Chemoenzymatic Formal Total Synthesis of Pancratistatin from Narciclasine-Type Compounds via Myers Transposition: Model Study for a Short Conversion of Narciclasine to Pancratistatin

Article abstract of DOI:10.1055/s-0036-1588515

A formal total synthesis of pancratistatin was accomplished by conversion of advanced intermediates, used in the synthesis of narciclasine, to pancratistatin precursors via Myers' reductive transposition as the key strategic step. The synthesis began with the whole cell fermentation of m -dibromobenzene with JM109(pDTG601a), a recombinant strain that over-expresses toluene dioxygenase, which provided the corresponding cis -dihydrodiol 16 as a single isomer with complete optical purity. The key reductive transposition of the allylic alcohol 8a to olefin 9a allowed for further installation of the C-1/C-2 trans -diol, required for the pancratistatin scaffold, through the introduction of a cyclic sulfate and its subsequent opening. The formal synthesis of pancratistatin was accomplished in 14 steps (12 operations) from commercially available m -dibromobenzene. Experimental and spectral data are provided for all new compounds.

Full text of DOI:10.1055/s-0036-1588515

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
R. Lapinskaite et al.
Letter
Synlett
Chemoenzymatic Formal Total Synthesis of Pancratistatin from
Narciclasine-Type Compounds via Myers Transposition: Model
Study for a Short Conversion of Narciclasine to Pancratistatin
OH
OH
OR
Br
HO
OH
OH
Ringaile Lapinskaite
Mukund Ghavre
Chelsea L. Rintelmann
Korey Bedard
OR
OH
8 steps
Myers'
5 steps
O
O
O
OR
O
O
OR
transposition
NHMoc
Br
OH
NH
O
NHMoc
OMe
R = >C(CH3)2, 68–79%
OH
O
OMe
R = >C(CH3)2, Ac
(+)-pancratistatin
Helen E. Dela Paz
Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology,
Brock University, 1812 Sir Isaac Brock Way, St. Catharines,
ON L2S 3A1, Canada
thudlicky@brocku.ca
Dedicated to Professor Victor Snieckus on the occasion of
his 80th birthday and in recognition of his many contribu-
tions to the art of organic synthesis
Received: 06.06.2017
Accepted after revision: 30.06.2017
Published online: 03.08.2017
OH
C
OH
HO
OH
OH
OH
OH
1
2
1
3
4
10
DOI: 10.1055/s-0036-1588515; Art ID: st-2017-r0439-l
10a
6a
4a
O
O
O
O
10b
6
B
A
NH
NH
Abstract A formal total synthesis of pancratistatin was accomplished
by conversion of advanced intermediates, used in the synthesis of narci-
clasine, to pancratistatin precursors via Myers’ reductive transposition
as the key strategic step. The synthesis began with the whole cell fer-
mentation of m-dibromobenzene with JM109(pDTG601a), a recombi-
nant strain that over-expresses toluene dioxygenase, which provided
the corresponding cis-dihydrodiol 16 as a single isomer with complete
optical purity. The key reductive transposition of the allylic alcohol 8a to
olefin 9a allowed for further installation of the C-1/C-2 trans-diol,
required for the pancratistatin scaffold, through the introduction of a
cyclic sulfate and its subsequent opening. The formal synthesis of pan-
cratistatin was accomplished in 14 steps (12 operations) from commer-
cially available m-dibromobenzene. Experimental and spectral data are
provided for all new compounds.
