Explorations of [4+2] and [5+2] cycloadditions of dienylcyclopropane derived enzymatically from cyclopropylbenzene

Article abstract of DOI:10.1055/s-0031-1289553

Fermentation of cyclopropylbenzene with E. coli JM109(pDTG601a) furnished optically pure 1-cyclopropyl-2,3-dihydroxycyclohexa-4,6-diene whose reactivity in [4+2]- and [5+2]-cycloaddition chemistry was explored. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289553

LETTER
2891
Explorations of [4+2] and [5+2] Cycloadditions of Dienylcyclopropane Derived
Enzymatically from Cyclopropylbenzene
E
xploratio
a
ns of [4+2]
s
and [5+2
o
]
Cycloadditi
n
ons of Dienylcyclo
R
propane eed Hudlicky, John Hopkins-Hill, Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, ON, L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
Received 18 September 2011
diols serve as convenient optically pure starting materials
Abstract: Fermentation of cyclopropylbenzene with E. coli
in creative syntheses of many natural products.4
We discovered that cyclopropylbenzene5 was, in fact, an
JM109(pDTG601a) furnished optically pure 1-cyclopropyl-2,3-di-
hydroxycyclohexa-4,6-diene whose reactivity in [4+2]- and [5+2]-
cycloaddition chemistry was explored.
excellent substrate for toluene dioxygenase, initially lead-
Key words: dienylcyclopropane, cyclopropylbenzene, [4+2] cyclo- ing to production of the 1-cyclopropylcyclohexadiene-
additions, [5+2] cycloadditions, enzymatic dihydroxylation of arenes
cis-2,3-diol 6 in yields of ca. 2.5 g/L. With further optimi-
zation, we were able to prepare 60–80 grams of 6 on a 10-
L fermenter scale. Such conversion was comparable to
that obtained from toluene, styrene, or halobenzenes,
which are among the best substrates for this enzyme,
yielding >20 g/L of diols.
Some time ago we tested cyclopropylbenzene as a sub-
strate for toluene dioxygenase in the whole-cell fermenta-
tion with E. coli JM109(pDTG601a).1 The original reason
for this investigation was based on an assumption that the
enzymatic dihydroxylation may proceed via a radical in-
termediate such as 2, rather than via a dioxetane interme-
diate of type 3, originally proposed by Gibson.2 The latter
postulate would require a singlet oxygen species present
in the active site of the enzyme. On the other hand, inter-
action of the substrate with a triplet species may generate
a radical of type 2 that might undergo unraveling of the di-
enylcyclopropyl system to 4 and subsequent potential co-
valent trapping within the enzyme active site to a species
such as 5, as shown in Scheme 1.
Calculations performed on the dienylcyclopropyl radical
2 indicated that the original anticipated unraveling would
not take place: DG for the transformation was calculated
to be 17.7 kcal/mol and the calculated rate constant kr =
1.1 s–1.6 While the parent cyclopropylcarbinyl system re-
arranges with a rate constant of 108 s–1 the dienyl system
enjoys the additional stabilization of the radical and thus
the unraveling would be an energetically demanding pro-
cess. It is well known that the presence of radical-stabiliz-
ing substituents near the carbinyl site effects lower the
rates of ring opening.7 Nevertheless, the availability of
diol 6, as well as other metabolites derived from function-
alized cyclopropyl benzenes,8 prompted us to investigate
its reactive tendencies in various cycloadditions. In this
paper we report the preliminary findings with regard to
[4+2] and [5+2] cycloadditions.
Such mechanistic options have recently been summa-
rized,3 although the actual mechanism of the enzymatic
dihydroxylation remains unknown. In spite of this fact the
toluene dioxygenase
The [4+2] cycloadditions of the diene unit in the protected
diol 6 were investigated. The diol was protected as its ac-
etonide 7, a compound that proved to be relatively unsta-
ble. Small amounts of the 2-cyclopropylphenol generated
during the protection led to further autocatalytic elimina-
tion. The acetonide was stable to degradation when kept
as a solution in ethyl acetate over solid sodium carbonate.
