Synthesis of (-)-hennoxazole A: Integrating batch and flow chemistry methods

Article abstract of DOI:10.1055/s-0032-1318109

A new total synthesis of (-)-hennoxazole A is reported. The synthetic approach is based on the preparation of three similarly sized fragments resulting in a fast and convergent assembly of the natural product. The three key reactions of the synthesis include a highly stereoselective 1,5-anti aldol coupling, a gold-catalyzed alkoxycyclization reaction, and a stereocontrolled diene cross-metathesis. The synthesis involves integrated batch and flow chemistry methods leading to the natural product in 16 steps longest linear sequence and 2.8% overall yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318109

5
14▌
LETTER
lSetyternthesis of (–)-Hennoxazole A: Integrating Batch and Flow Chemistry
Methods
Synthesis of (–)-Hennoxazole A
a
a
a
a
a
a
Amadeo Fernández, Zebulon G. Levine, Marcus Baumann, Sarah Sulzer-Mossé, Christof Sparr, Sabrina Schläger,
a
b
a
Albrecht Metzger, Ian R. Baxendale, Steven V. Ley*
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
b
Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
Received: 11.12.2012; Accepted: 30.12.2012
methylsilylacetylene. The desired ketone 11 was formed
as the major product together with a smaller quantity of
the protected compound 10. These two compounds were
Abstract: A new total synthesis of (–)-hennoxazole A is reported.
The synthetic approach is based on the preparation of three similar-
ly sized fragments resulting in a fast and convergent assembly of the
natural product. The three key reactions of the synthesis include a easily separated by flash column chromatography. More-
highly stereoselective 1,5-anti aldol coupling, a gold-catalyzed alk- over, the minor ketal 10 was conveniently converted to the
oxycyclization reaction, and a stereocontrolled diene cross-meta-
thesis. The synthesis involves integrated batch and flow chemistry
methods leading to the natural product in 16 steps longest linear
sequence and 2.8% overall yield.
ketone 11 under acidic acetal-cleavage conditions using
(
±)-CSA. Finally, protection of the free hydroxy group as
7
PMB ether afforded the desired fragment 4 in 56% over-
all yield.
Key words: flow chemistry, polymer-supported reagents, meta-
thesis, total synthesis, natural products
OH
2
8
4
OMe
1
3
2
7
6
(
–)-Hennoxazole A (1) was isolated in 1991 from the ma-
1
N
O
O
8
1
8
1
rine sponge Polyfibrospongia sp. This structurally inter-
esting natural product has succumbed to a number of total
syntheses over the intervening years. Given our interest
in bisoxazoles and in particular using the integration of
OMe
H
21
O
N
2
9
15
2
26
2
5
3
(–)-hennoxazole A (1)
4
batch and flow chemistry technologies, (–)-hennoxazole
A (1) presents itself as an attractive target for synthesis.
metathesis
OPMB
The synthesis plan relies on the preparation of three simi-
larly sized fragments, a central bisoxazole core 5, an al-
kynyl ketone 4 and a skipped diene side chain 3 (Scheme
4
OH
27
6
13
18
1
N
O
8
O
21
O
1
). In order to assemble these three fragments, a stereose-
+
OMe
H
N
OTBDPS
lective boron-promoted aldol reaction and a cross-metath-
esis process are considered as key steps in the planned
synthesis. Furthermore, given that flow chemistry can re-
place some of the labor and time-consuming processes
common to traditional batch methods by improving
downstream processing and reaction telescoping, this ma-
chine-assisted approach can be efficiently integrated with
29
26
1
5
2
3
3
2
3
1,5-anti aldol addition
O
2
PMBO
O
21
MeO
OH
O
5
13
conventional synthesis methods.
