Diastereoselective addition of arylzinc reagents to sugar aldehydes

Article abstract of DOI:10.1021/ol301724x

The diastereoselective arylation of sugar-derived aldehydes is described. The arylating reagents are generated in situ by a boron-to-zinc exchange reaction of arylboronic acids with Et₂Zn to generate arylethylzinc reagents. The exquisite reactivity of the arylzinc reagents allowed for an efficient and mild arylation, delivering the corresponding products in diastereoisomeric ratios of up to >20:1. The utility of the methodology is highlighted with an efficient formal synthesis of (+)-7-epi-goniofufurone, a member of the styryllactone family of natural products.

Full text of DOI:10.1021/ol301724x

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3962–3965
Diastereoselective Addition of Arylzinc
Reagents to Sugar Aldehydes
†
Ana D. Wouters and Diogo S. Ludtke*
,†,‡
€
^
^
~
Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, USP, Sao Paulo, SP,
Brazil and Instituto de Quımica, Universidade Federal do Rio Grande do Sul, UFRGS,
~
´
Av. Bento Gonc-alves 9500, 91501-970, Porto Alegre, RS, Brazil
dsludtke@iq.ufrgs.br
Received June 22, 2012
ABSTRACT
The diastereoselective arylation of sugar-derived aldehydes is described. The arylating reagents are generated in situ by a boron-to-zinc
exchange reaction of arylboronic acids with Et2Zn to generate arylethylzinc reagents. The exquisite reactivity of the arylzinc reagents allowed for
an efficient and mild arylation, delivering the corresponding products in diastereoisomeric ratios of up to >20:1. The utility of the methodology is
highlighted with an efficient formal synthesis of (þ)-7-epi-goniofufurone, a member of the styryllactone family of natural products.
The addition of organozinc reagents to carbonyl com-
pounds has been a subject of intense research over the past
few years.1 In this context, the addition of diethylzinc to
aldehydes in the presence of an amino alcohol has been
considered a test reaction for the development of new
ligands and catalysts and hundreds of chiral ligands have
been developed.2,3 On the other hand, the addition of
diarylzincs is a much more challenging reaction. The main
reason is because diarylzinc reagents are far more reactive
than the dialkyl ones and sometimes selectivity is difficult
to achieve because of a competitive background addition
that proceeds without the participation of the ligand. In
order to circumvent these selectivity problems and achieve
a neat aryl transfer to aldehydes, the generation of mixed
arylalkylzinc compounds has been investigated. However
the reaction of diphenylzinc with diethylzinc resulted in a
species with decreased reactivity compared to the parent
diphenylzinc.4 One disadvantage associated with the
Ar2Zn/Et2Zn system is that Ph2Zn is the only commer-
cially available arylzinc compound, thus limiting the reac-
tion to the transfer of a phenyl group.
An interesting alternative for the generation of arylal-
kylzinc is the boron to zinc exchange reaction between
~
(4) (a) Bolm, C.; Hildebrand, J. P.; Muniz, K.; Hermanns, N. Angew.
Chem., Int. Ed. 2001, 40, 3284–3308. (b) Schmidt, F.; Stemmler, R. T.;
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J. Am. Chem. Soc. 2009, 131, 12483–12493. (h) Wang, M.-C.; Wang,
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†
~
Universidade de Sao Paulo
‡ Universidade Federal do Rio Grande do Sul
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€
r
10.1021/ol301724x
Published on Web 07/24/2012
2012 American Chemical Society

