Synthesis of alcohols from m-fluorophenylsulfones and dialkylboranes: Application to the C14-C35 building block of E7389

Article abstract of DOI:10.1021/ol300672q

The reaction of m-fluorophenylsulfone anions with dialkylboranes, followed by alkaline hydroperoxide oxidation, yields alcohols in high yields. Optimization of the process, scope and limitation, and application to the synthesis of one of the C14-C35 building blocks of E7389, a right half analogue of halichondrin B, are reported.

Full text of DOI:10.1021/ol300672q

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2262–2265
Synthesis of Alcohols from
m-Fluorophenylsulfones and
Dialkylboranes: Application to the
C14ꢀC35 Building Block of E7389
ꢀ
Lei Liu, James A. Henderson, Akihiko Yamamoto, Paul Bremond, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, United States
kishi@chemistry.harvard.edu
Received March 16, 2012
ABSTRACT
The reaction of m-fluorophenylsulfone anions with dialkylboranes, followed by alkaline hydroperoxide oxidation, yields alcohols in high yields.
Optimization of the process, scope and limitation, and application to the synthesis of one of the C14ꢀC35 building blocks of E7389, a right half
analogue of halichondrin B, are reported.
The use of arylsulfones for the formation of carbonꢀ
carbon bonds is a well-recognized strategy in organic
synthesis.1 Transformations using this versatile auxiliary
include (1) alkylation, acylation, and aldol-type reactions
of R-arylsulfonyl carbanions, (2) Michael-type addition
of a nucleophile to R,β-unsaturated sulfones, and (3)
DielsꢀAlder reactions with electron-deficient dienophiles
such as phenyl vinyl sulfones and others. Once the task is
completed, the arylsulfone group is readily removed from
the intermediate by reduction, oxidation, or alkylative
desulfonylation, as well as β-elimination to form olefins
and vinyl sulfones or pyrolytic extrusion of sulfur dioxide.
Related to our ongoing program in the halichondrin
area,2 we were interested in the transformation of
RCH2SO2Ph to RCH2OH. A literature search revealed
only one example known. In 1981, Uguen reported the
conversion of n-heptylphenylsulfone to n-heptanol by
reaction of the R-lithiated phenylsulfone with 9-borabicyclo-
[3.3.0]nonane (9-BBN), followed by treatment with alka-
line hydroperoxide (Scheme 1).3 Despite its modest effi-
ciency, this example served as a lead to our current study.
In this letter, we report optimization of Uguen’s transfor-
mation to a synthetically useful level and its application to
the synthesis of one of the C14ꢀC35 building blocks of
E7389 (Eribulin).4
Considering the application of this process to the
β-branched phenylsulfone present in the C14ꢀC35 build-
ing block of E7389 (cf., 13 in Scheme 3), we first tested
Uguen’s transformation on cyclohexylmethyl phenylsul-
fone, i.e., the substrate in entry 2, Table 1. Employing the
conditions described by Uguen, we were able to detect only
a trace amount of the desired cyclohexylmethyl alcohol,
(3) Uguen, D. Bull. Soc. Chim. Fr. II 1981, 99.
(4) (a) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer,
L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.;
Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.;
Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551. (b)
Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle, M. J.; Yu, M. J.;
Zheng, W. U.S. Patents 6214865, 1999 and 6365759, 2000 and Interna-
tional Patent WO99/65894. (c) Yu, M. J.; Kishi, Y.; Littlefield, B. A. In
Anticancer Agentsfrom Natural Products; Cragg, G. M., Kingston, D. G. I.,
Newman, D. J., Eds.; CRC Press: Boca Raton, FL, 2005; p 41.
(1) For reviews, see: (a) Nielsen, M.; Jacobsen, C. B.; Holub, N.;
~
Paixao, M. W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 2668.
(b) El-Awa, A.; Noshi, M. N.; Jourdin, X. M.; Fuchs, P. L. Chem. Rev.
2009, 109, 2315. (c) Simpkins, N. S. Sulphones in Organic Synthesis;
Baldwin, J. E., Ed.; Pergamon Press: Oxford, 1993.
(2) Shan, M.; Kishi, Y. Org. Lett. 2012, 14, 660 and references
therein.
r
10.1021/ol300672q
Published on Web 04/24/2012
2012 American Chemical Society

Table 2. Studies on Base, Solvent, Concentration, and Reaction
Temperature
Scheme 1. Conversion of a Phenylsulfone to a Primary Alcohol
as Reported by Uguen
Table 1. Substitution Effect of Phenylsulfones
a Conversions: estimated from 1H NMR spectra of the crude
products.
As anticipated from the proposed step of A f B
(Scheme 1), we observed a better conversion for phenyl-
sulfones bearing an electron-withdrawing group(s);
indeed, a complete conversion was observed for m-fluor-
ophenylsulfone and m,p-dichlorophenylsulfone (entries 7
and 8, Table 1). However, the former was found far
superior to the latter in terms of the isolated yield.
With m-fluorophenylsulfone fixed, we then studied the
effect of base, solvent, concentration, and reaction tem-
perature (Table 2). This study revealed the conditions
employed for entries 2 and 3 to be optimum for this
transformation.
Under the optimized conditions, we then tested the
scope and limitation of this transformation (Figure 1).
In this study, we tested both Sia2BH and 9-BBN. For
nonconjugated primary and secondary substrates 1ꢀ5,
the efficiency of this transformation was good to excellent.
In addition, Sia2BH was superior to 9-BBN for primary
substrates1ꢀ3, whereas 9-BBN wassuperior for secondary
substrates 4 and 5.
a Conversions: estimated from 1H NMR spectra of the crude pro-
ducts. b Yields: chromatographically isolated product.
with the mass balance being recovered starting material.
Interestingly, we found that, with use of an excess of n-
butyllithium (2.1 equiv), this transformation vastly im-
proved (approximately 90% conversion; 77% isolated
yield). Yet, we desired to improve one aspect of the
transformation: the reaction never completed, even with
use of a large excess of n-butyllithium.
Uguen suggested that this transformation proceeds
through the intermediates A and B (Scheme 1). On the
basis of the fact that the starting material was recovered
even with an excess of n-BuLi, we assumed the formation
of A from the R-lithiated phenylsulfone and 9-BBN to be a
reversible step. Thus, we first studiedthe substitution effect
on the phenylsulfone, with the hope of facilitating the
elimination of PhSO2Li from A (Table 1). In this screening,
we used disiamylborane (Sia2BH), instead of 9-BBN,
because Sia2BH appeared to be slightly better for this
substrate than 9-BBN.
For the substrates bearing a carbanion-stabilizing
group(s), except 8, this reaction gave a substantial amount
of the starting materials back. This result is not totally
surprising, when one assumes the reversibility of
Org. Lett., Vol. 14, No. 9, 2012
2263

