Tetrahydroxy 10-Membered Cyclic Enediynes

Article abstract of DOI:10.1021/jo035250n

The preparation of cyclic 10-membered tetrahydroxy enediynes is reported. The synthesis starts from tartaric acid and allows the control of the relative stereochemistry. Acetal protection of the 2,3-hydroxy groups stabilizes the enediyne during synthesis.

Full text of DOI:10.1021/jo035250n

Tetr a h yd r oxy 10-Mem ber ed Cyclic En ed iyn es
Michael Klein,† Manfred Zabel,‡ Gu¨nther Bernhardt,§ and Burkhard Ko¨nig*,†
Institut fu¨r Organische Chemie, Universita¨t Regensburg, D-93040 Regensburg, Germany
burkhard.koenig@chemie.uni-regensburg.de
Received August 27, 2003
The preparation of cyclic 10-membered tetrahydroxy enediynes is reported. The synthesis starts
from tartaric acid and allows the control of the relative stereochemistry. Acetal protection of the
2,3-hydroxy groups stabilizes the enediyne during synthesis. Removal of the cyclic protecting group
with EtSH/TFA transforms the stable compounds into reactive enediynes, and the rate constants
of their cyclization were determined in benzene and water. The cytoxicity of the activated compounds
was assayed against tumor cells in vitro, but the growth inhibitory effect was weak compared to
cisplatin.
In tr od u ction
prohibits spontaneous cyclization,5 isomerization of ene-
diynes to the more reactive cumulene-eneynes,6 genera-
tion of the enediyne system by retro-Diels-Alder,7 SN2′
reaction,8 or alkyne deprotection9 or the induction of the
cyclization by catalytic antibodies,10 metal cations,11
oxidation,12 or light.13 Hydroxylated enediynes are well
suited to reversibly lock their conformation and therefore
modulate their reactivity by cyclic hydroxy protecting
The cytotoxic properties of natural products such as
calicheamicin γ1 , dynemicin A, or neocarzinostatin1 have
I
their origin in strained cyclic enediyne or cumulene-
eneyne structures. Their spontaneous thermal cyclization
yields reactive aryl or benzyl diradicals, which abstract
hydrogen atoms, leading to DNA strand cleavage and
ultimately to cell death.2 To fulfill their biological func-
tion, the reactivity of the unsaturated macrocycles must
be regulated. In the natural products this is achieved
either by trigger mechanisms that unlock conformation-
ally constrained precursors3 or by proteins, which tightly
bind and stabilize the enediyne or cumulene-eneynes
chromophore.4 To control the reactivity in synthetic
enediyne model compounds, several strategies have been
reported: release of a conformational constrain that
(4) Carrier protein to which the active enediyne chromophore is
tightly noncovalently bound plays an important role in the direction,
protection, and regulation of the chromophore, e.g., in the case of the
neocarzinostatin chromophore: Chin, D.-H. Chem. Eur. J . 1999, 5,
1084-1090 and refs cited therein.
(5) (a) Nicolaou, K. C.; Sorensen, E. J .; Discordia, R.; Hwang, C.-
K.; Minto, R. E.; Bharucha, K. N.; Bergman, R. G. Angew. Chem. 1992,
104, 1094-1096; Angew. Chem., Int. Ed. Engl. 1992, 31, 1044-1046.
(b) Nicolaou, K. C.; Dai, W.-M.; Hong, Y. P.; Tsay, S.-C.; Baldridge, K.
K.; Siegel, J . S. J . Am. Chem. Soc. 1993, 115, 7944-7953. (c) Banfi,
L.; Basso, A.; Guanti, G. Tetrahedron Lett. 1997, 53, 3249-3268. (d)
Banfi, L.; Guanti, G., Basso, A. Eur. J . Org. Chem. 2000, 939-946. (e)
Basak, A.; Khamrai, U. K. Tetrahedron Lett. 1996, 37, 2475-2478. (f)
Semmelhack, M. F.; Gu, Y.; Ho, D. M. Tetrahedron Lett. 1997, 38,
5583-5586.
(6) (a) Wu, M.-J .; Lin, C.-F.; Wu, J .-S.; Chen, H.-T. Tetrahedron Lett.
1994, 35, 1879-1882. (b) Nicolaou, K. C.; Maligres, P.; Shin, J .; de
Leon, E.; Rideout, D. J . Am. Chem. Soc. 1990, 112, 7825-7826. (c)
Suzuki, I.; Bando, N.; Nemoto, H.; Shibuya, M. Tetrahedron Lett. 1998,
39, 2361-2364.
(7) Bunnage, M. E.; Nicolaou, K. C. Chem. Eur. J . 1997, 3, 187-
192.
(8) Dai, W.-M.; Fong, K. C.; Lau, C. W.; Zhou, L.; Hamaguchi, W.;
Nishimoto, S. J . Org. Chem. 1999, 64, 682-683.
(9) (a) J ones, G. B.; Hynd, G.; Wright, J . M.; Purohit, A.; Plourde,
G. W., II; Huber, R. S.; Li, A.; Kilgore, M. W.; Bubley, G. J .; Yancisin,
M.; Brown, M. A. J . Org. Chem. 2001, 66, 3688-3695. (b) J ones, G.