arylboronic acids and diethylzinc.5 The BꢀZn exchange
occurs efficiently to generate the required mixed organo-
zinc species in situ greatly expanding the number of
transferable aryl groups,6,7 since a vast number of aryl-
boronic acids are commercially available or can be readily
prepared.8
Scheme 1. Diastereoselective Addition of Arylzinc Reagents to
Sugar Aldehydes
Despite their interesting reactivity, the synthetic poten-
tial of arylalkylzinc reagents has remained largely unex-
plored. Besides their use as nucleophiles for the addition
to aldehydes, arylzincs have also found use in asymmetric
Ni-catalyzed Negishi cross-couplings, in an elegant work
developed by Smith and Fu.9
Considering the exquisite reactivity displayed by the
arylethylzinc reagents and in connection with our recent
interest on the use of carbohydrates for the synthesis of
chiral molecules,10 we hypothesized that a mild and selec-
tive arylation of enantiopure sugar-derived aldehydes
would be possible to achieve. Herein we describe our
results on the diastereoselective addition to chiral alde-
hydes bearing an R-oxygenated stereogenic center, readily
available from carbohydrates (Scheme 1).
changing the solvent to dichloromethane, THF and
hexane proved fruitless. When dichloromethane and hex-
ane were used, the product 2 was obtained in good dr but in
low yields (entries 2 and 4). When the more Lewis basic
THF was employed as the solvent, the product yield was
moderate, but a sharp decrease in the diastereoselectivity
was observed (entry 3). Keeping toluene as the solvent and
changing the temperature of the addition to 0 °C resulted
in a decrease in the isolated yield, while maintaining high
diastereoselectivity (entry 5).
Our initial studies were focused on the screening of the
reaction conditions in order to optimize both yield and
diastereoselectivity. For the screening experiments phenyl-
ethylzinc was generated by the reaction of phenylboronic
acid with Et2Zn, and the enantiopure sugar aldehyde 1,
readily available from D-glucose, was chosen as the
substrate.11
Table 1. Diastereoselective Addition of PhZnEt to Aldehyde 1
Under the first set of conditions tested, toluene was used
as the solvent, and the desired product was obtained
in 73% yield and with a very high diastereoselectivity
(Table 1, entry 1, dr > 20:1). Attempts to improve the
yield by increasing the reaction time (up to 24 h) or
entry
solvent
temp (°C)
time (h)
yield (%)a
drb
1
2
3
4
5
6
7
toluene
DCM
25
25
25
25
0
3
2
2
2
4
1
1
73
40
60
20
43
67
85
>20:1
16:1
5:1
(7) (a) Moro, A. V.; Tiekink, E. R. T.; Zukerman-Schpector, J.;
Ludtke, D. S.; Correia, C. R. D. Eur. J. Org. Chem. 2010, 3696–3703.
€
(b) Wouters, A. D.; Trossini, G. H. G.; Stefani, H. A.; Ludtke, D. S. Eur.
€
THF
J. Org. Chem. 2010, 2351–2356.
hexane
toluene
toluene
toluene
14:1
>20:1
10:1
8:1
(8) For the addition of aryl Grignard reagents: (a) Itakura, D.;
Harada, T. Synlett 2011, 2875–2879. (b) Nakagawa, Y.; Muramatsu,
Y.; Harada, T. Eur. J. Org. Chem. 2010, 6535–6538. (c) Muramatsu, Y.;
Kanehira, S.; Tanigawa, M.; Miyawaki, Y. Bull. Chem. Soc. Jpn. 2010,
83, 19–32. (d) Muramatsu, Y.; Harada, T. Chem.;Eur. J. 2008, 14,
10560–10563. For the addition of arylaluminum reagents: (e) Biradar,
D. B.; Zhou, S. L.; Gau, H. M. Org. Lett. 2009, 11, 3386–3389. (f) Zhou,
S. L.; Chuang, D. W.; Chang, S. J.; Gau, H. M. Tetrahedron: Asymmetry
2009, 20, 1407–1412. (g) Zhou, S. L.; Wu, K. H.; Chen, C. A.; Gau,
H. M. J. Org. Chem. 2009, 74, 3500–3505. (h) Chen, C. A.; Wu, K. H.;
Gau, H. M. Adv. Synth. Catal. 2008, 350, 1626–1634. (i) Wu, K. H.;
Chuang, D. W.; Chen, C. A.; Gau, H. M. Chem. Commun. 2008, 2343–
2345. (j) Chen, C. A.; Wu, K. H.; Gau, H. M. Angew. Chem., Int. Ed.
2007, 46, 5373–5376. (k) Wu, K. H.; Gau, H. M. J. Am. Chem. Soc. 2006,
128, 14808–14809. For the addition of aryltitanium reagents: (l) Wu,
J. H.; Zhou, S. L.; Chen, C. A.; Yang, M. C.; Chiang, R. T.; Chen, C. R.;
Gau, H. M. Chem. Commun. 2011, 47, 11668–11670. (m) Zhou, S. L.;
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60
100
a Isolated yields. b Determined by 1H NMR
Attempts to improve the yield by conducting the addi-
tion reaction at higher temperatures resulted in a decrease
in the diastereoselectivity of the reaction (entries 6 and 7).
Therefore, performing the reaction at room temperature
for 3 h resulted in the best results in terms of yield and
diastereoselectivity.
In order to understand the high diastereoselectivity
observed for the arylation of aldehyde 1, a transition state
involving coordination of the zinc atom to the carbonyl
oxygen and at the furanoside oxygen is proposed
(Figure 1). The substrate 1 might coordinate to the Lewis
acidic PhZnEt as a bidentate Lewis base ligand, in an
analogous manner that occurs for Lewis bases used in the
standard diethylzinc additions.1 In this working model,
chelation would enhance the electrophilicity of the alde-
hyde, while the attack of the arylzinc reagent would occur
(9) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645–
12647.
€
(10) (a) Braga, H. C.; Wouters, A. D.; Zerillo, F. B.; Ludtke, D. S.
Carbohydr. Res. 2010, 345, 2328–2333. (b) Braga, H. C.; Stefani, H. A.;
~
€
Paixao, M. W.; Santos, F. W.; Ludtke, D. S. Tetrahedron 2010, 66, 3441–
3446. (c) Braga, A. L; Severo Filho, W. A.; Schwab, R. S.; Rodrigues,
€
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2009, 50, 3005–3007. (d) Vieira, A. S.; Fiorante, P. F.; Hough, T. L. S.;
€
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Org. Lett., Vol. 14, No. 15, 2012
3963

