Stereoselective total synthesis of (-)-Ovalicin

Article abstract of DOI:10.1055/s-0029-1219191

A new synthetic route for epoxyketone 3 is described, which is a key intermediate in Bartons synthesis of ovalicin (1), a powerful anti-angiogenetic inhibitor, from commercially available d-ribose. The key reactions involved in this synthesis are ring-closing metathesis, Rubottom oxidation and Corey-Chaykovsky epoxidation. The subsequent transformations are carried out according to Bartons strategy to complete the total synthesis of (-)-ovalicin. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219191

LETTER
457
Stereoselective Total Synthesis of (–)-Ovalicin
S
tereosele
.
ctive
Total
S
S
ynthesis of (–)
.
-Ovalicin Yadav,* P. Narayana Reddy, B. V. Subba Reddy
Division of Organic Chemistry I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 28 August 2009
(RCM). Our retrosynthetic analysis is outlined in
Scheme 1.
Abstract: A new synthetic route for epoxyketone 3 is described,
which is a key intermediate in Barton’s synthesis of ovalicin (1), a
powerful anti-angiogenetic inhibitor, from commercially available
D-ribose. The key reactions involved in this synthesis are ring-clos-
ing metathesis, Rubottom oxidation and Corey–Chaykovsky epoxi-
dation. The subsequent transformations are carried out according to
Barton’s strategy to complete the total synthesis of (–)-ovalicin.
The synthesis of ovalicin began with readily available
sugar, D-ribose. Accordingly, treatment of D-ribose with
2,2-dimethoxypropane in the presence of 2% methanolic
HCl in anhydrous acetone gave the O-methyl-2,3-O-
isopropylidene8 derivative 5. Treatment of the alcohol 5
with iodine and triphenylphosphine in the presence of im-
idazole in toluene at 120 °C for three hours afforded io-
dofuranoside 6.9 Reaction10 of iodofuranoside 6 with allyl
bromide in the presence of activated zinc dust in THF–
H2O (4:1) under sonication conditions gave diene 7 as an
inseparable diastereomeric mixture in 79% yield. RCM of
Keywords: ribose, Rubottom oxidation, ring-closing metathesis,
Corey–Chaykovsky epoxidation
(–)-Ovalicin (1), a sesquiterpene first isolated from cul-
tures of the fungus Pseudorotium ovalis Stolk1 was found
to be a nontoxic, noninflammatory and a more potent anti-
angiogenesis agent than the structural analogue of fumag-
illin. It inhibits selectively type 2 methionine aminopepti-
dase (MetAP 2), which is related to many physiological
activities such as angiogenesis.2 It also exhibits antibiotic,
antitumor and immunosuppressive properties.3,4 TNP-
470, a semi-synthetic derivative of fumagillin, has also
been shown to inhibit angiogenesis and reduce the prolif-
eration of endothelial cells5 (Figure 1). This wide range of
activities of ovalicin has attracted several research groups
to accomplish its synthesis using different chemical ap-
proaches.6,7
O
O
OH
O
H
O
OMe
OMe
O
H
O
OH
O
O
ovalicin
fumagillin
O
O
H
OMe
H
O
N
According to our strategy, ovalicin could be retrosynthet-
ically cleaved into two major fragments i.e. cyclohexane
core 3 and side chain 4. The synthesis of cyclohexane core
could in turn be achieved by ring-closing metathesis
Cl
O
O
TNP-470
Figure 1 Chemical structures of ovalicin, fumagillin and TNP-470
O
O
O
OH
1
+
Li
OMe
OMe
OTBS
O
2
3
4
OH
OH
O
O
D-ribose
O
O
O
7
12
Scheme 1 Retrosynthesis of ovalicin
SYNLETT 2010, No. 3, pp 0457–0461
1
2.
0
2.