B.; Plourde, G. W., II; Wright, J . M. Org. Lett. 2000, 2, 811-813.
(10) J ones, L. H.; Harwig, C. W.; Wentworth, P., J r.; Simeonov, A.;
Wentworth, A. D.; Py, S.; Ashley, J . A.; Lerner, R. A.; J anda, K. D. J .
Am. Chem. Soc. 2001, 1213, 3607-3608.
(11) (a) Ko¨nig, B. Eur. J . Org. Chem. 2000, 381-385 and refs cited
therein. (b) Rawat, D. S.; Zaleski, J . M. J . Am. Chem. Soc. 2001, 123,
9675-9676. (c) O’Connor, J . M.; Friese, S. J .; Tichenor, M. J . Am.
Chem. Soc. 2002, 124, 3506-3507.
(12) For induction of enediyne cyclization by oxidation, see: (a)
Ramkumar, D.; Kalpana, M.; Varghese, B.; Sankararaman, S. J . Org.
Chem. 1996, 61, 2247-2250. (b) Semmelhack, M. F.; Neu, T.; Foubelo,
F. J . Org. Chem. 1994, 59, 5038-5047. For pH-dependent cyclization
at higher temperatures, see: (c) Kim, C.-S.; Diez, C.; Russell, K. C.
Chem. Eur. J . 2000, 6, 1555-1558. For the effect of vinyl substitution,
see: (d) J ones, G. B.; Warner, P. M. J . Am. Chem. Soc. 2001, 123,
2134-2145.
* Fax (int.): +49-941-943-1717.
† Institut fu¨r Organische Chemie.
‡ Current address: Zentrale Analytik der NWF IV, Universita¨t
Regensburg, 93040 Regensburg, Germany.
§ Current address: Institut fu¨r Pharmazie, Universita¨t Regensburg,
D-93040 Regensburg, Germany.
(1) (a) Nicolaou, K. C.; Smith, L. A. In Modern Acetylene Chemistry;
Stang, P. J ., Diederich, F., Eds. VCH: Weinheim, 1995; pp 203-283.
(b) Maier, M. E. Synlett 1995, 13-26. (c) Sorensen, E. J .; Nicolaou, K.
C.; Winssinger, N. J . Chem. Edu. 1998, 75, 1225-1258. (d) Groneberg,
R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J .; Stahl, W.;
Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, L. A.; Nicolaou, K.
C. J . Am. Chem. Soc. 1993, 115, 7593-7611. (e) Myers, A. G.; Liang,
J .; Hammond, M.; Harrington, M. P.; Wu, Y.; Kuo, E. Y. J . Am. Chem.
Soc. 1998, 120, 5319-5320. (f) Clive, D. L. J .; Bo, Y.; Tao, Y.;
Daigneault, S.; Wu, Y.-Y.; Meignan, G. J . Am. Chem. Soc. 1998, 120,
10332-10349.
(2) Initially formed diradical is less reactive than the phenyl radical,
which is obtained after one hydrogen abstraction. This fact is of
importance for efficient DNA-strand cleavage by enediyne antibiotics.
Schottelius, M. J .; Chen, P. J . Am. Chem. Soc. 1996, 118, 4896-4903.
(3) In most cases, a strained, and therefore even at room temper-
ature highly reactive, cyclic enediyne or cumulene-eneyne is held in a
conformation that kinetically disfavors the cyclization reaction. A small
change in conformation, caused, e.g., by a nucleophile that adds to a
double bond or an epoxide, releases the constraint, and the cyclization
to the arene diradical proceeds instantaneously. (a) Haseltine, J . N.;
Cabal, M. P.; Mantlo, N. B.; Iwasawa, N.; Yamashita, D. S.; Coleman,
R. S.; Danishefsky, S. J .; Schulte, G. K. J . Am. Chem. Soc. 1991, 113,
3850-3866. (b) Nicolaou, K. C.; Dai, W.-M. J . Am. Chem. Soc. 1992,
114, 8908-8921.
10.1021/jo035250n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/30/2003
J . Org. Chem. 2003, 68, 9379-9383
9379

Klein et al.
groups.14 Nicolaou et al. reported an enediyne diol and
its carbonate as the first example of this kind.5a,15 We
present here the stereodefined synthesis of enediyne
tetraols. The cyclic enediynes become water soluble16 by
the additional hydroxy groups and still can be regulated
in their reactivity by cyclic protecting groups.
SCHEME 1. Syn th esis of P r otected Tetr a h yd r oxy
En ed iyn e 13
Resu lts a n d Discu ssion
Fallis et al.17 reported the first synthesis of a protected
tetrahydroxy enediyne18 using Cr(II)/Ni(II)-mediated cou-
pling of an iodoalkyne to an aldehyde for ring closure.
