A convergent synthesis of carbocyclic sinefungin and its C-5 epimer

Article abstract of DOI:10.1002/ejoc.201402812

A convergent synthesis of carbocyclic sinefungin (2), its C-5 epimer 3a, and adenine-modified derivative 3b is described. The key features of our approach include the use of commercially available L-methionine and readily available (1R,4S)-4-hydroxy-2-cyclopentenyl acetate as starting materials, a cross-metathesis reaction, an enzymatic kinetic resolution, and a Staudinger reduction. The current synthesis is flexible and, therefore, provides convenient access to the synthesis of various carbocyclic sinefungin analogues for biological evaluation. A convergent synthesis of carbocyclic sinefungin (2), its C-5 epimer 3a, and adenine-modified derivative 3b is described. The key features of this approach include the use of commercially available L-methionine and readily available (1R,4S)-4-hydroxy-2-cyclopentenyl acetate, a cross-metathesis reaction, an enzymatic kinetic resolution, and a Staudinger reduction.

Full text of DOI:10.1002/ejoc.201402812

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201402812
A Convergent Synthesis of Carbocyclic Sinefungin and its C-5 Epimer
Arun K. Ghosh*[a] and Kai Lv[a]
Keywords: Total synthesis / Natural products / Nucleobases / Cross-coupling / Kinetic resolution / Reduction
A convergent synthesis of carbocyclic sinefungin (2), its C-5
epimer 3a, and adenine-modified derivative 3b is described.
The key features of our approach include the use of commer-
cially available L-methionine and readily available (1R,4S)-
4-hydroxy-2-cyclopentenyl acetate as starting materials, a
cross-metathesis reaction, an enzymatic kinetic resolution,
and a Staudinger reduction. The current synthesis is flexible
and, therefore, provides convenient access to the synthesis
of various carbocyclic sinefungin analogues for biological
evaluation.
Introduction
Sinefungin (1, SIN, see Figure 1) was isolated from the
fermentation broth of Streptomyces griseoleus NRRL 3739
at Lilly research Laboratories in 1973.[1] It is structurally
similar to (S)-adenosylmethionine (AdoMet) and (S)-
adenosylhomocysteine (AdoHcy). It is a highly potent and
competitive inhibitor of AdoMet-dependent methyltrans-
ferase (MTase).[2] Preliminary bioassays of sinefungin have
displayed antifungal,[3] antitumor,[4] antiviral,[5] and anti-
parasitic activity.[6] However, toxicological studies have
shown that in goats the therapeutic and lethal doses of SIN
are very similar to each other, and severe nephrotoxic side
effects can result.[7] Sinefungin has a short plasma half-
life,[8] and an intravenous administration of SIN in rats re-
sulted in a blood clearance time that was less than 270 min,
and 50% of the SIN dose was eliminated by excretion into
the urine.[9] Schneller and co-workers have synthesized car-
bocyclic SIN (see Figure 1), in which the ribosyl oxygen was
replaced by an isosteric methylene unit.[10] Such a modifica-
tion may alleviate the metabolic instability associated with
sinefungin.
Figure 1. Design of new carbocyclic SIN derivatives.
Recently, Li and co-workers reported the X-ray crystal
structure of flavivirus MTase in complex with SIN.[11]
Analysis of the structure of the SIN-MTase complex re-
vealed an additional pocket adjacent to the AdoMet-bind-
ing pocket. On the basis of this molecular insight, it has
been proposed that the modification of the adenine base of
SIN may have enhanced binding affinities, thereby leading
to more potent and specific inhibitors of flavivirus
MTase.[11]
introduced into the adenine base unit. We sought to de-
velop an efficient and flexible synthesis of carbocyclic SIN
for the preparation of these analogues. Herein, we report
the convergent syntheses of carbocyclic SIN and its C-5 epi-
mer 3a. The present synthesis utilized commercially avail-
able l-methionine (7) and readily available (1R,4S)-4-
hydroxy-2-cyclopentenyl acetate (8) as starting materials.
Other key steps include a cross-metathesis reaction, an en-
zymatic resolution, and a Staudinger reduction.
Therefore, we designed and synthesized a series of carbo-
cyclic SIN derivatives, in which a different substituent was
Results and Discussion
[a] Department of Chemistry and Department of Medicinal
Chemistry, Purdue University,
Our retrosynthetic analysis of carbocyclic SIN and its
derivatives is outlined in Scheme 1. We plan to introduce
the adenine base in a late stage of the synthesis by em-
ploying an SN2 substitution with 4a and 4b. These deriva-
West Lafayette, Indiana 47906, USA
E-mail: akghosh@purdue.edu
www.chem.purdue.edu/ghosh/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402812.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
A. K. Ghosh, K. Lv
FULL PAPER
tives could be prepared by a cross-metathesis reaction be-
tween segment 5 and olefin 6a or 6b. Fragment 5 would
then be prepared from l-methionine (7). Alcohols 6a and
6b could be derived from (1R,4S)-4-hydroxy-2-cyclopent-
enyl acetate (8).
Scheme 2. Synthesis of segment 5.
hydride provided cis-adduct 13.[16] The decarboxylation of
13 in N,N-dimethylformamide (DMF) in the presence of KI
at 150 °C afforded ester 14. The dihydroxylation of 14 by
treatment with OsO4 and the subsequent protection of the
resulting cis-diol with 2,2-dimethoxypropane in the pres-
ence of a catalytic amount of para-toluenesulfonic acid (p-
TsOH) afforded isopropylidene derivative 15.[17] The sapon-
ification of 15 by employing potassium hydroxide in meth-
anol and tetrahydrofuran (THF) furnished alcohol 16. The
(R)-alcohol 16 was inverted into (S)-alcohol 17 upon oxi-
dation by treatment with Dess–Martin reagent and then a
selective reduction with sodium borohydride. The treatment
Scheme 1. Retrosynthesis of carbocyclic SIN and it derivatives.
The synthesis of vinyl glycine derivative 5 is shown in of the (S)-alcohol 17 with para-methoxybenzyl chloride
Scheme 2. l-Methionine (7) was converted into methyl ester (PMBCl) and sodium hydride yielded PMB-protected de-
9 by using thionyl chloride in methanol according to a re- rivative 18. The reduction of 18 with diisobutylaluminum
ported procedure.[12] The protection of the amine group as hydride (DIBAL) followed by treatment of the resulting al-
benzyloxycarbonyl (Cbz) derivative followed by oxidation dehyde with vinylmagnesium chloride afforded allyl alcohol
of the sulfide in the presence of NaIO4 provided sulfoxide 19 as a mixture of diastereomers (1:1). This mixture could
10.[13] The tert-butoxycarbonyl-protected (Boc-protected) not be separated by chromatography on a silica gel column.
