Enantioselective synthesis of (Z)-1,2-anti-2,5-anti-triol monosilyl ethers using a cross-metathesis allylboration sequence

Article abstract of DOI:10.1021/ol101789g

Figure Presented. The enantioselective synthesis of (Z)-1,2-anti-2,5-anti- triol monosilyl ethers via a two-step sequence involving olefin cross-metathesis of β-alkoxyallylboronate 4 and subsequent allylboration of the derived bisboryl intermediate 6 provides triol monoethers 7 with good to excellent diastereoselectivity.

Full text of DOI:10.1021/ol101789g

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4344-4347
Enantioselective Synthesis of
(Z)-1,2-anti-2,5-anti-Triol Monosilyl
Ethers Using a Cross-Metathesis
Allylboration Sequence
SusAnn M. Winbush and William R. Roush*
Department of Chemistry, The Scripps Research Institute, Scripps Florida,
Jupiter, Florida 33458
roush@scripps.edu
Received August 1, 2010
ABSTRACT
The enantioselective synthesis of (Z)-1,2-anti-2,5-anti-triol monosilyl ethers via a two-step sequence involving olefin cross-metathesis of
ꢀ-alkoxyallylboronate 4 and subsequent allylboration of the derived bisboryl intermediate 6 provides triol monoethers 7 with good to excellent
diastereoselectivity.
Stereodefined 1,2,5-triol subunits are present in many
biologically active natural products. The zooxanthellamides,
stagonolides, and annonaceous acetogenins are three classes
of natural products in which this moiety is found.1
The boron-mediated allylation reaction has proven to be
an important method for carbon-carbon bond formation.2
This reaction proceeds with predictable control of stereo-
chemistry via cyclic, chairlike transition states and has been
widely applied in the synthesis of natural products. In recent
years, our laboratory has focused on developing higher-order
applications of the allylboration reaction in which two C-C
bond forming events are performed in a single operation with
a bifunctionalized allylboron reagent (i.e., the double al-
lylboration reaction).3,4 One limitation to this methodology,
which provides 1,5-diols with excellent stereochemical
control, is the general difficulty of synthesizing reagents that
enable placement of additional substituents on the 1,5-diol
scaffold as a direct result of the double allylboration event.
In an effort to expand the utility of the double
allylboration reaction, we imagined that manipulation of
the terminal olefin of boronate ester 3 via cross metathesis
might provide a means to introduce additional functional-
(1) (a) Onodera, K.; Nakamura, H.; Oba, Y.; Ohizumi, Y. J. Am. Chem.
Soc. 2005, 127, 10406. (b) Giri, A, G.; Mondal, M. A.; Puranik, V. G.;
Ramana, C. V. Org. Biomol. Chem. 2010, 8, 398. (c) Zeng, L.; Zhang, Y.;
Ye, Q.; Shi, G.; He, K.; McLaughlin, J. L. Bioorg. Med. Chem. 1996, 4,
1271.
(2) For reviews of allylboration reactions, see: (a) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 2, p 1. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993,
93, 2207. (c) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; p 299. (d) Chemler,
S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; p 403. (e) Denmark, S. E.; Fu, J. Chem. ReV. 2003,
103, 2763. (f) Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1.
(3) (a) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
13644. (b) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am. Chem.
Soc. 2009, 131, 14174
.
(4) For other recent contributions to the double allylmetallation reaction:
(a) Peng, F.; Hall, D. G. J. Am. Chem. Soc. 2007, 129, 3070. (b) Gonza´lez,
A. Z.; Roma´n, J. G.; Alicea, E.; Canales, E.; Soderquist, J. A. J. Am. Chem.
Soc. 2009, 131, 1269.
10.1021/ol101789g  2010 American Chemical Society
Published on Web 08/31/2010