2
0
1
0
Advanced online publication: 11.01.2010
DOI: 10.1055/s-0029-1219191; Art ID: D23609ST
© Georg Thieme Verlag Stuttgart · New York

458
J. S. Yadav et al.
LETTER
O
O
OMe
OMe
I
HO
OH
2,2-dimethoxypropane
acetone, 2% MeOH–HCl
TPP, imidazole
I2, toluene
D-ribose
O
O
O
O
5
6
OH
O
allyl bromide, Zn
THF–H2O (4:1)
NaBH4, MeOH
Grubbs I catalyst
CH2Cl2
O
O
NiCl2⋅7H2O
7
O
8
OTMS
O
O
OH
LDA, THF
TMSCl
DMP, NaHCO3
CH2Cl2
1) m-CPBA, CH2Cl2
2) TBAF
O
O
O
O
O
9
10
11
OH
OTBDPS
O
O
TBDPSCl
imidazole, DMAP
O
O
O
O
12
13
Scheme 2
7 with 3 mol% of Grubbs’ first-generation catalyst11 under with TBAF gave the a-hydroxy cyclohexanone 12 as a
an argon atmosphere in dichloromethane at room temper- single isomer in 55% yield over two steps. Silylation of al-
ature afforded the desired cyclohexene derivative 8 in cohol 12 with tert-butyldiphenylsilyl chloride gave the si-
90% yield. Reduction of the double bond of compound 8 lyl ether 13.
with NaBH4 in methanol at 0 °C using a substoichiometric
amount of NiCl2·7H2O gave the substituted cyclohexanol
9 which was further oxidized to ketone 10 using Dess–
Martin periodinane.
As shown in Scheme 3, ketone 13 was converted into the
corresponding dithiane 14 in 79% yield with 1,3-pro-
panedithiol in the presence of Yb(OTf)3 in MeCN at re-
flux. The acetonide was concomitantly deprotected in the
Introduction of the 2-a-OH group was achieved by the above reaction to give the corresponding1,2-diol. Our ef-
Rubottom oxidation,12 via a sequence of silyl enol ether forts to protect the carbonyl group selectively without af-
formation, epoxidation and desilylation as depicted in fecting the acetonide failed. Therefore, the resulting 1,2-
Scheme 2. Accordingly, ketone 10 was deprotonated with diol was protected again as diacetate 15 in 93% yield.
LDA in anhydrous THF at –78 °C over 30 minutes and the Deprotection of the tert-butyldiphenylsilyl ether of 15
resulting lithium enolate was trapped with TMSCl to give with tetrabutylammonium fluoride in tetrahydrofuran
trimethylsilyl enol ether 11. Oxidation of the crude silyl over 12 hours gave compound 16 in 95% yield. Oxidation
enol ether 11 with m-CPBA at low temperature (–20 °C) of 16 with the Dess–Martin periodinane (DMP) afforded
in anhydrous CH2Cl2 and a subsequent silyl deprotection cyclohexenone 17 in 89% yield. Our next objective was
OTBDPS
O
TBDPSO
TBDPSO
S
S
1,3-propanedithiol
Yb(OTf)3
Ac2O, Et3N
TBAF
THF
S
S
, MeCN
DMAP, CH2Cl2
OH
OAc
O
OH
14
OAc
15
O
13
O
OH
S
S
S
DMP, NaHCO3
CH2Cl2
S
S
S
X
OAc
OAc
OAc
OAc
OAc
OAc
16
17
Scheme 3
Synlett 2010, No. 3, 457–461 © Thieme Stuttgart · New York

LETTER
Stereoselective Total Synthesis of (–)-Ovalicin
459
methylenation of the highly hindered ketone 17. Olefina- Next, we turned our attention to the conversion of the al-
tion of ketone 17 using either Corey’s reagent cohol 20 into its methyl ether 21. Although conventional
(Ph3P=CHLi)13 or the Tebbe reaction14 and direct methyl- reagents NaH and MeI failed, MeI in the presence of
enation of ketone 17 using Yan’s reaction conditions15 re- Ag2O in diethyl ether at 50 °C overnight gave the methy-
sulted only in recovery of the starting material; the steric lated product 21 in 74% yield. At this stage, we made sev-
environment of this ketone presumably impeding at- eral attempts to remove the dithiane group. All standard
tempts to effect this transformation directly. Therefore, methods for dithiane deprotection resulted in decomposi-
we modified our strategy and the following reaction se- tion of starting material. However, a two-step intramolec-
quence was successfully realized (Scheme 4). Since the ular Pummerer-based protocol18 was successful.