In their route, the sensitive enediyne was taken through
the synthesis, while we intended to build up the enediyne
in the last steps. Starting material 1 was prepared from
L-tartaric acid. The reaction of (-)-dimethyl-2,3-O-iso-
propylidene-L-tartrate19 with N,O-dimethylhydroxylamine
hydrochloride and AlMe3 gave the 2-fold Weinreb amide
in 85% yield.20 The reaction of compound 1 with the
lithium salt of THP-protected propargylic alcohol gave
single substitution as the major product pathway. Using
the magnesium salt 2 yielded 3 in 73% yield by clean
2-fold substitution. Initial attempts to continue the
enediyne synthesis at the oxidation level of the diketone
were not successful.21 Therefore, reduction was performed
at this stage using DIBAL-H at -78 °C. The diol was
obtained in good chemical yield but as an equal mixture
of two out of the three possible diastereomers. To improve
the diastereoselectivity of the reduction, several alterna-
tive reagents and conditions were tested, but the selec-
tivity did not improve and chemical yields decreased. The
isomeric mixture was carried through two further steps,
TBDMS protection and THP deprotection, to facilitate
separation and determination of configuration.22 Selective
THP deprotection requires magnesium dibromide in
diethyl ether as a reagent. Methanol/acidic ion-exchange
resin or methanol/iodine23 leads to partial TBDMS depro-
tection. The two isomers of compound 6 were separated
by column chromatography on silica gel. 1H and 13C NMR
spectra of one isomer reveal a full set of resonances not
reduced by symmetry, which corresponds to the nonsym-
metric (1R,4S)-6 isomer. The NMR spectra of the second
(13) (a) Evenzahav, A.; Turro, N. J . J . Am Chem. Soc. 1998, 120,
1835-1841. (b) J ones, G. B.; Wright, J . M.; Plourde, G., II; Purohit, A.
D.; Wyatt, K. J .; Hynd, G.; Fouad, F. J . Am. Chem. Soc. 2000, 122,
9872-9873.
isomer show a symmetry reduced half set of resonances,
which agrees with (1R,4R)-6 and (1S,4S)-6 but allows no
distinction. An X-ray structure analysis (see Supporting
Information) of the compound confirmed its structure to
be (1R,4R)-6. The pure isomers were taken separately
through the following synthetic steps to complete the
synthesis (only one isomer reaction is shown in Scheme
1). Oxidation of (1R,4R)-6 using the Dess-Martin reagent
gave dialdehyde (1R,4R)-8 in good yield. A pinacol-type
reaction was used in the next step for ring closure. The
Pederson vanadium(II) reagent is suitable to mediate the
reaction as shown in earlier reports,24 because it favors
the formation of the desired cis-diol,25 presumably by a
cyclic chelate transition state.26 Diol (1R,4R)-9 was
(14) Pitsch, W.; Klein, M.; Zabel, M.; Ko¨nig, B. J . Org. Chem. 2002,
67, 6805-6807.
(15) For a recent report on the synthesis of â-lactam fused cyclic
enediynes, see: Basak, A.; Mandal, S. Tetrahedron Lett. 2002, 43,
4241-4243.
(16) Unno, R.; Michishita, H.; Inagaki, H.; Suzuki, Y.; Baba, Y.;
J omori, T.; Nishikawa, T.; Isobe, M. Bioorg. Med. Chem. 1997, 5, 987-
999.
(17) Comanita, B. M.; Heuft, M. A.; Rietveld, T.; Fallis, A. G. Isr. J .
Chem. 2000, 40, 241-254.
(18) For the synthesis of a tetrahydroxy dienediyne, see: Toshima,
K.; Yanagawa, K.; Ohta, K.; Kano, T.; Nakata, M. Tetrahedron Lett.
1994, 10, 1573-1576.
(19) Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S. B.
Org. Synth. 1990, 68, 92-103.
(20) Nugiel, D. A.; J acobs, K.; Worley, T.; Patel, M.; Kaltenbach, R.
F., III; Meyer, D. T.; J adhav, P. K.; De Lucca, G. V.; Smyser, T. E.;
Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J . Med. Chem.
1996, 39, 2156-2169.
(24) Myers, A. G.; Dragovich, P. S. J . Am. Chem. Soc. 1992, 114,
5859-5860.
(21) Diketodialdehyde analogous to compound 8 is not stable.
(22) Additional racemic stereocenters of the THP groups lead to a
complex mixture of possible stereoisomers.
(23) Ramasamy, K. S.; Bandaru, R.; Averett, D. Synth. Commun.
1999, 29, 2881-2894.
(25) Thiocarbonyl reagent reacts preferably with cis-diols. trans-
Diols are converted slowly. Banfi, L.; Guanti, G.; Basso, A. Eur. J . Org.
Chem. 2000, 939-946.
(26) Konradi, A. W.; Pedersen, S. F. J . Org. Chem. 1992, 57, 28-
32.
9380 J . Org. Chem., Vol. 68, No. 24, 2003

Tetrahydroxy 10-Membered Cyclic Enediynes
SCHEME 2. Dep r otection of En ed iyn e 13
SCHEME 3. Th er m a l Cycliza tion of En ed iyn e 16
the isopropylidene group transforms the stabilized ene-
diynes into thermally reactive compounds.To investigate
if the concept of enediyne stabilization and activation
holds in vitro, the cytoxicity of compounds (1R,4R)-13,
(1R,4R)-14, (1R,4R)-15, and (1R,4R)-16 was tested against
human breast cancer cells MDA-MB-231 in the crystal
violet assay30 (see Supporting Information for data).