at the less hindered side in the most energetically favorable
conformation. Therefore, aryl transfer to the si face of the
aldehyde would resultinthe formationof the mainproduct
observed. The stereochemistry of the new stereogenic
center formed was assigned on the basis of literature
NMR data.12
the reaction was complete within 3 h. High conversion
was observed by TLC analysis; however, the isolated
yields were slightly reduced because of high water solubi-
lity of the products. Halogen substituentsare well tolerated
in the reaction with use of 4-chlorophenyl- and 3,4,5-
trifluorophenylboronic acids resulting in smooth addition,
delivering the products 2c and 2g with excellent diastereo-
selectivity (entries 3 and 7). A decrease in the selectivity
of the addition was observed with the 4-bromophenyl
and with the more sterically demanding ortho-tolyl deri-
vative, resulting in a dr of 14:1 and 16:1, respectively
(entries 4 and 6).
Table 2. Scope of the Aryl Transfer Reaction to Aldehyde 1
Figure 1. Proposed pathway to rationalize the high diastereo-
selectivity.
Importantly, the high diastereoselectivity of the aryla-
tion allows an efficient synthesis of a key intermediate in
the synthesis of (þ)-7-epi-goniofufurone, a styryllactone
isolated from the bark of Goniothalamus giganteus.13
The styryllactones are a family of natural products that
present a broad range of biological activities that include
anticancer, antibiotic, immunosuppressant, trypanocidal
and antifertility activities.14 Product 2a was previously
converted by Popsavin and co-workers to 7-epi-goniofu-
furone 3 in a three step sequence (Scheme 2).15
With the success obtained in the phenyl transfer to
aldehyde 1, we extended the scope of the methodology
to a broader range of aryl groups. As shown in Table 2, a
number of different arylboronic acids are suitable precur-
sors for the generation of transferable aryl groups.
Scheme 2. Structure of Product 2a and Styryllactone (þ)-7-epi-
Goniofufurone 3
a Isolated yields. b Determined by 1H NMR
Our optimized conditions represent an advance over pre-
viously reported organometallic additions to aldehyde 1,
using PhMgBr.12,15,16 Despite, in some cases, the benzylic
alcohol 2a being obtained in moderate to good diaste-
reoisomeric ratios (1.6 to 14:1), the Grignard addition was
reported only for the introduction of a phenyl group. Our
methodology allows the mild and highly diastereoselective
transfer of a broader range of aryl groups, since a number
of arylzinc reagents can be efficiently prepared from the
corresponding boronic acids, opening the door for the
synthesis of natural product analogues for structure ac-
tivity relationship studies.
Both electron-rich and electron-poor aryl groups are
transferred, resulting in the desired products in good yields
and in very good diastereomeric ratios. In all cases studied,
ꢀ
(12) (a) Gracza, T.; Szolcsanyi, P. Synthesis 1994, 1359–1368.
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(b) Gracza, T.; Szolcsanyi, P. Molecules 2000, 5, 1386–1398.
(13) Fang, X. F.; Anderson, J. E.; Chang, C. J.; Fanwik, P. E.;
McLaughlin, J. L. J. Nat. Prod. 1991, 54, 1034–1043.
(14) de Fatima, A.; Modolo, L. V.; Conegero, L. S.; Pilli, R. A.;
Ferreira, C. V.; Khon, L. K.; de Carvalho, J. E. Curr. Med. Chem. 2006,
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Francuz, J.; Kojic, V.; Bogdanovic, G. Org. Lett. 2007, 9, 4235–4238.
(16) Prakash, K. R. C.; Rao, S. P. Tetrahedron 1993, 49, 1505–1510.
Org. Lett., Vol. 14, No. 15, 2012
3964

