An integrated flow and batch-based approach for the synthesis of O -methyl siphonazole

Article abstract of DOI:10.1055/s-0030-1260573

The bisoxazole containing natural product O-methyl siphonazole was assembled using a suite of microreactors via a flow-based approach in concert with traditional batch methods. The use of a toolbox of solid-supported scavengers and reagents to aid purification afforded the natural product in a total of nine steps. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260573

LETTER
1375
An Integrated Flow and Batch-Based Approach for the Synthesis of O-Methyl
Siphonazole
A
C
ombined Flow and
a
Batch
S
yn
r
c
O
-
Methyl
S
u
iphonazoles Baumann, Ian R. Baxendale, Malte Brasholz, John J. Hayward, Steven V. Ley, Nikzad Nikbin
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
E-mail: theitc@cam.ac.uk
Received 21 February 2011
has transformed flow chemistry from an academic interest
Abstract: The bisoxazole containing natural product O-methyl si-
to a valuable enabling technology that overcomes several
phonazole was assembled using a suite of microreactors via a flow-
of the bottlenecks traditionally faced by synthetic chem-
based approach in concert with traditional batch methods. The use
ists.6 As such the generation and immediate use of hazard-
of a toolbox of solid-supported scavengers and reagents to aid puri-
fication afforded the natural product in a total of nine steps.
ous, toxic, or unstable intermediates7 has been reported as
well as the possibility to more reliably perform reaction
scale-up.8 Furthermore, flow reactors can be transformed
into automated platforms by the addition of liquid han-
dling and fraction collector modules expanding the work-
ing capabilities of the units and allowing for 24/7 working
regimes.9 Finally, individual reactions can be telescoped
into one continuous flow sequence, thus avoiding the iter-
ative isolation, purification, and reprocessing of interme-
diates.10 With these potential advantages in mind, we have
orchestrated an improved total synthesis of O-methyl si-
phonazole by making use of flow techniques in order to
expedite certain steps in the synthesis. Our first synthetic
target was the oxazole carboxylic acid 10 which we in-
tended to access from commercially available dimethoxy-
cinnamic acid (6, Scheme 2).
Key words: oxazoles, Claisen condensation, flow chemistry,
microreactors, solid-supported reagents
As part of our ongoing interest in oxazole-containing nat-
ural products,1 we have devised a synthetic route to the
bisoxazole alkaloid O-methyl siphonazole (2), which was
discovered by König and co-workers in 2006, along with
the C-21-demethylated parent compound siphonazole (1,
Scheme 1).2 While Moody3 and Ciufolini4 reported the
first syntheses of the siphonazoles in 2008 and 2009, a de-
tailed biological profile of these metabolites of Herpeto-
siphon sp. has not been thoroughly established. Thus, a
modular synthesis of the natural products 1 and 2, flexible
enough for the production of unnatural analogues, is of in-
terest.
In order to process this material quickly we decided to em-
ploy the Vapourtec R2+/R4 flow system11 where two
small HPLC pumps deliver streams of starting materials
which are subsequently mixed at either a T-piece or with-
in a microchip. The resulting stream can then be intro-
duced into a tubular convection flow coil (CFC) which is
In this article we disclose our results on the preparation of
O-methyl siphonazole (2) based on an integrated ap-
proach combining conventional batch and new flow
chemistry methods. The application of flow techniques in
organic synthesis as described by numerous laboratories5
19
18
O
4
O
21
13
RO
7
H
1
N
2
N
9
N
O
O
17
MeO
20
1 R = H siphonazole
2 R = Me O-methyl siphonazole
R1O2C
O
Cl
O
H2N
+
+
MeO
RO
N
O
N
5
R2
4a R1 = Et, R2 = CN
4b R1 = Me, R2 = CO2Me
4c R1 = Me, R2 = CO2Ph
3 R = Me
Scheme 1 Siphonazole (1) and its building blocks 3–5
SYNLETT 2011, No. 10, pp 1375–1380
x
x
.x
x
.2
0
1
1
Advanced online publication: 23.05.2011
DOI: 10.1055/s-0030-1260573; Art ID: D05911ST
© Georg Thieme Verlag Stuttgart · New York

1376
M. Baumann et al.
LETTER
Scheme 2 Flow synthesis of oxazole carboxylic acid 10
heated or cooled to a desired temperature. The reaction be quantitatively converted into acyl chloride 3 using
stream is then subjected to in-line purification using solid- oxalyl chloride in the presence of catalytic amounts of
supported quenching and scavenger resins prior to the DMF by a standard batch method.