4
6
N
26
O
H
8
6
The batch preparation of ketone 4 began from commer-
cially available (R)-epichlorohydrin. Treatment of this
compound with the lithium anion derived from dithiane 7
+
N
O
1
15
TMS
5
4
gave oxirane 8 as a single regioisomer in good yield
6
(
Scheme 2). However, reaction of 8 with different meta- Scheme 1 Retrosynthetic analysis
lated alkynyls gave low yields of the ring-opened product,
probably due to the coordinating behavior of the dithiane
moiety. To overcome this problem, a change in the pro-
tecting group was required. Interconversion of dithiane 8
to the oxirane 9 allowed ring opening using lithiated tri-
For the preparation of the bisoxazole core 5 we chose to
use flow-chemistry methods as these had worked well, on
scale, during a synthesis of O-methyl siphonazole, anoth-
4
er bisoxazole natural product. Therefore, straightforward
coupling between 5-pentenoic acid, in situ activated with
carbonyldiimidazole (CDI), and (±)-serine methyl ester in
the presence of triethylamine with subsequent cyclodehy-
dration using diethylaminosulfur trifluoride (DAST) fur-
SYNLETT 2013, 24, 0514–0518
Advanced online publication: 30.01.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318109; Art ID: ST-2012-D1062-L
Georg Thieme Verlag Stuttgart · New York
©

LETTER
Synthesis of (–)-Hennoxazole A
515
employed in this step to quench excess DAST and to trap
the generated HF, improving the safety profile for this re-
action set-up. Intermediate 12 was oxidized using bro-
PhI(CF3CO2)2
HO OH
a) n-BuLi,
THF, 0 °C
9
S S
O O
O
O
S
S
mochloroform in the presence of DBU to form oxazole
O
MeCN, r.t.
82%)
b)
8
Cl
8
9
derivative 13, which was subjected to saponification with
(
aqueous NaOH thus yielding the corresponding acid 14 in
excellent yield. Utilization of the oxazole-forming pro-
cess converted this precursor into the desired bisoxazole
ester 16 in a notable yield (90%). The overall flow synthe-
sis of bisoxazole 16 was carried out on multigram scales
7
TMS
Li
THF, –40 ºC to r.t.
91%)
(
3
BF ⋅OEt2
THF, –78 °C
97%; 11/10 = 2:1)
(
(
>5 g). Furthermore, it featured the use of polymer-sup-
O
OH
TMS
(
ported reagents and scavengers to afford clean intermedi-
ates without resource to time-consuming manual workup.
The flow process also eliminates the need for aqueous ex-
traction or column chromatography at any intermediate
stage and can be carried out conveniently and safely de-
spite the use of aggressive reagents such as diethylamino-
sulfur trifluoride (Scheme 3). Finally, a batch reduction of
O O
OH
TMS
+
11
10
NH
±)-CSA
Me2CO, r.t.
Cl3C
OPMB
Ph3CBF4
THF, 0 °C to r.t.
77%)
(quant.)
(
1
0
1
6 using DIBAL-H afforded aldehyde 5, the core frag-
ment of the natural product.
O
OPMB
TMS
5
6% from 7
With efficient methods available for the preparation of
these two fragments, we turned our attention to the prepa-
ration of the third coupling partner 3. Based on earlier
work by Walsh and Negishi a multicomponent ap-
proach to a skipped Z-diene bearing the stereogenic C22
center was investigated. The preparation of 3 in batch be-
gan with the protection of the commercially available (S)-
Roche ester with TBDPSCl under standard conditions.
Then, a reduction to alcohol 18 and reoxidation using
4
Scheme 2 Synthesis of ketone 4
11a
11b
nished the corresponding oxazoline 12 in 86% yield over
two steps (Scheme 3). This was achieved using a similar
flow-chemistry set-up to our previous oxazoline prepara-
tion. It is noteworthy that a CaCO /SiO scavenger was
8
4
3
2
O
CH2Cl2
SF3
CDI +
Et2N
O
N
HO
CH Cl2
2
SO3H
MeO
HO
O
12
6%
O
BrCCl3,
DBU,
MeCN
8
5
0 min
NMe2
CaCO3/SiO2
MeO
Et3N +
90 °C
NH2⋅HCl
CH2Cl2
NaOH,
H2O
3
8
0 min
0 °C
SO3H
NMe2
O
N
O
N
HO
MeO
O
MeOH
1
4
O
50 min, r.t.
