[3,3]-Sigmatropic rearrangement of boronated allylcyanates: A new route to α-aminoboronate derivatives and trisubstituted tetrahydrofurans

Article abstract of DOI:10.1021/ol401016x

[3,3]-Sigmatropic cyanate-isocyanate rearrangement provides a powerful tool for the preparation of α-isocyanato allylboronic esters, which can be further trapped with a variety of nucleophiles. Hydrogenation gave the corresponding α-aminoboronates derivatives while addition of aldehydes afforded homoallylic alcohols, (tetrahydrofuran-2-yl)carbamate, ether, or urea derivatives.

Full text of DOI:10.1021/ol401016x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
[3,3]-Sigmatropic Rearrangement of
Boronated Allylcyanates: A New Route
to r‑Aminoboronate Derivatives and
Trisubstituted Tetrahydrofurans
†
Sabrina Touchet, Aurelie Mace, Thierry Roisnel, Franc-ois Carreaux,*
†
,†
ꢀ
ꢀ †
Alexandre Bouillon,‡ and Bertrand Carboni†
ꢀ
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS, Universite de Rennes 1,
Campus de Beaulieu, CS 74205, 35042 Rennes Cedex, France, and BoroChem SAS,
7 rue Alfred Kastler, 14000 Caen, France
francois.carreaux@univ-rennes1.fr
Received April 12, 2013
ABSTRACT
[3,3]-Sigmatropic cyanateÀisocyanate rearrangement provides a powerful tool for the preparation of R-isocyanato allylboronic esters, which can
be further trapped with a variety of nucleophiles. Hydrogenation gave the corresponding R-aminoboronates derivatives while addition of
aldehydes afforded homoallylic alcohols, (tetrahydrofuran-2-yl)carbamate, ether, or urea derivatives.
Boronic acids have attracted considerable interest as
versatile intermediates in organic synthesis.1 Besides these
numerous and important synthetic applications, this class
of compounds has long been underevaluated in chemical
biology and drug discovery programs. This situation has
changed at the beginning of the 21th century. In May 2003,
bortezomib (Velcade) was the first boron compound to be
approved as a selective and reversible inhibitor of the 26S
proteasome for advanced multiple myeloma treatment.2
Another borodipeptide, Val-boroPro (Talabostat), has
antitumor activity against colorectal cancer via the inhibi-
tion of postproline cleaving enzymes, a ubiquitous class of
serine proteases (Figure 1).3
†
ꢀ
Universite de Rennes 1.
‡ BoroChem SAS.
Figure 1. Some examples of bioactive boropeptides.
(1) (a) Boron compounds. In Science of Synthesis, HoubenÀWeyl,
Methods of Molecular Transformations; Matteson, D. S., Kaufmann, D.,
Eds.; George Thieme Verlag: Stuttgart, 2004; Vol. 6. (b) Matteson, D. S.
Stereodirected synthesis with organoboranes; Springer: Berlin,1995; (c)
Hall, D. G., Ed. Boronic acids: Preparation, and Applications in Organic
Synthesis and Medicine; Wiley-VCH: Weinheim, 2011.
(2) Recent reviews: (a) Goldberg, A. L. J. Cell Biol. 2012, 199, 583. (b)
Ludwig, H.; Avet-Loiseau, H.; Blade, J.; Boccadoro, M.; Cavenagh, J.;
Cavo, M.; Davies, F.; de la Rubia, J.; Delimpasi, S.; Dimopoulos, M.;
Drach, J.; Einsele, H.; Facon, T.; Goldschmidt, H.; Hess, U.; Mellqvist,
U.-H.; Moreau, P.; San-Miguel, J.; Sondergeld, P.; Sonneveld, P.;
Udvardy, M.; Palumbo, A. Oncologist 2012, 17, 592. (c) Kale, A. J.;
Moore, B. S. J. Med. Chem. 2012, 55, 10317. (d) Gaultney, J. G.;
Redekop, W. K.; Sonneveld, P.; Uyl-de Groot, C. A. Expert Rev.