hydroxy group on C5 needs to be methylated in the final Accordingly, the dithiane was oxidized to the monosul-
product, compound 17 was treated with potassium car- foxide (m-CPBA, 0 °C), and the resulting crude monosul-
bonate in methanol to cleave the acetate groups so as to foxide was exposed to Ac2O, Et3N and H2O to give the
give vic-diol 18. Subsequently, we attempted selective desired ketone 3 in 59% yield. The 1H NMR and 13C NMR
protection of the vicinal diol moiety of 18. Since the hy- spectra and specific rotation of the ketone 3 were in agree-
droxy function at C5 is sterically encumbered by the vici- ment with the reported values.7c The ketone 3 is a key in-
nal dithiane group, we were able to protect selectively the termediate for the synthesis of ovalicin. Thus, the formal
axial hydroxy group at C6 with TBSCl. This was accom- synthesis of ovalicin was accomplished and subsequently
plished by performing the reaction in CH2Cl2 at 0 °C for the synthesis of (–)-ovalicin (1) was then completed as de-
30 minutes and then at room temperature to furnish the picted in Scheme 5.
monoprotected derivative 19 in 88% yield.
The next task was the diastereoselective introduction of formed according to Barton’s procedure.6c The alkenyl-
Introduction of the side chain onto ketone 3 was per-
the epoxide moiety in ketone 19. To introduce the oxirane lithium
was
prepared
from
acetone-2,4,6-
moiety stereoselectively, we used the Corey–Chaykovsky triisopropylbenzenesulfonylhydrazone and 3,3-dimethy-
protocol.16 The ylide derived from trimethylsulfoxonium lallyl bromide using the Shapiro reaction. Freshly pre-
iodide afforded the desired epoxide 20 as the major prod- pared alkenyllithium 4 was added to a solution of 3 in
uct in 50% yield (>94:6 dr) resulting from attack on the si anhydrous toluene at –78 °C, and the resulting solution
face of the ketone17. The major isomer was easily separat- was allowed to stir at the same temperature for three hours
ed from the minor isomer by silica gel column chromatog- and then warmed gradually to 0 °C to give compound 22
raphy. The absolute stereochemistry was confirmed by the in 69% yield. Desilylation of compound 22 with TBAF at
subsequent conversion of compound 20 into the known 0 °C gave the alcohol 23 in 64% yield. Oxidation of 23 us-
Barton intermediate 3.
ing Dess–Martin periodinane gave ketone 2 in 64% yield.
O
S
O
O
S
S
Me3S+OI–, NaH
K2CO3
MeOH
TBSCl
S
S
S
imidazole
CH2Cl2
LiI, DMSO–THF
0 °C to r.t.
OAc
OH
OH
OAc
OH
OTBS
17
18
19
O
O
S
O
S
O
MeI, Ag2O
Et2O
m-CPBA
S
S
Ac2O, Et3N, H2O
OMe
OH
OMe
OTBS
3
OTBS
20
OTBS
21
Scheme 4
O
OH
O
O
OH
O
Li
4
TBAF
THF
toluene, –78 °C, 3 h
OMe
OMe
OMe
OH
OTBS
OTBS
3
22
23
O
OH
O
OH
DMP, NaHCO3
CH2Cl2
VO(acac)2
O
TBHP, toluene, 0 °C
OMe
OMe
O
O
1
2
Scheme 5
Synlett 2010, No. 3, 457–461 © Thieme Stuttgart · New York

460
J. S. Yadav et al.
LETTER
(16) (a) Corey, E. J.; Chakovsky, M. J. Am. Chem. Soc. 1965, 87,
1353. (b) Harwood, L. M.; Casy, G.; Sherlock, J. Synth.
Commun. 1990, 1287.
(17) (a) Rodeschini, V.; Boiteau, J. G.; Weghe, P. V.; Tarnus, C.;
Eustache, J. J. Org. Chem. 2004, 69, 357. (b) Boiteau, J. G.;
Weghe, P. V.; Eustache, J. Org. Lett. 2001, 3, 2737.
(c) Mazitschek, R.; Huwe, A.; Giannis, A. Org. Biomol.
