Stereocontrolled total synthesis of (+)-trans-dihydronarciclasine

Article abstract of DOI:10.1002/chem.201201649

A highly stereoselective and efficient total synthesis of trans-dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester-enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six-ring vinylogous ester intermediate, which is generated from the γ,δ-unsaturated ester functional group of the Claisen rearrangement product in an efficient three-step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel-Crafts-type cyclization to form the B ring via an isocyanate intermediate derived from an N-Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N-Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence. A highly selective and efficient total synthesis of (+)-trans-dihydronarciclasine was developed. The synthesis defines two of the five stereocenters in an amino acid ester-enolate Claisen rearrangement. The other three stereocenters are created via a cyclic vinylogous ester intermediate, which was generated from the γ,δ-unsaturated ester functional group of the rearrangement product. The B ring is constructed by a Friedel-Crafts-type cyclization, exemplifying the use of an N-Boc group to generate an isocyanate intermediate (see scheme). Copyright

Full text of DOI:10.1002/chem.201201649

FULL PAPER
DOI: 10.1002/chem.201201649
Stereocontrolled Total Synthesis of (+)-trans-Dihydronarciclasine
Soonho Hwang, Deukjoon Kim, and Sanghee Kim*[a]
Abstract: A highly stereoselective and
ate, which is generated from the g,d-
unsaturated ester functional group of
the Claisen rearrangement product in
an efficient three-step sequence. This
concise total synthesis exemplifies the
use of a highly regioselective Friedel–
efficient total synthesis of trans-dihy-
dronarciclasine from a readily available
chiral starting material was developed.
The synthesis defines two of the five
stereogenic centers of the natural prod-
uct by an amino acid ester–enolate
Claisen rearrangement. The other
three stereogenic centers are created in
a highly stereocontrolled fashion via
a six-ring vinylogous ester intermedi-
Crafts-type cyclization to form the B
ring via an isocyanate intermediate de-
rived from an N-Boc group, which is
superior to the conventional method
using an imino triflate intermediate.
This same N-Boc group is employed to
give high selectivity in the Claisen re-
arrangement earlier in the sequence.
Keywords: acid-mediated cycliza-
tion · antitumor agents · Ireland–
Claisen rearrangement
· natural
products · total synthesis
Introduction
The isolation of (+)-1 from the Chinese medical plant
Zephyranthes candida was reported in 1990.[5] Interestingly,
long before its isolation from natural sources, it was pro-
duced synthetically through hydrogenation of narciclasine
(4) with low diastereoselectivity.[6] The first total synthesis of
the racemate was reported by Cho in 2007,[4a] which in-
volved a Diels–Alder cycloaddition of 3,5-dibromo-2-pyrone
for the preparation of the functionalized C ring. The first
enantioselective synthesis by Studer was published in
2008,[4b] in which the required absolute stereochemistry of
the C ring was introduced by a Cu-catalyzed enantioselec-
tive nitroso Diels–Alder reaction. Both syntheses employed
Banwellꢀs modified Bischler–Napieralski reaction at a late
stage of the sequence for closure of the B ring.
Herein, we wish to describe a short and highly stereocon-
trolled total synthesis of (+)-1 by a strategy that is unique
compared to other previous syntheses of Amaryllidaceae iso-
carbostyril alkaloids. Our route is characterized by the use
of an N-Boc group, first to steer the stereochemical course
of a Claisen rearrangement and then, to generate an isocya-
nate intermediate for a highly regioselective Friedel–Crafts-
type B-ring cyclization. This approach is superior to using
the conventional Bischler–Napieralski-type B-ring cycliza-
tion, especially in the sense of regioselectivity.
Based on their potent and selective anticancer activity, as
well as their unique structural features, Amaryllidaceae iso-
carbostyril alkaloids have been an attractive synthetic target
for the last two decades.[1,2] Some representative members
of this class of natural products are trans-dihydronarciclasine
(1), pancratistatin (2), lycoricidine (3), and narciclasine (4,
Figure 1). These natural isocarbostyrils exhibit potent cyto-
toxicity in the NCI 60 human tumor cell line panel with GI50
values in the nanomolar range.[3] Although trans-dihydronar-
ciclasine has far greater anticancer activity than the inten-
sively investigated pancratistatin (2) and other congeners,[3b]
less effort has been devoted to biological and synthetic stud-
ies on trans-dihydronarciclasine until recently.[4]
Figure 1. Chemical structures of compounds 1–4.