Anticancer Ther. 2012, 12, 839.
If R-aminoboronic acids and derivatives are widely
represented within bioactive boron compounds, other
boron derivatives have also shown interesting biological
properties.4
(3) (a) Poplawski, S. E.; Lai, J. H.; Sanford, D. G.; Sudmeier, J. L.;
Wu, W.; Bachovchin, W. W. J. Med. Chem. 2011, 54, 2022. (b) Connolly,
B. A.; Sanford, D. G.; Chiluwal, A. K.; Healey, S. E.; Peters, D. E.;
Dimare, M. T.; Wu, W.; Liu, Y.; Maw, H.; Zhou, Y.; Li, Y.; Jin, Z.;
Sudmeier, J. L; Lai, J. H; Bachovchin, W. W. J. Med. Chem. 2008, 51,
6005.
r
10.1021/ol401016x
XXXX American Chemical Society

Only a few methods have been reported for the synthesis
of R-aminoboronic esters. The most common approach is
certainly the one developed by Matteson et al. R-Halogen-
oboronates are readily prepared by diastereoselective in-
sertion of a CHCl group into a carbonÀboron bond.5 An
SN2 displacement of the halogen R to the boron atom with
amines and derivatives as nucleophiles led to R-amino-
boronic esters with high diastereomeric excesses. Boryla-
tion of organolithium or organomagnesium reagents with
trialkyl borates has also found useful applications, especially
in the highly enantioselective synthesis of boroproline.6
Another elegant diastereoselective method was based on
the addition of bis(pinacolato)diboron to N-tert-butanesul-
finyl aldimines in the presence of a copper catalyst,7 while
enantioselective organocatalytic pinacolboryl addition to
tosylaldimines was reported a few years later.8 Other
approaches of lower applicability include electrophilic
amination,9 Overman [3,3]-sigmatropic rearrangements,10
and iridium-catalyzed amination of potassium allyltrifluoro-
borates.11 Finally, more recently, the Yudin group disclosed
a new attractive and efficient access to a wide range of
R-amino N-methyliminodiacetyl (MIDA) boronates via
theCurtius rearrangementofthecorrespondingcarboxylic
acids.12
In parallel, we sought to develop a new approach, which
combines a versatile access to R-aminoboronic esters from
the corresponding allylisocyanates and the rich chemistry
of allylboronates13 (Scheme 1).
The rearrangement of allylcyanates, prepared from 5-
(2-alkenyloxy)-1,2,3,4-thiatriazoles, to allylisocyanates was
discovered by Holm in 1970.14 Eight years later, Overman
proposed another route based on the reaction of allylic
alkoxides with cyanogen chloride.15 But it was only with
the work of Ichikawa in 1991, who prepared allylcyanates
by dehydration of the corresponding allylcarbamates, that
this method proved to be a powerful tool in organic
synthesis.16 The [3,3]-sigmatropic rearrangement occurred
at room temperature, and the use of various nucleophiles
to trap the resulting isocyanate gave access to a large variety
of derivatives.17 Spino et al. also successfully used this ap-
proach for the stereocontrolled synthesis of amino acids and
N-heterocycles bearing a quaternary chiral carbon.18
Scheme 1. [3,3]-Sigmatropic Rearrangement of Boronated Allyl
Cyanates 2 and Further Transformations
On the basis of these results, we planned to study the
[3,3]-sigmatropic rearrangement of the allylcyanate 2 gen-
erated from the carbamate 1 (R = Me), chosen as a model
compound, and the reactivity of the resulting allylisocya-
nate 3 (Scheme 1). Compound 1 was efficiently synthesized
in a stereochemically pure (E)-form from 3-butyn-2-ol
(Scheme 2). Protection as its trimethylsilyl ether was follow-
ed by hydroboration with pinacolborane to afford the
corresponding alkenylboronate.19 Finally, after deprotec-
tion with KHSO4 in MeOH/H2O, the boronated allylic
alcohol was converted to the allylcarbamate 1 according to
the procedure described by Ichikawa et al.20 (51% overall
yield, four steps).