sulfoxide 11 was prepared by following similar course of The oxidation of allyl alcohol 19 with Dess–Martin
reactions. For the subsequent elimination reaction in mesit- periodinane afforded enone 20, which was then subjected
ylene at 170 °C, Boc-protected derivative 11 provided a to a Corey–Bakshi–Shibata (CBS) reduction by using the
complex mixture of unidentified products along with a (R)-2-Me-CBS reagent and borane–dimethyl sufide com-
trace amount of olefin 5. The Cbz-protected derivative 10, plex (BMS) to afford segment 6a in excellent distereoselec-
however, provided the desired terminal alkene 12 in 60% tivity (15:1 dr, by 1H and 13C NMR analysis).[18] Allylic
yield.[14] We then converted Cbz-protected derivative 12 alcohol 6a was obtained in 55% yield along with the olefin-
into Boc-protected derivative 5.
reduced byproduct. In addition, we investigated this reac-
The synthesis of segment 6a is shown in Scheme 3. We tion by using a borane–tetrahydrofuran complex or cate-
began with (1R,4S)-4-hydroxy-2-cyclopentenyl acetate (8), cholborane instead of BMS. The yield, however, did not
which is readily available in high enantiomeric purity on a improve.
large scale from cyclopentadiene by following a literature
In an alternative route, we attempted the isolation of dia-
procedures.[15] As shown in Scheme 3, coupling of 8 with stereomeric alcohol 19 by an enzymatic kinetic resolu-
methyl chloroformate followed by a selective palladium-cat- tion.[19] As shown in Scheme 4, alcohol 19 was treated with
alyzed nucleophilic substitution in the presence of sodium Amano lipase in the presence of vinyl acetate in dimethoxy-
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
Convergent Synthesis of Carbocyclic Sinefungin and its C-5 Epimer
1
dr, by H and 13C NMR analysis) in good yield and dia-
stereoselectivity. The stereochemistry was predicted by
Kazlauskas’ rule,[20] and the result is consistent with that of
the Corey–Bakshi–Shibata reduction. Acetate derivative 21
was hydrolyzed by treatment with aqueous NaOH to afford
the desired (S)-isomer 6a.
With segments 5, 6a, and 6b in hand, we then turned
our attention to construct the C-3–C-4 bond of the target
compound. As shown in Scheme 5, the cross-metathesis re-
action of the two fragments proceeded smoothly in the pres-
ence of Grubbs second-generation catalyst to afford alkenes
22a and 22b.[21] A homodimer was also formed from 6a and
6b in this reaction, even when the ratio of 6a and 6b to 5
was decreased to 1:4. The unreacted homodimer was recy-
cled under the same conditions to afford alkenes 22a and
22b in total yields of 75–78%. The mesylation of alkenes
22a and 22b followed by treatment with sodium azide did
not provide the expected azide derivatives 23a and 23b, but
instead resulted in the elimination of the hydroxy group
along with another byproduct.
Scheme 3. Synthesis of segment 6a (NMO = N-methylmorpholine
N-oxide).
Scheme 5. Cross-coupling reaction and examination of azide sub-
stitution (Ms = methylsulfonyl).
To circumvent this problem, we first carried out the
hydrogenation of alkenes 22a and 22b to provide saturated
alkanes 24a and 24b, respectively. The mesylation of the
respective alcohol afforded the corresponding mesylate, and
the displacement by azide proceeded well to afford azides
25a and 25b, respectively. The removal of the PMB group
by treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquin-
one (DDQ) in dichloromethane (DCM) afforded cyclo-
pentanols 4a and 4b, respectively, as shown in Scheme 6.
The treatment of cyclopentanol 4a and 4b with triflic an-
hydride and pyridine in DCM followed by an SN2 substitu-
tion afforded protected carbocyclic SIN 26a–26c. However,
the SN2 substitution, which followed a literature procedure
by using NaH as a base, gave a low yield.[10a] We found that
Scheme 4. Enzymatic kinetic resolution of alcohol 19.
ethane. The resolution afforded (R)-isomer 6b (13:1 dr, by carbocyclic SIN 26a–26c could be obtained in good yield
1H and 13C NMR analysis) and acetate derivative 21 (15:1 by using K2CO3 and 18-crown-6 in DMF at 50 °C.[22] The
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
A. K. Ghosh, K. Lv
FULL PAPER
Staudinger reduction of 26a–26c converted the azide moiety
into an amine.[23] The removal of the acetonide and Boc
protecting groups by employing trifluoroacetic acid pro-
vided the corresponding amine, and the saponification of
the methyl ester unit with aqueous LiOH furnished carbo-
cyclic SIN 2, C-5 epimer 3a, and adenine-modified deriva-
tive 3b (see Scheme 7).
Conclusions
In summary, a convergent synthesis of carbocyclic sine-
fungin (2), C-5 epimer 3a, and adenine-modified derivative
3b is described. The key features of our syntheses include
the use of commercially available l-methionine and readily
available (1R,4S)-4-hydroxy-2-cyclopentenyl acetate (8) as
the starting materials, a cross-metathesis reaction, an enzy-
matic kinetic resolution, and a Staudinger reduction. The
current synthesis is flexible and, therefore, provides conve-
nient access to the synthesis of various carbocyclic SIN an-
alogues for biological evaluation. A further study of the
chemistry and biology of carbocyclic SIN derivatives is an
active area of research in our laboratory.
Scheme 6. Synthesis of azides 4a and 4b.
Experimental Section
Amino Ester 5: A solution of 12 (2.49 g, 10 mmol) in a hydrobromic
acid solution (4 mL) was stirred at room temperature for 2 h and
then diluted with DCM. The resulting mixture was concentrated
under reduced pressure to give the crude product as a brown oil.
The crude product was dissolved in 1,4-dioxane (20 mL) and H2O
(15 mL), and the pH of the solution was then slowly adjusted to
pH = 12 by the addition of NaHCO3 at 0 °C. A solution of Boc2O
(4.36 g, 20 mmol) in 1,4-dioxane (10 mL) was added at the same
temperature. The resulting mixture was stirred overnight at room
temperature and then concentrated under reduced pressure. The
residue was treated with H2O (15 mL), and the resulting solution
was extracted with EtOAc (3ϫ 20 mL). The combined organic ex-
tracts were dried with MgSO4, filtered, and concentrated. The resi-
due was purified by chromatography on a silica gel column (hex-
anes/EtOAc, 15:1) to afford 5 (1.39 g, 65% over two steps) as a
colorless oil; [α]2D0 = +3.2 (c = 1, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 5.89 (m, 1 H), 5.35 (d, J = 17.2 Hz, 1 H), 5.26 (d, J
= 10.4 Hz, 1 H), 5.23 (br. s, 1 H), 4.87 (br. s, 1 H), 3.76 (s, 3 H),
1.45 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.10,
154.86, 132.55, 117.27, 79.92, 55.64, 52.42, 28.14 ppm. HRMS
(ESI): calcd. for [M + Na]+ C10H17O4Na 238.1055; found 238.1059.