Results and Discussion
Retrosynthetic analysis: As shown in Scheme 1, we planned
to construct the B ring of 1 at a late stage of the synthesis,
similar to many other Amaryllidaceae isocarbostyril synthet-
ic approaches. We envisioned that the construction of the B
ring could be achieved by utilizing the N-Boc carbamate
group in compound 5, in which this group is also essential
for attaining high stereocontrol in the subsequent transfor-
[a] S. Hwang, Prof. Dr. D. Kim, Prof. Dr. S. Kim
College of Pharmacy, Seoul National University
San 56-1, Shilim, Kwanak
Seoul 151-742 (Korea)
Fax : (+82)2-888-0649
E-mail: pennkim@snu.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201649.
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Scheme 1. Retrosynthetic analysis of trans-dihydronarciclasine (1).
mations (see below). Our strategy was premised on the se-
lective transformation of the b-keto enol ether function of 6
to the three contiguous hydroxyl groups of the C ring of 5.
We expected that cyclic vinylogous ester 6 could be ob-
tained regioselectively from the g,d-unsaturated ester 7 by
regioselective Wacker oxidation, Dieckmann condensation,
and regioselective vinylogous ester formation. We further
envisioned that an ester–enolate Claisen rearrangement of
the Boc-protected amino acid allylic ester 8 would provide
the g,d-unsaturated a-amino ester 7.[7] In this transforma-
tion, the required stereochemistry of the two contiguous
stereocenters at C-4a and C-10b could be installed with chir-
ality transfer from a preformed chiral center in substrate 8
via a chair-like transition state. The Boc group was chosen
as the amino protecting group, because the stereoselectivity
of ester–enolate Claisen rearrangements of Boc-protected
amino esters is generally superior to that of other carba-
mate-protected amino esters.[8] In addition, the bulkiness of
the Boc group was expected to promote high selectivity
through steric interactions or conformational reinforcement,
especially in the introduction of the three contiguous hy-
droxyl-group stereocenters.
Scheme 2. Synthesis of intermediate 15. DCC=N,N-dicyclohexylcarbodi-
imide, DMAP=4-dimethylaminopyridine, LHMDS=litium hexamethyl
disilazide, TBSCl=tert-butyldimethylsilylchloride, BQ=benzoquinone,
CSA=camphorsulfonic acid.
to afford 12 (93%) after treatment with TMS-diazo-
methane.[10] A single diastereomer was observed by NMR
and HPLC analysis. The absolute configurations of the two
new stereocenters were assumed to be 4aR and 10bR by in-
voking chair transition state A for the rearrangement, and
these configurations were ultimately confirmed by conver-
sion to the final natural product.
Synthesis of the A–C ring systems: As illustrated in
Scheme 2, the synthesis was initiated by preparing Claisen
substrate 8 from the enantiomerically enriched allylic alco-
hol 9. The synthesis of 9 from the aryl bromide 10 and
chiral building block (R)-11 (>99% ee) was previously re-
ported by us in the total synthesis of 2.[9] Allylic alcohol 9
was then coupled with N-Boc-glycine to provide the chiral
allylic amino acid ester 8. After some experimentation, we
identified conditions that led to the formation of the desired
rearranged product 12 in excellent stereoselectivity and
yield. Deprotonation of 8 at À788C with LHMDS in THF in
the presence of TBSCl resulted in the formation of the (Z)-
silyl ketene acetal intermediate, which underwent Claisen
rearrangement upon gradual warming to room temperature
Next, efforts were directed toward forming the C ring by
a two-step process that began with regioselective oxidation
of the internal olefin to afford methyl ketone 13. The result-
ing intermediate could then undergo Dieckmann condensa-
tion to give cyclic b-diketone 14. In the event, highly regio-
selective (8:1) Wacker oxidation of olefin 12 could be ach-
ieved in 82% yield with PdACHTNUGRTENUNG(OAc)2 and benzoquinone
(BQ).[11] Condensation of 13 by using tBuOK in THF pro-
vided the desired b-diketone 14, which was used directly in
the next step without further purification.[12]
C-Ring functionalization: Our approach to functionalize the
C3 position was to convert the cyclic b-diketone moiety of
14 to the corresponding vinylogous ester by enol etherifica-
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Total Synthesis of (+)-trans-Dihydronarciclasine
FULL PAPER
tion. The regiochemical outcomes of etherification of asym-
metric cyclic b-diketones are often difficult to predict, and
mixtures of the two possible products are frequently pro-
duced.[13] However, we envisioned that enol etherification of
14 would be regioselective under thermodynamic conditions,
since vinylogous ester 15 was expected to be thermodynami-
cally more stable than its regioisomer 16, primarily owing to
the lower steric strain. Some support was obtained from our
computational modeling studies, which predicted that 15b
would be more stable than 16b by 1.36 kcalmolÀ1.[14] As ex-
pected, treatment of crude 14 with benzyl alcohol and a cata-
lytic amount of CSA in toluene at 808C led to the selective
formation of vinylogous benzyl ester 15a (64% yield from
13), along with a minor amount of its regioisomer 16a (6:1).
