Total synthesis of (-)-Neplanocin A by using lithium thiolate-initiated Michael-aldol tandem cyclization reaction

Article abstract of DOI:10.1021/jo016090n

(-)-Neplanocin A (1), S-adenosylhomocystein hydrolase inhibitor, was synthesized. The characteristic of this synthesis is a stereoselective construction of five-membered ring of neplanocin A by intramolecular aldol reaction of the lithium enolate that was generated by conjugate addition of lithium thiolate. TBS-protected chiral ω-oxo-α,β-unsaturated ester 16, which was prepared from D-mannitol, was treated with 1.2 equiv of lithium be nzylthiolate in THF at -20 °C to give three separable cyclization products in good yields and stereoselectivity. After conversions of protective groups, the benzylsulfanyl part of 21 was removed by oxidation to sulfoxide and subsequent thermal elimination to give the requisite double bond. Through the functional group transformations of 30, total synthesis of (-)-neplanocin A (1) was accomplished.

Full text of DOI:10.1021/jo016090n

J . Org. Chem. 2001, 66, 8199-8203
8199
Tota l Syn th esis of (-)-Nep la n ocin A by Usin g Lith iu m
Th iola te-In itia ted Mich a el-Ald ol Ta n d em Cycliza tion Rea ction
Masashi Ono, Katsumi Nishimura, Hiroshi Tsubouchi, Yasuo Nagaoka, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, J apan
tomioka@pharm.kyoto-u.ac.jp
Received September 5, 2001
(-)-Neplanocin A (1), S-adenosylhomocystein hydrolase inhibitor, was synthesized. The charac-
teristic of this synthesis is a stereoselective construction of five-membered ring of neplanocin A by
intramolecular aldol reaction of the lithium enolate that was generated by conjugate addition of
lithium thiolate. TBS-protected chiral ω-oxo-R,â-unsaturated ester 16, which was prepared from
D-mannitol, was treated with 1.2 equiv of lithium benzylthiolate in THF at -20 °C to give three
separable cyclization products in good yields and stereoselectivity. After conversions of protective
groups, the benzylsulfanyl part of 21 was removed by oxidation to sulfoxide and subsequent thermal
elimination to give the requisite double bond. Through the functional group transformations of 30,
total synthesis of (-)-neplanocin A (1) was accomplished.
In tr od u ction
As an extension of asymmetric addition reaction of
lithium thiolate with R,â-unsaturated esters,9 we have
already developed a lithium thiolate-initiated Michael-
aldol tandem reaction of R,â-unsaturated esters with
aldehydes and its application to intramolecular cycliza-
tion reaction of ω-oxo-R,â-unsaturated esters.10 The latter
reaction constructs five-, six-, and seven-membered rings
in good yields with excellent stereoselectivity. This cy-
clization is constituted by formation of a transient lithium
enolate, which is generated by conjugate addition of
lithium thiolate, followed by its intramolecular aldol
reaction. Since the sulfur functional groups can be easily
removed, this cyclization reaction seems to be useful for
the chemical synthesis of carbosugars and cyclitols.11 To
verify the usefulness of this cyclization reaction, we chose
(-)-neplanocin A (1) as a synthetic target.
(-)-Neplanocin A (1) is a carbonucleoside1 isolated from
Ampullariella regularis in 19812 and has S-adenosylho-
mocystein hydrolase inhibitory activity.3 To date, several
resourceful examples of the total synthesis of neplanocin
A have been reported. In these approaches, the charac-
teristics were chemoenzymatic desymmetrization of bi-
cyclic Diels-Alder adducts derived from cyclopentadi-
ene;4 palladium-mediated rearrangement5 or desym-
metrization reaction of cyclopentene derivatives;6 con-
struction of five-membered ring by intramolecular Hor-
ner-Wadsworth-Emmons or Wittig reaction,7 or C-H
insertion reaction,8 respectively. However, there is no
precedent of ring construction by intramolecular aldol
reaction.
Our strategy is as follows: (1) stereoselective ring
construction by tandem Michael-aldol cyclization of 4
initiated by conjugate addition of lithium thiolate, (2)
thermal elimination of sulfide moiety in 3 affording an
olefin 2, and (3) functional group transformations to
provide (-)-neplanocin A (Scheme 1).
(1) Reviews on the synthesis of carbocyclic nucleosides. (a) Borth-
wick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623. (b)
Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl,
R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-10670. (c) Crimmins,
M. T. Tetrahedron 1998, 54, 9229-9272.
(2) (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J . Antibiot. 1981, 34, 359-366. (b) Hayashi, M.;
Yaginuma, S.; Yoshioka, H.; Nakatsu, K. J . Antibiot. 1981, 34, 675-
680.
(3) (a) Ueland, P. M. Pharmacol. Rev. 1982, 34, 223-253. (b) Inaba,
M.; Nagashima, K.; Tsukagoshi, S.; Sakurai, Y. Cancer Res. 1986, 46,
1063-1067. (c) Wolfe, M. S.; Borchardt, R. T. J . Med. Chem. 1991, 34,
1521-1530. (d) Shuto, S.; Obara, T.; Toriya, M.; Hosoya, M.; Snoeck,
R.; Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1992, 35,
324-331.
(4) (a) Arita, M.; Adachi, K.; Ito, Y.; Sakai, H.; Ohno, M. J . Am.