Compound 13: To a stirred solution of 8 (1.00 g, 7.0 mmol) in anhy-
drous DCM (20 mL) were added pyridine (0.85 mL, 10.5 mmol)
and methyl chloroformate (0.82 mL, 10.5 mmol) at 0 °C. The mix-
ture was stirred at the same temperature for 1 h and then quenched
by the addition of 5% HCl (10 mL). The resulting mixture was
extracted with DCM (3ϫ 20 mL), and the combined extracts were
dried with anhydrous Na2SO4, and filtered. The filtrate was con-
centrated under reduced pressure. The residue was purified by
chromatography on a silica gel column (hexanes/EtOAc, 10:1) to
afford a colorless oil. To a suspension of NaH (60% in mineral oil,
840 mg, 21 mmol) in THF (20 mL) was added dropwise a solution
of dimethyl malonate (1.60 mL, 14 mmol) in THF (20 mL) at 0 °C,
and the mixture was stirred at room temperature for 30 min. This
reaction mixture was added to a solution of Pd(Ph3P)4 (404 mg,
Scheme 7. Synthesis of carbocyclic SIN 2, C-5 epimer 3a, and ade-
nine-modified derivative 3b (Tf = trifluoromethylsulfonyl, TFA =
trifluoroacetic acid).
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
Convergent Synthesis of Carbocyclic Sinefungin and its C-5 Epimer
0.35 mmol) and the above prepared oil in THF (15 mL), and the
resulting mixture was then stirred at room temperature for 3 h. The
reaction mixture was quenched by the addition of 5% HCl
(20 mL), and the resulting mixture was extracted with DCM (3ϫ
20 mL). The combined extracts were dried with anhydrous Na2SO4
and filtered. The filtrate was concentrated under reduced pressure
to give a residue, which was purified by chromatography on a silica
gel column (hexanes/EtOAc, 10:1) to afford compound 13 (1.49 g,
83%) as a colorless oil; [α]2D0 = +17.5 (c = 1.01, CH2Cl2). 1H NMR
of 5% HCl. This mixture was diluted with water (15 mL) and then
extracted with EtOAc (3ϫ 30 mL). The combined organic extracts
were dried with MgSO4, filtered, and concentrated. The residue
was purified by chromatography on a silica gel column (hexanes/
EtOAc, 3:2) to afford 16 (400 mg, 95%) as a colorless oil; [α]2D0
=
1
+1.4 (c = 1, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 4.48–4.45
(m, 2 H), 4.24–4.22 (m, 1 H), 3.69 (s, 3 H), 2.70–2.45 (m, 3 H),
2.29 (dt, J = 13.8, 6.2 Hz, 1 H), 1.53 (d, J = 14.0 Hz, 1 H), 1.43 (s,
3 H), 1.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.02,
(400 MHz, CDCl3): δ = 6.02–6.00 (m, 1 H), 5.89–5.87 (m, 1 H), 110.54, 87.10, 85.02, 77.47, 51.54, 41.24, 37.96, 36.49, 26.51,
5.63–5.59 (m, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.36–3.26 (m, 2 H), 24.13 ppm. LRMS (ESI): m/z = 253.1 [M + Na]+.
2.58 (dt, J = 14.5, 7.5 Hz, 1 H), 2.02 (s, 3 H), 1.56 (dt, J = 14.5,
Compound 17: To a stirred solution of 16 (40 mg, 0.17 mmol) in
4.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.63,
DCM (3 mL) was added Dess–Martin periodinane (110 mg,
168.51, 168.44, 137.21, 131.36, 78.71, 56.75, 52.44, 52.38, 43.45,
0.26 mmol) at room temperature. The mixture was stirred at the
same temperature for 3 h and then quenched by the addition of
34.56, 21.09 ppm. LRMS (ESI): m/z = 279.1 [M + Na]+.
Acetate Derivative 14: To a stirred solution of 13 (240 mg,
0.94 mmol) in DMF (15 mL) were added KI (468 mg, 2.82 mmol)
and H2O (1.5 mL) at room temperature under argon. The mixture
was heated to 150 °C, stirred for 8 h, cooled to room temperature,
and then diluted with water. The resulting mixture was extracted
with Et2O, and the combined extracts were dried with anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by
chromatography on a silica gel column (hexanes/EtOAc, 10:1) to
afford compound 14 (130 mg, 70%) as a colorless oil; [α]2D0 = +23.3
saturated aqueous NaHCO3 (3 mL) and Na2S2O4 (3 mL) solutions.
The resulting mixture was extracted with DCM (3ϫ 20 mL), and
the combined extracts were dried with anhydrous Na2SO4 and fil-
tered. The filtrate was concentrated under reduced pressure to give
a residue, which was purified by chromatography on a silica gel
column (hexanes/EtOAc, 3:1) to afford a ketone as a colorless oil.
To a stirred solution of the ketone in EtOH (3 mL) was added
sodium borohydride (10 mg, 0.26 mmol) at 0 °C. The mixture was
stirred at the same temperature for 20 min and then quenched by
the addition of a saturated aqueous NH4Cl solution. The resulting
mixture was extracted with DCM. The combined extracts were
1
(c = 1.05, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 6.01 (d, J =
6.0 Hz, 1 H), 5.86–5.82 (m, 1 H), 5.65–5.60 (m, 1 H), 3.73 (s, 3 H),
3.08–3.01 (m, 1 H), 2.59 (dt, J = 14.5, 7.6 Hz, 1 H), 2.48 (dd, J = dried with anhydrous Na2SO4, filtered, and concentrated to give a
15.6, 7.0 Hz, 1 H), 2.38 (dd, J = 15.6, 8.2 Hz, 1 H), 2.07 (s, 3 H),
1.46 (dt, J = 14.1, 4.4 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 172.57, 170.71, 139.43, 130.07, 79.32, 51.50, 40.40, 40.34, 36.34,
21.17 ppm. HRMS (ESI): calcd. for C10H14O4Na [M + Na]+
221.0790; found 221.0786.
residue, which was purified by chromatography on a silica gel col-
umn (hexanes/EtOAc, 2:1) to afford 17 (37 mg, 93%) as a colorless
oil; [α]2D0 = –7.6 (c = 0.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ
= 5.75–5.65 (t, J = 5.7 Hz, 1 H), 4.38 (dd, J = 6.1, 1.5 Hz, 1 H),
4.09–4.03 (m, 1 H), 3.68 (s, 3 H), 2.55–2.48 (m, 1 H), 2.40 (d, J =
5.3 Hz, 1 H), 2.31 (dd, J = 15.5, 7.9 Hz, 1 H), 2.25 (dd, J = 15.5,
7.8 Hz, 1 H), 1.95 (dt, J = 13.3, 7.7 Hz, 1 H), 1.50 (s, 3 H), 1.33 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.21, 111.84, 84.10,
79.05, 70.98, 51.65, 37.93, 36.63, 36.49, 25.97, 24.25 ppm. LRMS
(ESI): m/z = 231.3 [M + H]+.
Isopropylidene Derivative 15: To a stirred solution of 14 (110 mg,
0.56 mmol) in acetone (5 mL) were added N-methylmorpholine-N-
oxide (195 mg, 1.67 mmol) and OsO4 (4% in water, 25 μL) at 0 °C,
and the resulting mixture was stirred at room temperature for 6 h.