With the success achieved in the arylation of enantiopure
aldehyde 1, derived from D-glucose, we turned our atten-
tion to test our protocol with two different sugar aldehydes
(Table 3). The arylation of aldehyde 4, obtained from
D-mannose,17 proceeded in good yield but with only moder-
ate diastereoselection for the majority of cases studied
(entries 1, 3, 5 and 9). An exception to this behavior was
the reaction performed using ortho-tolylboronic acid as the
precursor of the transferable aryl group, which delivered the
product 6d in 78% yield and in a dr of >20:1 (entry 7). Also
worth noting is that heating the reaction mixture to 60 °Cwas
necessary in order to achieve good yields of the product 6.
On the other hand, when the arylation reaction was
extended to aldehyde 5,18 which is prepared from D-ribose,
exceptional levels of diastereoselectivity resulted (Table 3).
For all the reactions studied, diastereomeric ratios
of >20:1 were observed, and the products 7aꢀe were
formed in yields ranging from 72 to 78%. The substitution
pattern of the aryl group seems to be irrelevant for the
reaction outcome, since the same high levels of selectivity
were achieved with electron-withdrawing (entry 4), elec-
tron-donating (entries 6) and ortho-substituted (entry 8)
aryl groups. Once again, performing the reaction at higher
temperature resulted in optimized yields, without any de-
crease in the diastereoselectivity of the addition. The stereo-
chemistry of the newly formed stereocenter was assigned by
analogy with the stereochemical outcome observed for the
arylation of aldehyde 1, assuming that aldehydes 4 and 5
undergo reaction through analogous chelation-controlled
transition states. An unequivocal proof of the absolute
stereochemistry remains to be achieved. Several attempts
to prepare suitable derivatives for X-ray crystallography
analysis have so far proven fruitless.
Table 3. Diastereoselective Arylation of Aldehydes 4 and 5
In summary, we have developed a diastereoselective
addition of arylzinc reagents to enantiopure sugar-derived
aldehydes. High diastereoselectivity was achieved using
aldehydes 1 and 5, which are derived from D-glucose and
D-ribose, respectively, while only moderate dr are observed
for aldehyde 4, derived from D-mannose, except when an
ortho substituent is present in the arylzinc reagent. Our
protocol further expands the utility of the BꢀZn exchange
reaction of arylboronic acids and allows the synthesis of
interesting chiral molecules, as exemplified by our formal
synthesis of (þ)-7-epi-goniofufurone. Further efforts
to expand the reaction to other substrates and for the
synthesis of natural products and analogues are underway.
a Isolated yields. b Determined by 1H NMR
Acknowledgment. We are grateful to FAPESP, CNPq
and FAPERGS for financial support. CAPES and CNPq
are also acknowledged for a PhD fellowship to A.D.W.
and research fellowship to D.S.L., respectively.
Supporting Information Available. Full experimental
procedures, analytical data and copies of NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Asymmetry 2006, 17, 142–150. (b) More, J. D.; Finney, N. S. Org. Lett.
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The authors declare no competing financial interest.
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