16a could be recycled by chromatographic separation, fol-
lowed by resubjection to the above etherification conditions
to isomerize it back to the 6:1 mixture in favor of 15a.[15]
Next, our study focused on the selective conversion of the
b-keto enol ether function of 15a into the triol 20
(Scheme 3). First, the carbonyl group of 15a was stereose-
lectively reduced with Red-Al to give exclusively the re-
quired 4b-hydroxy group. Since allylic alcohol 17 was unsta-
ble,[13c,16] it was immediately used in the next step without
chromatographic purification. Dihydroxylation of the enol
ether 17 under the Upjohn dihydroxylation conditions
(OsO4, NMO=N-methylmorpholine N-oxide)[17] afforded
exclusively the undesired C3 a-stereoisomer (79% from
15a) instead of 18. Even under the hydroxy-directed dihy-
droxylation conditions of Donohoe,[18] the same undesired
isomer was formed (76%). On the other hand, epoxidation
of the enol ether 17 by using m-CPBA or the VOACHTUNGTRENNUNG(acac)2/
TBHP system[19] did occur on the desired b-face of the mole-
cule to produce the a-hydroxy ketone 18 with the desired
C3 stereochemistry, but in a disappointingly low yield
(<5%). To overcome the problem of low yield, the domino
epoxidation–methanolysis protocol was employed.[20] Epoxi-
dation with m-CPBA in MeOH in the presence of NaHCO3
provided mixed ketal 19 as a single diastereoisomer in 82%
yield (2 steps) from 15a. Since a-hydroxy ketals are prone
to rearrange under acidic conditions,[21] the deketalization of
19 was effected gently by catalytic hydrogenation of the
benzyl group to give ketone 18. Dihydroxyketone 18 itself
was also found to be unstable[22] and readily decomposed to
unidentified polar material. Thus, the best approach was to
treat crude ketone 18 directly with the sterically demanding
l-Selectride to give triol 20 as the sole stereoisomer in 92%
overall yield from 19.[23] Triol 20 was then protected to give
triacetate 21 (92%).
B-Ring construction under Banwellꢀs modified Bischler–
Napieralski reaction conditions: After completing the func-
tionalization of the C ring, we turned our attention to the
construction of the B ring to complete the total synthesis.
Banwellꢀs modified Bischler–Napieralski reaction,[24] which
is thought to proceed via an imino triflate intermediate, has
been used widely for closure of the B ring in the synthesis
of Amaryllidaceae alkaloids, including trans-dihydronarcicla-
sine (1) and pancratistatin (2). However, literature examples
of this reaction show it only to be effective for primary alkyl
carbamate substrates.[2c–e] Thus, we were uncertain at that
time that the Banwell procedure would be applicable to B-
ring formation by using the N-Boc group in our case.
Under the standard Banwell reaction conditions (Tf2O/
DMAP=5:3 molar ratio,08C), we were able to obtain the
desired cyclization product 22, along with a minor amount
of the regioisomer 23 from the N-Boc carbamate 21, but in
a very low yield (38%, Scheme 4). Interestingly, although
the chemical yield was much lower (38 vs. 82%), the degree
of regioselectivity in the B-ring formation was considerably
higher than in the reported case, in which Banwellꢀs modi-
fied Bischler–Napieralski reaction conditions were applied
to the corresponding methoxycarbonyl compound 24 (11.5:1
vs. up to 3.6:1).[4a,b] This remarkable regioselectivity differ-
ence between the cyclization of substrates 21 and 24 under
the same reaction conditions implied that the two cycloaddi-
tion reactions might proceed via different intermediates.