Compounds (1R,4R)-13 and (1R,4R)-14, stabilized by the
isopropylidene protecting group, had no effect on cell
growth, while for (1R,4R)-15 and (1R,4R)-16 a weak
growth inhibition was observed. However, in comparison
to cisplatin, a clinically widely used cytostatic, the
inhibitory concentrations of enediynes 15 and 16 are
high.
obtained in 52% yield as a mixture of diastereomers,
which were not separated but reacted with N,N-thiocar-
bonylbisimidazole (10) to give thiocarbonate (1R,4R)-11.
The Corey-Hopkins elimination27 is completed by treat-
ment of the thiocarbonate with 1,3-dimethyl-2-phenyl-
[1,3,2]diazaphospholidine (12) to give enediyne (1R,4R)-
13 in 41%. Analogously, compound (1R,4S)-6 was con-
verted into (1R,4S)-13 in 15% overall yield (see Support-
ing Information for yields of the individual reactions).
Con clu sion s
Cyclic tetrahydroxy enediynes were synthesized from
tartaric acid in enantiomerically pure form. Each sp3-
hybridized carbon of the compounds is functionalized.
The hydroxy substituents make the compounds water
soluble and at the same time lock the ring conformation
and control enediyne reactivity by cyclic diol protecting
groups. The preparation of enediynes, which can be
activated by enzymes, light, or acid in vitro, can be
envisaged, choosing a suitable protecting method.
To investigate the properties of enediyne 13, the
protecting groups have to be removed under mild condi-
tions. Selective TBDMS deprotection is possible using
standard conditions, but the high polarity of the product
makes its isolation difficult and low yielding. The ene-
diyne will become reactive after cleavage of the isopro-
pylidene diol protecting group, so heating must be strictly
avoided. Removal of the isopropylidene protecting group
at room temperature requires treatment with EtSH and
concentrated TFA. Under these conditions, a partial loss
of the TBDMS groups cannot be avoided.The thermal
reactivity of enediynes (1R,4R)-13, (1R,4R)-16, and
(1R,4R)-15 was investigated by thermolysis and moni-
tored by HPLC analysis28 to derive kinetic data. The
cyclization of (1R,4R)-16 was performed in benzene/
cyclohexadiene at 69 °C, and the formation of the
expected Bergman cyclization product was confirmed by
HPLC-MS. Data analysis revealed pseudo-first-order
kinetics with a reaction rate constant of k ) 6.4 × 10-4
s-1 and a half-life t1/2 ) 18 min. The isopropylidene-
protected compound (1R,4R)-13 showed no reaction under
these conditions. Tetrahydroxy enediyne (1R,4R)-15 is
water soluble. Therefore, the thermal cyclization of this
compound was investigated in aqueous solution. Again
the data fit to pseudo-first-order kinetics with a rate
constant of k ) 4.3 × 10-3 s-1 and a half-life t1/2 ) 3 min
at 60 °C.29 The thermolysis data confirm that removal of
Exp er im en ta l Section
2,3-O-Isopropylidene-L-tartaric acid,17 2,2-dimethyl-[1,3]-
dioxolane-4,5-bis(methoxymethyl-carboxamide) 1,18 vanadium
tris(tetrahydrofuran) trichloride,31 and magnesiumbromide
Et2O32 were prepared according to reported procedures.
1-{2,2-Dim eth yl-5-[4-(tetr a h yd r op yr a n -2-yloxy)-bu t-2-
in oyl]-[1,3]d ioxola n e-4-yl}-4-(tetr a h yd r op yr a n -2-yloxy)-
bu t-2-in -1-on e (3). A mixture of 2-prop-2-inyloxy-tetrahydro-
pyran (3.22 g, 23.0 mmol) and EtMgBr, prepared from Mg
turnings (0.61 g, 25.0 mmol) and bromoethane (2.51 g, 23.0
mmol) in 10 mL of dry THF, was refluxed for 1 h. After cooling
to room temperature, the reaction mixture was added dropwise
to a solution of 2,2-dimethyl-[1,3]-dioxolane-4,5-bis-(meth-
oxymethylcarboxamide) 1 (1.00 g, 3.62 mmol) in 40 mL of THF,
refluxed for 4 h, poured into aqueous KH2PO4 (100 mL), and
extracted with EtOAc (3 × 50 mL). The combined organic
phases were washed twice with brine, dried over Na2SO4, and
evaporated to dryness in vacuo. Column chromatography
(petroleum ether/EtOAc, 3:1) gave 1.15 g (73%) of 3 (Rf ) 0.32)
as a yellow oil. IR (neat): ν˜ ) 2944, 2872, 2216, 1688, 1386,
1345, 1241, 1122, 1033, 968, 941, 902, 871, 816 cm-1. UV (CH3-
(29) J anda et al. have observed the formation of quinones from
thermal enediyne cyclization in oxygen-enriched water-DMSO mix-
tures. J ones, L. H.; Harwig, C. W.; Wentworth, P.; Simeonov, A.;
Wentworth, A. D.; Py, S.; Ashley, J . A.; Lerner, R. A.; J anda, K. D. J .
Am. Chem. Soc. 2001, 123, 3607-3608. We could observe neither
quinone nor Bergman product formation. The poor hydrogen donor
ability of water leads to a large extent of polymer formation.