Chem. 2005, 3, 2150. (d) Tabber, D. F.; Christos, T. E.;
Rheingold, A. L.; Guzei, A. J. Am. Chem. Soc. 1999, 121,
5589.
(18) (a) Kishi, Y.; Fukuyama, T.; Natatsuka, S. J. Am. Chem. Soc.
1973, 95, 6490. (b) Fukuyama, T.; Natatsuka, S.; Kishi, Y.
Tetrahedron 1981, 37, 2045. (c) Wu, Z.; Williams, L. J.;
Danishefsky, S. J. Angew. Chem. 2000, 39, 3866.
Selective allylic epoxidation of compound 2 using va-
nadyl acetylacetonate and t-BuOOH at C4 position gave
the target molecule (–)-ovalicin in 48% yield whose data
were identical in all respects with those reported in litera-
ture.7c
In summary we have accomplished the synthesis of (–)-
ovalicin19 by a chiron approach. The convergent nature of
the strategy described herein may facilitate the synthesis
of biologically active analogues of ovalicin.
Acknowledgment
(d) Smith, A. B.; Dorsey, B. D.; Visnick, M.; Maeda, T.;
Malamas, M. S. J. Am. Chem. Soc. 1986, 108, 3110.
(19) Spectroscopic Data for Selected Products:
(3aS,7aR)-2,2-Dimethyl-3a,4,5,7a-tetrahydro-1,3-
benzodioxol-4-ol (8): major isomer, brown solid; mp 88–
90 °C; [a]D –18.1 (c = 1, CHCl3). IR (neat): 3440, 2923,
1648, 1373, 1075 cm–1. 1H NMR (300 MHz, CDCl3): d =
1.37 (s, 3 H), 1.40 (s, 3 H), 1.96 (d, J = 8.7 Hz, 1 H), 2.25 (m,
2 H), 3.83 (m, 1 H), 4.34 (m, 1 H), 4.56 (s, 1 H), 5.69 (m, 2
H). 13C NMR (75 MHz, CDCl3): d = 126.6, 126.0, 109.4,
76.1, 73.4, 67.1, 28.7, 27.3, 26.3. MS (ESI): m/z = 193 [M +
Na]+.
P.N.R. thanks CSIR, New Delhi, for the award of a fellowship.
References and Notes
(1) (a) Sigg, H. P.; Weber, H. P. Helv. Chim. Acta 1968, 51,
1395. (b) Bollinger, P.; Sigg, H. P.; Weber, H. P. Helv.
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(2) Griffith, E. C.; Su, Z.; Niwayama, S.; Ramsay, C. A.; Chang,
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15183.
(3) Zimmermann, W. A.; Hartmann, G. R. Eur. J. Biochem.
1981, 118, 143.
(4) Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.; Kanamaru,
T.; Brem, H.; Folkman, J. Nature (London) 1990, 348, 555.
(5) Borel, J. F.; Lazary, S.; Staehelin, H. Agents Actions 1974,
4, 357.
(6) (a) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107,
256. (b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am.
Chem. Soc. 1994, 116, 12109. (c) Barton, D. H. R.; Bath, S.;
Billington, D. D.; Gero, S. D.; Quiclet-Sire, B.; Samadi, M.
Org. Bioorg. Chem. 1995, 12, 1551. (d) Barco, A.; Benetti,
S.; De Risi, C.; Marchetti, P.; Pollini, G. P.; Zanirato, V.
Tetrahedron: Asymmetry 1998, 9, 2857.
(7) (a) Yamaguchi, J.; Toyoshima, M.; Shoji, M.; Kakeya, H.;
Osada, H.; Hayashi, Y. Angew. Chem. Int. Ed. 2006, 45,
789. (b) Takahashi, S.; Hishinuma, N.; Koshino, H.; Nakata,
T. J. Org. Chem. 2005, 70, 10162. (c) Tiefenbacher, K.;
Arion, V. B.; Mulzer, J. Angew. Chem. Int. Ed. 2007, 46,
2690. (d) Yadav, J. S.; Sreedhar, P.; Dinesh, C. B.; Srihari,
P. Synlett 2007, 992. (e) Hua, H.; Zhao, H.; Battina, K.; Lou,
K.; Jimenez, L.; Desper, J.; Perchellet, M.; Perchellet, H.;
Chaiang, K. Bioorg. Med. Chem. 2008, 16, 5232.