7
OH
O
OH
O
(+)-pancratistatin (2)
(+)-narciclasine (1)
OH
OH
HO
OH
OH
OH
O
O
O
OH
NH
NH
O
O
O
(+)-7-deoxypancratistatin (4)
(+)-lycoricidine (3)
Figure 1 Representative Amaryllidaceae constituents
Key words narciclasine, pancratistatin, toluene dioxygenase, enzy-
matic dihydroxylation of arenes, reductive transposition of allylic alcohols
In 2001, Pettit reported a ten-step conversion of the
more abundant narciclasine to pancratistatin.5h Around that
time we published a twelve-step (nine-operations) total
synthesis of narciclasine that may be amenable to eventual
optimization and scale up.6,7 Commercially, narciclasine is
available at a cost of $100–160/mg, most probably through
isolation from daffodil bulbs.8 Given these constraints in
availability, we decided to investigate two distinct options:
a) de novo synthesis of pancratistatin from intermediates
that were utilized early on in our narciclasine synthesis and
b) conversion of natural or synthetic narciclasine into pan-
cratistatin. Both approaches rely on the Myers’ reductive
transposition of allylic alcohols9 and the resulting trans-di-
hydroxylation of the ring-C olefin. In this paper, we report
the successful preparation of the title natural product.
The highly bioactive Amaryllidaceae constituents (+)-
narciclasine (1), (+)-pancratistatin (2) and their congeners,
shown in Figure 1, have been the focus of intense investiga-
tions for many years. Their biological activity is unique as
these compounds induce apoptosis at very low concentra-
tions, targeting the tumor cells selectively.1 More advanced
evaluations, such as target identification, pharmacokinetics
and animal studies, are hampered by limited availability of
these compounds from natural sources. Pancratistatin is
isolated at levels of ca 19 mg/kg2 while narciclasine is avail-
able at higher levels of 30–140 mg/kg.3 It is this lack of
availability that has led to many attempts at providing these
compounds by total synthesis and, indeed, many creative
approaches to these compounds, as well as to their unnatu-
ral derivatives, have been published.4,5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
R. Lapinskaite et al.
Letter
Synlett
OH
NH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
3 steps
Myers'
NH
NH
transposition
4 steps
OH
O
OH
O
OH
O
(2)
5
6
narciclasine (1)
[natural or synthetic]
O
7 steps
OH
OR
OR
OR
OR
OR
O
O
O
Myers'
O
O
OR
NHMoc
1 step
transposition
NHMoc
7a,b
NHMoc
O
8a,b
9a,b
OMe
OMe
OMe
[advanced synthetic
intermediate]7
a: R = >C(CH3)2 b: R = Ac
Moc = CO2Me
Scheme 1 Approaches to pancratistatin via Myers’ reductive transposition
The two approaches to pancratistatin are shown in
Scheme 1. In the first, we would assume the availability of
either natural or synthetic narciclasine, which would be
converted to alcohol 5 in three steps (protection, oxidation,
reduction). Myers’ reductive transposition of 5 with o-nitro-
benzenesulfonylhydrazine (NBSH)9 would furnish olefin 6
convertible to pancratistatin by trans-dihydroxylation and
deprotection.
The second approach relies on the use of allylic alcohol
8a or 8b, either of which is produced by 1,2-reduction of
the intermediate enone 7a or 7b. The acetonide 7a was
used previously in our synthesis of narciclasine.7 The diace-
tate 7b was prepared in order to avoid aromatization during
the eventual closure of the phenanthridone ring B. If 7a is
used then acetonide/acetate exchange has to take place (the
Banwell protocol10 for the conversion of the carbamate to
the isocyanate requires the use of triflic anhydride).
We have performed the nitroso-Diels–Alder reaction on
the diacetate derived from diol 16a and converted it to 17b
(Scheme 2). This maneuver reduces the number of steps in
our previous synthesis of narciclasine from twelve to ten
steps.7 To confirm the stereochemical outcome of the
cycloaddition, the acetates in 17b were hydrolyzed and the
resulting diol was converted to acetonide 17a. In both cases
the oxazines were obtained with identical regio- and stereo-
selectivity in the [4+2] cycloaddition.