(30) Bernhardt, G.; Reile, H.; Birnbo¨ck, H.; Spruss, T.; Scho¨nen-
berger, H. J . Cancer Res. Clin. Oncol. 1992, 118, 35-43.
(27) Corey, E. J .; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 1979-
1982.
(28) Analytical method corresponds to previously described proce-
dures: (a) Choy, N.; Kim, C.-S.; Ballestero, C.; Artigas, L.; Diez, C.;
Lichtenberger, F.; Shapiro, J .; Russell, K. C. Tetrahedron Lett. 2000,
41, 6955-6958. (b) Wisniewski Grissom, J .; Calkins, T. L.; McMillen,
H. A.; J iang, Y. J . Org. Chem. 1994, 59, 5833-5835. (c) Kim, C.-S.;
Russell, K. C. J . Org. Chem. 1998, 63, 8229-8234.
(31) Manzer, E. L. Inorg. Synth. 1982, 21, 135-137.
(32) Ashby, E. C.; Arnott, R. C. J . Organomet. Chem. 1968, 14, 1-11.
J . Org. Chem, Vol. 68, No. 24, 2003 9381

Klein et al.
1
CN): λmax (lg ꢀ) ) 224 nm (4.114). H NMR: δ 1.40-1.88 (m,
(Cquat). MS (CI), m/z (%): 516.3 (100) [M + NH4+]. HRMS
C25H47O6Si2 calcd 499.2911, found 499.2915 (0.5 ppm. (1R,4R)-
6: Mp 116-118 °C. IR (neat): ν˜ ) 3400, 2956, 2956, 2896,
2886, 2859, 2361, 2342, 1472, 1381, 1254, 1131, 1131, 1075,
18 H), 3.50-3.61 (m, 2 H), 3.76-3.90 (s, 2 H), 4.48 (m, 4 H),
4.84 (m, 4 H). 13C NMR: δ 18.8 (-), 25.2 (-), 26.8 (+), 30.0
(-), 53.7 (-), 62.0 (-), 82.5 (Cquat), 82.7 (+), 94.6 (Cquat), 97.2
(+), 114.6 (Cquat), 183.8 (Cquat). MS (CI), m/z (%): 85 (12) [DHP],
102 (70), 118 (100), 368 (7) [M + NH4 - DHP+], 453 (40) [M +
NH4+]. Anal. Calcd for C23H30O8 (434.49): C, 63.58; H, 6.96.
Found: C, 63.18; H, 7.00.
1
1023, 838, 784 cm-1. H NMR (400 MHz, CDCl3): δ 0.12 (s, 6
H), 0.16 (s, 6 H), 0.91 (s, 18 H), 1.46 (s, 6 H), 2.35 (s, 2 H),
3
5
4.21 (dd, J ) 2.3 Hz, 1.3 Hz, 2 H), 4.31 (d, J ) 1.7 Hz, 2 H),
4.58-4.60 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ -4.9 (+),
-4.4 (+), 18.2 (Cquat), 25.8 (+), 27.6 (+), 51.0 (-), 64.1 (+), 80.2
(+), 84.3 (Cquat), 84.4 (Cquat), 111.0 (Cquat). MS (CI), m/z (%):
499 (4) [M + H+], 516 (100) [M + NH4+]. Anal. Calcd for
C25H46O6Si2 (498.81): C, 60.20; H, 9.30. Found C, 60.19; H,
9.47.
1-{5-[1-Hydr oxy-4-(tetr ah ydr opyr an -2-yloxy)bu t-2-in yl]-
2,2-d im et h yl-[1,3]d ioxola n -4-yl}-4-(t et r a h yd r op yr a n -2-
yloxy)bu t-2-in -1-ole ((1R,4S)-4, (1R,4R)-4). To a solution of
3 (5.40 g, 12.4 mmol) in THF (130 mL) was added DIBAL-H
(50 mL, 50 mmol, 1 M solution in THF) at -78 °C over 1 h.
The reaction mixture was stirred for 24 h; methanol (25 mL)
was added, and the solvent was removed in vacuo. The residue
was redissolved in saturated K/Na tartrate solution (340 mL)
and EtOAc (310 mL) and stirred for 30 min; the organic phase
was separated, and the aqueous phase was extracted with
EtOAc. The combined organic phases were washed with brine
and dried over Na2SO4, and the solvent was removed in vacuo;
column chromatography (petroleum ether/EtOAc, 1:1) yielded
4.31 g (79%) of 4 as a stereoisomeric mixture (Rf ) 0.45), yellow
oil. IR (neat): ν˜ ) 3415, 2942, 2871, 1738, 1455, 1373, 1243,
4-(ter t-Bu tyld im eth ylsila n yloxy)-4-{5-[1-(ter t-bu tyld i-
m eth ylsila n yloxy)-4-oxobu t-2-in yl]-2,2-d im eth yl-[1,3]d i-
oxola n -4-yl}bu t-2-in a l ((1R,4R)-8). To a solution of (1R,4R)-6
(498 mg, 1.00 mmol) in dry CH2Cl2 (20 mL) was added Dess-
Martin periodinane (1.28 g, 3 mmol) at room temperature, and
the suspension was stirred for 17 h. The reaction mixture was
filtered, washed with aqueous Na2S2O5 (100 mL, 0.4 M), and
dried over Na2SO4, and the solvent was removed in vacuo.