product being collected or relayed directly into the next
step of the synthesis sequence. Using this flow configura-
tion we established conditions for converting dimethoxy-
cinnamic acid (6) into oxazoline derivative 9 as shown in
Scheme 2. The carboxylic acid was activated with CDI
and coupled with threonine tert-butyl ester hydrochloride
Having accomplished an efficient synthesis of the left-
hand fragment 10, we next focused on the preparation of
a suitable coupling partner. As the central carbon–carbon
bond C5–C6 can be formed by a formal acylation, we syn-
thesized several acetyl oxazoles 4a–c. Whilst oxazole ni-
trile 4a is a known compound,15 oxazole diester building
(7) in situ before adding a third stream containing diethyl-
blocks 4b and 4c were prepared in two steps from diazo
aminosulfur trifluoride (DAST)12 to accomplish the cy-
esters 11 and 1216 as described in Scheme 3. An NH inser-
clodehydration of the intermediate amide. A set of
tion of the rhodium carbenoid derived from 11 and 12
heterogeneous scavengers such as a sulfonic acid (QP-
with methyl malonate monoamide17 led to keto amides 13
SA,13 to remove Et3N, imidazole and residual threonine
and 14, which cyclized to oxazoles 4b and 4c under
tert-butyl ester), a tertiary amine (QP-DMA,13 to remove
Wipf’s conditions.18 As this sequence involved the slow
residual acid), and plugs of CaCO3 and SiO2 (to quench
addition of methyl malonate monoamide, the use of a
and trap DAST and HF) were used in glass columns af-
standard syringe pump gave the best results. This was fol-
fording oxazoline 9 in greater than 95% purity. In a sec-
lowed by cyclodehydration of intermediates 13 and 14
ond step this oxazoline was then oxidized to the
where again all steps were performed by convenient batch
corresponding oxazole using a mixture of BrCCl3 and
methods (Scheme 3).
DBU14 followed by cleavage of the tert-butyl ester using
In order to progress the synthesis, acid chloride 3 was cou-
the previous mentioned QP-SA scavenger resin placed in
pled by a Claisen condensation with the oxazole esters
a heated glass column.
4a–c (Scheme 4). It was observed that the diesters 4b and
4c were prone to self-condensation upon treatment with
NaHMDS, therefore the base (2.3 equiv) was added, via a
syringe pump to the mixture of acid chloride 3 (1.3 equiv)
Using this flow sequence we achieved rapid access to pure
carboxylic acid 10 as a white, bench-stable solid in multi-
gram quantities without the need to perform any tradition-
al workup or purification steps. This material could then
and oxazole esters 4a–c in THF (1.0 equiv each) at –78
Synlett 2011, No. 10, 1375–1380 © Thieme Stuttgart · New York

LETTER
A Combined Flow and Batch Synthesis of O-Methyl Siphonazole
1377
O
O
(b) for 13
(c) for 14
MeO2C
O
(a)
O
CO2R
MeO2C
N
CO2R
H
N2
N
11 R = Me
12 R = Ph
13 R = Me
14 R = Ph
CO2R
4b R = Me
4c R = Ph
Scheme 3 Preparation of oxazoles 4b and 4c. Reagents and conditions: (a) methyl malonate monoamide, Rh2(OAc)4 (2 mol%), CH2Cl2, re-
flux, syringe pump addition, 84% for 13, 56% for 14; (b) I2, Ph3P, Et3N, CH2Cl2, r.t., 55%; (c) I2, Ph3P, i-Pr2NEt, PhMe, 80 °C, 71%.