Scheme 2. Example for the Transformation of a m-Fluorophe-
nylsulfone to a Secondary Alcohola
a Conversions: estimated from 1H NMR spectra of the crude pro-
ducts. Yields: chromatographically isolated product.
Scheme 3. Application to the C27ꢀC35 and C14ꢀC35 Building
Blocks of E7389a
Figure 1. Scope and limitation. Sia2BH and 9-BBN were tested
for all the substrates. Yields represent chromatographically
1
isolated products. Conversions are estimated from H NMR
spectra of the crude products. For compound 1, 1.4 equiv,
instead of 1.8, of n-BuLi was used.
(A to R-lithiated phenylsulfone þ R2BH). In addition, the
relative reactivity observed for 7ꢀ9 is consistent with this
explanation. It is noteworthy that 9-BBN was superior to
Sia2BH for all of 6ꢀ10.
a Yields: chromatographically isolated product. Conversions: chro-
matographically isolated starting material for 13b and estimated from
1H NMR spectrum of the crude product for 11b.
Although the starting materials were not completely
consumed, this reaction still gave the expected alcohol in
good yields for the benzyl phenylsulfones 6ꢀ9. However,
it was not yet satisfactory for some substrates such as
(3,3-dimethylallyl)phenylsulfone 10.
substrates, thereby demonstrating once again the beneficial
effect from the m-fluorophenylsulfone group (Scheme 2).
Finally, the transformation of phenylsulfones to pri-
mary alcohols was applied for the C27ꢀC35 and C14ꢀ
C35 building blocks of E7389 (Scheme 3).5 For this
As reported by Uguen, phenylsulfones yield secondary
alcohols on treatment with R3B, instead of Sia2BH or
9-BBN. To test the relative performance of m-fluorophe-
nylsulfones and phenylsulfones, we used cyclohexylmethyl
(6) During the review process, one of the reviewers suggested an
involvement of dianion, first R-sulfonylanion formation followed by
directed ortho-metalation. At the early stage of study, we had also
suspected an involvement of dianion and conducted deuterium exchange
experiments. Thus, ((cyclohexylmethyl)sulfonyl)benzene, the substrate
shown under entry 2 in Table 1, was treated with 2.2 equiv of n-BuLi in
THF at ꢀ78 °C and quenched with AcOH-d4, MeOH-d4, or D2O. The
product was then subjected to MS and 1H NMR analyses, thereby
demonstrating (1) a monodeuterium incorporation, (2) a deuterium
exchange at -CH2SO2Ph, and (3) no noticeable change in the aromatic
region in the 1H NMR. On the basis of these observations, we felt the
involvement of dianion to be unlikely. Obviously, further studies are
required to unveil the mechanistic reason for the requirement of an
excess base.
(5) Experimental procedure from 13a to 14. To a stirred solution of
13a (230 mg, 0.2 mmol) in THF (1.1 mL) at ꢀ78 °C was added n-BuLi
(206 μL, 1.9 M in hexane) dropwise. The resulting solution was stirred at
ꢀ78 °C for 5 min and subsequently warmed to 0 °C for 10 min. Sia2BH
(728 μL, 0.825 M in THF) was added dropwise, and the reaction was
allowed to warm to rt and was stirred overnight. The reaction was then
quenched by the sequential addition of H2O (0.3 mL), 3 N NaOH
(0.3 mL), and 30 wt % H2O2 (0.3 mL). After 30 min of stirring, the
mixture was extracted with EtOAc (3 ꢁ 10 mL). The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and con-
centrated. The crude residue was passed through a short silica gel
column to give 14 (177 mg, 89%).
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Org. Lett., Vol. 14, No. 9, 2012

demonstration, we compared m-fluorophenylsulfones
over phenylsulfones in each series, thereby revealing
(1) its remarkable effectiveness even for polyfunc-
tional substrates and (2) a beneficial effect from the
m-fluorophenylsulfone group, as seen in the C14ꢀC35
series.
one of the C14ꢀC35 building blocks of E7389, thereby
demonstrating its remarkable effectiveness even for a
polyfunctional substrate such as 13a.6
Acknowledgment. Financial support from the Eisai
USA Foundation is gratefully acknowledged.
In summary, we report a method to convert m-fluoro-
phenylsulfones to the corresponding alcohols in high
yields. Optimization study of the process revealed
the beneficial effect from the m-fluorophenyl group.
We then applied this transformation to the synthesis of
Supporting Information Available. Experimental de-
tails and 1H NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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