Chem. Soc. 1983, 105, 4049-4055. (b) Yoshida, N.; Kamikubo, T.;
Ogasawara, K. Tetrahedron Lett. 1998, 39, 4677-4678.
(5) Medich, J . R.; Kunnen, K. B.; J ohnson, C. R. Tetrahedron Lett.
1987, 28, 4131-4134.
(6) Trost, B. M.; Madsen, R.; Guile, S. D. Brown, B. J . Am. Chem.
Soc. 2000, 122, 5947-5956.
(7) (a) Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.;
Priest, M. A.; Khan, M. S.; Kaskar, B. J . Org. Chem. 1988, 53, 5709-
5714. (b) Bestmann, H. J .; Roth, D. Angew. Chem., Int. Ed. Engl. 1990,
29, 99-100. (c) Wolfe, M. S.; Anderson, B. L.; Borcherding, D. R.;
Borchardt, R. T. J . Org. Chem. 1990, 55, 4712-4717. (d) Hill, J . M.;
Hutchinson, E. J .; Le Grand, D. M.; Roberts, S. M.; Thorpe, A. J .;
Turner, N. J . J . Chem. Soc., Perkin Trans. 1 1994, 1483-1487. (e)
Hegedus, L. S.; Geisler L. J . Org. Chem. 2000, 65, 4200-4203.
Resu lts a n d Discu ssion
We started our synthesis from an acetonide-protected
chiral diol 5, which is readily available from D-mannitol
in large scale12 (Scheme 2).
One of the hydoxy groups in 5 was protected by
treating with p-methoxybenzyl chloride and KOH in
(8) (a) Ohira, S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995,
36, 1537-1538. (b) Niizuma, S.; Shuto, S.; Matsuda, A. Tetrahedron
1997, 53, 13621-13632.
(9) (a) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J . Am.
Chem. Soc. 1997, 119, 12974-12975; (b) Angew. Chem., Int. Ed. 2001,
40, 440-442.
(10) (a) Ono, M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetra-
hedron Lett. 1999, 40, 1509-1512; (b) 1999, 40, 6979-6982.
(11) Review on aminocyclopentitol glycosidase inhibitors. Berecibar,
A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779-844.
(12) Terashima, S.; Tamoto, K.; Sugimori, M. Tetrahedron Lett.
1982, 23, 4107-4110.
10.1021/jo016090n CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

8200 J . Org. Chem., Vol. 66, No. 24, 2001
Ono et al.
Sch em e 4. P r ep a r a tion of TBS-P r otected
Sch em e 1. Retr osyn th etic An a lysis of
(-)-Nep la n ocin A
ω-Oxo-r,â-u n sa tu r a ted Ester 16
Sch em e 5. Ster eoselective Mich a el-Ald ol
Ta n d em Cycliza tion Rea ction of 16 w ith Bn SLi
Sch em e 2. P r ep a r a tion of Aceton id e-P r otected
ω-Oxo-r,â-u n sa tu r a ted Ester 10
Sch em e 6. P la u sible Dia ster eoselection in
Mich a el-Ald ol Ta n d em Cycliza tion of 16 w ith
Bn SLi
Sch em e 3. Attem p ted Mich a el-Ald ol Ta n d em
Cycliza tion Rea ction of 10 w ith Bn SLi (F a iled )
The acetonide protection in 8 was removed by acid
hydrolysis giving diol 13, which was then protected by
TBS groups to afford 14. Deprotection of PMB group with
DDQ gave alcohol 15. Swern oxidation of 15 gave the
desired ω-oxo-R,â-unsaturated ester 16, which was stable
and could be purified by bulb-to-bulb distillation.
As a second trial, we examined a key cyclization
reaction of 16 with lithium thiolate (Scheme 5). The best
result was obtained in a reaction of 16 with 1.2 equiv of
lithium benzylthiolate in THF at -20 °C. The reaction
proceeded smoothly within 0.5 h giving, after silica gel
column chromatography, three cyclization products 17a ,b
and 18 in 34%, 28%, and 11% isolated yields, respectively
(47:38:15).
The stereochemistry of 17 and 18 was determined by
NOE spectra. Since 17b is a silyl-migrated product from
17a , the selectivity of thiolate conjugate addition in the
first step was estimated to be 85:15. Furthermore, the
selectivity of aldol cyclization in the second step was
perfect. The stereoselectivity of the addition of lithium
thiolate and subsequent aldol cyclization could be ex-
plained by the model shown in Scheme 6.
refluxing benzene to give alcohol 6. Swern oxidation of 6
afforded an aldehyde 7, which was then converted,
without purification, to R,â-unsaturated ester 8 by Hor-
ner-Wadsworth-Emmons reaction. Deprotection of the
PMB group by DDQ,13 giving 9, followed by Swern
oxidation gave the desired ω-oxo-R,â-unsaturated ester
10. Because 10 was too unstable to purify, the crude
product was used directly in the next step.
We examined the cyclization reaction of 10 with
lithium thiolate (Scheme 3). However, the reaction of 10
with 1.2 equiv of lithium benzylthiolate in THF at -20
°C for 0.5 h resulted in the formation of a complex
mixture, and the desired cyclization product 11 was not
detected. High distortion of the trans-bicyclo[3.3.0] struc-
ture 12 of 11 prevents the aldol cyclization of 10.14
To overcome the above problem, we changed substrate
10 to 16, which has two silyl protective groups instead
of acetonide, and does not form a trans-bicyclo[3.3.0] ring
after cyclization (Scheme 4).