R1O2C
O
CO2R1
N
O
R2
O
4a, 4b or 4c
N
MeO
MeO
R2
(a)
N
O
+
Cl
15a R1 = Et, R2 = CN
15b R1 = Me, R2 = CO2Me
15c R1 = Me, R2 = CO2Ph
O
MeO
MeO
N
O
3
Scheme 4 Claisen condensation of acid chloride 3 with oxazoles 4a–c. Reagents and conditions: (a) NaHMDS (2.3 equiv) added at –78 °C,
via a syringe pump, to 3 (1.3 equiv) and 4a–c (1.0 equiv) in THF.
°C. This procedure cleanly generated the desired adducts scavenging or column chromatography of the crude prod-
15a–c, which were employed without purification in the uct would be required. However, pleasingly it was discov-
subsequent decarboxylation step.
ered that when LiBr was added to the stock solution of
ester 4a, the desired product 15a could then be obtained
cleanly in 85% yield after aqueous quenching. It is pro-
posed that the addition of the LiBr leads to the formation
of the strongly chelated and highly soluble lithium enolate
adduct 16. This therefore enables flow processing of the
reaction with the advantage that the major potential con-
taminants of excess 4a and hydrolyzed carboxylic acid of
3 are more strongly bound on the polymeric support and
so removed from the product stream of enolate 16.
The use of a polymer-supported base for the Claisen con-
densation of acid chloride 3 with oxazole esters 4a–c was
also examined. As illustrated in Scheme 5, stock solutions
of 3 and 4a in MeCN were mixed in a microreactor, fol-
lowed by elution through a cartridge19 containing PS-BE-
MP.20 Unfortunately this procedure did not deliver the
expected coupled material. Ultimately, it was found that
both the product and excess starting material 4a were re-
tained as the corresponding enolates by the immobilized
base. This was potentially very problematic because ap- Next the decarboxylation of Claisen adducts 15a–c was
plying any standard release protocol involving displace- studied in detail (Table 1). Adduct 15a cleanly underwent
ment of the product from the column by treatment with an decarboxylation in the presence of excess NaCl (20 equiv)
acidic solution would also liberate the excess starting ma- in wet DMSO, to produce bisoxazole nitrile 17a in 73%
terial and acid via hydrolysis of the acyl chloride 3. As a overall yield (two steps from 4a). When the correspond-
result additional processing through subsequent in-line ing bismethylester 15b was reacted under identical condi-
Scheme 5 Claisen reaction of oxazole 3 and 4a induced by PS-BEMP as polymer-supported base in the presence of LiBr
Synlett 2011, No. 10, 1375–1380 © Thieme Stuttgart · New York

1378
M. Baumann et al.
LETTER
tions, surprisingly, no easily identified products could be corresponding carboxamide in low yields, accompanied
obtained, and recovery of the starting material after chro- by significant demethylation of the C-20 methoxy group.
matographic separation was poor. However, decarboxyla- Pleasingly, however, bisoxazole phenyl ester 17c readily
tion of 15b in the absence of NaCl did allow for the hydrolyzed when treated with barium hydroxide generat-
isolation of product 17b albeit in very low yield (7%). The ing the corresponding acid, which was obtained in 1:1
salt-free decarboxylation of adduct 15c, bearing a phenyl mixture with phenol. Purification and isolation of the acid
ester group at C-2 (instead of the methyl ester) on the oth- was possible, however, it was found that the crude mate-
er hand produced bisoxazole ester 17c in a corresponding- rial could be coupled with pentadienyl amine 522 directly
ly higher 40% overall yield from 4c.
even in the presence of the phenol (Scheme 6). When the
acid was activated with TBTU23 (1.5 equiv), and amine 5
(2.2 equiv) was added to the mixture after 15 minutes in-
cubation, no product derived from phenol addition was
observed, with O-methyl siphonazole (2)24 being formed
exclusively, and enabling isolation in 47% combined
yield over the two steps.