Column chromatography (petroleum ether/EtOAc, 1:1) gave
425 mg (86%) of (1R,4R)-8 (Rf ) 0.87), as an oil. IR (neat): ν˜
) 3054, 2987, 2360, 2411, 1671, 1422, 896, 740 cm-1. UV (CH3-
1119, 1025, 903, 872, 815 cm-1. H NMR: δ 1.34-1.92 (m, 18
1
1
H), 3.04 (s, 2 H), 3.45-3.61 (m, 2 H), 3.71-3.91 (m, 2 H), 4.10-
4.43 (m, 6 H), 4.53-5.07 (m, 4 H). MS (CI), m/z (%): 85 (100)
[DHP+], 102 (49), 118 (85), 288 (10) [M + NH4 - 2DHP+], 372
(10) [M + NH4 - DHP+], 456 (17) [M + NH4+]. Anal. Calcd
for C23H34O8 (438.52): C, 63.00; H, 7.81. Found: C, 62.68; H,
7.65.
CN): λmax (lg ꢀ) ) 218 nm (3.867). H NMR: δ 0.15 (s, 6 H),
0.20 (s, 6 H), 0.93 (s, 18 H), 1.48 (s, 6 H), 4.28 (dd, 3J ) 2.0
Hz, 1.2 Hz, 2 H), 4.76-4.80 (m, 2 H), 9.26 (s, 2 H). 13C NMR:
δ -4.9 (+), -4.5 (+), 18.2 (Cquat), 25.7 (+), 27.3 (+), 64.0 (+)
79.2 (+), 84.8 (Cquat), 93.9 (Cquat), 111.7 (Cquat), 176.1 (+). MS
(CI), m/z (%): 115 (33), 117 (26), 133 (49), 173 (11), 197 (18),
205 (11), 269 (12), 297 (11), 305 (10), 437 (14), 495 (100) [M +
H+], 296 (37). Anal. Calcd for C25H42O6Si2 (494.78): C, 60.69;
H, 8.56. Found: C, 59.61; H, 8.54.
4,5-Bis-[1-(t er t -b u t yld im e t h ylsila n yloxy)-4-(t e t r a -
h yd r op yr a n -2-yloxy)bu t-2-in yl]-2,2-d im eth yl-[1,3]d ioxo-
la n e ((1R,4S)-5, (1R,4R)-5). Diol 4 (745 mg, 1.70 mmol),
imidazole (748 mg, 11.0 mmol), and tert-butylchloro dimeth-
ylsilane (TBDMS-Cl, 640 mg, 4.25 mmol) were dissolved in
20 mL of CH2Cl2 and stirred for 16 h at room temperature.
The reaction mixture was washed with aqueous NaHCO3 and
brine and dried over Na2SO4, and the solvent was removed in
vacuo. Column chromatography (petroleum ether/EtOAc, 4:1)
gave 980 mg (87%) of 5 as a mixture of stereoisomers (Rf )
0.52), colorless oil. IR (neat): ν˜ ) 2931, 2857, 1742, 1464, 1370,
2,9-Bis-(ter t-bu tyld im eth ylsila n yloxy)-12,12-d im eth yl-
5,6-d ih y d r o x y -11,13-d io x o b ic y c lo -[8.3.0]t r id e c a -3,7-
d iyn e ((1R,4R)-9). To dry CH2Cl2 (12 mL) were added VCl3‚
3THF (1.37 g, 3.7 mmol) and zinc powder (160 mg, 2.46 mmol)
at room temperature, and the mixture was stirred for 30 min
and diluted with CH2Cl2 (12 mL) and DMF (1.4 mL). Com-
pound (1R,4R)-8 (236 mg, 0.48 mmol), dissolved in CH2Cl2 (12
mL), was added by syringe pump over 120 min. The mixture
was stirred for an additional 4 h and poured into water (30
mL); the organic phase was separated and washed with
aqueous Na/K tartrate (40%) and brine. The solvent was
removed in vacuo and the crude product purified by column
chromatography (petroleum ether/EtOAc, 1:1) to yield 124 mg
(52%) of (1R,4R)-9 (Rf ) 0.91), colorless solid. IR (neat): ν˜ )
3380, 2931, 2896, 2858, 2251, 1739, 1473, 1372, 1255, 1109,
1253, 1217, 1121, 1078, 1027, 945, 903, 838, 779, 669 cm-1
.
1H NMR: δ 0.06-0.19 (m, 12 H), 0.80-0.98 (m, 18 H), 1.36-
1.96 (m, 18 H), 3.43-3.56 (m, 2 H), 3.75-3.89 (m, 2 H), 4.00-
4.09 (m, 1 H), 4.14-4.22 (m, 1 H), 4.24-4.32 (m, 4 H), 4.58-
4.69 (m, 2 H), 4.75-4.85 (m, 2 H). MS (CI), m/z (%): 85 (36)
[DHP+], 118 (19), 499 (11), 516 (9) [M + NH4 - 2DHP+], 600
(3) [M + NH4 - DHP+], 685 (100) [M + NH4+]. Anal. Calcd
for C35H62O8Si2 (667.04): C, 63.02; H, 9.37. Found: C, 62.74;
H, 9.56.