93%
1
3
+
CDI, MeCN
95%
SF3
HO
Et3N + MeO
Et2N
CH2Cl2
BrCCl , DBU,
MeCN
3
NH2⋅HCl
CaCO3/
SiO2
r.t.
O
O
N
O
N
SO3H
r.t.
DIBAL-H
CH2Cl2
O
MeO
N
O
N
O
5
O
(93%)
ref. 10
MeO
16
15
30 min, 80 °C
90%
75%
Scheme 3 Continuous-flow synthesis of bisoxazole core 5
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 514–518

5
16
A. Fernández et al.
LETTER
1
) TBDPSCl, DIPEA,
DMAP, CH2Cl2, r.t.
quant.)
forded bromoalkyne 20. Subsequent hydroboration of 20
proceeded with high regioselectivity and treatment of the
bromoalkene with dimethylzinc gave the intermediate 21
which undergoes a rearrangement and further boron–zinc
exchange. Finally, this organozinc intermediate could be
trapped with allyl bromide in the presence of a copper
source. This one-pot sequence of reactions with formation
of two new C–C bonds and control of olefin geometry
leading directly to the coupling fragment 3 in quantity and
good overall yield is attractive and best suited to batch
methods (Scheme 4).
O
(
MeO
OH
HO
OTBDPS
2) LiBH4, Et2O, MeOH
0 °C to r.t.
1
8
6
(quant.)
1) SO3-pyridine, DMSO
DIPEA, CH2Cl2, –10 ºC
quant.)
) CBr4, Et3N, Ph3P
(
2
CH2Cl2, –78 °C to r.t.
(94%)
Br
LiHMDS, THF
78 °C to 0 °C
Br
–
OTBDPS
OTBDPS
With the three key fragments in hand and available in
gram quantities, we could begin the assembly process to
(94%)
Br
19
2
0
(
–)-hennoxazole A (1). While many coupling options
a) Br2BH-SMe2, toluene, 70 °C
b) Me2Zn, –78 °C to 0 °C
c) remove volatiles
d) THF, allyl bromide
CuBr-SMe2, –78 °C to r.t.
ZnMe
were available to us, we chose first to investigate the 1,5-
anti aldol reaction between ketone 4 and aldehyde 5.12
Me
BBr2
The best results were achieved using (–)-Ipc BCl and an
2
OTBDPS
in situ reduction of the boron intermediate to afford the
desired diol 22 in good yield and as a single diastereomer.
Next, we studied the gold-catalyzed alkoxycyclization re-
action to form the tetrahydropyran ring. After catalyst-
screening studies, we were pleased to observe the forma-
(
61%)
Br
21
OTBDPS
54% from 6
3
tion of the desired tetrahydropyran 2 as a single diastereo-
Scheme 4 Synthesis of diene fragment 3
13
mer using 5 mol% of (IMes)AuNTf in MeOH at 55 °C
2
14
in 91% yield. This intermediate was then methylated to
afford 23 using a standard protocol. We next investigated
the crucial cross-metathesis reaction. The best conditions
Parikh–Doering conditions gave the intermediate alde-
hyde ready for a subsequent Ramirez olefination to afford
gem-dibromoalkene 19. Elimination of 19 with a base af-
a) (–)-Ipc2BCl, Et3N
Et2O, 0 °C
b) 5, Et2O
78 °C to –20 °C
PMBO
OH OH
PMBO
O
N
O
–
N
c) LiBH4
78 °C to –20 °C
63%)
O
4
22
–
(
TMS
TMS
(
IMes)AuNTf2
MeOH, 55 °C
(91%)
OPMB
OH
N
O
O
OMe
H
N
O
2
a) NaH
DMF, 0 °C
b) MeI, 0 °C to r.t.