Alcohol 8a,b provides olefin 9a,b via Myers’ transposi-
tion and can be converted further to pancratistatin by
known transformations (trans-dihydroxylation, Banwell’s
modification of the Bischler–Napieralski reaction,10 and
OHC
HO
OHC
HO
Br
B(OH)2
HO
HO
Br
Br
O
O
O
O
iv
i
iii
ii
OMe
OMe
OMe
OMe
OMe
11
10
13
14
12
O
plane of symmetry
Br
OR1
OR1
Br
OR1
OR1
Br
R2
OR1
OR1
For 17a: vi
For 17b: vii
v
O
O
From 17a: 14, ix
From 17c: x
O
NHMoc
Br
Br
N
15
Moc
7a,b
16a R1 = H
16b R1 = >C(CH3)2
16c R1 = Ac
OMe
17a R1 = >C(CH3)2, R2 = Br
17b R1 = Ac, R2 = Br
17c R1 = Ac, R2 = 4-methoxy[d][1,3]benzodioxole
14, viii
Scheme 2 Synthesis of the key intermediates, enones 7a,b. Reagents and conditions: (i) Br2, AcOH, NaOAc (90–95%, crude); (ii) H2O2 (30%), NaOH (2%),
then HCl (2 M) (60–75%); (iii) CH2I2, K2CO3, DMF (59–78%); (iv) t-BuLi, THF, then B(OMe)3 (crude boronic acid 14 is used in Suzuki coupling, isolated:
68–88%); (v) toluene dioxygenase in E.coli JM109(pDTG601A) (0.5–0.8 g/L); (vi) DMP, TsOH, then MocNHOH, NaIO4, MeOH, H2O (45–70%); (vii) Ac2O,
pyridine, CH2Cl2, then MocNHOH, NaIO4, MeOH, H2O (60–68%); (viii) Pd(PPh3)4, KF, benzene, H2O, EtOH (51–86%); (ix) Pd(PPh3)4, Na2CO3, benzene,
H2O, EtOH, then Mo(CO)6, MeCN, H2O (60–72%); (x) Mo(CO)6, MeCN, H2O (50–80%).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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R. Lapinskaite et al.
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Synlett
deprotection). Because of the limited availability of natural
or synthetic narciclasine, we chose to pursue the latter al-
ternative first as a proof of principle study.
7-methoxy-8,9-[1,3]-benzodioxole moiety of ring A. The
use of classical procedures for epoxidation (bromohydrin,
Sharpless or Shi-type epoxidations) led to decomposition or
recovery of starting material. Only the use of m-CPBA led to
the formation of the desired epoxide in moderate yield in
McNulty’s study,12 while in our case these conditions did
not lead to the desired epoxide. Such problems were not
encountered in the epoxidations of ring C olefins in com-
pounds lacking the C-7 hydroxyl or methoxy groups or with
The synthesis of 7a,b was accomplished by repetition
and modest optimization of our published protocol6 and is
shown in an abbreviated form in Scheme 2. Bromide 13 is
commercially available, but can also be prepared by known
chemistry from o-vanillin, as described in our papers6,7 and
shown in Scheme 2. Oxazine 17a (R2 = Br) was subjected to
Suzuki coupling with 14 and converted to 7a directly with-
out isolation of the intermediate. Oxazine 17b (R1 = Ac) was
first converted to 17c by Suzuki coupling and then subject-
ed to the reduction with Mo(CO)6 to yield 7b (Scheme 2).
Luche reduction of enone 7a produced allylic alcohol 8a
(Scheme 3). The use of the original procedure for Myers’ re-
ductive transposition led to a mixture of products that were
difficult to separate and the protocol had to be modified.
