Two-step one-pot synthesis of benzoannulated spiroacetals by Suzuki-Miyaura coupling/acid-catalyzed spiroacetalization

Article abstract of DOI:10.1021/ol302088w

Substituted benzoannulated spiroacetals were prepared from (2-haloaryl)alkyl alcohols and dihydropyranyl or dihydrofuranyl pinacol boronates using a Suzuki-Miyaura coupling followed by an acid-catalyzed spirocyclization. Application of the reaction to a glycal boronate provides an approach to annulated spiroacetals in enantiopure form.

Full text of DOI:10.1021/ol302088w

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Two-Step One-Pot Synthesis of
Benzoannulated Spiroacetals by
SuzukiꢀMiyaura Coupling/Acid-Catalyzed
Spiroacetalization
Alexey N. Butkevich,† Andrei Corbu,† Lieven Meerpoel,‡ Ian Stansfield,§
Patrick Angibaud,§ Pascal Bonnet,‡ and Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231
Paris Cedex 05, France, Janssen Research & Development, Division of Janssen-Cilag
S.A., Oncology and Medicinal Chemistry, Campus de Maigremont, 27106 Val de Reuil,
Cedex, France, and Janssen Research & Development, Division of Janssen
Pharmaceutica N.V., Turnhoutsweg 30, 2340 Beerse, Belgium
janine.cossy@espci.fr
Received July 27, 2012
ABSTRACT
Substituted benzoannulated spiroacetals were prepared from (2-haloaryl)alkyl alcohols and dihydropyranyl or dihydrofuranyl pinacol boronates
using a SuzukiꢀMiyaura coupling followed by an acid-catalyzed spirocyclization. Application of the reaction to a glycal boronate provides an
approach to annulated spiroacetals in enantiopure form.
The spiroacetal ring system, in particular 1,6-dioxaspiro-
[4.4]nonanes, 1,6-dioxaspiro[4.5]decanes, and 1,7-dioxaspiro-
[5.5]undecanes, is present in a variety of natural products
of different origins.1 Several benzoannulated spiroacetals,
such as rubromycins, heliquinomycin, papulacandin,
paecilospirone, and berkelic acid, have demonstrated potent
biological activity2 and therefore remain attractive synthetic
targets.
Spiroacetals have been prepared by acid-catalyzed cycliza-
tion of ω,ω0-dihydroxyketones,3 1,3-dipolar cycloaddition,4
oxidative enolate coupling,5 addition of 2-lithiofurans to
phenylacetaldehydes followed by cyclization,6 or an aro-
matic Pummerer-type reaction.7 Metal-catalyzed (Ir, Rh,
and Au) double hydroalkoxylation of disubstituted alkynes
provides benzoannulated spiroacetals; however these
reactions are rarely regioselective.8 Several syntheses of
† ESPCI ParisTech.
(5) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett. 2006, 8,
2365–2367.
(6) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4709–4713.
‡ Janssen Research & Development, Janssen Pharmaceutica N.V.
§ Janssen Research & Development, Oncology and Medicinal Chemistry,
Campus de Maigremont.
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2007, 129, 2774–2776. Liu, G.; Wurst, J. M.; Tan, D. S. Org. Lett. 2009,
11, 3670–3673.
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1998, 81–82. Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org.
Lett. 2005, 7, 5437–5440. Messerle, B. A.; Vuong, K. Q. Organometallics
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2008, 2008, 940–944. Selvaratnam, S.; Ho, J. H. H.; Huleatt, P. B.;
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Prod. Rep. 2010, 27, 1117–1137 and references cited therein.
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r
10.1021/ol302088w
XXXX American Chemical Society