91%)
(
OPMB
O
OMe
N
O
OMe
H
N
O
23
3
, Grubbs II
CH2Cl2, 60 °C
(
59%)
OPMB
O
(80% BRSM)
OMe
N
O
OMe
H
N
O
OTBDPS
24
Scheme 5 Assembly of the key fragments
Synlett 2013, 24, 514–518
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (–)-Hennoxazole A
517
for this process employed the second-generation Grubbs Acknowledgment
catalyst and CH Cl as solvent, while heating at 60 °C in
a sealed tube which furnished 24 in 59% yield or 80%
based on recovered starting material (Scheme 5).
2
2
We are grateful to the Marie Curie Intra-European Fellowship
within the 7 European Community Framework Programme (A.F.),
th
the Williams College for a Dr Herchel Smith Fellowship (Z.G.L),
the Ralph Raphael studentship award (M.B.), the Swiss National
Science Foundation (S.S.-M. and C.S.), the Royal Society (I.R.B.),
the BP Endowment (S.V.L.), and the EPSRC EP/F0693685/1 for fi-
nancial support. Dr. Matthew L. Maddess, Dr. Malte Brasholz, and
Antti Kataja are acknowledged for alternative approaches not repor-
Final elaboration of 24 to the natural product involved de-
protection using TBAF and oxidation of the resulting free
alcohol 25 to the intermediate aldehyde using Dess–Mar-
tin periodinane. It is noteworthy that the aldehyde was not
isolated due to its potential to epimerize; rather it was used ted here.
directly in the next step.
This involved a modified Takai olefination with 1,1-diio-
doethane, giving 26 in moderate 35% yield over two steps http://www.thieme-connect.com/ejournals/toc/synlett. SupInpf oiogtrm rat
Supporting Information for this article is available online at
i
o
tnnrfmo at
o
as a single E-stereoisomer. Finally, cleavage of the PMB
2
c
ether using DDQ in a buffered solution was achieved in
References and Notes
good yield affording the natural product (–)-hennoxazole
1
5
A identical to an authentic sample (Scheme 6).
(1) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.;
Gravalos, D. G. J. Am. Chem. Soc. 1991, 113, 3173.
(
2) (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
b) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am.
24
(
TBAF
THF, 0 °C to r.t.
80%)
Chem. Soc. 1999, 121, 4924. (c) Yokokawa, F.; Asano, T.;
Shioiri, T. Tetrahedron 2001, 57, 6311. (d) Smith, T. E.;
Kuo, W.-H.; Bock, V. D.; Roizen, J. L.; Balskus, E. P.;
Theberge, A. B. Org. Lett. 2007, 9, 1153. (e) Smith, T. E.;
Kuo, W.-H.; Balskus, E. P.; Bock, V. D.; Roizen, J. L.;
Theberge, A. B.; Carroll, K. A.; Kurihara, T.; Wessler, J. D.
J. Org. Chem. 2008, 73, 142.
OPMB
O
(
OMe
N
O
OMe
H
N
O
OH
2
5
(3) (a) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.;
Ley, S. V. Chem. Eur. J. 2007, 13, 5515. (b) Enriquez-
Garcia, A.; Ley, S. V. Collect. Czech. Chem. Commun. 2009,
1
) Dess–Martin periodinane
CH2Cl2, 0 °C
74, 887.
2
) CrCl2, MeCHI2
DMF, THF 0 °C
(4) Baumann, M.; Baxendale, I. R.; Brasholz, M.; Hayward, J.
J.; Ley, S. V.; Nikbin, N. Synlett 2010, 1375.
5) For some recent reviews on flow synthesis of heterocycles,
(35% over 2 steps)
OPMB
O
(
OMe
see: (a) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675.
(
2
b) Baumann, M.; Baxendale, I. R.; Ley, S. V. Mol. Diversity
011, 15, 613.
N
O
OMe
H
N
(6) Fürstner, A.; Kattnig, E.; Kelter, G.; Fiebig, H.-H. Chem.
Eur. J. 2009, 15, 4030.
7) (a) Reddy, K. K.; Saady, M.; Falck, J. R.; Whited, G. J. Org.
Chem. 1995, 60, 3385. (b) Chavez, D. E.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2001, 40, 3667.
O
2
6
(
DDQ
phosphate buffer pH 7
CH2Cl2
(8) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D.