Scheme 2. Synthesis of Allylcarbamate 1
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Several conditions were screened to optimize the forma-
tion of the isocyanate 3 from 1: triflic anhydride, diisopropyl-
ethylamine;16 pivaloyl chloride, pyridine;21 trifluoroacetic
anhydride, triethylamine;18 oxalyl chloride, 2,6-lutidine.22
Best results were obtained with carbon tetrabromide,
(7) Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
6910.
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(8) Sole, C.; Gulyas, H.; Fernandez, E. Chem. Commun. 2012, 48,
3769.
(9) Zheng, B.; Deloux, L.; Pereira, S.; Skrzypczak-Jankun, E.;
Cheesman, B. V.; Sabat, M.; Srebnik, M. Appl. Organomet. Chem.
1996, 10, 267.
(10) Pietruszka, J.; Shc-ne, N.; Frey, W.; Gundl, L. Chem.;Eur. J.
2008, 14, 5178.
(11) Touchet, S.; Carreaux, F.; Molander, G. A.; Carboni, B.;
Bouillon, A. Adv. Synth. Catal. 2011, 353, 3391.
(12) He, Z.; Zajdlik, A.; St. Denis, J. D.; Assem, N.; Yudin, A. K.
J. Am. Chem. Soc. 2008, 130, 6910.
(17) (a) Ichikawa, Y.; Yamazaki, M.; Isobe, M. J. Chem. Soc., Perkin
Trans. 1 1993, 2429. (b) Ichikawa, Y.; Kobayashi, C.; Isobe, M. Synlett
1994, 919. (c) Ichikawa, Y.; Osada, M.; Ohtani, I. I.; Isobe, M. J. Chem.
Soc., Perkin Trans. 1 1997, 1449. (d) Ichikawa, Y.; Yamauchi, E.; Isobe,
M. Biosci. Biotechnol. Biochem. 2005, 69, 939. (e) Ichikawa, Y. Synlett
2007, 2927.
(18) Roy, S.; Spino, C. Org. Lett. 2006, 8, 939.
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(19) (a) Berree, F.; Gernigon, N.; Hercouet, A.; Lin, C. H.; Carboni,
(13) (a) Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1. (b) Hall, D.
G Pure Appl. Chem. 2008, 80, 913.
B. Eur. J. Org. Chem. 2009, 329. (b) Jehanno, E.; Vaultier, M. Tetra-
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(14) (a) Christophersen, C.; Holm, A. Acta Chem. Scand. 1970, 24,
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(15) Overman, L. E.; Kakimoto, M. J. Org. Chem. 1978, 43, 4564.
(16) Ichikawa, Y. Synlett 1991, 238.
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B
Org. Lett., Vol. XX, No. XX, XXXX

triphenylphosphine, and triethylamine in methylene chlor-
ide.17 The use of a polymer-supported phosphine to simplify
the purification step was finally selected despite a longer
reaction time. Although the expected isocyanate 3 was
peptidomimetics. The condensation of 3 with thioacetic
acid resulted in the formation of the amide 4g with loss of a
carbon oxysulfide as byproduct.23 The NMR data are in
full agreement with the proposed structures, the 11B che-
mical shifts varying from 12.3 to 22.7 ppm, which is
consistent with intramolecular BÀO dative bonds as pre-
viously demonstrated in the literature.24 Furthermore,
evidence for the tetrahedral structure of 4b in the solid
state is given by X-ray crystallographic analysis, which
revealed that the carbonyl oxygen atom of the urea moiety
1
observed in the crude H NMR spectrum, we were unable
to isolate it with satisfactory yield and purity and therefore
chose to add methanol to the crude mixture. The allylbo-
ronate 4a was then obtained in 81% yield. A single E-isomer
(1H NMR, JHCdCH = 15.4 Hz) was detected in agreement
with a chair transition state with the boronate and methyl
groups in pseudoequatorial positions, as previously
reported.17e
25
˚
is close to the boron (B9ÀO10 distance 1.60 A) (Figure 2).