Following the report by Movassaghi, o-nitrobenzenesulfo-
nylhydrazide (NBSH) was condensed with acetone to yield
2-nitro-N′-(propan-2-ylidene)benzenesulfonohydrazide
(IP-NBSH), which is more stable and allows for greater vari-
ations in temperature, solvent, order of addition, and dilu-
tion of reagents.11 Different azodicarboxylate and phos-
phine sources were screened and the use of di-tert-butyl
azodicarboxylate (DBAD) together with triphenylphosphine
gave the best results, with 68–79% yield of olefin 9a.
ring
A
containing additional electron-withdrawing
groups.5b,7 To overcome this obstacle, alternative route
through a cyclic sulfate was chosen. Olefin 9a was convert-
ed to the cis-diol 18a by Upjohn dihydroxylation with OsO4.
[Conversion of 8b to 9b was problematic presumably be-
cause of acyl migration(s) to β-C-2 alcohol. This problem is
not encountered in the synthesis of narciclasine where the
α-C-2 alcohol is a benzoate.] The cyclic sulfate 19a was syn-
thesized in one step using safer and easier to handle 1,1′-
sulfonyldiimidazole (SDI) than the more commonly used
thionyl chloride or sulfuryl chloride (the use of the former
reagent requires an additional oxidation step).
Nucleophilic opening of the cyclic sulfate 19a with am-
monium benzoate resulted in a mixture of esters 20 and 21,
with the preferential trans-diaxial attack at the desired C-1
position (20:21, 1:8.5; Scheme 4). Compound 21, resulting
OBz
O
OH
HO
OH
OH
OR
OR
OR
OR
O
S
O
O
O
O
O
O
O
For 8a: ii
i
O
NHMoc
NHMoc
NHMoc
O
O
O
7a, b
8a,b
OMe
20
OMe
OMe
O
O
OH
i
OH
NHMoc
19a
HO
OR
OR
OR
OR
BzO
OH
OH
OMe
iii
O
O
O
O
O
NHMoc
NHMoc
O
NHMoc
18a
9a
OMe
OMe
OMe
21
O
S
O
OAc
O
BzO
OAc
OAc
O
OR
iii
ii
O
O
iv
O
OR
a: R = >C(CH3)2 b: R = Ac
NHMoc
NHMoc
O
OMe
19a
OMe
22
Scheme 3 Synthesis of cyclic sulfate 19a. Reagents and conditions: (i)
CeCl3·7H2O, NaBH4, MeOH (a: 68–90%, b: 62–87%); (ii) DBAD, IP-NBSH,
PPh3, THF, then CF3CH2OH, H2O (a: 68–79%); (iii) OsO4, NMO, acetone,
H2O (a: 50–61%); (iv) NaH, SDI, THF (a: 58–81%).
OAc
OAc
BzO
OAc
BzO
OAc
2 steps5i,j
O
O
MeO
(2)
OAc
OAc
NH
NH
All attempts to accomplish the required trans-dihydrox-
ylation through previously established methods of epoxide
formation proved to be unsuccessful. Recent reports of the
synthesis of Amaryllidaceae constituents by Kim’s5j and
McNulty’s12 groups describe similar difficulties in epoxida-
tion of ring C in intermediates containing an electron-rich
O
OMe
O
O
O
23
24
Scheme 4 Synthesis of triacetate 24. Reagents and conditions: (i)
PhCO2NH4, DMF, then H2SO4, H2O, THF (20: 8%, 21: 73%); (ii) Ac2O,
DMAP, Et3N, CH2Cl2 (80%); (iii) Tf2O, DMAP, CH2Cl2 (42–61%).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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R. Lapinskaite et al.
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Synlett
from the acid-catalyzed deprotection of the acetonide
during workup, was protected as triacetate 22, which un-
derwent Banwell modified Bischler–Napieralski closure to
the known phenanthridone 23 and its regioisomer 24 in
the ratio of 1:9, respectively, as compared to the 1:7 ratio
reported by Magnus5e,f and Kim.5j Compound 24 is convert-
ed to 2 by the known two-step deprotection procedure.