The unsaturated ester 16 has two bulky tert-butyldim-
ethylsiloxy groups in the vicinal position. These TBSO
groups take an anti orientation to avoid mutual steric
repulsion as shown in Scheme 6.15 The addition of lithium
thiolate took place from the face opposite the terminal
aldehyde moiety to generate the transient lithium enolate
(13) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021-3028.
(14) trans-Bicyclo[3.3.0] ring formation. Ogura, K.; Yamashita, M.;
Tsuchihashi, G. Tetrahedron Lett. 1976, 17, 759-762.

Total Synthesis of (-)-Neplanocin A
J . Org. Chem., Vol. 66, No. 24, 2001 8201
Ta ble 1. Op tim iza tion of Rea ction Con d ition s in
Ster eoselective Mich a el-Ald ol Ta n d em Cycliza tion of 16
w ith Bn SLi (Sch em e 5)a
Sch em e 8. Com p letion of Tota l Syn th esis of
(-)-Nep la n ocin A
entry solvent T (°C) time (h) 17a b (%) 17bb (%) 18b (%)
1
2
3
4
DME
THF
CH3CN
dioxane
-20
-20
-20
rt
0.5
0.5
0.5
0.5
25
34
23
41
19
28
26
4
0
11
0
17
a
The reaction was carried out with 1.2 equiv of BnSLi.
b
Isolated yield.
Sch em e 7. Con ver sion of Cycliza tion P r od u cts 17
to 25
reduced to alcohols by treating with DIBALH in toluene
at -78 °C, giving diol 24, in which the configuration of a
secondary alcohol was inverted.
Selective protection of primary alcohol by TBS group
afforded the mono alcohol 25 that is a synthetic inter-
mediate in the total synthesis of neplanocin A developed
1
by Ogasawara’s group,4b and the H NMR spectrum of
25 agreed with those kindly provided from Ogasawara’s
group.
The remaining transformations to (-)-neplanocin A
followed Ogasawara’s route (Scheme 8). Thus, the hy-
droxyl group in 25 was substituted with adenine by
Mitsunobu reaction,17 and subsequent deprotection of
both an acetonide and a TBS group completed the total
synthesis of (-)-neplanocin A (1).
In conclusion, we have accomplished a total synthesis
of (-)-neplanocin A in 3% overall yield over 16 steps from
D-mannitol-derived chiral diol 5 by using lithium thiolate-
initiated stereoselective intramolecular Michael-aldol
tandem cyclization as a key reaction. This work demon-
strates the usefulness of this cyclization reaction in
organic synthesis.
19. Both conformational control of the enolate 19 by
allylic strain16 and coordination of an aldehyde oxygen
to lithium produce the cyclization product 17 selectively.
The results of examinations of reaction conditions are
summarized in Table 1. In nonpolar solvents such as
toluene, ether, and dichloromethane, the reaction did not
proceed. In polar solvents such as DME, THF, acetoni-
trile, and dioxane, bearing a heteroatom available for
coordination to lithium, the reaction proceeded to afford
cyclization products in moderate to good yields and
stereoselectivities (Table 1, entries 1-4).
The TBS groups in cyclization products 17a and 17b
were deprotected with aqueous HF in acetonitrile to
afford the same triol 20 in 99% yields, respectively
(Scheme 7). The cis vicinal hydroxyl groups in 20 were
selectively protected by treating with acetone in the
presence of p-TsOH giving 21. Oxidation of sulfide to
sulfoxide with sodium metaperiodinate in aqueous etha-
nol, followed by thermal syn elimination of the sulfoxide
in decalin at 180 °C, gave the olefin 22. The hydroxyl
group in 22 was converted to ketone 23 by PDC oxidation.
Both the ketone and ester of 23 were simultaneously
Exp er im en ta l Section
(4R,5R)-5-(4-Meth oxyben zyloxym eth yl)-2,2-d im eth yl-
1,3-d ioxola n -4-ylm eth a n ol (6). A mixture of diol 5 (4.86 g,
30 mmol), KOH (1.88 g, 85%, 28.5 mmol), and 4-methoxybenzyl
chloride (3.28 mL, 23.6 mmol) in benzene (50 mL) was heated
under reflux for 9 h. After cooling, the whole was filtered and
the filtrate was dried over Na2SO4. Concentration followed by
silica gel chromatography (hexane/EtOAc ) 2/1) gave 6 as a
colorless oil (5.5 g, 83%): 1H NMR (CDCl3) δ 1.41 (6H, s), 2.31
(1H, dd, J ) 4.3, 8.2 Hz), 3.51 (1H, dd, J ) 5.8, 9.8 Hz), 3.66
(1H, dd, J ) 5.2, 9.8 Hz), 3.68 (1H, ddd, J ) 4.3, 8.2, 11.6 Hz),
3.75 (1H, ddd, J ) 4.3, 4.6, 11.6 Hz), 3.80 (3H, s), 3.92 (1H,
ddd, J ) 4.3, 4.6, 8.2 Hz), 4.02 (1H, ddd, J ) 5.2, 5.8, 8.2 Hz),
4.51 (2H, s), 6.88 (2H, m), 7.26 (2H, m); 13C NMR (CDCl3) δ
26.9, 55.2, 62.4, 70.0, 73.3, 76.7, 79.8, 109.3, 113.8, 129.4, 129.5,
159.3; IR (neat) 3440, 1610, 1585 cm-1; MS m/z 282 (M+), 121;
[R]25D -10.6 (c 1.05, CHCl3). Anal. Calcd for C15H22O5: C, 63.81;
H, 7.85. Found: C, 64.10; H, 7.82.