Recently, Schofield and co-workers observed that upon
treatment with 2.0 equivalents of Tf2O and 2.2 equivalents
of Et3N or pyridine, N-Boc-protected phenylalanine ester
underwent dimerization to form a urea, most probably via
an isocyanate intermediate.[25] This observation suggested
the possibility that under Banwellꢀs acidic reaction condi-
tions, the N-Boc carbamate of 21 was converted to an isocy-
Scheme 3. Introduction of the stereocenters in the C ring. Red-Al=
sodium bis(2-methoxyethoxy)aluminum dihydride, m-CPBA=meta-
chloroperbenzoic acid, acac=acetylacetonate, TBHP=tert-butylhydro-
peroxide, l-Selectride=lithium tri-sec-butylborohydrate.
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S. Kim et al.
The total synthesis was completed by demethylation with
TMSCl/KI (75%) and removal of the acetate protecting
groups with NaOMe (95%) to give (+)-1. The spectroscopic
and optical-rotation data of the synthetic material were in
good agreement with those reported for the natural product.
Conclusions
In conclusion, the total synthesis of (+)-trans-dihydronarci-
clasine (1) has been accomplished in 16% overall yield in
a completely substrate-controlled manner from the readily
accessible chiral starting material 9. One of the unique fea-
tures of this synthesis is the highly stereocontrolled intro-
duction of the five contiguous stereogenic centers based on
a single stereocenter in the starting material. Two of the five
stereocenters were defined by an Ireland–Claisen rearrange-
ment and the other three centers were created through dia-
stereoselective reduction and oxidation reactions. The
stereoselectivity for introducing all of the stereogenic reac-
tions was excellent, with only a single diastereomer of each
product being observed. The concise nature of this total syn-
thesis hinges in part on the first demonstration of the suc-
cessful conversion of a Claisen rearrangement product into
a six-membered cyclic vinylogous ester by a regioselective
Wacker-oxidation- and Dieckmann-condensation-based se-
quence. The successful B-ring formation with high regiose-
lectivity from an N-Boc substrate via an isocyanate inter-
mediate is also worth noting, and the present transformation
is a useful complement to Banwellꢀs variant of the Bischler–
Napieralski reaction in the synthesis of dihydroisocarbosty-
rils from b-arylethylcarbamates.
Scheme 4. B-ring construction under Banwellꢀs reaction conditions.
Tf2O=trifluoromethanesulfonic anhydride.
anate through loss of its acid-labile tert-butyl group and de-
hydration, and this in situ generated isocyanate underwent
intramolecular Friedel–Crafts-type cyclization.[26] After care-
ful monitoring the reaction of 21 under the Banwell condi-
tions, we could identify an unstable intermediate that was
gradually converted to the cyclized products 22 and 23. The
identity of this intermediate was revealed to be isocyanate
25 (Scheme 5), primarily by IR spectroscopy (2253 cmÀ1).
With these considerations in mind, efforts were made to
find optimal reaction conditions for an intramolecular Frie-
del–Crafts-type cyclization of the N-Boc carbamate via an
isocyanate intermediate. By varying the reaction conditions,
we found that the desired conversion was greatly influenced
by the amount of base present and the acidity of the reac-
tion medium. We finally determined the optimal reaction
conditions to be 1.1 equivalents of Tf2O, 1.5 equivalents of
2-chloropyridine, and heating at 358C for 20 h. Under these
conditions, the product 22 was obtained with very high re-
gioselectivity (12.5:1) in 76% yield.
Experimental Section
General methods and additional experimental details are given in the
Supporting Information.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
in THF (8 mL) was added to a stirred solution of ester 8 (5.00 g,
13.18 mmol, 1.0 equiv) in THF (80 mL). After the mixture was cooled to
À788C, LHMDS (1.0m solution in THF, 40 mL, 39.54 mmol, 3.0 equiv)
was slowly added to the reaction flask over 30 min. The reaction mixture
was slowly warmed to room temperature and stirred for 20 h. The reac-
tion was quenched with saturated NH4Cl solution at 08C, stirred for an-
other 1 h at room temperature, and then the mixture was extracted twice
with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated under reduced pressure to give the de-
sired acid 12-acid as a single isomer, which was used in the next step
without further purification. A small amount of pure acid was isolated by
column chromatography on silica gel (hexane/EtOAc 2:1+1% AcOH)
for 1H NMR and HRMS analysis. 1H NMR (400 MHz, CD3OD): d=1.33
(s, 9H), 1.65 (d, J=5.9 Hz, 3H), 3.52 (t, J=8.6 Hz, 1H), 3.85 (s, 3H),
4.34 (d, J=8.8 Hz, 1H), 5.50–5.58 (m, 1H), 5.60–5.67 (m, 1H), 5.86 (d,
J=3.4 Hz, 2H), 6.42 (s, 1H), 6.44 ppm (s, 1H); MS (FAB): m/z: 402
[M+23]+; HRMS (FAB): m/z calcd for C19H25NO7: 379.1631 [M]+;
found: 379.1655.