It was also prone to slow dimerization via Diels–Alder cy-
cloaddition upon standing. Complete and stereoselective
dimerization of 7 was achieved by heating 7 in xylene at
reflux for 20 hours to yield 8 as a single stereoisomer in
ca. 95% yield, in agreement with previously investigated
dimerizations of this type. Past work from our laboratory
has shown that acetonides derived from bromo- and chlo-
rocyclohexadiene-cis-diols form the corresponding
dimers stereo- and regioselectively and the structures
were confirmed by X-ray crystallography.9 These obser-
vations were previously made by Ley10 for the acetonide
of the diol derived from bromobenzene and by Roberts11
1O2
?
3O2
?
•
O
O
OH
OH
O
O
•
1
2
3
6
Protein
•
X
OH
O
O
•
4
5
Scheme 1 Speculations on possible intermediates in enzymatic di-
hydroxylations of arenes
SYNLETT 2011, No. 19, pp 2891–2895
Advanced online publication: 25.10.2011
x
x
.x
x
.2
0
1
1
DOI: 10.1055/s-0031-1289553; Art ID: S08711ST
© Georg Thieme Verlag Stuttgart · New York

2892
J. R. Hudlicky et al.
LETTER
H
O
H
H
O
8
7
6
O
O
OH
1
4
O
O
DMP, p-TsOH, r.t.
xylene, reflux
~95%
8a
2
H
3
4a
OH
5
7
6
H
H
8
MeO2C
CO2Me
AcNHOH, NaIO4
H
O
toluene, reflux
43%, from 6
1O2, CH2Cl2
MeOH, H2O, r.t.
H
H
H
H
8
O
57–75%, from 6
7
O
1
4
8a
2
3
4a H
6
O
5
MeO2C
O
O
N
O
O
O
O
O
O
Ac
9
O
MeO2C
10
11
12
Scheme 2
for the acetonide of the diol obtained from trifluorometh- The endo-peroxide 11 was reduced with thiourea to fur-
ylbenzene.
nish the conduritol derivative 13 and its acetate 14 in 51%
yield over two steps. Reduction of the oxazine with
Mo(CO)6 gave the allylic alcohol 16 in 55% yield and
this material was converted into enone 19 by modified
Dauben–Michno oxidative transposition in 21% isolated
yield, as shown in Scheme 3. The low yield in the conver-
sion of 16 into 19 is the result of a rather arduous workup
and does not reflect the otherwise complete conversion.
1
The stereochemistry of 8 was determined by H NMR
NOESY experiment, which indicated strong NOE be-
tween H-8a/H-2, H-4a/H-3, and H-1/H-8. The latter NOE
confirmed the regiochemistry of the dimerization as
drawn in Scheme 2. The observed NOEs as well as the
value of the coupling constant between H-8a/H4a (J = 9.9
Hz) were identical to those observed in the NMR experi-
15
ments (COSY and HETCOR) performed on the dimer 9, The Dauben–Michno oxidation was investigated in detail
which we have prepared from the acetonide-protected diol in our laboratories with regard to allylic alcohols adjacent
from styrene.12 In those experiments irradiation of H-2 to electron-withdrawing groups such as carboxylates16
produced 8.3% enhancement at H-8a in 9. Similarly, irra- and nitriles.17 Previously, this oxidation was reported only
diation of H-3 resulted in 11.5% enhancement at H-4a. for allylic alcohols with electron-donating groups. It is as-
The structure of dimer 9 was also confirmed by X-ray sumed that it proceeds by a formation of a chromate ester
analysis of the corresponding C-7/C-8 diol obtained by that undergoes a [3,3]-sigmatropic rearrangement fol-
partial hydrolysis.
lowed by the normal oxidation of the rearranged chro-
mate. What is clear from the successful oxidation of 16 to
19 is that there very likely is no partial positive character
at the site of the cyclopropylcarbinyl alcohol during the
sigmatropic rearrangement otherwise substantial ring
opening would be observed. This is an interesting, and
somewhat surprising, result because the conditions of the
Dauben–Michno oxidation are strongly acidic.