(4S,5R)-5-(4-Met h oxyb en zyloxym et h yl)-2,2-d im et h yl-
1,3-d ioxola n e-4-ca r ba ld eh yd e (7). To a solution of oxalyl
chloride (6.98 mL, 80 mmol) in CH2Cl2 (100 mL) was added
DMSO (6.81 mL, 96 mmol) in CH2Cl2 (30 mL) at -60 °C. After
the mixture was stirred for 3 min, a solution of alcohol 6 in
CH2Cl2 (40 mL) was added, and the whole was further stirred
for 15 min. Triethylamine (28 mL, 200 mmol) was added to
the reaction mixture, and then the cooling bath was removed.
After the mixture was warmed to room temperature, the
reaction was quenched with saturated aqueous NH4Cl, and
the aqueous layer was extracted with CHCl3. The combined
organic layers were washed with brine and then dried over
MgSO4. Concentration gave a crude 7 (14.1 g) as an oil.
(15) (a) Saito, S.; Narahara, O.; Ishikawa, T.; Asahara, M.; Mori-
wake, T. Gawronski, J .; Kazmierczak, F. J . Org. Chem. 1993, 58, 6292-
6302. (b) Gung, B. W.; Zhu, Z.; Fouch, R. A. J . Am. Chem. Soc. 1995,
117, 1783-1788.
(16) An allylic strain model in alkylation of enolates. (a) Tomioka,
K.; Kawasaki, H.; Yasuda, K.; Koga, K. J . Am. Chem. Soc. 1988, 110,
3597-3601. Conformation of enolates, which were generated by
conjugate addition of thiolates, in protonation. (b) Miyata, O.; Shinada,
T.; Ninomiya, I.; Naito, T.; Date, T.; Okamura, K.; Inagaki, S. J . Org.
Chem. 1991, 56, 6556-6564. (c) Mohrig, J . R.; Rosenberg, R. E.;
Apostol, J . W.; Bastienaansen, M.; Evans, J . W.; Franklin, S. J .; Frisbie,
C. D.; Fu, S. S.; Hamm, M. L.; Hirose, C. B.; Hunstad, D. A.; J ames,
T. L.; King, R. W.; Larson, C. J .; Latham, H. A.; Owen, D. A.; Stein, K.
A.; Warnet, R. J . Am. Chem. Soc. 1997, 119, 479-486. (d) Reference
9b.
(17) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. In
Organic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1992; Vol.
42, Chapter 2, pp 335-656.

8202 J . Org. Chem., Vol. 66, No. 24, 2001
Ono et al.
(E)-Eth yl 3-[(4R,5R)-5-(4-Meth oxyben zyloxym eth yl)-
2,2-d im eth yl-1,3-d ioxola n -4-yl]p r op -2-en oa te (8). To a sus-
pension of NaH (2.4 g, 60% oil dispersion, 60 mmol) in THF
(60 mL) was added triethyl phosphonoacetate (11.9 mL, 60
mmol) at -20 °C. After the mixture was stirred for 1 h, a
solution of crude aldehyde 7 (14.1 g) in THF (40 mL) was
added. The whole was stirred for 1 h at -20 °C. The reaction
was quenched with water, and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were washed
with brine and then dried over Na2SO4. Concentration followed
by silica gel chromatography (hexane/EtOAc ) 9/1) gave 8 as
a yellow oil (7.49 g, 54% from 5): 1H NMR (CDCl3) δ 1.29 (3H,
t, J ) 7.0 Hz), 1.43 (3H, s), 1.45 (3H, s), 3.58 (1H, dd, J ) 4.6,
10.5 Hz), 3.61 (1H, dd, J ) 4.6, 10.5 Hz), 3.81 (3H, s), 3.94
(1H, ddd, J ) 4.6, 4.6, 8.2 Hz), 4.20 (2H, q, J ) 7.0 Hz), 4.40
(1H, ddd, J ) 1.5, 5.5, 8.2 Hz), 4.52 (2H, s), 6.08 (1H, dd, J )
1.5, 15.6 Hz), 6.88 (3H, m), 7.26 (2H, m); 13C NMR (CDCl3) δ
14.2, 26.7, 26.9, 55.2, 60.5, 69.0, 73.3, 77.5, 79.6, 110.2, 113.8,
122.5, 129.8, 129.8, 144.1, 159.3, 166.0; IR (neat) 1720, 1660
cm-1; MS m/z: 350 (M+), 121; [R]25D +27.3 (c 1.43, CHCl3). Anal.
Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 64.96; H,
7.41.
(E)-Eth yl (4R,5R)-4,5-Dih yd r oxy-6-(4-m eth oxyben zy-
loxy)h ex-2-en oa te (13). To a solution of 8 (6.0 g, 17.1 mmol)
in EtOH (34.2 mL) was added 2 N HCl (34.2 mL) at 0 °C, and
the mixture was stirred for 1.5 h at 40 °C. EtOH was removed
by evaporation. Brine was added to the mixture, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with saturated aqueous NaHCO3
and brine successively and then dried over Na2SO4. Concen-
tration gave a crude 13 (4.87 g) as an oil.