The crude mixture obtained above was dissolved in MeOH (44 mL), and
a solution of trimethylsilyl-diazomethane (2.0m solution in diethyl ether,
17 mL, 32.95 mmol, 2.5 equiv) was added dropwise, causing instantaneous
Scheme 5. Completion of the total synthesis. Py=pyridine.
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Total Synthesis of (+)-trans-Dihydronarciclasine
FULL PAPER
bubbling, along with a change from colorless to yellow. After allowing
the reaction to proceed for 1 h, the reaction was quenched with a small
amount of acetic acid, at which time gas evolved and the reaction mix-
ture became colorless. The solvent was removed in vacuo, and the resi-
due was purified by flash column chromatography on silica gel (hexane/
EtOAc 4:1) to give the desired ester 12 (4.82 g, 93% for 2 steps) as
was stirred for 2 h at room temperature and then quenched by the addi-
tion of saturated Na2S2O3 solution at 08C and extracted twice with
EtOAc. The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (hexane/EtOAc 1:2) to give ketal 19
(1.82 g, 82% for 2 steps from 15a) as a single isomer. [a]25D +11.8 (c=
0.51, CHCl3); 1H NMR (400 MHz, CDCl3 +D2O): d=1.29 (s, 9H), 2.02
(dd, J=2.0, 13.9 Hz, 1H), 2.12 (t, J=13.9 Hz, 1H), 2.51 (dt, J=3.5,
12.5 Hz, 1H), 3.27 (s, 3H), 3.73 (dd, J=2.5, 9.8 Hz, 1H), 3.86 (s, 3H),
3.91 (brs, 1H), 4.13 (s, 1H), 4.38 (d, J=7.9 Hz, 1H), 4.50 (d, J=11.4 Hz,
1H), 4.59 (d, J=11.4 Hz, 1H), 5.90 (d, J=3.2 Hz, 2H), 6.40 (d, J=
3.8 Hz, 2H), 7.26–7.38 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=
28.07 (3C), 34.95, 43.21, 47.81, 54.94, 56.46, 62.33, 70.87, 73.64, 79.77,
100.99, 101.19, 101.97, 106.77, 127.33, 127.42 (2C), 128.26 (2C), 133.89,
135.89, 138.08, 143.49, 148.71, 157.19 ppm; IR (CHCl3): n˜max =3398, 2973,
1691, 1635, 1515 cmÀ1; MS (FAB): m/z: 518 [M+1]+; HRMS (FAB): m/z
calcd for C27H36NO9: 518.2390 [M+H]+; found: 518.2377.
25
a pale yellow solid. [a]D À45.2 (c=0.88, CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.38 (s, 9H), 1.67 (d, J=5.1 Hz, 3H), 3.54–3.50 (m, 1H), 3.66
(s, 3H), 3.87 (s, 3H), 4.50 (t, J=7.3 Hz, 1H), 4.78 (d, J=7.6 Hz, 1H),
5.54–5.63 (m, 2H), 5.92 (s, 2H), 6.31 (s, 1H), 6.36 ppm (d, J=1.2 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=17.81, 28.02 (3C), 51.16, 51.71,
56.44, 57.76, 79.77, 101.23, 101.80, 107.36, 128.24, 128.87, 133.95, 134.10,
143.38, 148.88, 155.07, 172.02 ppm; IR (CHCl3): n˜max =3377, 2976, 1744,
1715, 1634, 1510, 1452 cmÀ1; MS (FAB): m/z: 394 [M+1]+; HRMS
(FAB): m/z calcd for C20H28NO7: 394.1866 [M+H]+; found: 394.1972.
The diastereomeric purity of ester 12 was determined by crude 1H NMR
spectrum analysis. The enantiomeric purity of ester 12 (>99% ee) was
determined by chiral HPLC analysis (CHIRALCEL OJ-H, 2-propanol/
hexane (0 to 10%, 60 min), flow rate: 0.5 mLminÀ1, tR (chiral sample)=
37.7 min [(À)-isomer]; tR (racemic sample)=37.1 [(À)-isomer], 42.5 min
[(+)-isomer], detected at 225 nm).