The bicyclic adduct 10 was obtained in 43% yield (over
two steps) upon heating 7 in the presence of acetylene di-
carboxylate in m-xylene for six hours. Singlet oxygen cy-
cloaddition produced endo-peroxide 11 with complete
conversion (this compound was not stable to isolation and
was immediately reduced). Acetonide 7 underwent a rapid
hetero-Diels–Alder cycloaddition with acyl nitroso dieno-
phile generated in situ from the corresponding hydroxam- We have also prepared enone 19 in 45% yield by oxida-
ic acid to yield oxazine 12 within a few minutes as a single tion of the allylic alcohol 18, which was obtained by a
isomer in 75% yield (small scale; 57% yield on 10-gram mild hydrolysis of oxazoline 17 (40% over two steps).
scale). The cycloadditions of nitroso dienophiles with the Such oxazolines are produced by the rearrangement of
electronically polarized dienes in cis-diols derived from mesylates, such as 20, derived from 1,4-acetamido alco-
bromo- and chlorobenzene13 or ethyl benzoate14 produced hols. We have investigated this rearrangement first in con-
single regioisomers of the corresponding oxazines. We nection with a synthesis of oseltamivir18 and later as a
did not expect complete regioselectivity in the cycloaddi- general method of synthesis for 1,2-amino alcohol deriv-
tions of less polarized alkyl-substituted dienes such as that atives from oxazines.19 The yields of enone 19 by this
in 7.
method are slightly higher than those obtained by the
Dauben–Michno transposition because of problems in
Synlett 2011, No. 19, 2891–2895 © Thieme Stuttgart · New York

LETTER
Explorations of [4+2] and [5+2] Cycloadditions of Dienylcyclopropane
2893
OH
O
O
CrO3, Ac2O, 0 °C
O
O
NH2CSNH2
51%
O
O
O
O
O
11
OR
OAc
13 R = H
15
14 R = Ac
OH
O
O
O
CrO3, Ac2O, 0 °C
21%
O
O
Mo(CO)6
55%
O
Ac
N
O
O
NHAc
19
NHAc
12
16
DMP
CH2Cl2
46%
MsCl, Et3N, DMAP
CH2Cl2, 4 h, r.t.
OMs
CaCO3, EtOH, H2O
reflux
O
O
O
O
O
O
40% from 16
HO
O
NHAc
20
N
NHAc
18
17
Scheme 3
workup. Although the conversion of 16 into 19 is com- dimethyl acetylene dicarboxylate in dichloroethane and in
plete, isolated yields tended to be quite low.
the presence of [Rh(CO)2Cl]2 at 105 °C generated only
traces of cycloheptadiene 22 after almost two weeks of
heating in a sealed tube. Normally, the reactions of vinyl-
cyclopropanes in [5+2] annulations reported by Wender
are complete within several hours. However, the reported
reactions did not involve vinylcyclopropanes where either
component would be part of a ring, as is the case with 21.
We attribute this apparent lack of reactivity to the fact that
the cyclopropyl ring does not appear to be ‘in conjuga-
tion’ with the olefin, and is likely in an essentially orthog-
onal arrangement with the alkene (vide infra NMR).
Enone 19 or its oxygen analogue 15 contain a vinylcyclo-
propane functionality amenable to either vinylcyclopro-
pane–cyclopentene rearrangement or [5+2] cyclo-
additions. Both processes would lead to annulated condu-
ritol and conduramine derivatives that have been shown to
have antiglycosidic properties.20 We therefore turned to
investigations of the chemistry of the vinylcyclopropane
moiety,21 namely the rhodium-catalyzed [5+2] cycloaddi-
tions discovered and reported by Wender.22 Diol 6 was re-
duced with potassium azodicarboxylate (PAD) as
previously described and protected as its acetonide 216 by Assuming that the intramolecular process would be more
treatment with 2,2-dimethoxypropane in the presence of feasible, we prepared ester 23 by acylation of 18 with me-
p-TsOH, as shown in Scheme 4. Exposure of 21 to excess thylpropiolic acid in the presence of DCC. When 23 was
MeO2C
1. PAD, AcOH, 0 °C
2. DMP, p-TsOH
[Rh(CO)2Cl]2
O
O
6
MeO2C
ClCH2CH2Cl, 105 °C
2 weeks
~60% over 2 steps
O
O
21
22 [trace]
tetrolic acid, DCC
O
O
O
O
O
[Rh(CO)2Cl]2
CH2Cl2, r.t., 24 h
O
O
ClCH2CH2Cl, 105 °C
2 days
O
77%
HO
O
O
NHAc
NHAc
18
NHAc
23
24 [<5%]
Scheme 4
Synlett 2011, No. 19, 2891–2895 © Thieme Stuttgart · New York

2894
J. R. Hudlicky et al.
LETTER
(5) For large-scale preparation (ca. 100-g scale) of this
subjected to the [5+2]-annulation protocol under the same
conditions employed with 21 the tetracyclic lactone 24
was detected to the tune of ca. 5% in a complex mixture
containing at least three other products. We will return to
the [5+2]-annulation issue with simpler model com-
pounds to establish the reason for such lack of reactivity
in vinylcyclopropanes in which one or the other moiety is
confined in a ring.
compound from cinnamyl aldehyde, see: (a) Petersen, R. J.;
Skell, P. S. Org. Synth. 1967, 47, 98. (b) Petersen, R. J.;
Skell, P. S. Org. Synth., Coll. Vol. V; Wiley: New York,
1973, 929.
(6) Bui, V. P.; Nguyen, M.; Hansen, J.; Baker, J.; Hudlicky, T.
Can. J. Chem. 2002, 80, 708.
(7) Beckwith, A. L. J.; Bowry, V. W. J. Am. Chem. Soc. 1994,
116, 2710.
(8) Finn, K. J.; Rochon, L.; Hudlicky, T. Tetrahedron:
Asymmetry 2005, 16, 3606.
(9) Hudlicky, T.; Boros, E. E.; Olivo, H. F.; Merola, J. S. J. Org.
Chem. 1992, 57, 1026.
In conclusion, preliminary investigations of cycloaddition
chemistry of the enzymatically derived dienylcyclopro-
pyl-cis-diol 6 were carried out.23 New optically pure de-
rivatives were obtained that can find utility in the
synthesis of annulated conduritol and conduramine deriv-
atives. The low reactivity of 21 and 23 in [5+2] cycload-
ditions will be revisited; our attempts constituted the first
example of this process with substrates in which one of
the moieties of vinylcyclopropane is constrained into a
ring.
(10) Ley, S. V.; Redgrave, A. J.; Taylor, S. C.; Ahmed, S.;
Ribbons, D. W. Synlett 1991, 741.
(11) (a) Pittol, C. A.; Pryce, R. J.; Roberts, S. M.; Ryback, G.;
Sik, V.; Williams, J. O. J. Chem. Soc., Perkin Trans. 1 1989,
1160. (b) Mahon, M. F.; Molloy, K.; Pittol, C. A.; Pryce,
R. J.; Roberts, S. M.; Ryback, G.; Sik, V.; Williams, J. O.;
Winders, J. A. J. Chem. Soc., Perkin Trans. 1 1991, 1255.
(12) Hudlicky, T.; Boros, C. H. Tetrahedron Lett. 1993, 34, 2557.
(13) (a) Hudlicky, T.; Olivo, H. F. Tetrahedron Lett. 1991, 32,
6077. (b) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am.
Chem. Soc. 1994, 116, 5108.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Experimen-
tal data for compounds 7, 8, 10, 11, 13, 14, 17–19, and 23, and 1H
NMR and 13C NMR spectra for compounds 8, 10, 12, 13, 14, 16–19,
and 23 are included.
(14) Fabris, F.; Collins, J.; Sullivan, B.; Leisch, H.; Hudlicky,
T. Org. Biomol. Chem. 2009, 7, 2619.
(15) (a) Marradi, M. Synlett 2005, 1195. (b) Ritter, A. R.; Miller,
M. J. Org. Chem. 1994, 59, 4602. (c) Zimmer, R.; Reissig,
H.-U. J. Org. Chem. 1992, 57, 339.
(16) Werner, L.; Machara, A.; Hudlicky, T. Adv. Synth. Catal.
Acknowledgment
2010, 352, 195.
(17) Hudlicky, J. R.; Werner, L.; Semak, V.; Simionescu, R.;
Hudlicky, T. Can. J. Chem. 2011, 89, 535.
(18) Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T. Angew.
Chem. Int. Ed. 2009, 48, 4229.
(19) Werner, L.; Hudlicky, J. R.; Wernerova, M.; Hudlicky, T.
Tetrahedron 2010, 3761.
(20) See, for example: (a) Mehta, G.; Ramesh, S. S. Can. J.
Chem. 2005, 83, 581. (b) Mehta, G.; Senaiar, R. S.; Bera,
M. K. Chem. Eur. J. 2003, 9, 2264. (c) Desjardins, M.;
Lallemand, M.-C.; Hudlicky, T.; Abboud, K. A. Synlett
1997, 728. (d) For a definition of cyclitol, conduritol, and
conduramine, see: Duchek, J.; Adams, D. R.; Hudlicky, T.
Chem. Rev. 2011, 111, 4223.
(21) For a recent review of the chemistry of vinylcyclopropanes,
see: Hudlicky, T.; Reed, J. W. Angew. Chem. Int. Ed. 2010,
49, 4864.
The authors are grateful to the following agencies for financial sup-
port of this work: Natural Sciences and Engineering Research
Council of Canada (NSERC) (Idea to Innovation and Discovery
Grants), Canada Research Chair Program, Canada Foundation for
Innovation (CFI), Ontario Innovation Trust (OIT), Research Corpo-
ration, Noramco, Inc., TDC Research, Inc., TDC Research Founda-
tion (fellowship to J.H.H), and Brock University. Dr. Razvan
Simionescu’s expertise in the structure elucidation of dimer 8 is gra-
tefully appreciated. Special thanks are also due to Dr. Ian Taschner
and David Adams for editing the experimental section.
References and Notes
(1) Endoma, M. A.; Bui, V. P.; Hansen, J.; Hudlicky, T. Org.
Process Res. Dev. 2002, 6, 525.
(2) (a) Gibson, D. T. Zentralbl. Bakt. 1976, 157. (b) Jeffrey,
A. M.; Yah, H. J. C.; Jerina, D. M.; Patel, T. R.; Davey, J. F.;
Gibson, D. T. Biochemistry 1975, 14, 575.
(22) For [5+2] annulation of vinylcyclopropanes with alkynes,
see: (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am.
Chem. Soc. 1995, 117, 4720. (b) Wender, P. A.; Claudia,
M.; Barzilay, C. M.; Dyckman, A. J. J. Am. Chem. Soc.
2001, 123, 179. (c) Liu, P.; Cheong, P. H.-Y.; Yu, Z.-X.;
Wender, P. A.; Houk, K. N. Angew. Chem. Int. Ed. 2008, 47,
3939. (d) Wender, P. A.; Sirois, L. E.; Stemmler, R. T.;
Williams, T. J. Org. Lett. 2010, 12, 1604.
(3) Hudlicky, T.; Reed, J. W. Synlett 2009, 685.
(4) For reviews on applications of these compounds to
synthesis, see: (a) Hudlicky, T.; Reed, J. W. Chem. Soc. Rev.
2009, 38, 3117. (b) Ref. 3 above. (c) Boyd, D. R.; Bugg,
T. D. H. Org. Biomol. Chem. 2006, 4, 181. (d) Johnson,
R. A. Org. React. (N.Y.) 2004, 63, 117. (e) Hudlicky, T.;
Gonzalez, D.; Gibson, D. T. Aldrichimica Acta 1999, 32,
35. (f) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe,
A. J. Chem. Rev. 1996, 96, 1195. (g) Hudlicky, T.; Reed, J.
W. In Advances in Asymmetric Synthesis, Vol. 1; Hassner,
A., Ed.; JAI Press: London, 1995, 271. (h) Brown, S. M.;
Hudlicky, T. In Organic Synthesis: Theory and
Applications, Vol. 2; Hudlicky, T., Ed.; JAI Press: London,
1993, 113.
(23) Selected Experimental Procedures
1-{4-Cyclopropyl-2,2-dimethyl-3a,4,7,7a-tetrahydro-
4,7-(epoxyimino)benzo[d][1,3]dioxol-8-yl}ethanone(12):
To a solution of diol 6 (0.50 g, 3.28 mmol) in 2,2-
dimethoxypropane was added a catalytic amount of p-
toluenesulfonic acid. After 5 min, the reaction was quenched
with the addition of solid NaHCO3 (100 mg). The reaction
mixture was then diluted with MeOH–H2O (4:1; 30 mL) and
sodium periodate (1.70 g, 8.13 mmol) was added in one
portion. The resulting solution was then cooled to 0 °C and
a solution of acetohydroxamic acid (0.61 g, 8.13 mmol) in
MeOH (30 mL) was added dropwise over 10 min. The
Synlett 2011, No. 19, 2891–2895 © Thieme Stuttgart · New York

LETTER
Explorations of [4+2] and [5+2] Cycloadditions of Dienylcyclopropane
2895
solution was allowed to warm to r.t. and the stirring was
Hz, 1 H), 5.90 (d, J = 8.1 Hz, 1 H), 5.20–5.28 (m, 1 H), 4.32
(dd, J = 6.6, 4.5 Hz, 1 H), 4.13 (d, J = 6.9 Hz, 1 H), 1.79 (s,
3 H), 1.13 (s, 7 H), 0.37–0.59 (m, 4 H). 13C NMR (75 MHz,
CDCl3): d = 171.2, 131.3, 131.0, 110.6, 79.9, 77.7, 73.3,
49.7, 25.7, 25.4, 21.5, 13.7, 1.1, 0.5. MS (EI+): m/z (%) =
265 (13), 250 (23), 207 (48), 178 (30), 135 (43), 123 (54),
118 (68), 107 (58), 91 (52), 85 (54). HRMS (EI+): m/z calcd
for C14H19NO4: 265.1314; found: 265.1317. Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22. Found: C, 62.92; H, 7.07.
N-{(3aS,4R,7S,7aS)-7-Cyclopropyl-7-hydroxy-2,2-
dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxol-4-
yl}acetamide (16): To a solution of oxazine 12 (248 mg,
0.94 mmol) in MeCN (7.5 mL) and distilled H2O (0.5 mL)
was added molybdenum hexacarbonyl (371 mg, 1.40 mmol)
in one portion. The resulting suspension was immersed in an
oil bath and heated to reflux. At reflux, the mixture changed
from a clear suspension to a black solution, which was
allowed to reflux for 2 h. Progress of the reaction was
monitored by TLC (EtOAc). After consumption of the
starting material was complete, the reaction mixture was
removed from the oil bath and allowed to cool to r.t. The
reaction mixture was then filtered through a plug of Celite
using EtOAc as the eluent and concentrated in vacuo.
The crude material was then purified via flash column
chromatography (EtOAc) to yield amido alcohol 16 (138
mg, 55%) as a white powder; Rf 0.29 (EtOAc); mp 189–192
°C (EtOAc); [a]20D –93.8 (c = 1.0, CHCl3). IR (CHCl3):
3404, 3009, 2511, 1661, 1512, 1415, 1382, 1243, 1064, 759
cm–1. 1H NMR (600 MHz, MeOD): d = 5.79 (d, J = 10.2 Hz,
1 H), 5.75 (dd, J = 10.2, 4.2 Hz, 1 H), 4.45 (td, J = 3.6, 1.2
Hz, 1 H), 4.27 (m, 2 H), 1.97 (s, 3 H), 1.43 (s, 3 H), 1.36 (s,
3 H), 1.19–1.26 (m, 1 H), 0.47–0.53 (m, 1 H), 0.35–0.47 (m,
3 H). 13C NMR (150 MHz, MeOD): d = 171.2, 133.9, 128.6,
108.3, 81.1, 76.9, 69.8, 48.8, 25.9, 23.8, 21.5, 16.3, –0.4,
–0.9. MS (FAB+): m/z (%) = 268 (5), 250 (85), 192 (49), 150
(98), 105 (26), 69 (70), 43 (100). HRMS (FAB+): m/z calcd
for C14H21NO4: 267.1471; found: 267.1471. Anal. Calcd for
C14H21NO4: C, 62.90; H, 7.92. Found: C, 63.01; H, 7.93.
continued for 17 h at r.t. After consumption of starting
material, the reaction mixture was filtered and concentrated
in vacuo. The oily residue was then diluted with EtOAc, and
the organic solution was washed with sat. aq. NaHCO3
followed by brine. The organic solution was dried over
MgSO4. The crude material was then purified by suction
column chromatography to yield oxazine 12 (0.65 g, 75%) as
an oil which slowly solidified.
Large-Scale Preparation of Oxazine 12:
Dimethoxypropane (15 mL) was cooled to 0 °C and a crystal
of p-TsOH was added. After 2 min diol 6 (5.0 g, 0.033 mol)
dissolved in acetone–EtOAc (15 mL) was added dropwise
over 5 min. TLC analysis indicated full conversion to
acetonide 7 accompanied by 5–10% of 2-cyclopropylphenol
resulting from aromatization of diol 6. The solution was
diluted with EtOAc (20 mL), washed once with 1 N NaOH
(3 mL), and added to a solution of NaIO4 (17.0 g, 0.081 mol,
2.5 equiv) in MeOH–H2O (4:1; 250 mL) cooled to 0 °C in
1-L Erlenmeyer flask. Acetohydroxamic acid (6.1 g, 0.081
mol, 2.5 equiv) dissolved in MeOH–H2O (4:1; 100 mL) was
added with vigorous stirring over 15 min. A thick white
precipitate formed immediately. The reaction mixture was
allowed to warm to r.t. over 1 h and the stirring was
continued for 1 h at r.t. at which time the mixture was
filtered, the precipitate was washed with EtOAc (200 mL)
and the solution was washed with brine (2 × 100 mL), sat.
NaHCO3 (2 × 100 mL), dried over Na2SO4, and evaporated.
The crude product, containing 5–10% of 2-cyclopropyl-
phenol, was purified by chromatography (silica, gradient
elution, hexane to hexane–EtOAc, 3:1) to furnish oxazine 12
(5.4 g, 64%) as an oil that slowly solidified. Repetition on
10-gram scale gave the oxazine (7.12 g, 57%).
Recrystallization from EtOAc–pentane gave white needles.
12: Rf 0.27 (hexane–EtOAc, 4:1); mp 44–46 °C (EtOAc–
pentane); [a]20D –20.5 (c = 1.0, CHCl3). IR (CHCl3): 3691,
3011, 2419, 1731, 1655, 1618, 1375, 1270, 1088, 1064, 760
cm–1. 1H NMR (300 MHz, CDCl3): d = 6.32 (dd, J = 8.0, 6.3
Synlett 2011, No. 19, 2891–2895 © Thieme Stuttgart · New York

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