THF (3.5 mL) was added BuLi (0.15 mL, 1.60 M in hexane,
0.24 mmol) at 0 °C. To the solution above was added a solution
of 16 (83 mg, 0.2 mmol) in THF (1.5 mL) at -20 °C. The whole
was stirred for 0.5 h at -20 °C, and the reaction was quenched
with saturated aqueous NH4Cl. The aqueous layer was ex-
tracted with ethyl acetate. The combined organic layers were
washed with brine and then dried over Na2SO4. Concentration
followed by silica gel chromatography (hexane/MTBE ) 20/1)
gave 17a (37 mg, 34%), 17b (30 mg, 28%), and 18 (12 mg, 11%),
respectively.
(1R,2R,3S,4R,5R)-Eth yl 2-ben zylsu lfa n yl-3,4-bis(ter t-
b u t yld im et h ylsiloxy)-5-h yd r oxycyclop en t a n eca r b oxy-
1
la te (17a ): colorless oil; H NMR (CDCl3) δ 0.01(3H, s), 0.03
(3H, s), 0.06 (3H, s), 0.10 (3H, s), 0.86 (9H, s), 0.87 (9H, s),
1.29 (3H, dd, J ) 7.3,7.3 Hz), 2.85 (1H, d, J ) 10.4 Hz), 3.21
(1H, dd, J ) 9.8, 9.8 Hz), 3.62 (1H, dd, J ) 3.7, 9.8 Hz), 3.67
(1H, d, J ) 13.4 Hz), 3.73 (1H, d, J ) 13.4 Hz), 3.73 (1H, dd,
J ) 1.8, 3.7 Hz), 3.86 (1H, dd, J ) 1.8, 4.9 Hz), 4.17 (1H, dq,
J ) 7.3, 10.7 Hz), 4.18 (1H, dq, J ) 7.3, 10.7 Hz), 4.50 (1H,
ddd, J ) 4.9, 9.8, 10.4), 7.19-7.37 (5H, m); 13C NMR (CDCl3)
δ -5.1, -4.7, -4.6, -4.5, 14.2, 17.9, 18.0, 25.6, 25.7, 36.4, 49.5,
54.7, 60.7, 71.9, 77.3, 79.0, 126.8, 128.4, 128.9, 139.0, 171.9;
IR (neat) 3500, 1730 cm-1; MS m/z 541 (MH+); [R]25 -14.8 (c
D
1.01, CHCl3); HRMS calcd for C27H49O5SSi2 541.2839, found
541.2834.
(1R,2R,3S,4R,5R)-Eth yl 2-ben zylsu lfa n yl-3,5-bis(ter t-
b u t yld im et h ylsiloxy)-4-h yd r oxycyclop en t a n eca r b oxy-
1
la te (17b): colorless oil; H NMR (CDCl3) δ 0.06 (3H, s), 0.08
(3H, s), 0.10 (3H, s), 0.11 (3H, s), 0.88 (18H, s), 1.26 (3H, dd,
J ) 7.3, 7.3 Hz), 3.06 (1H, d, J ) 3.7 Hz), 3.24 (1H, dd, J )
9.2, 9.2 Hz), 3.70 (1H, d, J ) 13.2 Hz), 3.73 (1H, d, J ) 13.2
Hz), 3.75 (1H, ddd, J ) 1.5, 3.7, 4.6 Hz), 3.80 (1H, dd, J ) 4.0,
9.2 Hz), 4.01 (1H, dd, J ) 1.5, 4.0 Hz), 4.02 (1H, dq, J ) 7.3,
11.0 Hz), 4.18 (1H, dq, J ) 7.3, 11.0 Hz), 4.67 (1H, dd, J )
4.6, 9.2 Hz), 7.20-7.36 (5H, m); 13C NMR (CDCl3) δ -5.3, -5.2,
-4.8, -4.8, 14.1, 18.0, 18.1, 25.6, 25.7, 36.7, 50.7, 55.5, 60.9,
73.1, 77.6, 78.7, 126.9, 128.4, 128.8, 138.7, 172.3; IR (neat)
(E)-Eth yl (4R,5R)-4,5-Bis(ter t-bu tyld im eth ylsiloxy)-6-
(4-m eth oxyben zyloxy)h ex-2-en oa te (14). To a solution of
crude 13 (4.87 g) in CH2Cl2 (50 mL) were added triethylamine
(19.0 mL, 136 mmol) and tert-butyldimethylsilyl trifluo-
romethanesulfonate (15.6 mL, 68 mmol), and the mixture was
stirred for 0.5 h at 0 °C. The mixture was diluted with ether,
and water was added. The organic layer was separated and
washed with saturated aqueous NaHCO3 and brine succes-
sively and then dried over MgSO4. Concentration gave crude
14 (14.7 g) as an oil.
3500, 1730 cm-1; MS m/z 541 (MH+); [R]25 -25.8 (c 1.36,
D
CHCl3); HRMS calcd for C27H49O5SSi2 541.2839, found 541.2834.