(8) Leonard, N. J.; Carraway, K. L. J. Heterocycl. Chem. 1966,
3, 485.
(3aS,7aR)-2,2-Dimethylperhydro-1,3-benzodioxol-4-ol
(9): mixture of isomers, yellow oil; [a]D –26.6 (c = 1,
CHCl3). IR (neat): 3446, 2937, 1376, 1032, 876 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.35 (s, 3 H), 1.50 (s, 3 H),
1.54–1.80 (m, 6 H), 2.07 (s, 1 H), 3.68–3.76 (m, 1 H), 4.14–
4.22 (m, 2 H). 13C NMR (75 MHz, CDCl3): d = 108.5, 81.5,
75.7, 74.4, 72.6, 68.2, 30.4, 28.3, 27.6, 27.5, 27.0, 26.7, 26.2,
25.6, 18.6, 17.4. MS (ESI): m/z = 195 [M + Na]+.
(3aR,7aR)-2,2-Dimethylperhydro-1,3-benzodioxol-4-one
(10): white solid; mp 112–114 °C; [a]D –63.2 (c = 1, CHCl3).
IR (neat): 3447, 2937, 1726, 1376, 1220 cm–1. 1H NMR (200
MHz, CDCl3): d = 1.36 (s, 3 H), 1.41 (s, 3 H), 1.82–2.06 (m,
3 H), 2.14–2.38 (m, 2 H), 2.43–2.56 (m, 1 H), 4.22 (d, J =
5.4 Hz, 1 H), 4.53–4.61 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 208.4, 109.4, 79.1, 39.9, 26.9, 26.7, 25.8, 20.2,
17.4. MS (ESI): m/z = 171 [M + H]+.
(3aR,5R,7aR)-5-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-2,2-
dimethylperhydro-1,3-benzodioxol-4-one (13): colorless
liquid; [a]D –62.4 (c = 1.7, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 1.08 (s, 9 H), 1.36 (s, 3 H), 1.37 (s, 3 H), 1.73–
1.92 (m, 2 H), 1.95–2.05 (m, 1 H), 2.41–2.55 (m, 1 H), 4.18
(dd, J = 2.2, 3.7 Hz, 1 H), 4.61 (m, 1 H), 4.82 (d, J = 5.2 Hz,
1 H), 7.31–7.46 (m, 6 H), 7.50–7.54 (m, 2 H), 7.58–7.62 (m,
2 H). 13C NMR (75 MHz, CDCl3): d = 206.4, 135.5, 135.4,
134.7, 132.9, 130.1, 129.5, 127.8, 127.6, 109.6, 78.5, 77.8,
76.3, 29.2, 26.9, 26.8, 26.5, 26.1, 20.6. MS (ESI): m/z = 447
[M + Na]+.
(7R,8R,11R)-11-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1,5-
dithiaspiro[5.5]undecane-7,8-diol (14): semi solid; [a]D
+16.7 (c = 1.3, CHCl3). IR (neat): 3446, 2925, 2854, 1109,
702 cm–1. 1H NMR (200 MHz, CDCl3): d = 1.09 (s, 9 H),
1.32–2.16 (m, 7 H), 2.56–2.70 (m, 1 H), 2.75–2.89 (m, 2 H),
2.92–3.11 (m, 2 H), 3.91 (dd, J = 3.8 Hz, 1 H), 4.08–4.22 (m,
2 H), 7.28–7.47 (m, 6 H), 7.65–7.81 (m, 4 H). 13C NMR (75
MHz, CDCl3): d = 136.5, 135.5, 132.7, 132.2, 130.1, 129.6,
127.8, 127.4, 75.0, 74.4, 73.1, 29.6, 29.2, 27.2, 26.8, 23.3,
19.2. MS (ESI): m/z = 497 [M + Na]+.
(9) Garegg, P. J.; Samuelson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866.
(10) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000, 122, 8444.