These results suggest that in the case of substrate 15b,
with a methyl ester in the 2-position, both the BAL2 and
BAC2 cleavage mechanisms operate with almost the same
efficiency. This is supported by the observation that al-
though both pathways might be possible in the presence of
chloride ions, presumably only the latter mechanism is
possible when water is the sole nucleophile.21 However,
the disappointingly low yield of bisoxazole 17b (7%)
from the salt-free reaction indicates that the C-2 methyl
ester is highly reactive towards hydrolysis at elevated
temperatures, and so it was not possible to tune the reac-
tivity by switching the external nucleophile from chloride
to water. Furthermore, it would appear that the free C-2
carboxylate generated from 15b is highly unstable and
prone to thermal decarboxylation, followed by a further
decomposition of the resulting C-2 carbanion precluding
this as a viable synthetic route. Compared to substrate
15b, the alternative diester substrate 15c demonstrated
improved stability, as the BAL2 mechanism cannot operate
at the site of the C-2 phenyl ester. Thus, it was possible to
isolate the decarboxylation product 17c in 40% yield. This
was lower than the 73% yield of the C-2 cyano compound
17a, due to partial hydrolysis of the phenyl ester of 15c via
the BAC2 mechanism.
O
O
H
N
MeO
(a),(b)
N
N
O
17c
O
MeO
2
Scheme 6 Conversion of bisoxazole ester 17c into O-methyl si-
phonazole 2. Reagents and conditions: (a) BaOH2·8H2O, THF–H2O,
r.t.; (b) TBTU (1.5 equiv), 5 (2.2 equiv), DMF, r.t., 47% (2 steps).
The outcome of our efforts presented in this article shows
that the synthesis of the natural product O-methyl siphon-
azole (2) from oxazole units 3 and 4c, and amine 5 was ac-
complished via a short sequence including a Claisen
condensation and Krapcho decarboxylation as key steps.
Furthermore, the use of flow techniques in concert with
immobilized reagents and scavengers greatly improved
the overall efficiency of the synthesis by circumventing
unnecessary isolation and purification steps. In summary,
this work exemplifies the benefit of an integrated ap-
proach combining traditional batch procedures with ap-
propriate enabling techniques such as flow chemistry.
This strategy afforded O-methyl siphonazole in nine
steps.
Table 1 Decarboxylation of Keto Esters 15a–c to Bisoxazole
Ketones 15a–c
O
O
N
MeO
MeO
decarboxylation
N
R
O
15a–c
17a–c
Acknowledgment
R
Conditions
Yield from 4a–c (%)
The authors thank the Deutsche Forschungsgemeinschaft (M.
Brasholz), the Cambridge European Trust, and the Ralph Raphael
Studentship (M. Baumann), the Royal Society (I.R.B.), the EPSRC
(N.N. and J.J.H.) and the BP endowment (S.V.L.) for financial sup-
port.
CN
NaCl, DMSO, H2O
MW, 160 °C, 1 h
17a
17b
17b
17c
73
CO2Me
CO2Me
CO2Ph
NaCl, DMSO, H2O
MW, 160 °C, 1 h
0
DMSO, H2O
MW, 150 °C, 1 h
7
References and Notes
(1) (a) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.;
Ley, S. V. Angew. Chem. Int. Ed. 2006, 45, 6714. (b) Bull,
J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.; Ley,
S. V. Chem. Eur. J. 2007, 13, 5515. (c) Enriquez-Garcia,
A.; Ley, S. V. Collect. Czech. Chem. Commun. 2009, 74,
887.
(2) Nett, M.; Erol, ; Kehraus, S.; Köck, M.; Krick, A.; Eguevera,
E.; Neu, E.; König, G. M. Angew. Chem. Int. Ed. 2006, 45,
3863.
DMSO, H2O
MW, 150 °C, 1 h
40
Nevertheless, the bisoxazole nitrile 17a was not a suitable
precursor to the natural product 2 as the cyano group at C-
2 resisted all attempts at hydrolysis to the carboxylic acid.
Even strongly acidic or basic conditions only led to the
Synlett 2011, No. 10, 1375–1380 © Thieme Stuttgart · New York

LETTER
A Combined Flow and Batch Synthesis of O-Methyl Siphonazole
1379
(3) (a) Linder, J.; Moody, C. J. Chem. Commun. 2007, 1508.