To the reaction was added NaHSO3 (20 mg), and the resulting mix-
ture was stirred for an additional 30 min. EtOAc (10 mL) was then
added, and the resulting mixture was filtered and concentrated. The
residue was dissolved in H2SO4 (0.5 m, 10 mL), and the solution
was extracted with EtOAc (3ϫ 20 mL). The combined extracts
were dried with anhydrous Na2SO4, filtered, and concentrated to
give a brown oil. The prepared oil was dissolved in 2,2-dimeth-
oxypropane (3 mL) at room temperature. To the solution was
added p-TsOH (10 mg, 0.06 mmol), and the reaction mixture was
stirred for 2 h and then quenched by the addition of a saturated
aqueous NaHCO3 solution. The mixture was extracted with EtOAc
(3ϫ 20 mL), and the combined organic extracts were dried with
MgSO4, filtered, and concentrated. The residue was purified by
chromatography on a silica gel column (hexanes/EtOAc, 3:2) to
Compound 18: To a stirred solution of NaH (6 mg, 0.15 mmol) in
DMF (2 mL) were added a solution of 17 (30 mg, 0.13 mmol) in
DMF (1 mL) and 4-methoxybenzyl chloride (20 μL, 0.15 mmol) at
0 °C under argon. The mixture was stirred for 3 h and then
quenched with a saturated aqueous solution of NH4Cl (5 mL). The
resulting mixture was extracted with DCM (3ϫ 10 mL), and the
combined extracts were dried with anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by chromatography on a
silica gel column (hexanes/EtOAc, 3:1) to afford 18 (40 mg, 88%)
as a colorless oil; [α]2D0 = –16.1 (c = 0.9, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.29 (d, J = 8.7 Hz, 1 H), 6.87 (d, J =
8.8 Hz, 1 H), 4.60 (d, J = 11.9 Hz, 1 H), 4.55–4.51 (m, 2 H), 4.28
(d, J = 5.6 Hz, 1 H), 3.80 (s, 3 H), 3.78–3.74 (m, 1 H), 3.66 (s, 3
H), 2.46–2.41 (m, 1 H), 2.22 (dd, J = 15.3, 8.3 Hz, 1 H), 2.21–2.09
(m, 2 H), 1.63–1.60 (m, 1 H), 1.52 (s, 3 H), 1.31 (s, 3 H) ppm. 13C
afford 15 (102 mg, 68% over two steps) as a colorless oil; [α]2D0
–6.7 (c = 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 5.03 (d, J
=
1
= 3.0 Hz, 1 H), 4.52 (d, J = 5.6 Hz, 1 H), 4.44 (d, J = 5.5 Hz, 1 NMR (125 MHz, CDCl3): δ = 172.29, 159.15, 130.17, 129.41,
H), 3.68 (s, 3 H), 2.65–2.31 (m, 4 H), 2.04 (s, 3 H), 1.58 (d, J = 113.66, 111.08, 83.74, 78.33, 71.26, 55.17, 51.67, 37.85, 37.04,
16.1 Hz, 1 H), 1.44 (s, 3 H), 1.27 (s, 3 H) ppm. 13C NMR
32.45, 29.59, 26.21, 24.26 ppm. HRMS (ESI): calcd. for
(125 MHz, CDCl3): δ = 172.35, 169.79, 110.94, 84.78, 84.53, 79.54, C19H26O6Na [M + Na]+ 373.1627; found 373.1630.
51.61, 41.01, 37.41, 33.98, 26.45, 24.08, 21.06 ppm. HRMS (ESI):
Alcohol 19: To a stirred solution of 18 (50 mg, 0.14 mmol) in DCM
(3 mL) was added dropwise DIBAL (1 m in hexanes, 0.16 mL) un-
calcd. for C13H20O6Na [M + Na]+ 295.1158; found 295.1163.
Alcohol 16: To a stirred solution of 15 (500 mg, 1.8 mmol) in der argon at –78 °C. The reaction mixture was stirred for 10 min
MeOH (10 mL) and THF (10 mL) was added KOH (110 mg,
2.0 mmol) at room temperature, and the resulting mixture was
stirred for 30 min and then adjusted to pH = 6.0 by the addition
and then treated with H2O (1 mL), and the resulting mixture was
warmed to room temperature and then diluted with DCM (10 mL).
The mixture was washed with water (4 mL) and brine (4 mL), dried
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
A. K. Ghosh, K. Lv
FULL PAPER
with anhydrous Na2SO4, and filtered. The filtrate was concentrated
under reduced pressure to give a residue, which was purified by
chromatography on a silica gel column (hexanes/EtOAc, 10:1) to
afford an aldehyde as a colorless oil, which was immediately em-
ployed in the next step. To a stirred solution of the prepared color-
less oil in anhydrous THF (5 mL) was added dropwise vinylmagne-
sium chloride (1 m in THF, 0.16 mL) at 0 °C over 5 min. The reac-
tion mixture was stirred at the same temperature for 1 h and then
quenched by the addition of a saturated aqueous NH4Cl solution
(20 mL). The resulting solution was extracted with EtOAc (3ϫ
20 mL), and the combined organic extracts were dried with
MgSO4, filtered, and concentrated. The residue was purified by
chromatography on a silica gel column (hexanes/EtOAc, 3:2) to
12.1 Hz, 1 H), 4.56–4.47 (m, 2 H), 4.28 (d, J = 5.9 Hz, 1 H), 4.17–
4.10 (m, 1 H), 3.79 (s, 3 H), 3.79–3.77 (m, 1 H), 2.20–2.02 (m, 3
H), 1.78–1.50 (m, 2 H), 1.51 (s, 3 H), 1.31 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.11, 140.60, 130.44, 129.32, 115.12,
113.65, 111.24, 84.54, 78.64, 77.48, 71.55, 71.28, 55.17, 39.76,
37.65, 33.50, 26.28, 24.44 ppm. LRMS (ESI): m/z = 371.3 [M +
Na]+.
Compound 22a: To a stirred solution of 6a (174 mg, 0.50 mmol) in
anhydrous DCM (10 mL) were added 5 (537 mg, 2.50 mmol) and
Grubbs second-generation catalyst (26 mg, 0.03 mmol) at room
temperature under argon. The reaction mixture was stirred at the
same temperature for 24 h and then concentrated. The residue was
purified by chromatography on a silica gel column (hexanes/
1
afford 19 (37 mg, 75% over two steps) as a colorless oil. H NMR
EtOAc, 1:1) to afford 22a (201 mg, 75%) as a colorless oil; [α]2D0
=
(300 MHz, CDCl3): δ = 7.30 (d, J = 8.4 Hz, 1 H), 6.87 (d, J =
8.5 Hz, 1 H), 5.90–5.79 (m, 1 H), 5.27–5.20 (m, 1 H), 5.13–5.10 (m,
1 H), 4.70–4.48 (m, 3 H), 4.37–4.38 (m, 1 H), 4.15–4.13 (m, 1 H),
3.80 (s, 3 H), 3.80–3.78 (m, 1 H), 2.07–2.02 (m, 3 H), 1.78–1.50 (m,
2 H), 1.52 (s, 3 H), 1.32 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.10, 140.72, 140.61, 130.39, 129.37, 129.33, 115.07,
114.97, 113.65, 111.22, 84.79, 84.49, 78.60, 77.50, 72.04, 71.46,
71.30, 55.16, 39.85, 39.77, 38.32, 37.60, 33.49, 26.26, 24.43 ppm.
