Enantioselective synthesis of the AB-ring system of the antitumor antibiotic tetrazomine

Article abstract of DOI:10.1021/jo015512q

The synthesis of the 1,2,3,4-tetrahydroisoquinoline moiety of tetrazomine was accomplished in 18 steps and in 3% overall yield from commercially available o-anisaldehyde. The reaction sequence utilizes a Sharpless asymmetric dihydroxylation to install the stereocenter and an intramolecular Friedel-Crafts hydroxyalkylation with an N-protected 2-oxo-acetamide to close the heterocyclic ring.

Full text of DOI:10.1021/jo015512q

J . Org. Chem. 2001, 66, 3133-3139
3133
En a n tioselective Syn th esis of th e AB-Rin g System of th e
An titu m or An tibiotic Tetr a zom in e
Peter Wipf* and Corey R. Hopkins
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
pwipf+@pitt.edu
Received J anuary 10, 2001
The synthesis of the 1,2,3,4-tetrahydroisoquinoline moiety of tetrazomine was accomplished in 18
steps and in 3% overall yield from commercially available o-anisaldehyde. The reaction sequence
utilizes a Sharpless asymmetric dihydroxylation to install the stereocenter and an intramolecular
Friedel-Crafts hydroxyalkylation with an N-protected 2-oxo-acetamide to close the heterocyclic
ring.
In tr od u ction
Tetrazomine was isolated from Saccharothrix muta-
bilis in 1991 and is part of the naphthyridinomycin/
bioxalomycin class of antitumor antibiotics that includes
the Cdc25 inhibitor dnacin A1 (Figure 1).1 Preliminary
biological testing of tetrazomine indicated cytotoxic activ-
ity against a P388 leukemia cell line as well as significant
antimicrobial activity.1d,e,i To date, synthetic efforts to-
ward tetrazomine have been limited and include ap-
proaches toward the racemic AB-ring system as well as
studies to determine the absolute stereochemistry of the
amino acid side-chain and lipase-resolution of this build-
ing block.2 Herein, we report our efforts toward the
asymmetric synthesis of the isoquinoline AB-ring system
of tetrazomine.
The key step in our retrosynthetic approach toward
this natural product is an intramolecular Heck annula-
tion of enamide 1 to give the core 3,8-diaza-bicyclo[3.2.1]-
octane scaffold (Figure 2). This strategy requires the
preparation of an enol triflate or a related electrophile
from isoquinoline amide 2. In earlier studies, we have
reported an application of the Moore-Liebeskind quinone
synthesis toward the preparation of 1,4-dihydro-2H-
isoquinoline-3,5,8-triones.3 Unfortunately, we were un-
able to extend this approach to include the functionalities
necessary for the AB-ring system of tetrazomine. Accord-
ingly, we decided to construct the isoquinoline ring by
an intramolecular Friedel-Crafts hydroxyalkylation of
a 2-oxo-acetamide derivative of 3.
F igu r e 1. Structures of the polycyclic alkaloids tetrazomine,
dnacin A1 and naphthyridinomycin.
(1) (a) Danishefsky, S.; O’Neill, B. T. Tetrahedron Lett. 1984, 25,
4203. (b) Fukuyama, T.; Laird, A. A. Tetrahedron Lett. 1986, 27, 6173.
(c) Garner, P.; Sunitha, K.; Ho, W.-B.; Youngs, W. J .; Kennedy, V. O.;
Djebli, A. J . Org. Chem. 1989, 54, 2041. (d) Sato, T.; Hirayama, F.;
Saito, T. J . Antibiot. 1991, 44, 1367. (e) Suzuki, K.; Sato, T.; Morioka,
M.; Nagai, K.; Abe, K.; Yamaguchi, H.; Saito, T.; Ohmi, Y.; Susaki, K.
J . Antibiot. 1991, 44, 479. (f) Hida, T.; Muroi, M.; Tanida, S.; Harada,
S. J . Antibiot. 1994, 47, 917. (g) Zaccardi, J .; Alluri, M.; Ashcroft, J .;
Bernan, V.; Korshalla, J . D.; Morton, G. O.; Siegel, M.; Tsao, R.;
Williams, D. R.; Maiese, W.; Ellestad, G. A. J . Org. Chem. 1994, 59,
4045. (h) Martinez, E. J .; Owa, T.; Schreiber, S. L.; Corey, E. J . Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 3496. (i) Williams, R. M.; Flanagan,
M. E.; Tippie, T. N. Biochemistry 1994, 33, 4086.
F igu r e 2. Retrosynthetic approach toward tetrazomine.
Resu lts a n d Discu ssion
Wittig olefination of o-anisaldehyde followed by dihy-
droxylation of the resulting styrene derivative with
Sharpless’s AD-Mix-R installed the desired benzylic
stereocenter in diol 5 in 76% yield and 94% enantio-
selectivity as determined by Mosher ester analysis
(Scheme 1).4-6 Diacetylation of 5 with Ac2O and pyridine
proceeded in 94% yield and allowed subsequent nitration
(2) (a) Ponzo, V. L.; Kaufman, T. S. J . Chem. Soc., Perkins Trans. 1
1997, 3131. (b) Scott, J . D.; Tippie, T. N.; Williams, R. M. Tetrahedron
Lett. 1998, 39, 3659. (c) Scott, J . D.; Williams, R. M. Tetrahedron Lett.
2000, 41, 8413.
(3) Wipf, P.; Hopkins, C. R. J . Org. Chem. 1999, 64, 6881.
10.1021/jo015512q CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/28/2001