1
839, 780 cm-1. H NMR: δ -0.04-0.26 (m, 12 H), 0.76-1.03
(m, 18 H), 1.39 (m, 6 H), 4.02-4.17 (m, 4 H), 4.21-4.39 (m, 4
H), 4.41-4.64 (m, 2 H). MS (FI/FD), m/z (%): 439 (100) [M +
(CH3)2CO+], 497 (68) [M + H+].
4-(ter t-Bu tyld im eth ylsila n yloxy)-4-{5-[1-(ter t-bu tyld i-
m eth ylsilan yloxy)-4-h ydr oxybu t-2-in yl]-2,2-dim eth yl-[1,3]-
dioxolan -4-yl}bu t-2-in -1-ol ((1R,4S)-6 an d (1R,4R)-6). Com-
pound 5 (1.8 g, 2.7 mmol) and MgBr2‚Et2O, prepared in situ
from Mg turnings (0.58 g, 24 mmol) and 1,2 dibromoethane
(1.8 mL, 3.93 g, 21 mmol), in dry diethyl ether (30 mL) was
stirred at room temp for 24 h. The organic phase was washed
with water (three times) and dried over Na2SO4, and the
solvent was removed in vacuo. Column chromatography gave
two fractions: (1) (1R,4S)-6 (0.52 mg, 39%) (Rf ) 0.39), yellow
oil, and (2) (1R,4R)-6 (0.47 mg, 35%) (Rf ) 0.24), colorless soft
2,9-Bis-(ter t-bu tyld im eth ylsila n yloxy)-12,12-d im eth yl-
5,6-(th iocar bon yldioxy)-11,13-dioxo-bicyclo-[8.3.0]tr ideca-
3,7-d iyn e ((1R,4R)-11). A mixture of diol (1R,4R)-9 (73 mg,
0.15 mmol) and N,N-thiocarbonyldiimidazole (10) (79 mg, 0.42
mmol) in 20 mL of dry THF was refluxed for 6 h. The solvent
was removed in vacuo, and the crude product was purified by
column chromatography (petroleum ether/EtOAc, 5:1) yielding
56 mg (71%) of (1R,4R)-11 (Rf ) 0.61), yellow oil. IR (neat): ν˜
) 2956, 2858, 2240, 1825, 1727, 1472, 1347, 1168, 983, 844,
solid. (1R,4S)-6: [R]25 -18 (c 0.84 in CH3CN). IR (neat): ν˜ )
781, 670 cm-1. UV (CH3CN): λmax (lg ꢀ) ) 237 nm (4.031). H
1
D
3406, 2931, 2896, 2858, 1742, 1253, 1135, 1072, 1026, 977, 940,
NMR (400 MHz, CDCl3): δ 0.13 (s, 6 H), 0.14 (s, 3 H), 0.15 (s,
838, 779, 670 cm-1
.
1H NMR: δ 0.13 (s, 3 H), 0.14 (s, 3 H),
3 H), 0.91 (s, 9 H), 0.92 (s, 9 H), 1.39 (s, 3 H), 1.40 (s, 3 H),
3
3
0.16 (s, 3 H), 0.17 (s, 3 H), 0.92 (s, 18 H), 1.45 (s, 6 H), 1.91 (s,
3.99 (dd, J ) 9.0 Hz, 5.4 Hz, 1 H), 4.12 (dd, J ) 9.0 Hz, 5.4
3 5 3
2 H), 4.09 (dd, 3J ) 7.3 Hz, 3.2 Hz, 1 H), 4.18 (dd, 3J ) 7.3 Hz,
Hz, 1 H), 4.32 (dd, J ) 9.0 Hz, J ) 2.0 Hz, 1 H), 4.37 (d, J
3 5
5
5
4.0 Hz, 1 H), 4.29 (d, J ) 1.7 Hz, 2 H), 4.31 (d, J ) 1.7 Hz,
2 H), 4.60 (dt, 3J ) 4.0 Hz, 5J ) 1.7 Hz, 1 H), 4.64 (dt, 3J ) 7.3
) 9.0 Hz, 1 H), 5.56 (dd, J ) 8.0 Hz, J ) 2.0 Hz, 1 H), 5.58
(d, J ) 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ -4.8 (+),
3
Hz, J ) 1.7 Hz, 1 H). 13C NMR: δ -5.0 (+), -4.8 (+), -4.6
-4.8 (+), -4.7 (+), 18.3 (Cquat), 25.7 (+), 27.6 (+), 66.6 (+),
66.7 (+), 74.6 (+), 74.8 (+), 82.4 (+), 82.6 (+), 93.3 (Cquat), 94.3
(Cquat), 110.9 (Cquat), 188.7 (Cquat). MS (CI), m/z (%): 556 (100)
[M + NH4+].
