45
18
20 + 20 80
20 + 20 75
a Reactions were conducted by adding 1.0 equiv of freshly prepared
B-alkylboron reagent in THF/H2O to (i) a stirred solution of 0.96 equiv of
3, 0.10 equiv of PdCl2(PPh3)2, and 2.0 equiv of 3 M K3PO4 in DMF
(procedure A) or (ii) a stirred suspension of 0.96 equiv of 3, 0.10 equiv of
PdCl2(dppf), 0.10 equiv of Ph3As, and 2.0 equiv of Cs2CO3 in DMF
(procedure B). b Isolated yields after column chromatography. c Isolated with
minor amounts of inseparable impurities from the complex reaction mixture.
d Another 0.25 equiv of 3 was added during the course of the reaction.
(7) For a review, see: Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4544.
(8) Stereoselectively prepared via Zr-catalyzed syn-carboalumination
reaction of a terminal alkyne: Negishi, E.; Van Horn, D. E.; Yoshida, T.
J. Am. Chem. Soc. 1985, 107, 6639.
(9) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768.
(10) The enantiomeric excess of the intermediate diol 4 was found to be
96%, as determined via 1H NMR analysis of the derived (2S)-methoxy-
phenylacetic esters.
(11) Compound 10 was prepared with 91% ee (GC), using a procedure
first reported in: Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am.
Chem. Soc. 1985, 107, 273.
Application of the classical high-temperature conditions
(procedure A) used in the model experiment (Scheme 3) gave
satisfactory results for 9a but were unsuccessful for the more
demanding substrate 12b (entries 1 and 2, Table 1). From a
small screening of the most commonly reported catalyst/
ligand/base systems,14 the widely used combination of
PdCl2(dppf) catalyst with Ph3As ligand and Cs2CO3 as a base
(procedure B) emerged as the only case where coupling was
(12) A full discussion of this rather lengthy sequence is beyond the main
focus of this communication. A scheme is included in the Supporting
Information with detailed experimental procedures and spectral data.
(13) Krief, A.; Laval, A. M. Bull. Soc. Chim. Fr. 1997, 134, 869 and
references therein.
4816
Org. Lett., Vol. 8, No. 21, 2006

observed, albeit in very low yield (entry 3). Prolonged
heating only led to a complex reaction mixture.
Table 2. Cross-Coupling Reactions of Some B-Alkylboron
Compounds with 6 under Various Conditions
Johnson and Braun have reported that B-alkyl Suzuki-
Miyaura cross-coupling can be effected at room temperature
when Cs2CO3 is used as a base (procedure B).15 Here, this
mild procedure led to a clean coupling reaction with
acceptable yield (entry 4). The only detected side product
was a homodimeric species arising from head-to-head
coupling of the electrophile 3. Therefore, more electrophile
was added to the reaction after the initial iodoalkene was
consumed. Thus, a significant increase in yield was achieved
(entry 5). These optimized conditions gave similar results
for the aromatic substrate 9b (entry 6).
temp
time
(h)
yieldb
(%)
entry substrate product procedurea (°C)
1
2
3
4
5
6
7
8
9
16a
12a
12a
12b
12b
12b
12b
12b
16b
18
1
A
A
B
B
B
B
Be
B
B
B
60
60
60
60
60
rt
rt
rt
rt
rt
3
3
1
1
3
35
0
19
19
19
19
19
19
19
1
9c
25
10d
55
The further synthesis of epoxypolyenes 1 and 2 is
delineated in Scheme 4. Deprotection and Grieco-Sharpless
24
20 + 20e 35
18f
20f
16f
70g
45g
50g
Scheme 4
10
2
a Reactions were conducted by adding 1.0 equiv of freshly prepared
B-alkylboron reagent in THF/H2O to (i) a stirred solution of 0.96 equiv of
6, 0.10 equiv of PdCl2(PPh3)2, and 2.0 equiv of 3 M K3PO4 in DMF
(procedure A) or (ii) a stirred suspension of 0.96 equiv of 6, 0.10 equiv of
PdCl2(dppf), 0.10 equiv of Ph3As, and 2.0 equiv of Cs2CO3 in DMF
(procedure B). b Isolated yields after column chromatography. c Unexpected
compound was isolated as major reaction product; see text for details.
d Isolated with inseparable impurities from the complex reaction mixture.
e Another 0.25 equiv of 6 was added during the course of the reaction.
f Reaction worked up as soon as all of 6 was consumed. g See ref 18 for a
general procedure.
surprisingly, the major reaction product was the coupled
compound 20, in which the conjugated diene was reduced
(Scheme 5).16
Scheme 5
This unexpected reduction, however, did not occur when
dicyclohexylborane derivative 12b was coupled under the
same conditions (entry 4).17 The yield was still low and
seemed to rapidly decrease upon longer reaction times (entry
5). In accordance with the earlier results for 3, acceptable
yields for the cross-coupling were achieved with the Johnson-
Braun room temperature procedure (entry 6). Conversely,
adding more electrophile with extended reaction times led
to a significantly lower yield in this case (entry 7). This
elimination of silyloxypolyenes 15 and 17, followed
by hydroboration, gave the B-alkylboron reagents 16a,b and
18. At this stage, we focused on coupling the more
challenging electrophile 6. The outcome is summarized in
Table 2.
We were pleased to note that the we could obtain
epoxypolyene 1 even under the harsher conditions (entry 1,
Table 2). As expected, no reaction occurred with the less
reactive boron reagent 12a (entry 2). The latter species did
cross-couple with 6 using procedure B (entry 3), but
(16) Similar problems have been reported regarding the unexpected
reduction of a nitro group during Suzuki reaction with a 9-alkyl-9-BBN
reagent; see: Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58,
2201.
(14) Some common combinations of the bases NaOH, K3PO4, or Cs2CO3
with Pd(PPh3)4, PdCl2(dppf), or PdCl2(PPh3)2 catalysts were tested in DMF
or THF with or without extra ligands (AsPh3 or PPh3); see refs 6 and 7.
(15) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.
(17) This indicates the alkyl-9-BBN reagent as the hydride source for
reduction, a process that has been described for dialkyl-9-BBN “ate”
complexes: van Bergen, T. J.; Kellogg, R. M. J. Am. Chem. Soc. 1976, 98,
1964.
Org. Lett., Vol. 8, No. 21, 2006
4817

observation can be attributed to the expected limited stability
of the assembled compounds under nucleophilic conditions.
Optimal yields of epoxypolyenes were thus obtained by
working up as soon as the epoxy iodoalkene 6 was consumed
(entries 8-10, Table 2).18
way to assemble analogues of (3S)-oxidosqualene in a direct
and stereoselective fashion. This approach offers a straight-
forward alternative to the established methods and excludes
the need for possibly inconvenient organometallic reagents.
Furthermore, this study clearly indicates dicyclohexyl-
borane as the hydroboration reagent of choice. The required
terminal alkenes are readily accessible via the reliable
Grieco-Sharpless elimination of the corresponding primary
alcohol.
In summary, the scope of the B-alkyl Suzuki-Miyaura
cross-coupling reaction has been extended with a general
(18) General procedure for cross-coupling 6: Under argon atmosphere,
the terminal alkene substrate (1.0 mmol) was added to a freshly prepared
slurry of dicyclohexylborane (1.5 mmol) in THF (4.8 mL) and stirred at 0
°C. Stirring was continued for 15 min at 0 °C and for 45-60 min without
cooling. Upon completion, excess borane reagent was quenched with water
(16 mmol, purged with argon). After stirring for 30 min at room temperature,
the resulting clear solution was transferred via cannula to another reaction
flask containing a stirred mixture of PdCl2(dppf) (0.096 mmol), Ph3As (0.096
mmol), Cs2CO3 (1.92 mmol), and 6 (0.96 mmol) in DMF (6.4 mL, purged
with argon). The reaction was stirred in the dark at room temperature for
16-20 h. Upon complete consumption of 6, saturated aqueous NaCl solution
was added, and the aqueous phase was extracted with pentane/ether (1:1).
The combined organic phase was washed with water, dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, ethyl acetate in iso-octane) to afford the pure
coupled epoxypolyene (0.45-0.70 mmol).
Acknowledgment. We thank the FWO Vlaanderen and
UGent for financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
11 and precursors thereof. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL061962Z
4818
Org. Lett., Vol. 8, No. 21, 2006