(2S,3R,4S,4aR,11bR)-7-Methoxy-6-oxo-1,2,3,4,4a,5,6,11b-octahydro-
[1,3]dioxoloACTHNUTRGNE[NUG 4,5-j]phenanthridine-2,3,4-triyl triacetate (22): 2-Chloropyri-
dine (1.0m solution in CH2Cl2, 0.3 mL, 0.29 mmol, 1.5 equiv) and triflic
anhydride (0.2m solution in CH2Cl2, 1.1. mL, 0.21 mmol, 1.1 equiv) were
added to a stirred solution of triacetate 21 (100 mg, 0.19 mmol, 1.0 equiv)
in CH2Cl2 (9 mL) at À788C. After stirring at À788C for 30 min, the reac-
tion mixture was warmed to 358C and stirred for an additional 20 h.
After that, the reaction mixture was quenched by the addition of saturat-
ed NaHCO3 solution at 08C. This was diluted with CH2Cl2, washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (hexane/acetone 1:1)
to give the major isomer 22 (65 mg, 76%) as a white solid, along with the
minor isomer 23 (5 mg, 6%). [a]25D +131.3 (c=0.15, CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.64 (brs, 1H), 1.85 (dt, J=2.8, 13.6 Hz, 1H), 2.05
(s, 6H), 2.12 (s, 3H), 2.38 (d, J=14.4 Hz, 1H), 3.05 (dt, J=3.8, 12.4 Hz,
1H), 3.64 (t, J=11.6 Hz, 1H), 4.04 (s, 3H), 5.13 (d, J=3.0 Hz, 1H), 5,16
(d, J=3.0 Hz, 1H), 5.40 (t, J=3.0 Hz, 1H), 5.98 (d, J=7.8 Hz, 2H), 6.14
(brs, 1H), 6.44 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=20.68,
20.76, 21.02, 26.95, 35.94, 52.12, 60.81, 67.37, 68.57, 71.49, 98.98, 101.68,
115.51, 137.13, 137.41, 145.08, 152.06, 163.75, 169.13, 169.38, 170.37 ppm;
IR (CHCl3): n˜max =3197, 2926, 1752, 1669, 1612 cmÀ1; MS (FAB): m/z:
450 [M+1]+; HRMS (FAB): m/z calcd for C21H24NO10: 450.1400 [M+H]+
; found: 450.1409.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(685 mg, 3.05 mmol, 0.3 equiv) and 1,4-benzoquinone (1.10 g,
10.17 mmol, 1.0 equiv) in CH3CN/H2O (7:1, v/v, 51 mL). The resulting so-
lution was stirred 1 h at room temperature and ester 12 (4.00 g,
10.17 mmol, 1.0 equiv) was added to the reaction flask. After being
stirred for 6 h at room temperature, the reaction was quenched with satu-
rated NaHCO3 solution at 08C, and then the mixture was extracted twice
with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. Owing to similar Rf values for
the hydroquinone generated and the product under various eluent condi-
tions, hydroquinone was acetylated under standard conditions (Ac2O,
Et3N, DMAP, CH2Cl2). The resulting crude mixture was purified by flash
column chromatography on silica gel (hexane/EtOAc 2:1) to give the de-
sired methyl ketone 13 (3.41 g, 82%) as a pale brown oil. [a]25DÀ55.3
(c=0.72, CHCl3); 1H NMR (500 MHz, CDCl3): d=1.43 (s, 9H), 2.13 (s,
3H), 2.67 (dd, J=5.4, 17.7 Hz, 1H), 2.98 (dd, J=8.4, 17.8 Hz, 1H), 3.70
(s, 3H), 3.78 (brs, 1H), 3.86 (s, 3H), 4.60 (d, J=5.0 Hz, 1H), 4.97 (d, J=
8.3 Hz, 1H), 5.92 (s, 2H), 6.26 (d, J=1.3 Hz, 1H), 6.31 ppm (d, J=
1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=28.14 (3C), 30.14, 42.25,
45.14, 52.10, 56.47, 56.58, 79.96, 101.31, 101.64, 108.10, 133.00, 134.46,
143.30, 148.94, 155.70, 171.40, 205.80 ppm; IR (CHCl3): n˜max =3381, 2978,
1714, 1633, 1510, 1452, 1435 cmÀ1; MS (FAB): m/z: 409 [M]+; HRMS
(FAB): m/z calcd for C20H27NO8: 409.1737 [M]+; found: 409.1749.