HRMS (ESI): calcd. for C20H28O5Na [M + Na]+ 371.1834; found
371.1837.
1
–3.1 (c = 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.28 (d, J
= 8.4 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 5.74–5.68 (m, 2 H), 5.27
(br. s, 1 H), 4.82 (br. s, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.52–4.45
(m, 2 H), 4.23 (d, J = 5.3 Hz, 1 H), 4.17 (br. s, 1 H), 3.79 (s, 3 H),
3.77–3.75 (m, 1 H), 3.73 (s, 1 H), 2.18–2.08 (m, 2 H), 1.58–1.54 (m,
1 H), 1.49 (s, 3 H), 1.39–1.36 (m, 2 H), 1.27 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 171.18, 159.10, 154.89, 133.83,
130.36, 129.33, 125.27, 113.65, 111.32, 84.36, 80.12, 78.71, 77.43,
71.31, 70.31, 55.16, 54.77, 52.55, 39.78, 37.67, 33.80, 28.20, 26.27,
24.42 ppm. HRMS (ESI): calcd. for C28H41O9NNa [M + Na]+
558.2679; found 558.2683.
Enzymatic Kinetic Resolution of Compound 19: To a stirred solution
of 19 (0.53 g, 1.52 mmol) in dimethoxyethane (30 mL) were added
vinyl acetate (2.80 mL, 30.4 mmol) and Amano lipase (2.65 g) at
room temperature. The reaction mixture was stirred for 24 h and
then filtered. The filtrate was concentrated to give a residue, which
was purified by chromatography on a silica gel column (hexanes/
EtOAc, from 4:1 to 3:2) to afford 6b (249 mg, 47%) and 21
(291 mg, 48%) as colorless oils. Data for 6b: [α]2D0 = –40.3 (c = 1.01,
Compound 22b: Employing 6b and 5 in a similar procedure as that
for the preparation of 22a afforded compound 22b (78% yield) as
a colorless oil, which was used directly in the next step.
Compound 24a: To a stirred solution of 22a (54 mg, 0.10 mmol) in
anhydrous methanol (5 mL) was added Pd/C (10% palladium on
activated charcoal, 6 mg). The mixture was stirred under H2 at
room temperature for 1 h, filtered, and then concentrated. The re-
sulting residue was purified by chromatography on a silica gel col-
umn (hexanes/EtOAc, 1:1) to afford 24a (46 mg, 85%) as a color-
less oil; [α]2D0 = –17.2 (c = 1, CH2Cl2). 1H NMR (400 MHz, CDCl3):
δ = 7.28 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 5.20 (br.
s, 1 H), 4.62 (d, J = 11.8 Hz, 1 H), 4.53–4.48 (m, 2 H), 4.33 (br. s,
1 H), 4.25 (m, 1 H), 3.84 (s, 3 H), 3.83–3.80 (m, 1 H), 3.66 (s, 3
H), 3.65–3.63 (br. s, 1 H), 2.46–1.95 (m, 4 H), 1.70–1.52 (m, 3 H),
1.51 (s, 3 H), 1.50–1.48 (m, 2 H), 1.42 (s, 9 H), 1.24 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.05, 159.08, 155.46, 130.45,
129.29, 113.64, 111.47, 84.30, 79.96, 78.94, 77.44, 71.33, 69.38,
55.16, 52.99, 52.21, 40.55, 38.02, 34.08, 32.86, 29.37, 28.20, 26.32.
24.51 ppm. LRMS (ESI): m/z = 560.5 [M + Na]+.
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.4 Hz, 2
H), 6.84 (d, J = 8.4 Hz, 2 H), 5.79 (ddd, J = 17.2, 10.4, 6.8 Hz, 1
H), 5.19 (d, J = 17.2 Hz, 1 H), 5.07 (d, J = 10.0 Hz, 1 H), 4.59 (d,
J = 12.0 Hz, 1 H), 4.53–4.45 (m, 2 H), 4.32 (d, J = 6.0 Hz, 1 H),
4.10–4.08 (m, 1 H), 3.77 (s, 3 H), 3.77–3.75 (m, 1 H), 2.18–2.04 (m,
3 H), 1.64–1.50 (m, 2 H), 1.49 (s, 3 H), 1.29 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.09, 140.82, 130.39, 129.36,
114.85, 113.64, 111.13, 84.78, 78.51, 77.38, 71.87, 71.27, 55.14,
39.83, 38.20, 33.40, 26.25, 24.43 ppm. LRMS (ESI): m/z = 371.2
1
[M + Na]+. Data for 21: [α]2D0 = –34 (c = 1.02, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 7.29 (d, J = 8.4 Hz, 2 H), 6.86 (d, J =
8.4 Hz, 2 H), 5.79 (ddd, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.26–5.16 (m,
3 H), 4.61 (d, J = 12.0 Hz, 1 H), 4.53–4.45 (m, 2 H), 4.25–4.23 (m,
1 H), 3.78 (s, 3 H), 3.77–3.75 (m, 1 H), 2.15–2.04 (m, 6 H), 1.64–
1.50 (m, 2 H), 1.46 (s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.04, 159.12, 135.74, 130.36, 129.40,
117.46, 113.65, 110.98, 84.47, 78.20, 77.49, 73.40, 71.31, 62.07,
55.15, 37.27, 36.89, 32.67, 26.15, 24.26, 21.12 ppm. HRMS (ESI):
calcd. for C22H30O6Na[M + Na]+ 413.1940; found 413.1944.
Compound 24b: Employing 22b in a similar procedure as that for
the preparation of 24a afforded compound 24b (80% yield) as a
colorless oil; [α]2D0 = –11.6 (c = 1, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.29 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H),
5.13 (br. s, 1 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.54 (t, J = 5.2 Hz, 1
H), 4.48 (d, J = 11.7 Hz, 1 H), 4.30 (br. s, 2 H), 3.79 (s, 3 H), 3.78–
3.74 (m, 1 H), 3.73 (s, 3 H), 3.69–3.64 (br. s, 1 H), 2.38–1.90 (m, 4
H), 1.85–1.55 (m, 3 H), 1.51 (s, 3 H), 1.50–1.44 (m, 2 H), 1.43 (s,
9 H), 1.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.15,
159.09, 155.40, 130.48, 129.29, 113.65, 111.66, 85.14, 79.81, 79.09,
71.40, 70.16, 55.15, 53.16, 52.17, 40.30, 39.10, 33.90, 32.97, 28.82,
28.20, 26.32, 24.60 ppm. LRMS (ESI): m/z = 560.4 [M + Na]+.