5
(+), -4.4 (+), 18.3 (Cquat), 18.4 (Cquat), 25.8 (+), 25.9 (+), 27.3
(+), 27.6 (+), 51.1 (-), 51.2 (-), 63.6 (+), 64.2 (+), 79.9 (+),
80.5 (+), 84.1 (Cquat), 84.2 (Cquat), 84.3 (Cquat), 84.5 (Cquat), 110.6
9382 J . Org. Chem., Vol. 68, No. 24, 2003

Tetrahydroxy 10-Membered Cyclic Enediynes
2,9-Bis-(ter t-bu tyld im eth ylsila n yloxy)-12,12-d im eth yl-
11,13-d ioxo-bicyclo-[8.3.0]tr id eca -5-en -3,7-d iyn e ((1R,4R)-
13). To a solution of (1R,4R)-11 (40 mg, 74.2 µmol) in 4 mL of
dry dioxane was added 1,3-dimethyl-2-phenyl-1,3,2-diazaphos-
pholidine (12, 96 µL, 101 mg, 520 µmol), and the reaction
mixture was stirred for 4 h at 40 °C. The solvent was removed
in vacuo and column chromatography (petroleum ether/EtOAc,
5:1) was performed on the crude product. Yield: 14 mg (41%)
2 H), 6.05 (s, 2 H). 13C NMR (100 MHz, CD3CN): δ 28.0 (C12,
C13), 66.7 (C1, C4), 85.2 (C2, C3), 87.6 (C6, C9), 100.5 (C5,
C10), 111.7 (C11), 124.6 (C7, C8). MS (CI), m/z (%): 234 (28)
[M+ - H2O], 252 (100) [M + NH4+]. HRMS C13H15O4 calcd
235.0970, found 235.0969 ( 1.5 ppm.
Gen er a l P r oced u r e for Clea va ge of t h e Isop r op yli-
d en e P r otectin g Gr ou p . Enediyne (15 µmol) to be depro-
tected was dissolved in 1 mL of EtSH and 1 mL of concentrated
TFA. The reaction mixture was stirred for 1 h at room
temperature; the solvents were removed in vacuo at 0 °C, and
the reaction products were used without further purification.
of (1R,4R)-13 (Rf ) 0.95), colorless oil. [R]25 -79 (c 0.67 in
D
CH3CN). IR (neat): ν˜ ) 2928, 2856, 1824, 1731, 1463, 1378,
1332, 1259, 1109, 1018, 840, 780, 752 cm-1. UV (CH3CN): λmax
(lg ꢀ) ) 271 nm (4.021). 1H NMR (400 MHz, CDCl3): δ 0.14 (s,
6 H), 0.15 (s, 6 H), 0.91-0.99 (m, 18 H), 1.42 (s, 6 H), 4.10-
4.15 (m, 2 H), 4.41-4.46 (m, 2 H), 5.94 (s, 2 H). 13C NMR (100
MHz, CDCl3): δ -4.7 (+), -4.7 (+), 18.4 (Cquat), 25.8 (+), 28.0
(+), 67.2 (+), 84.5 (+), 86.7 (Cquat), 100.3 (Cquat), 110.5 (Cquat),
123.4 (+). MS (EI, 70 eV), m/z (%): 73 (100), 75 (24) [Me2-
SiOH+], 347 (88) [M+ - Me2SiC4H9], 348 (25), 462 (8) [M+].
HRMS C25H42O4Si2 calcd 462.2621, found 462.2621 ( 1.5 ppm.
2,3-O-Isop r op ylid en cyclod ec-7-en -5,9-d iyn e-1,2,3,4-tet-
r a ol ((1R,4R)-14). To a solution of (1R,4R)-13 (110 mg, 0.24
mmol) in 20 mL of THF was added TBAF (1.1 mL, 1.1 mmol,
1 M solution in THF), and the mixture was stirred for 90 min
at 0 °C, diluted with diethyl ether, washed with brine (three
times), and dried over Na2SO4. The solvent was removed in
vacuo, and column chromatography (petroleum ether/EtOAc,
1:1) gave 16 mg (29%) of (1R,4R)-14 (Rf ) 0.32), colorless oil.
IR (neat): ν˜ ) 3996, 3429, 3428, 2884, 1807, 1730, 1639, 1467,
1354, 1280, 1114, 947, 843 cm-1. UV (CH3CN): λmax (lg ꢀ) )
Ack n ow led gm en t. We thank the Fonds der Che-
mischen Industrie, the Deutsche Forschungsgemein-
schaft (GRK 760 “Medicinal Chemistry”), and the DAAD
(International Quality Network Medicinal Chemistry)
for support of this research.
Su p p or tin g In for m a tion Ava ila ble: Structure of com-
pound (1R,4R)-6 in crystalline form; experimental procedures
for the preparation of compound (1R,4S)-13; kinetic analyses
of the thermolysis of (1R,4R)-16 and (1R,4R)-15; in vitro
cytoxicity cell assay; copies of proton and carbon NMR spectra
of compounds 3, (1R,4S)-6, (1R,4R)-6, (1R,4S)-8, (1R,4R)-13,
(1R,4S)-13, and (1R,4R)-14; and copies of proton NMR spectra
of compounds 4, 5, (1R,4S)-9, (1R,4R)-9, (1R,4S-)11, and
(1R,4R)-11. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
269 nm (3.926). H NMR (400 MHz, CD3CN): δ 1.41 (s, 6 H),
3.67 (dd, 3J ) 4.6 Hz, 2 H), 4.00-4.05 (m, 2 H), 4.44-4.50 (m,
J O035250N
J . Org. Chem, Vol. 68, No. 24, 2003 9383