(+)-trans-Dihydronarciclasine (1): KI (18.4 mg, 0.11 mmol, 1.0 equiv)
and TMSCl (0.5m solution in CH3CN, 0.3 mL, 0.14 mmol, 1.3 equiv) were
added to a stirred solution of lactam 22 (50.0 mg, 0.11 mmol, 1.0 equiv)
in CH3CN (5 mL). The reaction mixture was stirred for 1 h at 608C and
quenched by the addition of H2O at 08C. This was diluted with EtOAc,
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel
(hexane/EtOAc 1:1) to give 22-OH (36.2 mg, 75%) as a white solid.
[a]25D +81.8 (c=0.21, CHCl3); 1H NMR (400 MHz, CDCl3): d=1.90 (dt,
J=2.7, 13.5 Hz, 1H), 2.07 (s, 6H), 2.12 (s, 3H), 2.41 (d, J=14.5 Hz, 1H),
3.12 (dt, J=3.6, 12.6 Hz, 1H), 3.76 (dd, J=11.0, 12.7 Hz, 1H), 5.14–5.20
(m, 2H), 5.42 (t, J=3.0 Hz, 1H), 5.98 (brs, 1H), 6.02 (d, J=4.1 Hz, 2H),
6.31 (s, 1H), 12.29 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=20.70,
20.78, 21.03, 26.67, 34.55, 52.75, 67.23, 68.43, 71.62, 96.71, 102.33, 106.94,
133.18, 135.78, 146.47, 152.95, 169.15, 169.33, 170.13 ppm (2C); IR
(CHCl3): n˜max =3335, 2924, 1752, 1673, 1627 cmÀ1; MS (FAB): m/z: 436
[M+1]+; HRMS (FAB): m/z calcd for C20H22NO10: 436.1244 [M+H]+;
found: 436.1245.
tert-Butyl (1R,2R,6R)-4-(benzyloxy)-2-hydroxy-6-(7-methoxybenzo[d]-
ACHTUNGTRENNUNG[1,3]dioxol-5-yl)cyclohex-3-enylcarbamate (17): Red-Al (sodium bis(2-
methoxyethoxy)aluminum dihydride, 70% in toluene, ca. 3.6m, 1.8 mL,
6.42 mmol, 1.5 equiv) was slowly added to a stirred solution of vinylogous
benzyl ester 15a (2.00 g, 4.28 mmol, 1.0 equiv) in THF (43 mL) at 08C.
The reaction mixture was stirred for 30 min at 08C and then quenched by
the addition of saturated NH4Cl solution at 08C and extracted twice with
EtOAc. The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo to give allylic alcohol 17 as
a single isomer. Owing to its instability under acidic conditions, the re-
sulting pale yellow oil was used in the next step without further purifica-
tion. The diastereomeric purity of alcohol 17 was determined by crude
1H NMR spectrum analysis. 1H NMR (300 MHz, CDCl3): d=1.35 (s,
9H), 2.40 (dd, J=5.1, 16.8 Hz, 1H), 2.52 (t, J=16.8 Hz, 1H), 2.89 (dt, J=
5.5, 11.5 Hz, 1H), 3.69 (td, J=7.1, 11.8 Hz, 1H), 3.89 (s, 3H), 4.41 (brs,
2H), 4.67–4.90 (m, 3H), 5.90–6.00 (m, 2H), 6.38–6.44 (m, 2H), 7.27–
7.42 ppm (m, 5H).
NaOMe (1.0m solution in MeOH, 0.7 mL, 10.0 equiv) was added to a so-
lution of 22-OH (30.0 mg, 0.07 mmol, 1.0 equiv) in THF (7 mL). After
being stirred at room temperature for 1 h, the reaction was quenched by
the addition of saturated NH4Cl solution and extracted three times with
EtOAc. The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash chromatog-
raphy on silica gel (EtOAc/MeOH 10:1) to give (+)-trans-dihydronarci-
clasine 1 (20.3 mg, 95%) as a white solid. [a]25D +4.0 (c=0.16, THF), (lit-
tert-Butyl (1R,2S,3S,4R,6R)-4-(benzyloxy)-2,3-dihydroxy-4-methoxy-6-(7-
methoxybenzo[d]ACHTUNGTRENNUNG[1,3]dioxol-5-yl)cyclohexylcarbamate (19): NaHCO3
(1.08 g, 12.84 mmol, 3.0 equiv) and m-CPBA (1.11 g, 6.42 mmol,
1.5 equiv) were added at 08C to the crude mixture of allylic alcohol 17
obtained in the previous step in MeOH (22 mL). The reaction mixture
1
erature[4b] [a]25D +4.1 (c=0.22, THF)); H NMR (400 MHz, CD3OD): d=
1.78–1.87 (m, 1H), 2.17–2.25 (m, 1H), 2.99 (dt, J=3.4, 12.6 Hz, 1H), 3.46
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S. Kim et al.