(1S,2S,3S,4R,5S)-E t h yl 2-b en zylsu lfa n yl-3,4-b is(ter t-
b u t yld im et h ylsiloxy)-5-h yd r oxycyclop en t a n eca r b oxy-
1
(E)-Eth yl (4R,5R)-4,5-Bis(ter t-bu tyld im eth ylsiloxy)-6-
h yd r oxyh ex-2-en oa te (15). To a solution of crude 14 (14.7
g) in CH2Cl2 (170 mL) and H2O (8.9 mL) was added DDQ (5.82
g, 26.6 mmol). After the mixture was stirred for 80 min at room
temperature, saturated aqueous NaHCO3 was added, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with saturated aqueous NaHCO3
and brine successively and then dried over Na2SO4. Concen-
tration followed by silica gel chromatography (benzene/ether
) 9/1) gave 15 as a pale yellow oil (3.79 g, 53% from 8): 1H
NMR (CDCl3) δ 0.08 (3H, s), 0.11 (3H, s), 0.12 (3H, s), 0.13
(3H, s), 0.92 (9H, s), 0.93 (9H, s), 1.30 (3H, dd, J ) 7.0, 7.0
Hz), 2.02 (1H, dd, J ) 5.5, 7.0 Hz), 3.46 (1H, ddd, J ) 5.7, 7.0,
11.6 Hz), 3.65 (1H, ddd, J ) 5.5, 5.5, 11.6 Hz), 3.85 (1H, ddd,
J ) 5.5, 5.5, 5.5 Hz), 4.18 (1H, dq, J ) 7.0, 11.0 Hz), 4.22 (1H,
dq, J ) 7.0, 11.0 Hz), 4.41 (1H, ddd, J ) 1.8, 3.7, 5.5 Hz), 6.14
la te (18): colorless oil; H NMR (CDCl3) δ -0.01 (3H, s), 0.04
(3H, s), 0.10 (6H, s), 0.84 (9H, s), 0.90 (9H, s), 1.29 (3H, dd, J
) 7.0, 7.0 Hz), 3.19 (1H, d, J ) 11.0 Hz), 3.35 (1H, dd, J )
5.2, 7.6 Hz), 3.55 (1H, dd, J ) 1.5, 7.6 Hz), 3.73 (1H, d, J )
13.4 Hz), 3.77 (1H, d, J ) 13.4 Hz), 3.91 (1H, dd, J ) 1.5, 1.5
Hz), 3.95 (1H, ddd, J ) 1.5, 1.5, 1.5 Hz), 4.17 (1H, dddd, J )
1.5, 1.5, 5.2, 11.0), 4.20 (1H, dq, J ) 7.3, 10.7 Hz), 4.21 (1H,
dq, J ) 7.3, 10.7 Hz), 7.20-7.36 (5H, m); 13C NMR (CDCl3) δ
-5.1, -5.0, -4.8, -4.8, 14.2, 17.8, 17.9, 25.6, 25.7, 37.1, 51.1,
58.9, 60.9, 81.0, 81.0, 86.6, 126.9, 128.4, 129.0, 138.4, 172.0;
IR (neat) 3480, 1735 cm-1; MS m/z 541 (MH+); [R]25 +21.7 (c
D
1.21, CHCl3); HRMS calcd for C27H49O5SSi2 541.2839, found
541.2813.
(1R,2R,3S,4R,5R)-E t h yl 2-Ben zylsu lfa n yl-3,4,5-t r ih y-
d r oxycyclop en ta n eca r boxyla te (20). A solution of 17a (5.0
mg, 0.009 mmol) and aqueous HF (0.05 mL, 47%) in acetoni-
trile (0.95 mL) was stirred for 3 h at 0 °C. Filtration of the
mixture through a silica gel column (acetonitrile) gave 20 (2.8
mg, 99%) as a white solid of mp 73.5-74.5 °C. By the same
procedure as described above, treatment of 17b (4.0 mg, 0.007
mmol) with aqueous HF (0.05 mL, 47%) in acetonitrile (0.95
mL) gave 20 (2.2 mg, 99%) as a white solid: 1H NMR (CD3-
CN) δ 1.20 (3H, t, J ) 7.3 Hz), 2.89 (1H, dd, J ) 7.3, 9.8 Hz),
3.08 (1H, s), 3.35 (1H, s), 3.37 (1H, s), 3.67 (1H, dd, J ) 5.2,
9.8 Hz), 3.77 (2H, s), 3.82 (1H, m), 3.83 (1H, m), 4.09 (2H, q,
J ) 7.3 Hz), 4.31 (1H, m), 7.14-7.36 (5H, m); 13C NMR (CD3-
CN) δ 14.6, 36.7, 49.0, 54.2, 61.5, 72.4, 76.7, 78.3, 128.0, 129.4,
129.8, 139.9, 172.0; IR (Nujol) 3400, 1725 cm-1; MS (FAB) m/z
313 (MH+), 267, 91; [R]25D +9.8 (c 0.5, EtOH); HRMS calcd for
(1H, dd, J ) 1.8, 15.6 Hz), 7.12 (1H, dd, J ) 3.7, 15.6 Hz); 13
C
NMR (CDCl3) δ -5.1, -5.0, -4.7, -4.7, 14.2, 18.0, 18,1, 25.7,
60.4, 63.5, 74.1, 74.2, 121.3, 146.6, 166.3; IR (neat) 3460, 1725,
1655 cm-1; [R]25 +27.3 (c 1.43, CHCl3). Anal. Calcd for
D
C
20H42O5Si2: C, 57.37; H, 10.11. Found: C, 57.44; H, 10.09.