Spectral data of compounds 21 and 24 were matched with
those reported by Kim’s group in 2004 in their synthesis of
pancratistatin, thus completing the formal synthesis of
pancratistatin.5i,j
A formal total synthesis of pancratistatin was accom-
plished in 14 steps from commercially available m-dibro-
mobenzene (12 operations) via advanced intermediates
from our previously described synthesis of narciclasine.13
The crucial reductive transposition of 8a to 9a by the use of
Myers’ protocol worked nicely and this result bodes well for
the eventual conversion of natural narciclasine (obtained by
extraction of daffodil bulbs) to pancratistatin. We will re-
port on this conversion and the comparison of its efficiency
with the Pettit’s synthesis in due course.
(4) For reviews on synthesis, see: (a) Ghavre, M.; Froese, J.; Pour,
M.; Hudlicky, T. Angew. Chem. Int. Ed. 2016, 55, 5642. (b) Jin, Z.
Nat. Prod. Rep. 2009, 26, 363. (c) Kornienko, A.; Evidente, A.
Chem. Rev. 2008, 108, 1982. (d) Manpadi, M.; Kornienko, A. Org.
Prep. Proced. Int. 2008, 40, 107. (e) Chapleur, Y.; Chrétien, F.; Ibn
Ahmed, S.; Khaldi, M. Curr. Org. Synth. 2006, 3, 341. (f) Rinner,
U.; Hudlicky, T. Synlett 2005, 365. (g) Hoshino, O. In The Alka-
loids: Cordell G. A;V5o1
l
Academic Press: New York, 1998, 323–424.
(h) Bridges, A. Chemtracts: Org. Chem. 1996, 9, 101. (i) Martin, S.
F. In The Alkaloids;
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Brossi A., Academic Press: New York, 1987,
251–376. (j) Yingjie, L.; Zeyang, D.; Chong, T.; Hongliang, Y.;
Yubin, J. Chin. J. Org. Chem. 2015, 35, 1009.
(5) For previous syntheses of pancratistatin, see: (a) Danishefsky,
S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829. (b) Tian, X.;
Hudlicky, T.; Kēnigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643.
(c) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
(d) Doyle, T. J.; Hendrix, M.; VanDerveer, D.; Javanmard, S.;
Haseltine, J. Tetrahedron 1997, 53, 11153. (e) Magnus, P.;
Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341. (f) Magnus, P.;
Sebhat, I. K. Tetrahedron 1998, 54, 15509. (g) Rigby, J. H.;
Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000, 122,
6624. (h) Pettit, G. R.; Melody, N.; Herald, D. L. J. Org. Chem.
2001, 66, 2583. (i) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett.
2002, 4, 1343. (j) Ko, H.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J.
Org. Chem. 2004, 69, 112. (k) Li, M.; Wu, A.; Zhou, P. Tetrahedron
Lett. 2006, 47, 3707. (l) Dam, J. H.; Madsen, R. Eur. J. Org. Chem.
2009, 27, 4666. (m) Jung, Y.-G.; Kang, H.-U.; Cho, H.-K.; Cho, C.-
G. Org. Lett. 2011, 13, 5890. (n) Cagide-Fagin, F.; Nieto-Garcia,
O.; Lago-Santome, H.; Alonso, R. J. Org. Chem. 2012, 77, 11377.
(o) Akai, S.; Kojima, M.; Yamauchi, S.; Kohji, T.; Nakamura, Y.;
Sato, K. Asian J. Org. Chem. 2013, 2, 299. (p) Cho, H.-K.; Lim, H.-
Y.; Cho, C.-G. Org. Lett. 2013, 15, 5806. (q) Potter, T. J.; Ellman, J.
A. Org. Lett. 2017, 19, 2985.
Funding Information
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), TDC
Research, Inc., TDC Research Foundation, the Ontario Partnership for
Innovation and Commercialization (OPIC), and The Advanced Bio-
(6) Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999,
40, 3077.
manufacturing Centre (Brock University).
)(
(7) Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun, H.; Schilling, S.;
Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002,
67, 8726.