(dd, J=10.1, 13.0 Hz, 1H), 3.85 (dd, J=3.0, 10.1 Hz, 1H), 3.90 (t, J=
2.9 Hz, 1H), 4.04–4.09 (m, 1H), 5.99 (d, J=2.4 Hz, 2H), 6.44 ppm (s,
1H); 13C NMR (125 MHz, CD3OD): d=0.43, 36.06, 57.17, 71.35, 72.33,
74.14, 98.47, 104.22, 109.05, 134.72, 140.53, 148.06, 155.10, 172.70 ppm; IR
S. B. Chang, Y. H. Kim, Synlett 2005, 2183; b) J. P. Tellam, G.
Kociok-Kçhn, D. R. Carbery, Org. Lett. 2008, 10, 5199; c) J. P.
Tellam, D. R. Carbery, J. Org. Chem. 2010, 75, 7809. See also
ref. [8].
(neat): n˜max =3354, 2923, 1625 cmÀ1
;
MS (FAB): m/z: 310 [M+1]+;
[11] a) D. G. Miller, D. D. M. Wayner, J. Org. Chem. 1990, 55, 2924; b) F.
Cachoux, M. Ibrahim-Ouali, M. Santelli, Synth. Commun. 2002, 32,
3549.
HRMS (FAB): m/z calcd for C14H16NO7: 310.0927 [M+H]+; found:
310.0928.
[12] Diketone 14 exhibited keto–enol tautomerism.
[13] a) A. Clerici, N. Pastori, O. Porta, Tetrahedron 2001, 57, 217; b) F.
Li, S. S. Tartakoff, S. L. Castle, J. Org. Chem. 2009, 74, 9082; c) G.
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[14] The energy-minimized conformations of 15b and 16b were opti-
mized by the density functional theory method (PBE) at the DNP
level (DMol3). See the Supporting Information.
[15] For previous examples of acid-catalyzed isomerizations of vinylo-
gous ester, see: a) A. G. Myers, N. J. Tom, M. E. Fraley, S. B. Cohen,
D. J. Madar, J. Am. Chem. Soc. 1997, 119, 6072; b) R. B. Grossman,
R. M. Rasne, Org. Lett. 2001, 3, 4027.
Acknowledgements
This work was supported by the SRC/ERC program (R-11-2007-107-
02001-0) and the WCU program (R32-2008-000-10098-0) of the National
Research Foundation of Korea (NRF) grant founded by Korea govern-
ment (MEST).
[16] In slightly acidic conditions, a-hydroxyl enol ether 17 was readily
transformed to the corresponding enone.
[17] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976, 17,
1973.
[18] T. J. Donohoe, P. R. Moore, M. J. Waring, N. J. Newcombe, Tetrahe-
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[19] a) T. Itoh, K. Jitsukawa, K. Kaneda, S. Teranishi, J. Am. Chem. Soc.
1979, 101, 159; b) S. Tanaka, H. Yamamoto, H. Nozaki, K. B. Sharp-
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[20] For examples of hydroxy-directed epoxidation/methanolysis reaction
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Chem. 2003, 115, 1686; Angew. Chem. Int. Ed. 2003, 42, 1648;
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[22] Unlike 18, its C3 a-isomer was stable.
[23] The use of Zn
C2 epimers.
ACHTUGNTREN(UNNG BH4)2 or Red-Al gave approximately a 1:1 mixture of
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´
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Received: May 10, 2012
Published online: && &&, 0000
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Total Synthesis of (+)-trans-Dihydronarciclasine
FULL PAPER
Natural Product Synthesis
S. Hwang, D. Kim, S. Kim* &&&& — &&&&
Stereocontrolled Total Synthesis of
(+)-trans-Dihydronarciclasine
A highly selective and efficient total
synthesis of (+)-trans-dihydronarcicla-
sine was developed. The synthesis
defines two of the five stereocenters in
an amino acid ester–enolate Claisen
rearrangement. The other three stereo-
centers are created via a cyclic vinylo-
gous ester intermediate, which was
generated from the g,d-unsaturated
ester functional group of the rear-
rangement product. The B ring is con-
structed by a Friedel–Crafts-type cycli-
zation, exemplifying the use of an N-
Boc group to generate an isocyanate
intermediate (see scheme).
Chem. Eur. J. 2012, 00, 0 – 0
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These are not the final page numbers!