Alcohol 6a: To a solution of 21 (273 mg, 0.70 mmol) in THF (4 mL)
and H2O (4 mL) was added NaOH (84 mg, 2.10 mmol) at room
temperature. The reaction mixture was stirred at the same tempera-
ture for 4 h and then poured into H2O (8 mL). The aqueous phase
was extracted with DCM (3ϫ 10 mL). The combined organic ex-
tracts were dried with MgSO4, filtered, and concentrated under re-
duced pressure to give a residue, which was purified by chromatog-
raphy on a silica gel column (hexanes/EtOAc, 3:2) to afford 6a
(238 mg, 98%) as a colorless oil; [α]2D0 = –25.8 (c = 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.4 Hz, 2 H), 6.87
(d, J = 8.4 Hz, 2 H), 5.82 (ddd, J = 17.2, 10.4, 6.8 Hz, 1 H), 5.22
(d, J = 17.2 Hz, 1 H), 5.11 (d, J = 10.4 Hz, 1 H), 4.61 (d, J =
Azide 25a: To a stirred solution of 24a (40 mg, 0.074 mmol) in an-
hydrous DCM were added triethylamine (103 μL, 0.74 mmol) and
methanesulfonyl chloride (29 μL, 0.37 mmol) at 0 °C. The mixture
was stirred for 5 min and then quenched with water. The aqueous
phase was extracted with DCM, and the combined extracts were
dried with MgSO4, filtered, and concentrated to give the crude
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
Convergent Synthesis of Carbocyclic Sinefungin and its C-5 Epimer
product as a colorless oil. The crude product was dissolved in DMF
(5 mL), and then NaN3 (24 mg, 0.37 mmol) was added. After stir-
ring at 45 °C for 3.5 h, the solution was cooled in an ice-water bath.
Then, the reaction mixture was diluted with Et2O (10 mL) and
quenched with water (5 mL). The aqueous phase was extracted
with Et2O (3ϫ 10 mL), and the combined organic phases were
washed with water (2ϫ 5 mL). The organic phase was dried with
MgSO4, filtered, and concentrated. The residue was purified by
chromatography on a silica gel column (hexanes/EtOAc, 2:1) to
give the desired azide 25a (32 mg, 77% over two steps) as a color-
less oil; [α]2D0 = –6.4 (c = 1, CH2Cl2). 1H NMR (400 MHz, CDCl3):
temperature. The resulting mixture was heated to 50 °C and then
stirred for 5 h. The mixture was cooled in an ice-water bath, diluted
with Et2O (10 mL), and then quenched with water (5 mL). The
aqueous phase was extracted with Et2O (3ϫ 10 mL), and the com-
bined organic phases were washed with water (2ϫ 5 mL). The or-
ganic phase was dried with MgSO4, filtered, and concentrated. The
residue was purified by chromatography on a silica gel column
(hexanes/EtOAc, 2:1) to give compound 26a (15 mg, 75%) as a
colorless oil; [α]2D0 = +5.2 (c = 1, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 8.35 (s, 1 H), 7.85 (s, 1 H), 5.76 (s, 2 H), 5.17 (br. s, 1
H), 5.13 (dd, J = 5.7, 6.9 Hz, 1 H), 4.74 (ddd, J = 11.7, 6.6, 5.1 Hz,
δ = 7.28 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H), 5.07 (br. 1 H), 4.56 (t, J = 6.5 Hz, 1 H), 4.37 (br. s, 1 H), 3.79 (s, 3 H), 3.42
s, 1 H), 4.61 (d, J = 11.7 Hz, 1 H), 4.58–4.48 (m, 2 H), 4.31 (br. s,
1 H), 4.23 (d, J = 5.8 Hz, 1 H), 3.79 (s, 3 H), 3.76–3.60 (m, 4 H),
3.28–3.22 (m, 1 H), 2.40–1.60 (m, 7 H), 1.51 (s, 3 H), 1.50–1.46 (m,
2 H), 1.43 (s, 9 H), 1.30 (s, 3 H) ppm. 13C NMR (100 MHz,
(br. s, 1 H), 2.50–2.40 (m, 1 H), 2.35–2.30 (m, 1 H), 2.02–1.55 (m,
8 H), 1.59 (s, 3 H), 1.46 (s, 3 H), 1.33 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.76, 155.43, 152.61, 149.83, 140.06,
120.44, 114.00, 84.29, 83.26, 79.99, 61.67, 60.45, 52.81, 52.36,
CDCl3): δ = 172.72, 159.15, 155.26, 130.30, 129.35, 113.67, 111.29, 41.16, 37.91, 36.69, 29.99, 29.10, 28.20, 27.42, 25.05 ppm. HRMS
84.64, 79.98, 78.40, 77.37, 71.37, 60.28, 55.16, 52.78, 52.35, 38.31,
37.14, 32.55, 30.04, 29.28, 28.19, 26.21, 24.37 ppm. HRMS (ESI):
calcd. for C28H42O8N4Na [M + Na]+ 585.2900; found 585.2903.
(ESI): calcd. for C25H38N9O6 [M + H]+ 560.2945; found 560.2949.
Compound 26b: Employing 4b and adenine in a similar manner as
that for the preparation of 26a afforded compound 26b (68% yield)
as a colorless oil; [α]2D0 = +0.8 (c = 1, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 8.34 (s, 1 H), 7.84 (s, 1 H), 5.84 (s, 2 H), 5.22 (d, J =
10.1 Hz), 5.13 (dd, J = 5.8, 6.9 Hz, 1 H), 4.74 (ddd, J = 11.8, 6.4,
5.0 Hz, 1 H), 4.52 (t, J = 10.1 Hz, 1 H), 4.37 (br. s, 1 H), 3.79 (s,
3 H), 3.53 (m, 1 H), 2.50–2.30 (m, 3 H), 2.07–2.03 (m, 1 H), 1.94–
1.60 (m, 5 H), 1.59 (s, 3 H), 1.47 (s, 9 H), 1.32 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.78, 155.47, 155.24, 152.62,
149.81, 140.04, 120.43, 114.16, 84.51, 83.56, 79.98, 61.49, 61.16,
53.08, 52.34, 41.70, 38.31, 37.10, 31.06, 29.24, 28.20, 27.36,
25.13 ppm. HRMS (ESI): calcd. for C25H38N9O6 [M + H]+
560.2945; found 560.2944.