(b) Linder, J.; Blake, A. J.; Moody, C. J. Org. Biomol. Chem.
2008, 6, 3908.
(4) (a) Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389.
(b) Zhang, J.; Polishchuk, E. A.; Chen, J.; Ciufolini, M. A.
J. Org. Chem. 2009, 74, 9140.
(5) (a) Noël, T.; Naber, J. R.; Hartman, R. L.; McMullen, J. P.;
Jensen, K. F.; Buchwald, S. L. Chem. Sci. 2011, 2, 287.
(b) Ceylan, S.; Coutable, L.; Wegner, J.; Kirschning, A.
Chem. Eur. J. 2011, 17, 1884. (c) Polyzos, T.; O’Brien, M.;
Petersen, T. P.; Baxendale, I. R.; Ley, S. V. Angew. Chem.
Int. Ed. 2011, 50, 1190. (d) Ngamsom, B.; Hickey, A. M.;
Greenway, G. M.; Littlechild, J. A.; McCreedy, T.; Watts,
P.; Wiles, C. Org. Biomol. Chem. 2010, 8, 2419.
P.; Zimmermann, B. Chem. Eng. Technol. 2005, 28, 318.
(9) (a) Rasheed, M.; Wirth, T. Angew. Chem. Int. Ed. 2011, 50,
357. (b) Smith, C. J.; Smith, C. D.; Nikbin, N.; Ley, S. V.;
Baxendale, I. R. Org. Biomol. Chem. 2011, 9, 1927.
(c) Venturoni, F.; Nikbin, N.; Ley, S. V.; Baxendale, I. R.
Org. Biomol. Chem. 2010, 8, 1798. (d) Baxendale, I. R.;
Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Synlett
2006, 427.
(10) (a) Baumann, M.; Baxendale, I. R.; Kirschning, A.; Ley, S.
V.; Wegner, J. Heterocycles 2011, 82, 1297. (b)Hopkin,M.
D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46,
2450. (c) Qian, Z.; Baxendale, I. R.; Ley, S. V. Chem. Eur.
J. 2010, 16, 12342. (d) Brasholz, M.; Johnson, B. A.;
Macdonald, J. M.; Polyzos, A.; Tsanaktsidis, J.; Saubern, S.;
Holmes, A. B.; Ryan, J. H. Tetrahedron 2010, 66, 6445.
(e) Tamborini, L.; Conti, P.; Pinto, A.; Micheli, C. D.
Tetrahedron: Asymmetry 2010, 21, 222. (f) Herath, A.;
Dahl, R.; Cosford, N. D. P. Org. Lett. 2010, 12, 412.
(g) Baxendale, I. R.; Schou, S.; Sedelmeier, J.; Ley, S. V.
Chem. Eur. J. 2010, 16, 89. (h) Baxendale, I. R.; Ley, S. V.;
Mansfield, A. C.; Smith, C. D. Angew. Chem. Int. Ed. 2009,
48, 4017. (i) Baxendale, I. R.; Deeley, C. M.; Griffiths-
Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Chem.
Commun. 2006, 24, 2566. (j) Baxendale, I. R.; Ley, S. V.;
Smith, C. D.; Tranmer, G. K. Chem. Commun. 2006, 4835.
(11) Vapourtec© R2+/R4 system was used; website:
www.vapourtec.co.uk.
(12) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(b) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165 . Use of DAST in flow:
(c) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008,
2111. (d) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley,
S. V. Tetrahedron 2009, 65, 6611.
(13) QP-SA and QP-DMA resins are commercially available
from Johnson Matthey. Website: http://www.matthey.com/.
(14) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A.
Tetrahedron Lett. 1997, 38, 331.
(e) Bagley, M. C.; Fusillo, V.; Jenkins, R. L.; Lubinu, M. C.;
Mason, C. Org. Biomol. Chem. 2010, 8, 2245. (f) Wegner,
J.; Ceylan, S.; Friese, C.; Kirschning, A. Eur. J. Org. Chem.