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371. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036. (d) Furstner, A. Angew. Chem. Int.
Ed. 2000, 39, 3013.
(12) (a) Rubottom, G. M.; Vazquez, M. A.; Pellagrina, D. R.
Tetrahedron Lett. 1974, 4319. (b)Rubottom, G. M.; Gruber,
J. M.; Juve, H. D.; Charleson, D. A. Org. Synth. 1986, 64,
118. (c) Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org.
Chem. 1975, 40, 3427. (d) Brook, A. G.; Macrae, D. M.
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(7R,8R,11R)-7-(Acetyloxy)-11-[1-(tert-butyl)-1,1-
diphenylsilyl]oxy-1,5-dithiaspiro[5.5]undec-8-yl Acetate
(15): semi solid; [a]D +25.2 (c = 1, MeOH). IR (neat): 3451,
2929, 2856, 1743, 1245, 703 cm–1. 1H NMR (300 MHz,
555.
(14) Pine, S. H.; Shen, G. S.; Hoang, H. Synthesis 1991, 165.
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Synlett 2010, No. 3, 457–461 © Thieme Stuttgart · New York

LETTER
CDCl3): d = 1.10 (s, 9 H), 1.24–1.61 (m, 5 H), 1.93 (s, 3 H),
Stereoselective Total Synthesis of (–)-Ovalicin
461
2.87–3.00 (m, 2 H), 3.26–3.38 (m, 1 H), 3.97 (d, J = 2.2 Hz,
1 H), 4.35–4.42 (m, 1 H). 13C NMR (75 MHz, CDCl3): d =
207.2, 78.2, 77.7, 75.6, 30.8, 29.4, 27.0, 26.1, 25.5, 20.4,
17.9, –5.12, –5.17. MS (ESI): m/z = 371 [M + Na]+.
tert-Butyl[(3S,10R,11R)-10-methoxy-1-oxa-5,9-
1.96 (s, 3 H), 2.02–2.16 (m, 1 H), 2.50–2.60 (m, 1 H), 2.74–
2.84 (m, 1 H), 2.98–3.10 (m, 1 H), 3.14–3.26 (m, 1 H), 3.88
(dd, J = 4.5, 12.0 Hz, 1 H), 5.53–5.62 (m, 1 H), 5.77 (d, J =
1.5 Hz, 1 H), 7.31–7.41 (m, 6 H), 7.68–7.73 (m, 2 H), 7.76–
7.81 (m, 2 H). 13C NMR (75 MHz, CDCl3): d = 136.3, 136.0,
135.2, 134.7, 129.6, 129.4, 127.5, 127.3, 73.4, 69.1, 60.5,
26.9, 26.5, 25.6, 24.8, 23.5, 20.8, 20.6, 19.6, 18.9. MS (ESI):
m/z = 581 [M + Na]+.
(7R,8R)-7-(Acetyloxy)-11-oxo-1,5-dithiaspiro[5.5]undec-
8-yl Acetate (17): white solid; mp 82–84 °C; [a]D +163.1
(c = 1, CHCl3). IR (neat): 2924, 2854, 1747, 1236, 721 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.95–2.07 (m, 6 H), 2.11
(s, 3 H), 2.13–2.31 (m, 1 H), 2.41–2.55 (m, 1 H), 2.66–2.84
(m, 2 H), 2.91–3.24 (m, 3 H), 5.72–5.83 (m, 2 H). 13C NMR
(75 MHz, CDCl3): d = 200.9, 170.0, 169.5, 73.9, 67.5, 59.6,
33.8, 26.9, 26.4, 24.6, 24.0, 20.7, 20.4. MS (ESI): m/z = 319
[M + H]+.
(10R,11R)-10,11-Dihydroxy-1,5-dithiaspiro[5.5]undecan-
7-one (18): white solid; mp 101–103 °C; [a]D +145.9 (c = 1,
CHCl3). IR (neat): 3446, 2924, 1705, 1219, 771 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (s, 1 H), 1.52–1.69 (m,
1 H), 1.76–1.93 (m, 1 H), 2.03–2.26 (m, 2 H), 2.34–2.44 (m,
1 H), 2.60–2.70 (m, 3 H), 2.87–3.03 (m, 1 H), 3.18–3.32 (m,
1 H), 3.52 (d, J = 9.0 Hz, 1 H), 3.70–3.81 (m, 1 H), 4.08–4.18
(m, 1 H). 13C NMR (75 MHz, CDCl3): d = 202.7, 78.9, 68.4,
67.0, 33.3, 27.3, 26.9, 26.1, 24.2. MS (ESI): m/z = 257 [M +
Na]+.