(E)-Eth yl (4R,5S)-4,5-Bis(ter t-bu tyld im eth ylsiloxy)-6-
oxoh ex-2-en oa te (16). By the same procedure for oxidation
of 6, treatment of 15 (836 mg, 2 mmol) with oxalyl chloride
(0.36 mL, 4 mmol), DMSO (0.36 mL, 4.8 mmol), and triethy-
lamine (2.4 mL) in CH2Cl2 (45 mL) gave, after bulb-to-bulb
distillation (200 °C, 0.3 mmHg), 16 as a pale yellow oil (716
mg, 86%): 1H NMR (CDCl3) δ 0.05 (3H, s), 0.06 (3H, s), 0.08
(6H, s), 0.92 (18H, s), 1.29 (3H, t, J ) 7.3 Hz), 4.02 (1H, dd, J
) 1.6, 4.9 Hz), 4.16-4.25 (2H, m), 4.56 (1H, ddd, J ) 1.8, 4.9,
4.9 Hz), 6.05 (1H, dd, J ) 1.8, 15.5 Hz), 7.05 (1H, dd, J ) 4.9,
15.5 Hz), 9.60 (1H, d, J ) 1.6 Hz).
C
15H21O5S 313.1110, found 313.1113.
(3a R,4R,5R,6S,6a S)-Eth yl 5-Ben zylsu lfa n yl-6-h yd r oxy-
2,2-d im et h ylt et r a h yd r o-3a H -cyclop en t a [1,3]d ioxole-4-
ca r boxyla te (21). To a solution of 20 (2.0 mg, 0.006 mmol) in
acetone (1 mL) was added p-toluenesulfonic acid monohydrate
Ster eoselective Mich a el-Ald ol Cycliza tion of 16 w ith
Bn SLi. To a solution of benzylthiol (0.03 mL, 0.24 mmol) in

Total Synthesis of (-)-Neplanocin A
J . Org. Chem., Vol. 66, No. 24, 2001 8203
(0.1 mg), and the mixture was stirred for 4 h at room
temperature. K2CO3 was added to the solution, and the
mixture was filtered. Concentration followed by silica gel
chromatography (hexane/EtOAc ) 1/1) gave 21 (2.0 mg, 89%)
as a colorless oil: 1H NMR (CDCl3) δ 1.24 (3H, s), 1.26 (3H,
dd, J ) 7.0, 7.0 Hz), 1.36 (3H, s), 2.48 (1H, brs), 2.91 (1H, ddd,
J ) 1.5, 6.4, 13.1 Hz), 3.65 (2H, m), 3.83 (2H, s), 4.17 (1H, dq,
J ) 7.0, 10.7 Hz), 4.23 (1H, dq, J ) 7.0, 10.7 Hz), 4.53 (1H, d,
J ) 5.8 Hz), 4.84 (1H, dd, J ) 5.8, 6.4 Hz), 7.25-7.40 (5H, m);
13C NMR (CDCl3) δ 14.2, 24.2, 25.8, 36.6, 49.4, 52.0, 60.8, 73.8,
79.8, 83.4, 111.0, 127.4, 128.7, 128.8, 137.8, 169.3; IR (neat)
stirred for 1 h at -78 °C, the mixture was diluted with ether
and the reaction was quenched with saturated aqueous NH4-
Cl. The resulting mixture was stirred for 1 h at room
temperature and then dried over MgSO4. Filtration followed
by concentration gave a crude 24 as an oil.
(3a S,4S,6a R)-6-(ter t-Bu t yld im et h ylsiloxym et h yl)-2,2-
dim eth yl-4,6a-dih ydr o-3aH-cyclopen ta[1,3]dioxol-4-ol (25).
To a solution of crude 24, triethylamine (0.09 mL, 0.66 mL),
and DMAP (5 mg, 0.04 mmol) in CH2Cl2 (3 mL) was added
tert-butyldimethylsilyl chloride (99 mg, 0.66 mmol). After being
stirred for 4 h at room temperature, the mixture was diluted
with ether. The organic layer was washed with saturated
aqueous NaHCO3 and saturated aqueous NH4Cl successively
and then dried over Na2SO4. Concentration followed by silica
gel chromatography (hexane/EtOAc ) 5/1) gave 25 (78 mg, 59%
from 23) as a colorless oil: 1H NMR (CDCl3) δ 0.08 (3H, s),
0.08 (3H, s), 0.92 (9H, s), 1.40 (3H, s), 1.43 (s, 3H), 2.67 (1H,
d, J ) 10.1 Hz), 4.24 (1H, d, J ) 15.3 Hz), 4.35 (1H, d, J )
15.3 Hz), 4.56 (1H, m), 4.76 (1H, dd, J ) 5.5, 5.5 Hz), 4.90
(1H, d, J ) 5.5 Hz), 5.73 (1H, s); 13C NMR (CDCl3) δ -5.6,
-5.6, 18.2, 25.7, 26.5, 27.5, 59.8, 73.1, 77.8, 82.6, 112.3, 129.1,
3450, 1730 cm-1; MS m/z 352 (M+), 261, 185, 91; [R]25 +8.33
D
(c 0.48, CHCl3); HRMS calcd for C18H24O5S 352.1344, found
352.1349.