Supporting Information
(8) For Commercial sources of narciclasine, see: (a) http://www.mol-
base.com/en/cas-29477-83-6.html?p6=336. (b) https://www.med-
chemexpress.com/Narciclasine.html?gclid=CMnaoNWtjdACFQM-
paQodqW8N8w. (c) McNulty, J.; Thorat, A.; Vurgun, N.; Nair, J. J.;
Makaji, E.; Crankshaw, D. J.; Holloway, A. C.; Pandey, S. J. Nat.
Prod. 2011, 74, 106.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588515.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(9) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841.
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(11) (a) Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew.
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Org. Chem. 2007, 72, 1838. (c) Movassaghi, M.; Ahmad, O. K.
Angew. Chem. Int. Ed. 2008, 47, 8909. (d) For the synthesis of IP-
NBSH, see: Willwacher, J.; Ahmad, O. K.; Movassaghi, M. Org.
Synth. 2012, 89, 230.
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2013, 33, 439. (b) Van Goietsenoven, G.; Andolfi, A.; Lallemand,
B.; Cimmino, A.; Lamoral-Theys, D.; Gras, T.; Abou-Donia, A.;
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Methyl {(3aS,4R,7R,7aR)-7-Hydroxy-7′-methoxy-2,2-dimethyl-
3a,4,7,7a-tetrahydro(5,5′-bibenzo[d][1,3]dioxol)-4-yl}carba-
mate (8a; see ref 7): The solution of enone 7a (50 mg, 0.13
mmol) in MeOH (0.5 mL) was degassed with a stream of argon
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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for 15 min. After addition of cerium (III) chloride heptahydrate
(71 mg, 0.19 mmol) the reaction mixture was stirred for 20 min,
then cooled to 0 °C and sodium borohydride (6 mg, 0.14 mmol)
was added in 2 portions. The reaction mixture was allowed to
warm slowly to r.t. and stirred for 3 h. The reaction mixture was
diluted with EtOAc (5 mL) and the grey precipitate was filtered
through a plug of Celite. After concentration under reduced
pressure the product was purified by preparative TLC (hexanes–
EtOAc, 1:1) to furnish 8a as a white foamy oil (48 mg, 96%).
Compound 8a: Rf 0.2 (hexanes–EtOAc, 1:1); [α]D24 –61.6 (c = 0.8,
100:1]. The product was obtained as a white foamy glassy oil
(345 mg, 64%).
Compound 9a: Rf 0.1 (hexanes–EtOAc, 1:1); [α]D24 +14.3 (c = 0.9,
CHCl3). IR (neat): 3331, 2984, 2936, 1705, 1607, 1524, 1475,
1071, 1048 cm–1 1H NMR (600 MHz, CDCl3): δ = 6.36 (s, 1 H),
.
6.34 (s, 1 H), 5.90–6.01 (m, 4 H), 4.68 (m, 1 H), 4.62 (m, 1 H),
4.42 (m, 1 H), 3.87 (s, 3 H), 3.56 (s, 4 H (methyl group plus NH)),
3.38 (s, 1 H), 1.54 (s, 3 H), 1.41 (s, 3 H). 13C NMR (150 MHz,
CDCl3): δ = 156.6, 149.0, 143.7, 136.3, 135.6, 134.3, 123.7, 109.8,
107.5, 102.3, 101.6, 76.0, 72.6, 57.3, 56.7, 52.1, 45.8, 28.4, 26.1.
Methyl {(3aS,4R,5R,6S,7S,7aR)-6,7-Dihydroxy-7′-methoxy-2,2-
dimethyl-3a,4,5,6,7,7a-hexahydro-(5,5′-bibenzo[d][1,3]dioxol)-
4-yl}carbamate (18a): Olefin 9a (1.35 g, 3.579 mmol) was dis-
solved in 20 mL of acetone and 5 mL of H2O. Then OsO4 (250 mg,
0.9834 mmol) and N-methylmorpholine-N-oxide (NMO, 419
mg, 3.579 mmol) were added. The reaction mixture was stirred
at r.t. for 4 d, then quenched with sat. NaHSO3 solution (20 mL).