Azide 25b: Employing 24b in a similar procedure as that for the
preparation of 25a afforded azide 25b (80% yield) as a colorless
1
oil; [α]2D0 = –14.5 (c = 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 7.28 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H), 5.08 (br. s,
1 H), 4.61 (d, J = 11.7 Hz, 1 H), 4.58–4.48 (m, 2 H), 4.31–4.18 (m,
2 H), 3.82 (s, 3 H), 3.75–3.70 (m, 4 H), 3.15–3.12 (m, 1 H), 3.11 (s,
3 H), 2.18–1.95 (m, 3 H), 1.80–1.50 (m, 6 H), 1.50 (s, 3 H), 1.42 (s,
9 H), 1.32 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.71,
159.14, 155.22, 130.30, 129.34, 113.68, 111.45, 84.23, 79.99, 78.66,
77.32, 71.36, 60.75, 55.16, 53.05, 52.34, 38.45, 37.30, 33.47, 30.18,
29.10, 28.19, 26.24, 24.41 ppm. LRMS (ESI): m/z = 585.4 [M +
Na]+.
Compound 26c: Employing 4b and N-(3-methylbenzyl)-9H-purin-6-
amine in a similar procedure as that for the preparation of 26a
afforded compound 26c (63% yield) as a colorless oil; [α]2D0 = –2.4
Alcohol 4a: To a stirred solution of 25a (30 mg, 0.053 mmol) in
anhydrous DCM (4 mL) was added DDQ (18 mg, 0.080 mmol) at
room temperature. The mixture was stirred at the same temperature
for 3 h and then quenched with a saturated solution of NaHCO3
(5 mL). The aqueous phase was extracted with DCM, and the com-
bined organic extracts were dried with MgSO4, filtered, and con-
centrated. The residue was then purified by chromatography on a
silica gel column (hexanes/EtOAc, 3:2) to afford 4a (24 mg, 92%)
as a colorless oil; [α]2D0 = +10.2 (c = 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 5.08 (br. s, 1 H), 4.48 (t, J = 6.2 Hz, 1 H),
4.32–4.30 (br. s, 2 H), 3.80 (br. s, 1 H), 3.74 (s, 3 H), 3.33 (br. s, 1
H), 2.47 (br. s, 1 H), 2.24–2.20 (m, 1 H), 2.01–1.56 (m, 8 H), 1.52
(s, 3 H), 1.43 (s, 9 H), 1.32 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.73, 155.25, 112.23, 85.06, 79.97, 79.24, 70.51,
60.61, 52.80, 52.36, 38.67, 36.95, 30.04, 29.21, 28.20, 26.03,
24.35 ppm. LRMS (ESI): m/z = 443.2 [M + H]+.
1
(c = 0.5, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.38 (s, 1 H),
7.72 (s, 1 H), 7.24–7.15 (m, 1 H), 7.09 (d, J = 7.3 Hz, 1 H), 6.06
(br. s, 1 H), 5.13–5.08 (m, 2 H), 4.82 (br. s, 2 H), 4.73–4.67 (m, 1
H), 4.54–4.48 (m, 1 H), 4.34 (br. s, 1 H), 3.55–3.48 (m, 1 H), 2.50–
2.40 (m, 2 H), 2.37 (s, 3 H), 2.36–2.35 (m, 1 H), 1.75–1.60 (m, 5
H), 1.52 (s, 3 H), 1.43 (s, 9 H), 1.29 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.75, 155.22. 154.65, 152.79, 139.34,
138.31, 138.18, 128.50, 128.35, 128.17, 124.68, 120.59, 114.15,
84.53, 83.61, 80.02, 61.49, 61.18, 60.28, 53.09, 52.36, 41.73, 38.34,
37.18, 31.06, 29.29, 28.21, 27.37, 25.14 ppm. HRMS (ESI): calcd.
for C33H45N9O6Na [M + Na]+ 686.3390; found 686.3396.
Compound 2: To a stirred solution of 26a (10 mg, 0.02 mmol) in
anhydrous methanol (3 mL) was added triphenylphosphine at room
temperature. The mixture was stirred at the same temperature for
4 h, and then trifluoroacetic acid (1.5 mL) was added. The resulting
mixture was stirred for an additional 2 h and then concentrated.
The residue was dissolved in THF (1.5 mL), and the solution was
slowly adjusted to pH = 12 by the addition of LiOH (1 m solution)
at 0 °C. The mixture was stirred overnight at room temperature,
adjusted to pH = 7 by the addition of HCl (1 m solution), and
concentrated. The residue was purified by preparative TLC (DCM/
MeOH/aqueous NH3, 5:3:1) to afford carbocyclic sinefungin (2,
4 mg, 60%) as an amorphous solid; [α]2D0 = +3.4 (c = 0.1, H2O).
1H NMR (500 MHz, D2O): δ = 8.15 (s, 1 H), 8.14 (s, 1 H), 4.45 (t,
Alcohol 4b: Employing 25b in a similar procedure as that for the
preparation of 4a afforded alcohol 4b (88% yield) as a colorless
oil, which was used directly in the next step.
Compound 26a: To a stirred solution of 4a (20 mg, 0.04 mmol) in
anhydrous DCM (5 mL) were added pyridine (36 μL, 0.45 mmol)
and triflic anhydride (30 μL, 0.18 mmol) at 0 °C. The mixture was
stirred for 5 min and then quenched by the addition of water. The
aqueous phase was extracted with DCM. The combined extracts
were dried with MgSO4, filtered, and concentrated. The residue
was purified by chromatography on a silica gel column (hexanes/
EtOAc, 2:1) to afford a colorless oil, which was used immediately J = 7.1 Hz, 1 H), 3.96 (t, J = 6.1 Hz, 1 H), 3.73 (t, J = 6.0 Hz, 1
in the next step. To a stirred solution of prepared oil in anhydrous
DMF (4 mL) were added adenine (10 mg, 0.07 mmol), K2CO3
(48 mg, 0.35 mmol), and 18-crown-6 (4 mg, 0.015 mmol) at room
H), 3.37 (td, J = 12.7, 6.6 Hz, 1 H), 2.47–2.43 (m, 1 H), 2.15–2.11
(m, 1 H), 1.96–1.69 (m, 7 H) ppm. 13C NMR (125 MHz, D2O): δ
= 174.42, 155.52, 152.28, 149.18, 140.89, 118.83, 74.55, 74.48,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
A. K. Ghosh, K. Lv
FULL PAPER
[3] R. S. Gordee, T. F. Butler, J. Antibiot. 1973, 26, 466–470.
[4] J. M. Zingg, J. C. Shen, A. S. Yang, H. Rapoport, P. A. Jones,
Nucleic Acids Res. 1996, 24, 3267–3275.
[5] a) C. S. Pugh, R. T. Borchardt, Biochemistry 1982, 21, 1535–
1541; b) H. Chen, B. Zhou, M. Brecher, N. Banavali, S. A.
Jones, Z. Li, J. Zhang, D. Nag, L. D. Kramer, A. K. Ghosh,
H. Li, PloS one 2013, 8, e76900.
[6] D. K. Dube, G. Mpimbaza, A. C. Allison, E. Lederer, L. Rovis,
Am. J. Trop. Med. Hyg. 1983, 32, 31–33.
[7] E. Zweygarth, D. Schillinger, W. Kaufmann, D. Rottcher, Trop.
Med. Parasitol. 1986, 37, 255–257.