(3a R,6R,6a S)-Eth yl 6-Hyd r oxy-2,2-d im eth yl-6,6a -d ih y-
d r o-3a H-cyclop en ta [1,3]d ioxole-4-ca r boxyla te (22). To a
solution of 21 (30 mg, 0.09 mmol) in EtOH (0.5 mL) and water
(0.5 mL) was added sodium metaperiodinate (36 mg, 0.017
mmol), and the mixture was stirred for 20 min at room
temperature. Brine was added to the mixture, and the aqueous
solution was extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4 and concentrated to
give a crude sulfoxide as an oil. The oil was dissolved in decalin
(1 mL), and the solution was heated for 20 min at 180 °C. After
cooling, the mixture was directly applied to silica gel chroma-
tography (hexane/ether ) 1/2) to give 22 (14 mg, 68%) as a
colorless oil: 1H NMR (CDCl3) δ 1.32 (3H, dd, J ) 7.0, 7.0 Hz),
1.37 (3H, s), 1.41 (3H, s), 1.98 (1H, brs), 4.17 (1H, dq, J ) 7.0,
10.7 Hz), 4.23 (1H, dq, J ) 7.0, 10.7 Hz), 4.60 (1H, d, J ) 5.8
Hz), 4.88 (1H, s), 5.47 (1H, dd, J ) 1.5, 5.8 Hz), 6.70 (1H, d, J
) 1.5 Hz); 13C NMR (CDCl3) δ 14.2, 25.4, 27.1, 61.1, 80.3, 82.6,
145.5; IR (neat) 3480 cm-1; [R]27 +22.4 (c 0.66, CHCl3).
D
(3a S,4R,6a R)-9-[6-(ter t-Bu t yld im et h ylsiloxym et h yl)-
2,2-d im eth yl-4,6a -d ih yd r o-3a H-cyclop en ta [1,3]d ioxol-4-
1
yl]-9H-p u r in -6-yla m in e (26): H NMR (CDCl3) δ 0.11 (6H,
s), 0.93 (9H, s), 1.36 (3H, s), 1.49 (s, 3H), 4.41 (1H, d, J ) 16.2
Hz), 4.46 (1H, d, J ) 16.2 Hz), 4.72 (1H, d, J ) 5.8 Hz), 5.31
(1H, d, J ) 5.8 Hz), 5.60 (1H, s), 5.79 (1H, s), 5.99 (2H, s),
7.69 (1H, s), 8.39 (1H, s); 13C NMR (CDCl3) δ -5.4, -5.4, 18.4,
25.9, 27.4, 60.4, 64.4, 83.6, 84.9, 112.7, 120.1, 121.1, 138.5,
149.9, 152.5, 153.3, 155.6; IR (CHCl3) 3480, 3390, 1630, 1580
86.3, 112.6, 139.3, 143.2, 163.8; IR (neat) 3470, 1725 1615 cm-1
;
cm-1; [R]29 -31.8 (c 0.40, CHCl3).
D
MS m/z 228 (M+); [R]25 +7.34 (c 1.03, CHCl3); HRMS calcd
(-)-Nep la n ocin A (1): white solid; mp 214-216 °C dec; 1H
NMR (DMSO-d6) δ 4.10 (2H), 4.29 (1H), 4.42 (1H), 4.90 (1H),
4.94 (1H), 5.12 (1H), 5.32 (1H), 5.69 (1H), 7.16 (2H), 8.04 (1H),
D
for C11H16O5 228.0998, found 226.0986.
(3a R,6a R)-Eth yl 2,2-Dim eth yl-6-oxo-6,6a -d ih yd r o-3a H-
cyclop en ta [1,3]d ioxole-4-ca r boxyla te (23). To a solution
of 22 (7 mg, 0.033 mmol) in CH2Cl2 (1 mL) was added PDC
(46 mg, 0.12 mmol), and the mixture was stirred for 3 h at
room temperature. The resultant suspension was diluted with
ether, Celite was added to the mixture, and whole was filtered.
Concentration of the filtrate, followed by silica gel chroma-
tography (hexane/ether ) 1/2), gave 23 (6.2 mg, 89%) as a pale
yellow oil: 1H NMR (CDCl3) δ 1.38 (3H, dd, J ) 7.0, 7.0 Hz),
1.42 (3H, s), 1.44 (3H, s), 4.37 (1H, dq, J ) 7.0, 11.0 Hz), 4.40
(1H, dq, J ) 7.0, 11.0 Hz), 4.59 (1H, d, J ) 5.8 Hz), 5.48 (1H,
d, J ) 5.8 Hz), 6.72 (1H, s); 13C NMR (CDCl3) δ 14.1, 26.0,
27.3, 62.2, 77.1, 78.1, 116.1, 137.2, 159.6, 163.1, 202.4; IR (neat)
1725 1615 cm-1; MS m/z 226 (M+); [R]25D +7.34 (c 1.03, CHCl3);
HRMS calcd for C11H14O5 226.0841, found 226.0846.
8.11 (1H); [R]29 -145.4 (c 0.11, H2O).
D
Ackn owledgm en t. We thank Professor Kunio Ogasa-
wara, Tohoku University, for kindly providing spectra
of the intermediates of neplanocin A. This research was
supported by a Grant-in-Aid for Scientific Research on
Priority Areas (A) “Exploitation of Multi-Element Cyclic
Molecules” from the Ministry of Education, Culture,
Sports, Science and Technology, J apan. K.N. was sup-
ported by a fellowship from the J SPS and a research
grant from Ajinomoto Co., Ltd.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure and spectroscopic data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(3a S,4S,6a R)-6-h yd r oxym eth yl-2,2-d im eth yl-4,6a -d ih y-
d r o-3a H-cyclop en ta [1,3]d ioxol-4-ol (24). To a solution of
23 (100 mg, 0.44 mmol) in toluene (10 mL) was added DIBALH
(3.98 mL, 1.0 M in hexane, 3.98 mmol) at -78 °C. After being
J O016090N