2010, 4372. (g) McMullen, J. P.; Stone, M. T.; Buchwald, S.
L.; Jensen, K. F. Angew. Chem. Int. Ed. 2010, 49, 7076.
(h) McMullen, J. P.; Jensen, K. F. Org. Process Res. Dev.
2010, 14, 1169. (i) Damm, M.; Glasnov, T. N.; Kappe, C. O.
Org. Process Res. Dev. 2010, 14, 215. (j) Riva, E.;
Gagliardi, S.; Martinelli, M.; Passarella, D.; Vigo, D.;
Rencurosi, A. Tetrahedron 2010, 66, 3242. (k) Amemiya,
F.; Fuse, K.; Fuchigami, T.; Atobe, M. Chem. Commun.
2010, 46, 2730. (l) Brandt, J. C.; Elmore, S. C.; Robinson,
R. I.; Wirth, T. Synlett 2010, 3099. (m) Nagaki, A.;
Takabayasi, N.; Tomida, Y.; Yoshida, J. Beilstein J. Org.
Chem. 2009, 5, No. 16. (n) Gustafsson, T.; Pontén, F.;
Seeberger, P. H. Chem. Commun. 2008, 26, 1100.
(o) Sahoo, H. R.; Kralji, J. G.; Jensen, K. F. Angew. Chem.
Int. Ed. 2007, 46, 5704. (p) Mason, B. P.; Price, K. E.;
Steinbacher, J. L.; Bogdan, A. R.; MacQuade, D. T. Chem.
Rev. 2007, 107, 2300.
(6) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V. Mol. Diversity
2011, in press; DOI: 10.1007/s11030-010-9282-1.
(b) Bogdan, A. R.; James, K. Chem. Eur. J. 2010, 16, 14506.
(c) Hessel, V. Chem. Eng. Technol. 2009, 32, 1655.
(d) Ley, S. V.; Baxendale, I. R. Chimia 2008, 62, 162.
(7) (a) Irfan, M.; Glasnov, T. N.; Kappe, C. O. Org. Lett. 2011,
13, 984. (b) Martin, L. J.; Marzinzik, A. L.; Ley, S. V.;
Baxendale, I. R. Org. Lett. 2011, 13, 320. (c) Smith, C. J.;
Nikbin, N.; Ley, S. V.; Lange, H.; Baxendale, I. R. Org.
Biomol. Chem. 2011, 9, 1938. (d) Malet-Sanz, L.; Madrzak,
J.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8,
5324. (e) McPake, C. B.; Murray, C. B.; Sandford, G.
Chimica oggi 2010, 26, 6. (f) O’Brien, M.; Baxendale, I. R.;
Ley, S. V. Org. Lett. 2010, 12, 1596. (g) Bartrum, H. E.;
Blakemore, D. C.; Moody, C. J.; Hayes, C. J. J. Org. Chem.
2010, 75, 8674. (h) Brandt, J. C.; Wirth, T. Beilstein J. Org.
Chem. 2009, 5, No. 30. (i) Bogdan, A. R.; Sach, N. W. Adv.
Synth. Catal. 2009, 351, 849. (j) Baumann, M.; Baxendale,
I. R.; Nikbin, N.; Ley, S. V.; Smith, C. D.; Tierney, J. P. Org.
Biomol. Chem. 2008, 6, 1577. (k) Wiles, C.; Watts, P. Eur.
J. Org. Chem. 2008, 5597. (l) Sandford, G. J. Fluorine
Chem. 2007, 128, 90.
(8) (a) Hodgkinson, J. T.; Galloway, W. R. J. D.; Shreya, S.;
Baxendale, I. R.; Ley, S. V.; Ladlow, M.; Welch, M.; Spring,
D. R. Org. Biomol. Chem. 2011, 9, 57. (b) Carter, C. F.;
Baxendale, I. R.; Pavey, J. B. J.; Ley, S. V. Org. Biomol.