[8] L. Deng, L. Zhang, Y. Yao, C. Wang, M. S. Redell, S. Dong,
Y. Song, MedChemComm 2013, 4, 822–826.
[9] S. Kalimouttou, M. Skiba, P. Bon, P. Dechelotte, P. Arnaud,
M. Lahiani-Skiba, J. Nanosci. Nanotechnol. 2009, 9, 150–158.
[10] a) X. Yin, G. Zhao, S. W. Schneller, Tetrahedron Lett. 2007, 48,
4809–4811; b) Q. Chen, C. Liu, T. S. Shulyak, S. W. Schneller,
Tetrahedron 2014, 70, 892–900.
[11] H. Dong, L. Liu, G. Zou, Y. Zhao, Z. Li, S. P. Lim, P. Y. Shi,
H. Li, J. Biol. Chem. 2010, 285, 32586–32595.
[12] C. C. G. Scully, P. J. Rutledge, Tetrahedron 2010, 66, 5653–
5659.
59.91, 54.09, 50.00, 39.48, 36.06, 31.80, 28.18, 26.18 ppm. HRMS
(MALDI): calcd. for C16H26N7O4 [M + H]+ 380.2046; found
380.2049.
Compound 3a: Employing 26b in a similar procedure as that for the
preparation of 2 afforded compound 3a (58% yield) as an amorph-
ous solid; [α]2D0 = –5.6 (c = 0.35, H2O). H NMR (500 MHz, D2O,
1
313 K): δ = 8.10 (s, 1 H), 8.06 (s, 1 H), 4.68–4.65 (m, 1 H), 4.39
(dd, J = 8.0, 6.5 Hz, 1 H), 3.89 (t, J = 6.1 Hz, 1 H), 3.38–3.34 (m,
1 H), 3.11–3.08 (m, 1 H), 2.42–2.36 (m, 1 H), 2.08–2.02 (m, 1 H),
1.88–1.57 (m, 6 H), 1.52–1.42 (m, 1 H) ppm. 13C NMR (125 MHz,
D2O, 313 K): δ = 155.88, 152.71, 149.60, 141.20, 119.21, 75.02,
74.92, 60.26, 55.65, 49.55, 39.81, 39.28, 32.48, 29.49, 26.65 ppm.
HRMS (ESI): calcd. for C16H26N7O4 [M + H]+ 380.2046; found
380.2051.
Compound 3b: Employing 26c in a similar procedure as that for the
preparation of 2 afforded compound 3b (75% yield) as an amorph-
1
ous solid; [α]2D0 = –3.1 (c = 0.38, H2O). H NMR (500 MHz, D2O,
313 K): δ = 8.38 (s, 1 H), 8.35 (s, 1 H), 7.42 (t, J = 7.5 Hz, 1 H),
7.39–7.31 (m, 3 H), 5.00–4.92 (m, 3 H), 4.67 (t, J = 5.9 Hz, 1 H),
4.18 (t, J = 5.6 Hz, 1 H), 3.72 (t, J = 5.9 Hz, 1 H), 3.44–3.36 (m,
1 H), 2.71–2.65 (m, 1 H), 2.46 (s, 3 H), 2.40–2.31 (m, 1 H), 2.16–
1.75 (m, 7 H) ppm. 13C NMR (125 MHz, D2O, 313 K): δ = 152.70,
140.58, 139.09, 138.79, 128.90, 128.12, 127.66, 124.16, 74.91, 74.78,
60.17, 55.30, 49.65, 39.60, 38.23, 32.35, 29.76, 28.65, 20.54 ppm.
HRMS (ESI): calcd. for C24H33N7O4 [M + H]+ 484.2672; found
484.2666.
[13] D. Marchand, J. Martinez, F. Cavelier, Eur. J. Org. Chem. 2008,
18, 3107–3112.
[14] a) M. Carrasco, R. J. Jones, S. Kamel, H. Rapoport, T. Truong,
Org. Synth. 1992, 70, 29–32; b) A. Lumbroso, V. Coeffard, E.
Le Grognec, I. Beaudet, J. P. Quintard, Tetrahedron Lett. 2010,
51, 3226–3228.
[15] a) C. Kanko, A. Sugimoto, S. Tanaka, Synthesis 1974, 12, 876–
877; b) D. R. Deardorff, C. Q. Windlham, C. L. Craney, Org.
Synth. 1996, 73, 25–28.
Supporting Information (see footnote on the first page of this arti-
[16] K. Ambe-Suzuki, Y. Ohyam, N. Shirai, S. Ikeda, Adv. Synth.
Catal. 2012, 354, 879–888.
1
cle): Copies of the H and 13C NMR spectra of all synthetic com-
[17] C. Marschner, G. Penn, H. Griengl, Tetrahedron 1993, 49,
pounds.
5067–5078.
[18] a) E. J. Corey, C. J. Helal, Angew. Chem. Int. Ed. 1998, 37,
1986–2012; Angew. Chem. 1998, 110, 2092; b) S. Xu, D. Unab-
ara, D. Uemura, H. Arimoto, Chem. Asian J. 2014, 9, 367–375.
[19] A. Chojnacka, R. Obara, C. Wawrzenczyk, Tetrahedron: Asym-
metry 2007, 18, 101–107.
Acknowledgments
This research was supported by the National Institutes of Health
(NIH) (AI07079201A1). The authors would like to thank the
Purdue University Center for Cancer Research, which supports the
shared NMR and mass spectrometry facilities. Dr. Hongmin Li is
thanked for helpful discussions.
[20] R. J. Kazlauskas, A. N. E. Weissfloch, A. T. Rappaport, L. A.
Cuccia, J. Org. Chem. 1991, 56, 2656–2665.
[21] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999,
1, 953–956.
[22] H. S. Kim, K. A. Jacobson, Org. Lett. 2003, 5, 1665–1668.
[23] T. K. Chakraborty, P. K. Gajula, D. Koley, J. Org. Chem. 2008,
73, 6916–6919.
[1] R. L. Hamil, M. M. Hoehn, J. Antibiot. 1973, 26, 463–465.
[2] C. S. Pugh, R. T. Borchardt, H. O. Stone, J. Biol. Chem. 1978,
253, 4075–4077.
Received: June 24, 2014
Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42812
/KAP1
Date: 08-09-14 18:09:03
Pages: 9
Convergent Synthesis of Carbocyclic Sinefungin and its C-5 Epimer
Total Synthesis
A convergent synthesis of carbocyclic sine-
fungin (2), its C-5 epimer 3a, and adenine-
modified derivative 3b is described. The key
features of this approach include the use of
commercially available l-methionine and
readily available (1R,4S)-4-hydroxy-2-
cyclopentenyl acetate, a cross-metathesis
reaction, an enzymatic kinetic resolution,
and a Staudinger reduction.
A. K. Ghosh,* K. Lv ......................... 1–9
A Convergent Synthesis of Carbocyclic Si-
nefungin and its C-5 Epimer
Keywords: Total synthesis / Natural prod-
ucts / Nucleobases / Cross-coupling / Kin-
etic resolution / Reduction
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9