benzoannulated spiroacetals have relied on a Pd-catalyzed
cross-coupling between aryl halides and stannylated dihy-
dropyrans or dihydropyranyl silanols leading to 6-aryl-3,4-
dihydro-2H-pyrans. These pyrans underwent spirocycliza-
tion with a side chain at the C-2 position of the aryl group
when reacted with an electrophilic epoxidation reagent,
such as DMDO or m-CPBA.9 Recently, the treatment
of 6-(ω-hydroxyalkyl)-3,4-dihydro-2H-pyrans and related
dihydrofurans and tetrahydrooxepins with binaphthol-
phosphoric acids10a or binaphthol-derived iminodiphos-
phoric acids10b has been reported to lead to optically active
spiroacetals.
entry 4). The palladium catalyst loading could be success-
fully decreased to 2 mol %; however using smaller amounts
of catalyst (0.5 mol %) resulted in a significantly lower yield
of 4a (Table 1, entry 5).
Table 1. Optimization of the Reaction Conditions
Due to the known toxicity and persistence of organo-
stannanes, and as the preparation of silanols has to
be realized in several steps, we have planned to access
benzoannulated spiroacetals A in an efficient convergent
manner from the corresponding (2-haloaryl)alkyl alco-
hols B and pinacol boronates C, employing a one-pot
SuzukiꢀMiyaura coupling/acid-catalyzed spiroacetaliza-
tion approach (Scheme 1).
Pd cat.
(mol %)
yield
yield
entry
base
3a
4a
1
Pd(PPh3)4 (5)
Na2CO3
Na2CO3
Na2CO3
NaOH
67%
64%
82%
ꢀ
ꢀ
2
Pd(MeCN)2Cl2 (5) PCy3 (10)
Pd(dppf)Cl2 (5)
3%
3
6%
4a
5a
Pd(dppf)Cl2 (2)
86%b
58%b
Pd(dppf)Cl2 (0.5)
NaOH
ꢀ
a Reaction time 10 min. b Yield of 4a after cyclization with TsOH
(3 equiv) for 10 min at rt.
Scheme 1. Retrosynthetic Approach
Spiroacetals of type A were prepared from various
(2-haloaryl)alkyl alcohols B, such as iodide 1b, chloride
1c, and tosylate 1d, by using the conditions reported in
Table 2.
Table 2. Scope of the Leaving Groupa
In a test reaction, the starting boronate 2b11 was reacted
with 2-bromobenzyl alcohol 1a followed by an acidic
treatment of the obtained intermediate 3a. At first, differ-
ent palladium catalysts and bases were tested in order to
optimize the conditions of the SuzukiꢀMiyaura coupling.
The reaction was carried out in 1,4-dioxane/H2O (3:1) at
100 °C under microwave irradiation. Among the palla-
dium catalysts and bases tested, Pd(dppf)Cl2 (5 mol %) in
the presence of Na2CO3 or NaOH (2 equiv) led to the
highest yield of the couplingproduct 3a(82%). The desired
spiroacetal 4a was also obtained in 6% yield, likely due to
Lewis acid properties of the Pd catalyst (Table 1, entry 3).
To achieve the complete transformation of 3a into 4a,
p-TsOH (3 equiv) was added to the reaction mixture,
leading directly to spiroacetal 4a in 86% yield (Table 1,
entry
X, 1
cond
yield 4a
1
2
3
4
5
6
Br, 1a
I, 1b
A
86%
92%
0%
A
Cl, 1c
Cl, 1c
OTs, 1d
OTs, 1d
A
B
84%
0%
A or B
C
21%
a Conditions A: Pd(dppf)Cl2 (2 mol %), NaOH (2 equiv), 1,4-dioxane/
H2O (3:1), MW, 100 °C, 10 min, then TsOH H2O (2.2 equiv), rt, 10 min.
3
Conditions B: Pd(MeCN)2Cl2 (3 mol %), XPhos (6 mol %), NaOH
(2 equiv), 1,4-dioxane/H2O (3:1), MW, 100 °C, 10 min, then TsOH H2O
3
(2.2 equiv), rt, 10 min. Conditions C: Pd(OAc)2 (2 mol %), BrettPhos
(4 mol %), K3PO4 (3 equiv), t-BuOH, MW, 110 °C, 2 h, then TsOH H2O
(5.5 equiv), rt (monitored by TLC).
3
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J. M.; Liu, G.; Tan, D. S. J. Am. Chem. Soc. 2011, 133, 7916–7925.
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13796–13797. Dubois, E.; Beau, J.-M. J. Chem. Soc., Chem. Commun.
1990, 1191–1192. Elsley, D. A.; MacLeod, D.; Miller, J. A.; Quayle, P.;
Davies, G. M. Tetrahedron Lett. 1992, 33, 409–412.
2-Iodobenzyl alcohol 1b was converted to 4a in 92%
yield under conditions A (Table 2, entry 2), while 2-chloro-
benzyl alcohol 1c was not reactive and required a more
active catalytic system, Pd(MeCN)2Cl2 (3 mol %)/XPhos
(6 mol %), to produce 4a in 84% yield after acid-catalyzed
cyclization (conditions B, Table 2, entry 4). The cross-
coupling with 2-(hydroxymethyl)phenyl tosylate 1d was
(10) (a) Sun, Z.; Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am.
ꢀ
ꢁ
Chem. Soc. 2012, 134, 8074–8077. (b) Coric, I.; List, B. Nature 2012, 483,
315–319.
(11) Boronate 2b was prepared on a multigram scale by metalation of
3,4-dihydro-2H-pyran with the n-BuLi/t-BuOK system followed by
treatment with trimethyl borate, pinacol, and acetic acid (see Supporting
Information).
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Substitution of the Aromatic Ring: Scope and Limitationsa
a Conditions A: Pd(dppf)Cl2 (2 mol %), NaOH (2 equiv), 1,4-dioxane/H2O (3:1), MW, 100 °C, 10 min, then TsOH H2O (2.2 equiv), rt, 10 min.
3
Conditions B: Pd(PPh3)2Cl2 (5 mol %), Na2CO3 (2 equiv), 2,2,2-trifluoroethanol, MW, 100 °C, 1 h. Conditions C: Pd(MeCN)2Cl2 (3 mol %), XPhos
(6 mol %), NaOH (2 equiv), 1,4-dioxane/H2O (3:1), MW, 100 °C, 10 min, then TsOH H2O (2.2 equiv), rt, 10 min.
3
Table 4. Side Chain and Cycle Size Variationa
a Conditions: Pd(dppf)Cl2 (2 mol %), NaOH (2 equiv), 1,4-dioxane/H2O (3:1), MW, 100 °C, 10 min, then TsOH H2O (2.2 equiv), rt, 10 min.
3
Org. Lett., Vol. XX, No. XX, XXXX
C