Chem. 2010, 8, 1588. (c) Wheeler, R. C.; Benali, O.; Deal,
M.; Farrant, E.; MacDonald, S. J. F.; Warrington, B. H. Org.
Process Res. Dev. 2007, 11, 704. (d) Hornung, C. H.;
Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Org. Process
Res. Dev. 2007, 11, 399. (e) Smith, C. J.; Iglesias-Sigüenza,
F. J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2007,
5, 2758. (f) Roberge, D. M.; Ducry, L.; Bieler, N.; Cretton,
(15) Doleschall, G.; Seres, P. J. Chem. Soc., Perkin Trans. 1
1988, 1875.
(16) Compound 12 was prepared by ring opening of 2,2,6-
trimethyl-4H-1,3-dioxin-4-one with phenol, see: Clemens,
R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431. Followed by
diazo group transfer, see: Tullis, J. S.; Helquist, P. Org.
Synth. 1997, 74, 229.
(17) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.
J. Chem. Soc., Perkin Trans. 1 1998, 591.
(18) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(19) An Omnifit column was used, www.omnifit.com.
(20) For related applications of PS-BEMP iminophosphorane
base, see: (a) Bensa, D.; Constantieux, T.; Rodriguez, J.
Synthesis 2004, 923. (b) Baumann, M.; Baxendale, I. R.;
Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8,
5231.
(21) (a) Krapcho, A. P.; Jahngen, E. G. E. Jr.; Lovey, A. J.
Tetrahedron Lett. 1974, 15, 1091. (b) Krapcho, A. P.;
Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E. Jr.;
Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138.
(22) (a) Mori, K. Tetrahedron 1974, 30, 3810. (b) Grieco, P. A.;
Galatsis, P.; Spohn, R. F. Tetrahedron 1986, 42, 2847.
(23) Poulain, R. F.; Tartar, A. L.; Déprez, B. P. Tetrahedron Lett.
2001, 42, 1495.
(24) NMR Data
1H NMR (600 MHz, CDCl3): d = 2.64, 2.67 (2 s, 2 × 3 H, 18-
H, 19-H), 3.92, 3.93 (2 s, 2 × 3 H, 20-H, 21-H), 4.03 (t,
J = 5.8 Hz, 2 H, 1¢-H), 4.41 (s, 2 H, 5-H), 5.06 (d, J = 10.3
Hz, 1 H, 5¢-H), 5.18 (d, J = 17.0 Hz, 1 H, 5¢-H), 5.73 (td,
J = 5.8, 15.0 Hz, 1 H, 2¢-H), 6.22 (dd, J = 10.3, 15.0 Hz, 1 H,
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3¢-H), 6.31 (td, J = 10.3, 17.0 Hz, 1 H, 4¢-H), 6.75 (d,
J = 16.4, 1 H, 10-H), 6.88 (d, J = 8.2 Hz, 1 H, 16-H), 7.00 (t,
J = 5.8 Hz, 1 H, NH), 7.07 (d, J = 1.6 Hz, 1 H, 13-H), 7.09
(dd, J = 1.6, 8.2 Hz, 1 H, 17-H), 7.44 (d, J = 16.4 Hz, 1 H,
11-H) ppm. 13C NMR (150 MHz): d = 11.7, 12.4 (2 q, C-18,
C-19), 39.4 (t, C-5), 40.3 (t, C-1¢), 55.9, 56.0 (2 q, C-20, C-
21), 108.9 (d, C-13), 110.8 (d, C-10), 111.2 (d, C-16), 117.4
(t, C-5¢), 121.5 (d, C-17), 128.1 (s, C-12), 129.45, 129.49 (2
d, C-2¢, C-3¢), 132.8 (s, C-2), 134.5 (s, C-7), 136.1 (d, C-4¢),
137.3 (d, C-11), 149.3, 150.6 (2 s, C-14, C-15), 153.8 (s, C-
3), 155.3 (s, C-8), 155.6 (s, C-4), 159.1 (s, C-9), 161.7 (s, C-
1), 189.4 (s, C-6) ppm.
Synlett 2011, No. 10, 1375–1380 © Thieme Stuttgart · New York