0
°C to r.t.
OH
O
R. Org. Lett. 2000, 2, 1165.
(68%)
(
9) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008,
111. (b) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley,
S. V. Tetrahedron 2009, 65, 6611.
OMe
2
N
O
(
10) For some examples of selective reduction reactions using
diisobutylaluminum hydride in flow, see: (a) Carter, C. F.;
Lange, H.; Sakai, D.; Baxendale, I. R.; Ley, S. V. Chem. Eur.
J. 2011, 17, 3398. (b) Webb, D.; Jamison, T. F. Org. Lett.
OMe
H
N
O
1
2
012, 14, 568.
Scheme 6 Final steps
(
11) (a) Chen, Y. K.; Walsh, P. J. J. Am. Chem. Soc. 2004, 124,
3
702. (b) Huang, Z.; Negishi, E. J. Am. Chem. Soc. 2007,
In summary, the total synthesis of (–)-hennoxazole A has
been completed in 16 steps longest linear sequence and 26
steps overall. Highlights of this work include the develop-
ment of a new flow process for the synthesis of the bisox-
azole core in concert with traditional batch methods, an
efficient assembly of the three similarly sized fragments
taking advantage of organometallic processes, cross-me-
tathesis, a highly stereocontrolled boron-promoted aldol
reaction, and a stereoselective gold-promoted alkoxycy-
clization process.
129, 14788.
(12) Paterson, I.; Gibson, R. G.; Oballa, R. M. Tetrahedron Lett.
1996, 37, 8585.
13) Ricard, L.; Gagosz, F. Organometallics 2007, 26, 4704.
14) Data for Compound 2
(
(
2
9.4
Mp 74–79 °C. R = 0.34 (EtOAc–PE, 1:1); [α]
–23 (c
f
D
0.13, CHCl ). IR (neat): 3464, 2984, 2932, 2837, 2365,
3
2337, 1639, 1615, 1578, 1512, 1449, 1380, 1362, 1302,
–
1 1
1247, 1171 cm . H NMR (500 MHz, CDCl ): δ = 8.09 (1
H, s), 7.61 (1 H, s), 7.24 (2 H, d, J = 8.7 Hz), 6.86 (2 H, d, J
=
3
8.7 Hz), 5.84 (1 H, ddt, J = 17.0, 10.3, 6.6 Hz), 5.08 (1 H,
Synlett 2013, 24, 514–518
©
Georg Thieme Verlag Stuttgart · New York

5
18
A. Fernández et al.
LETTER
dq, J = 17.1, 1.6 Hz), 5.01 (1 H, dq, J = 10.2, 1.4 Hz), 4.97
137.8, 136.1, 134.1, 130.6, 129.7, 116.1, 113.8, 100.1, 70.8,
70.4, 69.7, 68.5, 55.2, 47.8, 42.1, 41.8, 37.7, 30.7, 27.5, 23.6.
(
1 H, d, J = 9.7 Hz), 4.46 (2 H, d, J = 2.7 Hz), 4.18 (1 H, s),
.94–3.83 (2 H, m), 3.79 (3 H, s), 3.21 (3 H, s), 2.93 (2 H, t,
J = 7.6 Hz), 2.56 (2 H, q, J = 7.1 Hz), 2.26–2.19 (2 H, m),
+
+
3
ESI-HRMS: m/z calcd for C H N NaO [M + Na] :
27 34 2 7
521.2258; found: 521.2250.
2
1
.03–2.00 (1 H, m), 1.90 (1 H, dt, J = 14.6, 10.2 Hz), 1.42–
(15) An authentic sample of (–)-hennoxazole A was kindly
provided by Prof. Thomas E. Smith (Williams College).
.39 (1 H, m), 1.36 (3 H, s), 1.26 (1 H, q, J = 11.8 Hz). 13
C
NMR (125 MHz, CDCl ): δ = 165.5, 159.1, 155.3, 144.8,
3
Synlett 2013, 24, 514–518
© Georg Thieme Verlag Stuttgart · New York

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