was attributed to the steric bulk associated with the tetraphe-
nyl-substituted dioxaborolane unit of 4a (R1 ) CH2CH2Ph,
X ) H), along with the bulky pinacol boronate ester of the
coupling partner 5. Therefore, we turned to use of the more
robust Hoveyda-Grubbs’ second generation catalyst10 in
order to accommodate the increase in reaction temperature
necessary to effect the cross metathesis reaction. However,
treating a mixture of 4a (R1 ) CH2CH2Ph, X ) H, -SiR3 )
TBS), 5 and the second generation Grubbs-Hoveyda catalyst
in toluene at 80 °C led to olefin 14-24% isomerization of
4a to the corresponding vinylboronate after 24 h, presumably
due to a Ru-H species generated in situ upon decomposition
of the ruthenium catalyst.11 Following an extensive screening
of additives to suppress the olefin isomerization, tetrafluoro-
1,4-benzoquinone was selected as the most effective reagent
to prevent this side reaction.12
Scheme 1. Allylboration-Cross-Metathesis Allylation Sequence
A third variable that had to be optimized to maximize
selectivity for the (E)-olefin geometry in the cross metathesis
product 6 is the size of the alcohol protecting group. Because
it is known that steric bulk at the allylic position generally
enhances selectivity for the (E)-olefinic metathesis product,13
we studied the cross metathesis of a series of silyl ethers
generated from 3a (R1 ) PhCH2CH2, X ) H) (Table 1).
Table 1. (E)-Selectivity in the Cross-Metathesis Reactions of
Silyl Ether Derivatives of Allylboronate 3a
ity (Scheme 1).5 Owing to our long-standing interest in
the synthesis of polyhydroxylated natural products,6 we
concentrated on metathesis partners that would enable us
to access 1,2-anti-2,5-anti triols of type 7. Specifically,
we studied the cross metathesis reactions of silyl ether
protected allylboronates 4 and pinacol vinyl boronate (5),
which is a well-established metathesis coupling partner.7
Accordingly, we report herein a highly diastereoselective
synthesis of (Z)-1,2-anti-2,5-anti-1,2,5-triols 7 by the
sequence summarized in Scheme 1.
Allylboronate 3a (R1 ) CH2CH2Ph, X ) H) was synthe-
sized via the hydroboration of allene 1a (X ) H) with
lIpc2BH followed by treatment of allylboronate 2 with
hydrocinnamaldehyde at -78 °C.3a,8 Initial attempts to effect
cross metathesis reactions of silyl ethers 4a (derived from
3a) with pinacol vinylboronate 5 using Grubbs’ second
generation catalyst were unsuccessful.9 The lack of reactivity
entrya
R3Si
E/Z ratio in 5b
1
2
3
4
5
TMS
TES
TBS
TBDPS
TIPS
3:1
6:1
8:1
16:1
g20:1
a Reactions were performed by treating silyl ethers derived from
allylboronate 3a (R1 ) CH2CH2Ph, X ) H; 1.0 equiv) and pinacol vinyl
boronate 5 (1.5 equiv) with the 2nd generation Hoveyda-Grubbs catalyst
in toluene (0.5 M) at 80 °C for 24 h in the presence of tetrafluoro-1,4-
b
1
benzoquinone (0.10 equiv). Olefin geometry in 6 was determined by H
NMR analysis of the crude product.
These experiments led to the identification of the TIPS ether
as the alcohol protecting group that gives greatest selectivity
for (E)-6.
The results of cross-metathesis reactions of a range of
allylboronate substrates are summarized in Table 2. In all
cases, the selectivity for the (E)-olefinic product was excellent
(g20:1). Most of these reactions provided the vinylboronate
products 6a-k in 60-75% yield, along with some recovered
4a-k. Presumably, these reactions did not proceed to
(5) For reviews of olefin metathesis: (a) Grubbs, R. H. Handbook of
Metathesis; Wiley-VCH: Weinheim Germany, 2003. (b) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490. (c) Connon,
S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (d) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036.
(6) For representative examples, see: (a) Roush, W. R.; Straub, J. A.;
VanNieuwenhze, M. S. J. Org. Chem. 1991, 56, 1636. (b) Roush, W. R.;
Grover, P. T. Tetrahedron 1992, 48, 1981. (c) Hunt, J. A.; Roush, W. R. J.
Org. Chem. 1997, 62, 1112. (d) Roush, W. R.; Hartz, R. A.; Gustin, D. J.
J. Am. Chem. Soc. 1999, 121, 1990. (e) Heo, J.-N.; Holson, E. B.; Roush,
W. R. Org. Lett. 2003, 5, 1697.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
38, 2416.
(7) (a) Morrill, C.; Grubbs, R. H J. Org. Chem. 2003, 68, 6031. (b)
Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.;
Bussman, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58. (c)
Esteban, J.; Costa, A. M.; Vilarrasa, J. Org. Lett. 2008, 10, 4843. (d) White,
B. H.; Snapper, M. L. J. Am. Chem. Soc. 2003, 125, 14901. (e) Nicolaou,
K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J. Am. Chem. Soc.
2009, 131, 16905.
(10) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. 2000, 122, 8168.
(11) (a) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.;
Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961. (b) Hong, S. H.; Day,
M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414.
(12) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(8) (a) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411. (b) Hicks,
(13) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim
Germany, 2003; Vol. 2.
J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509
.
Org. Lett., Vol. 12, No. 19, 2010
4345