difficult to achieve and required an even more active
catalyst (Pd(0)/BrettPhos)12 (conditions C, Table 2,
entry 6). Importantly, under conditions A, chloride and
tosylate substituents present on the aromatic ring are
tolerated and not involved in cross-coupling reactions.
The results are summarized in Table 3.
protodeboronation of 6 to the starting glycal 5). The
product of this reaction was spiroacetal 7 as the anomeri-
cally stabilized diastereoisomer, isolated in 55ꢀ63% yield
(Scheme 2).
Substituted 2-halobenzyl alcohols 1eꢀ1n were trans-
formed into the corresponding spiroacetals 4eꢀ4n in mod-
erate to excellent yields (38ꢀ90%). As can be concluded
from the results, electron-withdrawing groups were gen-
erally well tolerated (Table 3, entries 1 and 4), while very
electron-rich substrates suffered from diminished yields
due to side reactions during the cyclization step. Alterna-
tive reaction conditions (conditions B) had to be employed
to attain practical yields (Table 3, entry 8).
Scheme 2. Preparation of 2-Deoxy-D-glucose-Derived
Spiroacetal 7a
Benzoannulated[5,5]-, [5,6]-, [5,7]-and [6,6]-spiroacetals
were successfully prepared under conditions A depending
on the length of the hydroxyalkyl side chain of the aryl
halide as well as on the ring size of the boronates 2a,b
(Table 4, entries 1ꢀ4). A diastereomeric ratio of 60:40 was
observed when secondary benzyl alcohols 1s and 1t were
used; however, the diastereomeric spiroacetals were found
to interconvert rapidly in the presence of a catalytic
amount of acid (Table 4, entries 5 and 6).
To demonstrate the applicability of our method to the
synthesis of chiral spiroacetals, boronate ester 6, prepared
from trimethyl-D-glucal 5,13 was reacted with either 1a
or 1c in the presence of a Pd catalyst and Na2CO3 as a
base in anhydrous 1,4-dioxane or MeCN (use of NaOH
in a 1,4-dioxane/water mixture resulted in complete
a Conditions: Pd(dppf)Cl2 (2 mol %), Na2CO3 (2 equiv), MeCN, 1a
or Pd(MeCN)2Cl2 (3 mol %), XPhos (6 mol %), Na2CO3 (2 equiv),
1,4-dioxane, 1c.
In summary, we have developed a rapid convergent
microwave-assisted synthesis of benzoannulated spiroace-
tals using a one-pot SuzukiꢀMiyaura coupling reaction/
spiroacetalization. This versatile and chemoselective pro-
cess is potentially applicable to the synthesis of complex
biologically active natural products.
Acknowledgment. Janssen Pharmaceutica is gratefully
acknowledged for financial support.
(12) (a) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11,
3954–3957. (b) Pd/XPhos-catalyzed SuzukiꢀMiyaura coupling of aryl
tosylates has also been reported but was not successful in our case; see:
Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
11818–11819.
(13) (a) Kikuchi, T.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem.
Lett. 2008, 37, 664–665. (b) Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama,
T.; Miyaura, N. Chem.ꢀAsian J. 2008, 3, 2082–2090.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR, IR,
and HRMS) for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX