Divergent and Concise Syntheses of Spiroisoxazolines: First Total Synthesis of 11-Deoxyfistularin-3

Article abstract of DOI:10.1002/ejoc.201500603

A divergent and concise base-promoted Dieckmann-type keto-ester condensation strategy is demonstrated to generate two unique spiro[cyclohexadiene-isoxazoline] moieties. The consecutive di-bromination-elimination-bromination of the corresponding spiro moiety has been successfully utilized to furnish the desired core structure of many bromotyrosine derived spiroisoxazoline natural products. The spiroisoxazoline acid was further coupled with the desired diamine to accomplish the first total synthesis of 11-deoxyfistularin-3. This strategy could serve as an efficient alternative to previously developed oxidative dearomatizing spirocyclization of phenol as the essential step to synthesize this class of natural products. A complementary route for spiroisoxazolines leads to the total synthesis of 11-deoxyfistularin-3.

Full text of DOI:10.1002/ejoc.201500603

FULL PAPER
DOI: 10.1002/ejoc.201500603
Divergent and Concise Syntheses of Spiroisoxazolines: First Total Synthesis of
11-Deoxyfistularin-3
Prasanta Das[a] and Ashton T. Hamme II*[a]
Keywords: Total synthesis / Natural products / Spiro compounds
A divergent and concise base-promoted Dieckmann-type
keto-ester condensation strategy is demonstrated to generate
two unique spiro[cyclohexadiene-isoxazoline] moieties. The
consecutive di-bromination–elimination–bromination of the
corresponding spiro moiety has been successfully utilized to
furnish the desired core structure of many bromotyrosine de-
rived spiroisoxazoline natural products. The spiroisoxazoline
acid was further coupled with the desired diamine to ac-
complish the first total synthesis of 11-deoxyfistularin-3. This
strategy could serve as an efficient alternative to previously
developed oxidative dearomatizing spirocyclization of
phenol as the essential step to synthesize this class of natural
products.
diverse range of amine and diamine spacers attached to the
spiroisoxazolines. Owing to the diverse biological activity
along with structural diversity, the synthesis of this unique
and challenging spiro-skeleton has been of great interest to
many chemists.[15,16]
Introduction
The natural occurrence and the discovery of new syn-
thetic agents displaying antineoplastic activity are impor-
tant topics of research in medicinal chemistry.[1] Since the
first reports pertaining to the herbicidal and plant hor-
monal activity,[2] spiroisoxazoline containing natural prod-
ucts and their analogues have stimulated a great deal of
interest in biomedicinal chemistry.[3] Among the broad
spectrum of α-oximinotyrosine derived natural products
isolated from marine sponges, in particular 11-deoxy-
fistularin-3 (1),[4a] purealidin P (6),[4b] and Q (7)[4d] are cyto-
Hitherto, the most reported synthetic methodology to
this class of natural products fundamentally relies on classi-
cal aromatic oxidation.[16a,16b,16c,16d] Since the first synthesis
of spiroisoxazolines via oxidative dearomatization achieved
by a toxic metal[16a,16b] and electroorganic oxidation,[16c,16d]
further modification was also reported using other oxidiz-
ing agents (NBS, and PIDA)[16f,16j] shortly thereafter. How-
ever, the oxidative methods for spiroisoxazoline synthesis
remain restricted to aromatic systems with moderate iso-
lated yields, and often required the use of toxic metallic
based oxidants.[16a–16d] However, the oxidative cyclization
of oxime esters using diacetoxyiodosobenzene was proven
to be the most suitable oxidation reagent for phenolic α-
oximino ester to date.[16e,16g–16i] Very recently we also re-
ported an efficient and alternative process to access spiro-
isoxazoline core structures as a model study toward this
family of natural products.[17]
The rich background for the synthesis of the challenging
spiroisoxazoline moiety, in conjunction with their potential
as precursors to a range of alkaloid derivatives with diverse
biological activity, stimulated our desire to develop a new
synthetic route for this unique spiro-moiety. Having experi-
enced the efficacy of our multifunctionalization approach
towards model spiroisoxazoline core structures,[17] we fo-
cused on synthesizing the appropriate functionalized syn-
thetic precursors, which would allow us to access the natu-
ral product. In this paper, we further exploit our preceding
approach[17] to accomplish the first total synthesis of 11-
deoxyfistularin-3 (1) (Figure 1). This synthetic approach
also facilitates the construction of a new class of spiroisox-
toxic against the MCF-7 breast cancer cell line (LD50
=
17 μg/L),[4a] murine lymphoma K1210 (IC50 2.8 and 0.95 μg
mL–1, respectively),[4b] and human epidermal carcinoma
KB (nasopharynx) (IC50 7.6 and 1.2 μg mL–1, respective-
ly)[4d] cell lines (Figure 1). The other members from the
same family are also widely known for their diverse phar-
macological activities including antiviral,[5] antimicrobial,[6]
anti-HIV,[7] antifungal,[8] antifouling,[9] Na+/K+ ATPase in-
hibition,[10] HDAC inhibition,[11] histamine H3 antago-
nism,[12] mycothiol S-conjugate amidase inhibition,[13] and
isoprenylcysteine carboxymethyl transferase (Icmt) inhibi-
tion.[14] The distinguishable molecular diversity arises due
to several prominent structural features including; (a)
brominated spiroisoxazoline core that contains a cyclohexa-
diene, a bromo epoxy ketone, or a bromohydrin moiety, (b)
the R or S absolute stereochemistry of the spiro stereogenic
center of spiroisoxazoline amide core, (c) the presence of a
[a] Department of Chemistry & Biochemistry, Jackson State
University,
Jackson, MS 39217, USA
E-mail: ashton.t.hamme@jsums.edu
http://www.jsums.edu/chemistry/ashton-t-hamme-ii/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500603.
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Figure 1. Spiroisoxazoline natural products.
azolines which could be beneficial in producing a library of
spiroisoxazoline analogues of potential biological interest.
The execution of our synthetic strategy commenced with
the key intermediate keto ester derivative 14 (Scheme 2).
The racemic isoxazoline precursor containing the keto ester
could be regioselectively synthesized by means of a 1,3-di-
polar cycloadition of an in situ generated nitrile oxide from
the corresponding chloro oximidoacetate or a base-cata-
lyzed reaction of methyl nitroacetate with a 2-substituted
methyl vinyl ketone 15.[17] In our case the 1,3-dipolar cyclo-
addition with chlorooximido acetate favored the dimerized
furoxan over the required isoxazoline 14. On the other hand
1,3-dipolar cycloaddition with methyl nitro acetate afforded
the desired isoxazoline in poor yield with the α,β-unsatu-
rated ketone and is consistent with the literature observa-
tions.[18] Therefore, we pursued a two step conventional
Results and Discussion
The retrosynthetic analysis in Scheme 1 depicts our strat-
egy for the spiroisoxazoline core of the targeted natural
product as well as an isomeric spiroisoxazoline. Our unique
synthetic design highlights a convergent strategy that uti-
lizes a 1,3-dipolar cycloaddition which would immediately
establish the tertiary isoxazoline 14 thereby positioning the
two complementary functional groups for a subsequent in-
tramolecular annulation. After a Dieckmann-like conden-
sation, a divergent pathway would be followed to generate
two regioisomeric enolates.
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthesis of spiro-methoxyenone.
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Divergent and Concise Syntheses of Spiroisoxazolines
method to facilitate the 1,3-dipolar cycloaddition. As
The zinc mediated chelate controlled intramolecular
shown in Scheme 2, the methyl vinyl ketone derivative 15 hydride delivery[20] favored the trans isomer 19 over cis iso-
was reduced under Luche reaction conditions[18b] to afford mer 20. The relative configurations of diastereomers 19 and
the allylic alcohol 16 as a racemic mixture in 78% yield. 20 were assigned using H and 13C NMR which were con-
1
Based on a recently described method,[18b] the base-cata- sistent with literature data[16a] Accomplishing the synthesis
lyzed condensation between methyl nitroacetate and the all- of the known spiroisoxazoline ketone 9 and alcohol 19 also
ylic alcohol 16 afforded the desired isoxazoline 17 as a facilitated the formal syntheses of aerophobin-1,[16b] aero-
syn/anti mixture in 99% yield. Subsequent allylic oxidation thionin,[16a] homoaerothionin,[16k] aeroplysinin-1,[21] (Ϯ)-
with PCC/Al2O3 afforded δ-keto ester 14 in 92% yield, purealin A,[22] calafianin,[23] subereamollines A and B[16e]
which was followed by sodium methoxide promoted intra- through previously developed routes.
molecular cyclization, and in situ methylation of the corre-
While isomer 11 was employed as a suitable precursor
sponding enolates with methylsulfate to gave rise to the for the synthesis of the desired spiroisoxazoline, the minor
spiro-methoxy ketone 11 and to 13 in 86% yield in a 2.4:1 isomer 13 generated a new class of dibromo spiro-quinone
regioisomeric ratio (Scheme 2).
resembling derivative 12 through following a similar set of
Owing to the fact that both regioisomers 11 and 13 were reactions as shown in Scheme 4. It was anticipated that
isolated, divergent synthetic pathways were explored where enolate formation followed by mono and dibromination of
spiroisoxazoline 11 was utilized as a precursor for the natu- the minor isomer 13 would be more facile than 11 due to
ral product core structure, while spiroisoxazoline 13 was de- the presence of a more acidic proton of 13 in contrast to
veloped into a spiroisoxazoline that is more comparable to the less acidic allylic proton for major isomer 11. Upon se-
the other classes of natural products such as calafianin, quential treatment of 13 with LHMDS and Br2, a DABCO-
agelorin A and B (Figure 1) where the carbonyl and isox- mediated elimination afforded the desired mono-bromo
azoline moieties have a 1,4-relationship.
quinone derivative 22 in 70% yield. Further bromination
Based upon our experience in a model spiroisoxazoline using PTB/K2CO3 provided the desired α-dibromo quinine-
synthesis,[17] the major methoxyenone isomer 11 was ex- like derivative 12 in 82% yield (Scheme 4).
posed to excess LHMDS (2.5 equiv.) at –78 °C and bromine
(2.5 equiv.). From this reaction sequence, we realized the
formation of allylic geminal dibromo compound 18
(Scheme 3). At this stage, the expected dibromo derivative
18 was treated in situ with DABCO under reflux reaction
conditions to afford the mono-bromo eliminated product
10 in 68% yield. Further bromination adjacent to the carb-
onyl was achieved with NBS/CH2Cl2 to afford compound
9 in 75% yield (Scheme 3). Finally, diastereoselective re-
[19]
duction of 9 with Zn(BH4)2
afforded the desired spiro-
isoxazoline core structures (Ϯ)-19 and (Ϯ)-20 in a 2.5:1 dia-
stereomeric ratio in 76% yield (Scheme 3).
Scheme 4. Synthesis of dibromo-spiroquinone.
Herein we must emphasize that this approach also en-
couraged us to develop a new class of synthetic analogues
for future biological investigation; however, this article’s pri-
mary focus is on the first total synthesis of 11-deoxy-
fistularin-3.
Having accomplished the precise construction of core
unit 19, we subsequently directed our attention toward the
most effective way to synthesize the required diamine spacer
26 for further coupling. The targeted diamine is also well
known as hydroxymoloka‘i-amine (26) which was isolated
from the Red Seasponge Pseudoceratna arabica as a brom-
inated metabolite.[24] Even though the first total synthesis
of racemic hydroxymoloka‘i-amine (26), was reported[25] by
Ullah in six steps, herein we report an alternative and
straight forward synthetic strategy for the synthesis of 26
Scheme 3. Synthesis of dibromo-spiroisoxazoline.
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from commercially available (Ϯ)-octopamine 23 as a start-
ing material (Scheme 5). According to literature pre-
cedent,[26] consecutive dibromination of 23 with bromine in
hydrochloric acid at room temp., and protection of the free
amine as its –NHBoc by treatment with (Boc)2O and 10%
NaOH, provided the 3,5-dibromo derivative 24 with an
overall yield of 81% for the two steps. Through following a
similar protocol,[26] the aromatic O-alkylation of 24 with
tert-butyl (3-chloropropyl)carbamate using potassium carb-
onate and potassium iodide in (Me)2CO/MeCN (1:1) at re-
flux temperature produced the di-Boc-protected diamine 25
in 95% yield. Finally, both of the Boc groups in 25 were
deprotected with 50% trifluoroacetic acid (TFA) in CH2Cl2
to obtain the hydroxymoloka‘i-amine (26) in 97% yield,
and an overall yield of 75% (Scheme 5).
Scheme 6. Total synthesis of 11-deoxyfistularin-3.
ferentiating the diastereomers where the stereocenters are
remote. The desired structure of the final product 1 was
further corroborated with HRMS which shows the presence
of three isotopic peaks at m/z 1118.6898, 1120.6882 and
1122.6857.
Conclusions
We successfully synthesized the spiro-methoxyenones as
key precursors for further functional group transformation
to furnish the desired spiro[cyclohexadiene-isoxazoline]
core moieties 11 and 13 and developed an alternative path-
way for the synthesis of hydroxymoloka‘i-amine (26). The
major isomer 11 was not only employed for the formal syn-
thesis of few of the spiroisoxazoline natural products, it was
also successfully utilized for the first total synthesis of the
natural product 11-deoxyfistularin-3 as well. The minor iso-
mer 13 was in addition converted into its regioisomeric di-
bromo-spiroisoxazoline moiety resembling the agelorin and
calafianin natural product cores which also provides an op-
portunity to investigate the biological activity of this class
of spiroisoxazolines in near future.
Scheme 5. Synthesis of hydroxymoloka‘i-amine (26).
Having in hand the coupling partners, we then executed
our final set of reactions to furnish the desired natural
product. In doing so, ester 19 was first hydrolyzed with
LiOH-MeOH to afford the corresponding carboxylic acid
27 which was further coupled with diamine 26 with ®T3P
in CH2Cl2[16e] to afford (Ϯ)-11-deoxyfistularin-3 (1) in 75%
yield as an inseparable diastereomeric mixture (Scheme 6).
The structural characterization of the final product was
1
confirmed by H and 13C NMR spectroscopy (in CDCl3
and [D5]pyridine), and HRMS. The 1H NMR chemical
shifts of the two characteristic amide protons for 1 are δ =
7.12 and 6.99 ppm in CDCl3, whereas in [D5]pyridine both
Experimental Section
General Considerations: All the reactions mentioned above were
performed in standard oven-dried glassware under an inert atmo-
which are consistent with the H NMR resonances for the sphere of nitrogen. HPLC grade CH2Cl2, commercial grade EtOH
of the amide protons shifted to δ = 9.78 and 9.32 ppm
1
isolated natural 11-deoxyfistularin-3 (1).[4a] It is worth not-
and deionized water were used as a solvent. All reagents were used
as supplied without prior purification unless otherwise stated. The
ing that upon combining three racemic building blocks (the
progression of the reaction was monitored by analytical thin-layer
hydroxyphenylamine and two chiral spiroisoxazolines),
would result in four possible diastereomeric combinations
(each as a racemate). However the observed results and
chromatography using 60 Å silica gel medium and 250 μm layer
thickness, and compounds were visualized by 254 nm light, a mix-
ture of iodine and silica gel, and basic KMnO4 (20 g of K2CO3 +
NMR studies indicated the presence of a single dia-
3 g of KMnO4 in 300 mL of water, then 2.5 mL of 10% NaOH
stereomer. It is reported that the possibility of diastereomer
discrimination by NMR spectroscopy generally depends on
the number of bonds between the chiral centers.[27,28] As a
added) and subsequent development either no or gentle heating.
Purifications by flash column chromatography were performed
using flash silica gel (60 Å, 0.060–0.200 mm) with the indicated elu-
result, NMR spectroscopy was incapable of effectively dif- ent.
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Divergent and Concise Syntheses of Spiroisoxazolines
1H NMR and 13C NMR spectra were recorded in 500 MHz and 28.1, 27.9, 16.8, 16.7, 13.9 ppm. HRMS (ESI): m/z calcd. for
125 MHz, respectively. All NMR spectra were measured at 25 °C
in the indicated deuterated solvents. Proton and carbon chemical
shifts (δ) are reported in ppm, and coupling constants (J) are re-
C12H19NO6Na [M + Na+]: 296.1104, found 296.1105.
Methyl 5-Acetyl-5-(4-ethoxy-3,4-dioxobutyl)-4,5-dihydroisoxazole-
3-carboxylate (14): PCC/Al2O3 (3 equiv.) was added to a solution
of (Ϯ)-syn/anti-17 (4.7 g, 17.2 mmol, 1 equiv.) in CH2Cl2 (75 mL),
and the reaction mixture was stirred at reflux temperature for 24 h.
The PCC was filtered through Celite, washed with CH2Cl2, and the
combined organic solvent was evaporated under reduced pressure.
The crude ketone was purified by silica gel column chromatography
using 15% ethyl acetate in hexanes to afford 14 as colorless oil
(4.28 g, 92%). Rf = 0.79 (50% ethyl acetate in hexanes). IR (KBr):
1
ported in Hertz [Hz]. The resonance multiplicities in the H NMR
spectra are described as “s” (singlet), “d” (doublet), “t” (triplet),
and “m” (multiplet), and broad resonances are indicated by “br.”.
The residual protic solvent of CDCl3 (1 H, δ = 7.26 ppm; 13C, δ =
77.0 ppm) (central resonance of the triplet), and [D4]CD3OD (1 H,
δ = 3.34 ppm; 13C, δ = 49.9 ppm) were used as the internal refer-
1
ences in the H and 13C NMR spectra. Melting points are uncor-
rected. Fourier transform infrared (FTIR) spectra were measured
on neat NaCl. The absorptions are given in wave numbers (cm–1).
High-resolution mass spectrometry (HRMS) analyses were per-
formed on the basis of positive electrospray ionization on a Bruker
12 Tesla APEX – Qe FTICR-MS with and Apollo II ion source.
Either protonated molecular ions [M + nH]n+ or sodium adducts
[M + Na]+ were used for empirical formula confirmation.
ν = 3022, 2984, 2957, 1731, 1595, 1444, 1379, 1264, 1216, 1122,
˜
1926, 767 cm–1. 1H NMR (500 MHz, CDCl3): δ = 4.06 (q, J =
7.1 Hz, 2 H), 3.82 (s, 3 H), 3.46 (d, J = 18.5 Hz, 1 H), 3.00 (d, J =
18.5 Hz, 1 H), 2.30–2.21 (m, 6 H), 2.12–2.06 (m, 1 H), 1.18 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 207.2, 171.8,
160.1, 151.3, 95.5, 60.8, 52.8, 40.0, 30.5, 28.3, 25.3, 14.0 ppm.
HRMS (ESI): m/z calcd. for C12H17NO6Na [M + Na+]: 294.09480,
found 294.09487.
Ethyl 6-Hydroxy-5-methylene-2-oxoheptanoate (16): Sodium
borohydride (2.22 g, 57.75 mmol) was added to a solution of keto
ester 15[17] (10 g, 57.75 mmol) and cerium chloride (8.6 g,
23.08 mmol) in MeOH (60 mL) at 0 °C portion wise under N2 me-
dium. The resultant mixture was allowed to stir at this temperature
for 30 min. The TLC analysis showed the complete consumption
of starting material. Then the reaction mixture was quenched with
1 n HCl carefully, and methanol was removed under reduced pres-
sure. The residue was extracted with ethyl acetate and washed with
water, brine and dried with MgSO4 and filtered. The filtrate was
evaporated under reduced pressure. The crude allylic alcohol was
purified by silica gel column chromatography using 10% ethyl acet-
ate in hexanes as an eluent to provide the pure alcohol 16 as oil
(7.78 g, 78% yield). Rf = 0.58 (1:1ethyl acetate/hexanes). IR (thin
General Method for Intramolecular Cyclization/Methylation: To a
solution of NaOMe (304 mL, 0.5 m in methanol) under N2 atmo-
sphere, was added drop wise a solution of ketone 14 (5.17 g,
19.06 mmol) in dry MeOH (20 mL) at room temp. The resulting
mixture was heated to reflux for 3 h. TLC analysis showed the con-
sumption of ketone and formation of very polar compound (cyclic
enolate). Then the reaction mixture was cooled and solvent was
removed under reduced pressure. To the residue was added dry
CH2Cl2 (100 mL), and Me2SO4 (6.0 g, 47.65 mmol) was added
slowly, and the reaction mixture was further refluxed for 24 h. After
the reaction was complete, NH4OH (3 mL) was added, and the
mixture was stirred for 30 min to 3 h. The reaction mixture was
washed with water (3ϫ 100 mL), and the organic layer was dried
with anhydrous MgSO4 and filtered. The filtrate was concentrated
under reduced pressure and the crude mixture was purified by silica
gel column chromatography using 30% ethyl acetate in hexanes as
an eluent to afford methoxyenone 11 (2.93 g, 61% yield) and 13
(1.22 g, 25% yield) as a 2.4:1 regioisomeric ratio in 86% isolated
yield.
layer): ν = 3421, 2980, 2933, 2909, 1733, 1372, 1159, 1106, 904,
˜
1
758 cm–1. H NMR (500 MHz, CDCl3): δ = 5.01 (s, 1 H), 4.72 (s,
1 H), 4.22 (br., m, 1 H), 4.10–4.05 (m, 2 H), 2.60 (br., s, 1 H -OH),
2.47 (t, J = 7.2 Hz, 2 H), 2.42–2.36 (m, 1 H), 2.31–2.25 (m, 1 H),
1.25–1.18 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.5,
151.5, 108.8, 70.8, 60.5, 32.8, 26.0, 22.0, 14.2 ppm. HRMS (ESI):
m/z calcd. for C9H16O3Na [M + Na+]: 195.0992, found 195.0992.
Methyl
8-Methoxy-6-oxo-1-oxa-2-azaspiro[4.5]deca-2,7-diene-3-
carboxylate (11): Rf = 0.57 (50% ethyl acetate in hexanes). IR (thin
Methyl 5-[2-(Ethoxycarbonyl)ethyl]-4,5-dihydro-5-(1-hydroxyethyl)-
isoxazole-3-carboxylate (17): A solution of allylic alcohol 16 (3.0 g,
17.4 mmol), methyl nitroacetate (5.18 g, 43.5 mmol) and DABCO
(0.390 g, 3.48 mmol) in methanol (50 mL) was heated at 80 °C for
five days in a sealed tube. The organic solvent was evaporated un-
der reduced pressure and the mixture of diastereoisomers
(Ϯ)syn/anti-17 was purified by silica gel column chromatography
using 30% ethyl acetate in hexanes as an eluent to afford the com-
pound as a colorless oil 17 (4.71 g, 99% yield). The ratio (Ϯ)-
syn:anti (1:1) was determined by means of the integration of the
doublet relative to the methyl groups at 1.17 and 1.22 d, respec-
tively, in the 1H NMR spectroscopy. Rf = 0.53 (1:1 ethyl acetate/
film): ν = 3020, 2956, 2927, 2853, 1732, 1655, 1602, 1444, 1384,
˜
1
1256, 1215, 930, 753, 668 cm–1. H NMR (500 MHz, CDCl3): δ =
5.49 (s, 1 H), 3.94 (d, J = 17.6 Hz, 1 H), 3.88 (s, 3 H), 3.75 (s, 3
H), 2.93–2.87 (m, 1 H), 2.84 (d, J = 17.6 Hz, 1 H), 2.42–2.33 (m,
2 H), 2.10–2.04 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
190.1, 178.8, 160.7, 151.0, 100.6, 88.4, 56.1, 52.8, 39.2, 31.7, 25.7
ppm. HRMS (ESI): m/z calcd. for C11H13NO5Na [M + Na+]:
262.0686, found 262.0685.
Methyl
6-Methoxy-8-oxo-1-oxa-2-azaspiro[4.5]deca-2,6-diene-3-
carboxylate (13): Rf = 0.21 (50% ethyl acetate in hexanes). IR (thin
film): ν = 3019, 2957, 2927, 2855, 1727, 1662, 1615, 1460, 1375,
˜
1
1269, 1215, 929, 761 cm–1. H NMR (500 MHz, CDCl3): δ = 5.45
hexanes). IR (thin layer): ν = 3481, 3020, 2983, 2953, 1733, 1445,
˜
(s, 1 H), 3.90 (s, 3 H), 3.74–3.71 (m, 4 H), 3.02 (d, J = 17.8 Hz, 1
H), 2.79–2.72 (m, 1 H), 2.43–2.35 (m, 2 H), 2.19–2.13 (m, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 197.3, 170.4, 160.6, 150.8,
104.5, 97.0, 56.5, 52.9, 41.1, 33.6, 33.3 ppm. HRMS (ESI): m/z
calcd. for C11H13NO5Na [M + Na+]: 262.0685, found 262.0685.
1372, 1267, 1216, 1123, 935, 767 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 4.14 (qd, J = 4.9, 7.1 Hz, 4 H), 3.99 (q, J = 6.51 Hz,
1 H), 3.88 (s, 6 H), 3.82 (q, J = 6.51 Hz, 1 H), 3.39 (d, J = 17.9 Hz,
1 H), 3.26 (d, J = 18.3 Hz, 1 H), 2.91 (d, J = 18.3 Hz, 1 H), 2.80
(d, J = 17.9 Hz, 1 H), 2.78 (br. s, 1 H, -OH), 2.64 (br. s, 1 H, -OH),
2.49–2.42 (m, 1 H), 2.40–2.32 (m, 3 H), 2.29–2.23 (m, 1 H), 1.99–
1.92 (m, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H),
Methyl 7-Bromo-8-methoxy-10-oxo-1-oxa-2-azaspiro[4.5]deca-2,6,8-
triene-3-carboxylate (10): To a previously cooled (–78 °C) solution
1.22 (d, J = 6.5 Hz, 3 H), 1.17 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR of 11 (0.27 g, 1.06 mmol) in anhydrous THF (10 mL) was added
(125 MHz, CDCl3): δ = 173.2, 172.6, 160.7, 160.6, 151.5, 151.3, slowly a solution of LHMDS (2.7 mL, 1 m in THF). The resulting
95.7, 93.9, 70.1, 69.5, 60.7, 60.6, 52.61, 52.6, 38.5, 36.3, 30.8, 29.3, solution was warmed to –10 °C over a period of 1 h. After re-cool-
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P. Das, A. T. Hamme II
FULL PAPER
ing to –78 °C, bromine (0.140 mL, 1.41 mmol) was added slowly to
the reaction mixture. The solution was warmed to 0 °C over a
period of 30 min. TLC observation showed the formation of less
polar bromo intermediate. Once this conversion was complete,
DABCO (0.3 g, 2.67 mmol) was added to the reaction mixture, and
the resulting mixture was refluxed for 3 h. After the disappearance
of the less polar material, as evidenced by TLC, the reaction mix-
ture was diluted with EtOAc (50 mL) and washed with H2O, brine,
dried with MgSO4 and concentrated in vacuo. The crude mixture
was purified by flash column over silica gel using 20% ethyl acetate
in hexanes as an eluent to afford 10 (0.229 g, 68% yield) as a yellow
18.1 Hz, 1 H), 3.28 (d, J = 18.1 Hz, 1 H), 2.39 (d, J = 9.1 Hz, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 106.2, 151.7, 148.1, 129.8,
122.8, 112.9, 90.2, 74.7, 60.2, 53.0, 43.0 ppm. HRMS (ESI): m/z
calcd. for C11H11Br2NO5Na [M + Na+]: 417.8896, found 417.8896.
Methyl 9-Bromo-6-methoxy-8-oxo-1-oxa-2-azaspiro[4.5]deca-2,6,9-
triene-3-carboxylate(22): To a previously cooled (–78 °C) solution
of 13 (0.143 g, 0.564 mmol) in anhydrous THF (5 mL) was added
slowly a solution of LHMDS (1.41 mL, 1M in THF). The resulting
solution was warmed to –10 °C over a period of 1 h. After re-cool-
ing to –78 °C, bromine (0.10 mL, 1.41 mmol) was added slowly to
the reaction mixture. The solution was warmed to 0 °C over a
period of 30 min. TLC observation showed the formation of a less
polar bromo intermediate. Once this conversion was complete,
DABCO (0.158 g, 1.41 mmol) was added to the reaction mixture,
and the resulting mixture was refluxed for 3 h. After disappearance
of the less polar material, as evidenced by TLC, the reaction mix-
ture was diluted with EtOAc (50 mL) and washed with H2O
(10 mL), brine, dried with MgSO4 and concentrated in vacuo. The
crude mixture was purified by flash column over silica gel using
35% ethyl acetate in hexanes as an eluent to afford 22 (0.124 g,
70% yield) as a yellow oil. Rf = 0.53 (50% ethyl acetate in hexanes).
oil. R = 0.64 (50% ethyl acetate in hexanes). IR (thin film): ν =
˜
f
3020, 2954, 2926, 2852, 1732, 1661, 1573, 1442, 1372, 1256, 1212,
1
1131, 1006, 909, 759 cm–1. H NMR (500 MHz, CDCl3): δ = 7.06
(s, 1 H), 5.72 (s, 1 H), 3.93 (s, 3 H), 3.82 (s, 3 H), 3.60 (d, J =
18.0 Hz, 1 H), 3.34 (d, J = 18.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 178.4, 169.7, 159.8, 150.4, 139.8, 126.3,
101.5, 85.0, 56.7, 53.2, 42.7 ppm. HRMS (ESI): m/z calcd. for
C11H10BrNO5Na [M + Na+]: 337.9634, found 337.9634.
Methyl 7,9-Dibromo-8-methoxy-10-oxo-1-oxa-2-azaspiro[4.5]deca-
2,6,8-triene-3-carboxylate (9): To
a solution of 10 (0.140 g,
0.44 mmol) in CH2Cl2 (5 mL) was added NBS (0.158 g,
0.88 mmol), and the resulting mixture was stirred for 24 h at room
temp. in absence of light. Completion of the reaction was moni-
tored by TLC analysis. The reaction mixture was then diluted with
CH2Cl2 (10 mL) and washed with H2O (50 mL), saturated Na2S2O3
(2ϫ 50 mL), brine, dried with MgSO4 and concentrated under re-
duced pressure. The crude product was purified by flash column
over silica gel using 15% ethyl acetate in hexanes as an eluent to
afford 9 (0.130 g, 75% yield) as a yellow oil. Rf = 0.60 (1:1 hexanes/
IR (thin film): ν = 3019, 2955, 2926, 2853, 1732, 1664, 1603, 1443,
˜
1374, 1260, 1215, 767 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.06
(s, 1 H), 5.72 (s, 1 H), 3.93 (s, 3 H), 3.82 (s, 3 H), 3.60 (d, J =
18.0 Hz, 1 H), 3.34 (d, J = 18.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 178.4, 169.7, 159.8, 150.4, 139.8, 126.3,
101.5, 85.0, 56.7, 53.2, 42.7 ppm. HRMS (ESI): m/z calcd. for
C11H10BrNO5Na [M + Na+]: 337.9634, found 337.9637.
Methyl 7,9-Dibromo-6-methoxy-8-oxo-1-oxa-2-azaspiro[4.5]deca-
2,6,9-triene-3-carboxylate (12):
A
solution of 22 (0.05 g,
EtOAc). IR (thin film): ν = 3020, 2949, 2924, 2852, 1733, 1604,
˜
1543, 1457, 1216, 1131, 909, 758 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 6.77 (s, 1 H), 4.18 (s, 3 H), 3.91 (s, 3 H), 3.62 (d, J =
17.8 Hz, 1 H), 3.29 (d, J = 17.8 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 188.6, 163.2, 159.7, 149.9, 135.8, 120.9,
106.7, 86.8, 62.1, 53.1, 44.4 ppm. HRMS (ESI): m/z calcd. for
C11H9Br2NO5Na [M + Na+]: 415.8739, found 415.8739.
0.158 mmol) and K2CO3 (0.043 g, 0.316 mmol) in 2 mL of dry
dichloromethane was stirred in an ice-water bath. Pyridinium tri-
bromide (0.101 g, 0.316 mmol) was added slowly to the cold mix-
ture. The reaction mixture was stirred for 2 h at 0 °C, and was al-
lowed to slowly warm to room temp. overnight. The reaction mix-
ture was stirred at room temp. until the disappearance of the start-
ing materials, as evidenced by TLC. The reaction mixture was
poured into a cold, saturated NH4Cl solution (10 mL), extracted
with ethyl acetate (3ϫ 20 mL), and washed with saturated CuSO4
solution (3ϫ 20 mL). The organic layer was dried with MgSO4,
filtered, and concentrated under reduced pressure. The crude prod-
ucts were purified by flash column chromatography over silica gel
using 15% ethyl acetate in hexanes as an eluent to obtain the pure
compound 12 as yellow solid (0.051 g, 82% yield). Rf = 0.63(40%
General Method for Zn(BH4)2 Reduction: To a stirred solution of 9
(0.140 g, 0.356 mmol) in CH2Cl2 (5 mL) at room temperature un-
der N2 atmosphere, was added a freshly prepared solution of
Zn(BH4)2 (1.0 mL, 0.25 m in Et2O).[19] After 10 min, H2O (0.5 mL)
was added, and the reaction mixture was stirred for a further
30 min. Following the addition of anhydrous MgSO4, the mixture
was filtered and concentrated in vacuo. The crude residue was puri-
fied carefully by flash column chromatography over silica gel using
16% ethyl acetate in hexanes to obtain (Ϯ)-19 (0.077 g, 55% yield)
and (Ϯ)-20 (0.030 g, 21% yield) in 2.5:1 diastereomeric ratio. The
stereochemical assignments for both isomers were confirmed based
ethyl acetate in hexanes), m.p. 140–142 °C. IR (KBr): ν = 3015,
˜
2955, 2926, 2854, 1733, 1593, 1457, 1263, 1215, 1139, 759 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 7.13 (s, 1 H), 4.16 (s, 3 H), 3.94 (s,
3 H), 3.65 (d, J = 18.1 Hz, 1 H), 3.34 (d, J = 18.1 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 173.5, 166.8, 159.6, 150.9, 140.6,
123.8, 108.3, 87.8, 62.6, 53.2, 42.3 ppm. HRMS (ESI): m/z calcd.
for C11H9Br2NO5Na [M + Na+]: 415.8739, found 415.8746.
1
upon the H and 13C NMR which were consistent with literature
data.[16a]
Methyl 7,9-Dibromo-10-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]-
deca-2,6,8-triene-3-carboxylate (19): Rf = 0.53 (40% ethyl acetate
in hexanes). H NMR (500 MHz, CDCl3): δ = 6.34 (s, 1 H), 4.47
tert-Butyl [2-(3,5-Dibromo-4-hydroxyphenyl)-2-hydroxyethyl]carb-
amate (24):[26] To a solution of racemic octopamine 23 (0.5 g,
2.63 mmol) in distilled H2O (4 mL) was added 6 n HCl (4 mL), and
the mixture was cooled to 5 °C. Bromine (0.5 mL, 8.9 mmol) was
then injected into the stirred solution. The reaction was performed
in 1 h and then dried in vacuo. The mixture was then basified with
NaOH 10% (7 mL), and Boc2O (0.651 g, 3.156 mmol) was added
with stirring at room temp. for 30 min. The solvent was removed
1
(d, J = 5.6 Hz, 1 H), 3.93 (d, J = 18.3 Hz, 1 H), 3.90 (s, 3 H), 3.76
(s, 3 H), 2.98 (d, J = 18.3 Hz, 1 H), 2.28 (d, J = 5.9 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 106.3, 151.5, 148.2, 130.9, 121.2,
112.3, 92.1, 73.8, 60.1, 52.9, 38.6 ppm. HRMS (ESI): m/z calcd.
for C11H11Br2NO5Na [M + Na+]: 417.8896, found 417.8895.
Methyl 7,9-Dibromo-10-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]-
deca-2,6,8-triene-3-carboxylate (20): Rf = 0.45 (40% ethyl acetate in vacuo, and the residue was subjected to purified by silica gel
1
in hexanes). H NMR (500 MHz, CDCl3): δ = 6.36 (s, 1 H), 4.42 column chromatography using 3% MeOH/CH2Cl2 to afford 24
(d, J = 9.0 Hz, 1 H), 3.90 (s, 3 H), 3.77 (s, 3 H), 3.46 (d, J =
(0.651 g, 81% yield in two steps). Rf = 0.74 (10% MeOH in
5164
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5159–5166

Divergent and Concise Syntheses of Spiroisoxazolines
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 7.46 (s, 2 H), 5.91 (s,
2 H), 4.87–4.81 (m, 1 H), 4.42 (d, J = 7.7 Hz, 2 H), 4.10 (t, J =
4.9 Hz, 2 H), 3.95 (d, J = 18.3 Hz, 2 H), 3.76 (s, 3 H), 3.75 (s, 3
1 H), 4.92 (s, 1 H), 4.75 (s, 1 H), 3.56 (s, 1 H), 3.43 (d, J = 10.8 Hz,
1 H), 3.22–3.17 (m, 1 H), 1.45 (s, 9 H) ppm. 13C NMR (125 MHz, H), 3.71–3.69 (m, 3 H), 3.65 (br. m, 1 H), 3.02 (d, J = 18.5 Hz, 1
CDCl3): δ = 157.3, 148.7, 136.5, 129.5, 109.9, 80.3, 72.7, 48.5, 28.3 H), 3.00 (d, J = 18.6 Hz, 1 H), 2.13–2.09 (m, 2 H) ppm. 13C NMR
ppm.
(125 MHz, CDCl3): δ = 159.06, 159.03, 156.7, 156.4, 153.8, 148.2,
148.1, 139.9, 131.3, 131.2, 130.2, 121.5, 121.4, 118.45, 118.44,
112.34, 91.9, 91.5, 74.8, 74.0, 71.9, 71.1, 60.2, 47.1, 38.8, 38.7, 37.0,
29.7 ppm. HRMS (ESI): m/z calcd. for C31H30Br6N4O10Na [M +
Na+]: 1114.6954; found isotopic peaks 1118.6898, 1120.6882,
1122.6857.
Compound 25: To a racemic mixture of compound 24 (0.425 g,
1.03 mmol), K2CO3 (1.15 g, 8.32 mmol), and KI (1.38 g,
8.312 mmol) in dry Me2CO/MeCN (1:1, 10 mL) was added tert-
butyl (3-chloropropyl)carbamate (0.5 g, 2.58 mmol), and the mix-
ture was refluxed for 16 h. The solvent was evaporated in vacuo,
and the crude product was extracted with EtOAc. The organic layer
was concentrated and purified by silica gel column chromatography
using 25% ethyl acetate in hexanes to afford 25 (0.555 g, 95%). Rf
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H/13C NMR spectra of all new compounds.
= 0.77 (50% ethyl acetate in hexanes). IR (thin film): ν = 3440,
˜
3362, 3008, 2977, 2931, 2880, 1694, 1513, 1454, 1367, 1253, 1168,
Acknowledgments
1
658 cm–1. H NMR (500 MHz, CDCl3): δ = 7.51 (s, 2 H), 4.99 (d,
J = 22.0 Hz, 2 H), 4.76 (br. s, 1 H), 4.04 (t, J = 5.27 Hz, 2 H), 3.86
(br. s, 1 H), 3.43 (br. m, 3 H), 3.22–3.16 (m, 1 H), 2.04–2.02 (m, 2
H), 1.44 (s, 18 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 157.2,
156.0, 152.1, 140.7, 130.2, 118.2, 80.3, 79.1, 72.6, 71.2, 48.3, 38.0,
30.0, 28.4, 28.3 ppm. HRMS (ESI): m/z calcd. for
C21H32Br2N2O6Na [M + Na+]: 589.0519, found 589.0514.
The project described was supported by the National Institutes of
Health (NIH) (NIH/NIGMS: Award Number 2SC3GM094081-05;
NIH/NCRR: Award Number G12RR013459, support of the Ana-
lytical and NMR CORE Facilities, NIH/NIMHD: Award Number
G12MD007581).
2-Amino-1-[4-(3-aminopropoxy)-3,5-dibromophenyl]ethanol
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Compound 25 (0.216 g, 0.38 mmol) was taken in 5 mL of CH2Cl2/
TFA (1:1) and stirred for 30 min. After the solvent was removed,
the crude product was purified by silica gel column chromatog-
raphy using 5, 10, and 25% MeOH in CH2Cl2 gave the product as
a white solid 26 (0.135 g, 97%). Rf = 0.27 (20% MeOH in CH2Cl2).
1H NMR (500 MHz, CD3OD): δ = 7.68 (s, 2 H), 4.13 (t, J =
5.49 Hz, 2 H), 3.31 (t, J = 7.43 Hz, 2 H), 3.18 (dd, J = 12.8, 2.7 Hz,
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δ = 152.2, 140.6, 130.2,
117.8, 70.2, 67.8, 37.4, 27.6 ppm. HRMS (ESI): m/z calcd. for
C11H16Br2N2O2Na [M + Na+]: 388.9470, found 388.9470.
7,9-Dibromo-10-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,6,8-
triene-3-carboxylic Acid (27): To a solution of trans (Ϯ)-19 (0.1 g,
0.250 mmol) in H2O/MeOH (1:3, 12 mL) was added LiOH mono-
hydrate (0.031 mg, 0.738 mmol). After 1 h 3 n HCl (1.5 mL) was
added followed by H2O (25 mL). The mixture was extracted with
EtOAc (50 mLϫ2) and the combined organic extracts were dried
(anhyd. MgSO4) and the solvents evaporated to dryness in vacuo
1
to furnish (Ϯ)-27 (0.93 g, 98%) as a light brown foam. H NMR
(500 MHz, CD3OD): δ = 6.42 (s, 1 H), 4.10 (s, 1 H), 3.78 (d, J =
18.4 Hz, 1 H), 3.72 (s, 3 H), 3.09 (d, J = 18.4 Hz, 1 H) ppm. 13C
NMR (125 MHz, CD3OD): δ = 166.4, 158.6, 149.2, 132.5, 122.4,
114.1, 92.2, 75.5, 60.3, 41.3 ppm. HRMS (ESI): m/z calcd. for
C10H9Br2NO5Na [M + Na+]: 403.8739, found 403.8742.
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Received: May 11, 2015
Published Online: July 14, 2015
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