third allylboronate, 9, would be produced in the allylboration
of reactions of 6, and that 9 could, in principle, react with a
second equivalent of the aldehyde partner to provide double
allylboration products of type 10 or 11 (Scheme 2). Indeed,
Table 2. Cross-Metathesis Reactions of Allylboronates 4a-k
Scheme 2
.
Allylboronate Intermediate 9 May Undergo a Second
Allylboration
in experiments performed using 6a (with the para substituent
X ) H), mixtures of 7 (major) and 10/11 were obtained when
6a was treated with 1.0 equiv of aldehydes at various reaction
temperatures and concentrations (data not shown). These
results indicated that the reactivities of 6a and 9a (X ) H)
toward aldehydes are comparable.
Consequently, we directed our attention to adjusting the
reactivity of the allylboronate functional group in 6 relative
to that of the intermediate allylboronate species 9. Based on
earlier studies in which we observed that a p-nitrophenyl
substituent on a 1,3,2-dioxaborolane increased the Lewis
acidity of the allylboronate and correspondingly increased
the rate of its reaction with aldehydes, compared to the parent
allylboronate with a phenyl-substituted dioxaborolane,14 we
synthesized the tetra-p-fluorophenyl substituted allylboronate
6b (X ) F) by a sequence paralleling that used for the
synthesis of 6a (X ) H). Treatment of 6b with hydrocin-
namaldehyde in CH2Cl2 (0.1 M) for 24 h, and subsequent
workup with H2O2 and NaOH afforded triol 7a in 67% yield
with g20:1 d.s. Increasing the allylboration reaction period
to 36 h provided 7a in 71% yield, and while after 48 h the
yield of 7a was 77% (see Scheme 3). In all cases, the double
allylboration products 10/11 were not observed. Thus, this
proof of principle experiment established that the inductive
effect of the p-fluoro substituents increased the reactivity of
6b such that allylboration reactions of intermediate 9 were
no longer competitive.
a X ) H. b X ) F. c Tetrafluorobenzoquinone was added to prevent
olefin isomerization. d Isolated yields of 6a-k. e Yield based on recovered
starting material. f Olefin geometry determined by 1H NMR analysis of the
crude reaction products.
completion owing to the high steric demands of the cross
coupling partners-a consequence of the TIPS ether used to
maximize selectivity for the (E)-olefin product in the
metathesis reaction.
At the outset, we anticipated that the allylboration reactions
of 6 would proceed via the chairlike transition state TS-A
(see Scheme 1) with the R-silyloxy carbon chain residing in
an axial position to avoid nonbonded steric interactions with
the tetraphenyl-1,3,2-dioxaborolane unit of the reagent, which
become quite significant in the alternative (disfavored)
transition state TS-B.3a Accordingly, it was anticipated that
this allylboration sequence would provide (Z)-1,2-anti-2,5-
anti-1,2,5-triol monoethers 7 with excellent selectivity fol-
lowing oxidative workup. However, we recognized that a
The scope of allylboration reactions of 6b with additional
aldehydes is presented in Scheme 3, and results of allylbo-
ration reactions of 6c, d, f, g and j with hydrocinnamaldehyde
are presented in Scheme 4. In the vast majority of cases (the
one exception being the reaction of 6b with hydrocinnama-
(14) Roush, W. R.; Banfi, L.; Park, J. C.; Hoong, L. K. Tetrahedron
Lett. 1989, 30, 6457.
4346
Org. Lett., Vol. 12, No. 19, 2010

Scheme 3
.
Allylboration Reactions of 6bsScope of Aldehyde
Scheme 4
.
Allylboration Reactions of 6c, 6d, 6f, 6g and 6j with
Substrates
Hydrocinnamaldehyde
a Determined by advanced Mosher ester analysis. b Diastereomer ratio
1
determined by H NMR analysis of the crude reaction product.
In summary, the allylboration-cross metathesis-allylbora-
tion sequence presented in Scheme 1 constitutes a convergent
and highly enantio- and diastereoselective method for
synthesis of (Z)-1,2-anti-2,5-anti-triol monosilyl ethers 7 with
synthetically useful efficiency. This new method represents
an expansion of our double allylboration methodology,3 and
defines a strategy for introduction of substituents at positions
internal to the 1,5-diol motif. Applications of this new
method in the synthesis of natural products, along with
further extensions of the double allylboration methodology,
are in progress and will be reported in due course.
a Unless indicated otherwise, all allylboration reactions were performed
for 36, h at ambient temperature. b Determined by advanced Mosher ester
analysis. c Diastereomer ratio determined by 1H NMR analysis of the crude
product.
ldehyde in Scheme 3), the reactions were performed at
ambient temperature for 36 h. The triol monoethers 7 were
obtained in 52-89% yield, 82-93% e.e., and g14:1 d.s.
for all examples except 7g (10:1 d.s., Scheme 3) and 7n (9:1
d.s., Scheme 4).
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436) is gratefully
acknowledged. S.M.W. thanks the NIH for a predoctoral
NRSA Fellowship Award (1 F31 GM087953-01). We also
thank Mr. James D. Trenkle (University of Michigan) for
developing the synthesis of tetra-(p-fluorophenyl)ethylene
glycol used in the synthesis of 6b-6j.
The relative and absolute stereochemistry of the triol
monoethers presented in Schemes 3 and 4 were assigned via
advanced Mosher ester analysis of the corresponding MPTA
esters.15,16
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) (a) Hoye, T. R.; Jeffrey, C. S.; Feng, S. Nature Protoc. 2007, 2,
2451. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. (c) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1968, 90, 3732
.
(16) See Supporting Information for data.
OL101789G
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