The reaction mixture was filtered through a plug of Celite, fil-
trate was concentrated, the residue was adsorbed on 10 wt%
deactivated silica, and subjected to purification by column chro-
matography (hexanes–EtOAc, 1:2). Diol 18a was isolated as a
white foamy oil (785 mg, 53%)
25
CHCl3) {lit. [α]D –14.4 (c = 0.8, CHCl3)}. 1H NMR (600 MHz,
CDCl3): δ = 6.57 (m, 2 H), 6.08 (s, 1 H), 5.96 (s, 2 H), 4.67 (dd, J =
10.6, 6.3 Hz, 3 H), 4.55 (s, 1 H), 4.41 (d, J = 10.2 Hz, 1 H), 3.89 (s,
3 H), 3.68 (s, 3 H), 2.77 (d, J = 10.3 Hz, 1 H), 1.34 (s, 3 H), 1.30 (s,
3 H). 13C NMR (150 MHz, CDCl3): δ = 156.6, 149.3, 143.7, 137.3,
135.4, 133.7, 130.8, 109.4, 105.7, 101.8, 100.1, 75.3, 66.7, 56.8,
52.6, 51.1, 29.8, 26.3, 24.8.
Methyl {(3aS,4R,5R,7aR)-7′-Methoxy-2,2-dimethyl-3a,4,5,7a-
tetrahydro(5,5′-bibenzo[d][1,3]dioxol)-4-yl}carbamate (9a; see
ref. 14): Allylic alcohol 8a (629 mg, 1.60 mmol), triphenylphos-
phine (839 mg, 3.20 mmol), 2-nitro-N′-(propan-2-ylidene)ben-
zenesulfonohydrazide (IP-NBSH; 823 mg, 3.20 mmol) was
charged into Schlenk flask and kept under high vacuum for 1 h,
then dissolved in THF (6 mL). Reaction mixture was cooled to 0
°C and di-tert-butyl azadicarboxylate (DBAD; 737 mg, 3.20
mmol) solution in THF (3 mL) was added dropwise. The reaction
mixture was allowed to warm slowly to r.t. and stirred for 8 h.
The reaction mixture was cooled to 0 °C and the mixture of
2,2,2-trifluoroethanol (3 mL) and H2O (3 mL) was added drop-
wise and stirred for 16 h whereupon it was evaporated and sub-
mitted to two consecutive chromatographical columns [10 wt%
deactivated silica gel, hexanes–EtOAc (1:1), then CH2Cl2–MeOH,
25
Compound 18a: Rf 0.1 (hexanes–EtOAc = 1:2); [α]D –55.4 (c =
0.5, CHCl3). 1H NMR (600 MHz, CDCl3): δ = 6.44 (s, 2 H), 5.96 (s,
2 H), 4.60 (s, 1 H), 4.26–4.45 (m, 2 H), 4.19 (s, 1 H), 3.81–4.04
(m, 5 H), 3.54 (s, 3 H), 2.92 (s, 1 H), 2.65 (s, 1 H), 1.82 (s, 1 H),
1.60 (s, 3 H), 1.39 (s, 3 H). 13C NMR (150 MHz, CDCl3): δ = 156.7,
149.4, 144.0, 134.8, 132.1, 109.4, 102.5, 101.7, 77.6, 76.6, 72.7,
69.5, 56.7, 55.1, 52.3, 48.3, 29.9, 28.1, 26.0. Anal. Calcd for
C
19H25NO9: C, 55.47; H, 6.13. Found: C, 54.80; H, 6.44.
(14) Shukla, K. H.; DeShong, P. Heterocycles 2012, 86, 1055.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E