(10R,11R)-10-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-11-
hydroxy-1,5-dithiaspiro[5.5]undecan-7-one (19): semi
solid; [a]D +93 (c = 1.25, CHCl3). IR (neat): 3504, 2928,
2855, 1709, 1109, 837 cm–1. 1H NMR (300 MHz, CDCl3):
d = 0.12 (s, 3 H), 0.15 (s, 3 H), 0.92 (s, 9 H), 1.42 (s, 1 H),
1.74–1.93 (m, 2 H), 2.01–2.21 (m, 2 H), 2.54–2.68 (m, 3 H),
dithiadispiro[2.0.5.4]tridec-11-yl]oxydimethylsilane
(21): yellow oil; [a]D –21.9 (c = 0.35, CHCl3). IR (neat):
3373, 2922, 2853, 2365, 1466, 756 cm–1. 1H NMR (200
MHz, CDCl3): d = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.90 (s, 9 H),
1.53–2.19 (m, 5 H), 2.37–2.74 (m, 4 H), 3.21–3.40 (m, 2 H),
3.42–3.54 (m, 2 H), 3.56 (s, 3 H), 4.17–4.29 (m, 1 H). 13
C
NMR (75 MHz, CDCl3): d = 88.6, 83.0, 71.3, 69.8, 52.7,
32.0, 31.1, 30.6, 29.6, 29.3, 28.1, 27.4, 25.8, 24.5, –4.7.
MS (ESI): m/z = 399 [M + Na]+.
(3S,5R,6R)-6-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-5-
methoxy-1-oxaspiro [2.5]octan-4-one (3): yellow oil; [a]D
–1.20 (c = 1, CH2Cl2). IR (neat): 2922, 2852, 1737, 1461,
762 cm–1. 1H NMR (200 MHz, CDCl3) : d = 0.07 (s, 3 H),
0.08 (s, 3 H), 0.92 (s, 9 H), 1.40–1.60 (m, 1 H), 2.00–2.20
(m, 2 H), 2.40–2.60 (m, 1 H), 2.77 (d, J = 4.7 Hz, 1 H), 3.29
(d, J = 4.7 Hz, 1 H), 3.44 (s, 3 H), 3.98 (d, J = 2.5 Hz, 1 H),
4.44 (m, 1 H). 13C NMR (75 MHz, CDCl3): d = 202.4, 87.5,
72.3, 60.7, 58.5, 51.4, 28.9, 27.1, 25.9, 18.3, –4.4, –5.0. MS
(ESI): m/z = 309 [M + Na]+.
(–)-Ovalicin (1): white solid; mp 94–95 °C; [a]D –112 (c =
0.2, CHCl3). IR (neat): 3438, 2923, 2853, 1728, 1627, 1459,
1216, 761 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.37 (s, 3
H), 1.41–1.45 (m, 1 H), 1.66 (s, 3 H), 1.75 (s, 3 H), 2.12–2.18
(m, 1 H), 2.30–2.45 (m, 2 H), 2.61–2.71 (m, 2 H), 2.73 (d,
J = 4.2 Hz, 1 H), 2.90 (t, J = 6.3 Hz, 1 H), 3.10 (d, J = 4.2
Hz, 1 H), 3.14 (s, 1 H), 3.57 (s, 3 H), 4.23 (s, 1 H), 5.18 (t,
J = 6.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 206.8,
135.7, 118.2, 86.3, 78.8, 60.7, 60.5, 59.5, 57.0, 51.5, 36.9,
30.5, 27.2, 25.9, 18.2, 14.6. MS (ESI): m/z = 319 [M + Na]+.
Synlett 2010, No. 3, 457–461 © Thieme Stuttgart · New York

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