In addition, the torsional angles between O14ÀB9À
O18ÀC19 and O18ÀB9ÀO14ÀC15 are, respectively, 2.9°
and 20.8°, which shows a distortion of the five-membered
1,3,2-dioxaborolane ring due to the coordination between
the oxygen and boron atoms. It is also worth noting that, in
the case of compounds 4dÀf, a second peak was observed at
22.4À22.7 ppm in 11B NMR, which suggests a possible
competitive chelation with the nitrogen atom.
Table 1. Preparation of a-Boryl Allyl Ureas, Carbamates, and
Amides 4aÀg
Figure 2. X-ray crystallographic structure of urea 4b.
The transformation of these R-aminoboronate deriva-
tives into the corresponding boronic acids was evaluated
using 4c as a model substrate (Scheme 3). We were unable
to obtain the desired unsaturated product in good yield
under various conditions due to a facile deborylation
reaction. This failure was attributed to the presence of an
allylic moiety that weakens the BÀC bond. Indeed, hydro-
genation of the double bond gave 5 and treatment with
2-methylpropylboronic acid in a biphasic mixture of
methanol/hexane afforded the acid 6.
Besides the presence of a boronic ester and a carbamate,
urea, or amide functional group in the same core, 4aÀg
present the interesting feature of also having an allylic
moiety. Allylboronic esters have been proven to be highly
a Isolated yields after column chromatography. b Mixture of two dia-
stereomers (50/50). c In the presence of a supplementary equivalent of NEt3
(23) Crich, D.; Sasaki, K. Org. Lett. 2009, 11, 3514.
(24) (a) Matteson, D. S.; Michnick, T. J.; Willett, R. D.; Patterson,
C. D. Organometallics 1989, 8, 726. (b) Biedrzycki, M.; Scouten, W. H.;
Biedrzycka, Z. J. Organomet. Chem. 1992, 431, 255. (c) Besong, G.;
Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol.
Chem. 2006, 4, 2193. (d) Lai, J. H.; Liu, Y.; Wu, W.; Zhou, Y.; Maw,
H. H.; Bachovchin, W. W.; Bhat, K. L.; Bock, C. W. J. Org. Chem. 2006,
71, 512. (e) Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc.
2010, 132, 13191. (f) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem.
2011, 3, 894.
(25) CCDC 927328 contains the supplementary crystallographic
data for compound 4b. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Using these optimized conditions, we then assessed the
scope and limitations of this reaction using various other
nucleophiles (Table 1). Primary and secondary amines also
reacted with 3 to afford the corresponding urea in good
yields. WhenR-aminoester hydrochlorideswereusedinthe
presence of a supplementary equivalent of triethylamine,
comparable results were obtained, thus opening a valuable
route to hitherto unknown boron analogues of urea
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Synthesis of Ureidoboronic Acid 6
Scheme 4. Reaction of Allylboronates 4a,b with Aldehydes
versatile carbon nucleophiles, usually showing very good
levels of chemo-, regio-, and stereocontrol in various
reactions with electrophiles.26 Exposure of the carbamate
4a to an aldehyde effectively afforded the anti (Z)-homo-
allylic alcohols 7 and 8,27 which, in the presence of HCl for
7 or spontaneously for 8, cyclized respectively to the
(tetrahydrofuran-2-yl)carbamates 9 and 10 (Scheme 4).28
Regarding the mechanism of this process, we assume, in
agreement with previous reports,29 that the acid activation
of the enecarbamate was followed by an intramolecular
addition of the alcohol to afford9 and 10 as 1/1 mixtures of
epimers at C2.30 A similar behavior was observed with the
urea derivative 4b. The corresponding tetrahydrofuran 11
was obtained in a 80% yield as a 65:35 diastereomeric
mixture. Further treatment of 9 or 11 with HCl in dioxane
in the presence of an excess of methanol gave, respectively,
the (tetrahydrofuran-2-yl)ethers 12 or 13,31,32 some repre-
sentative examples of a useful class of intermediates for
natural products synthesis.33 This transformation was also
achieved in a one-pot process from 4b to 13, albeit in a
slightly lower isolated yield.
In conclusion, we have developed a new route to
R-isocyanato allylboronic esters via a [3,3]-sigmatropic
cyanateÀisocyanate rearrangement that enables the pre-
paration of R-aminoboronic derivatives. Furthermore,
their addition to aldehydes, followed by the intramolecular
cyclization of the corresponding homoallylic alcohols,
gave access to variously trisubstituted tetrahydrofurans.
Further studies directed to the transposition of these
results in a nonracemic series as well as the use of the
enecarbamate or eneurea intermediates in natural product
synthesis are under investigation.
(26) (a) Kennedy, J. W.; Hall, D. G. In Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH:Weinheim, 2005; pp 241À277. (b) Lachance, H.; Hall, D. G.
Org. React. 2008, 73, 1. (c) Elford, T. G.; Hall, D. G. In Boronic Acids;
Hall, D. G., Ed.; Wiley-VCH:Weinheim, 2011; pp 393À426.
Acknowledgment. We are indebted to BoroChem and
ANRT for financial support for S.T. (CIFRE scholarship).
This work was also supported by the CNRS and the
University of Rennes 1.
(27) The stereochemical course of the allylation step resulted from
a preferred transition state where the carbamate or urea group adopts
a pseudoaxial position, as mentioned in the literature for polar
R-substituents. (a) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123.
(b) Hoffmann, R. W.; Wolff, J. J. Chem. Ber. 1991, 124, 563.
(28) For synthesis and Lewis acid catalyzed ring-opening reactions of
this type of semicyclic N,O-acetals possessing an exocyclic nitrogen
atom, see: Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S.
J. Am. Chem. Soc. 2001, 123, 12510.
Supporting Information Available. Experimental pro-
cedures and characterizations of new compounds as well
as crystallographic data for 4b. This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) For recent reviews on the enecarbamate chemistry, see:
(a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292. (b)
Kovuru, G.; Kagan, H. Chem. Rev. 2011, 111, 4599.
(30) We never succeeded to isolate 8 free of 10. The spontaneous
cyclization of this enecarbamate can be attributed to the presence of
traces of a boron compound resulting from the hydrolysis of the allylic
O-Bpin, the first intermediate produced in the allylation step. In the case
of 7, without being able to explain this difference, the ene carbamate can
be isolated and acid addition is necessary to achieve its complete
conversion to 9.
(31) The conversion of 9 to 12 required only 30 min while it is
necessary to wait for 24 h to observe a complete transformation for 11.
(32) For similar transformations, see, for example: (a) Gaul, C.; Seebach,
D. Helv. Chim. Acta 2002, 85, 772. Whisler, M. C.; Vaillancourt, L.; Beak, P.
Org. Lett. 2000, 2, 2655.
(33) For some recent references, see: (a) Enev, V. S.; Felzmann, W.;
Gromov, A.; Marchart, S.; Mulzer, J. Chem.;Eur. J. 2012, 18, 965. (b)
Yadav, J. S.; Venkateshwar Rao, C.; Prasad, A. R.; Al Khazim Al
Ghamdib, A. Synthesis 2011, 3894. (c) Kong, K.; Moussa, Z.; Lee, C.;
Romo, D. J. Am. Chem. Soc. 2011, 133, 19844. (d) Yadav, J. S.; Srinivas
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The authors declare no competing financial interest.
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