3134 J . Org. Chem., Vol. 66, No. 9, 2001
Wipf and Hopkins
Sch em e 1
Sch em e 2
Sch em e 3
under mild conditions (KNO3, TFAA, CHCl3) to give the
ortho-nitrated product 6 as the sole product in 83% yield.7
Nitrodiacetate 6 was then converted to the primary silyl
ether 7 by saponification and selective silylation with
TBDPS-Cl and imidazole in DMF in 74% overall yield.
Conversion to the benzylic amine and concomitant inver-
sion of the stereochemistry in 7 was accomplished in 89%
yield by a Mitsunobu reaction with phthalimide, DEAD,
and triphenylphosphine.8 Hydrazinolysis of the imide
provided the primary amine 8 in quantitative yield.9
Conversion of the primary amine 8 to the N-protected
tertiary amide 10 was necessary to effect ring closure to
the isoquinolinone (Scheme 2). Attempts to cyclize sec-
ondary amides had failed, presumably because the
required (Z)-amide conformation was sterically signifi-
cantly destabilized. After conversion of 8 to the p-
methoxybenzyl-protected secondary amine 9 in 84% yield
by reductive amination, mixed anhydride coupling with
acetoxyacetic acid/isobutyl chloroformate (IBCF) led to
amide 10 in 74% yield.10 From this intermediate, the
cyclization precursor alcohol 12 was readily obtained in
three steps and 72% yield by catalytic reduction of the
nitroarene, N-acetylation, and finally ester saponification
with K2CO3 in aqueous MeOH.
thereof, we decided to abandon plans for a Friedel-Crafts
alkylation in favor of a hydroxyalkylation sequence, even
though the latter required an additional deoxygenation
step (Scheme 3). Swern oxidation of 12 to the sensitive
R-formyl amide 13 followed by treatment with pTsOH
in dioxane yield the desired isoquinoline 14 in 75%
overall yield as a single diastereomer.11 Our first attempt
to deoxygenate the benzylic carbon utilized the SmI2
protocol optimized by Simpkins et al. for R-functionalized
amides.12 Thus, 14 was converted to the requisite ben-
zoate ester and then subjected to SmI2 in THF in the
presence of LiCl; however, we were unable to drive this
reaction to completion and product isolation was ham-
pered by unreacted starting material as well as signifi-
cant amounts of saponified product. In contrast, after
conversion of alcohol 14 to the corresponding thionocar-
bonate with PhOC(S)Cl, DMAP, and pyridine, Barton
After extensive experimentation with a variety of
methods to effect direct ring closure of 12 and derivatives
(4) Hollywood, F.; Suschitzky, H. Synthesis 1982, 662.
(5) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(6) Diol 5 was converted to the terminal silyl ether with TBDMS-
Cl and imidazole in DMF and converted to the Mosher ester with (R)-
MTPA. The enantiomeric excess of this derivative was determined to
be 94% by integration of the methine 500 MHz 1H NMR signals. (a)
Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543.
(b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512. (c) Ward,
D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.
(7) (a) Crivello, J . V. J . Org. Chem. 1981, 46, 3056. (b) Spitzer, U.
A.; Stewart, R. J . Org. Chem. 1974, 39, 3936.
(8) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. Prep.
Proc. Int. 1996, 28, 127.
(9) Sasaki, T.; Minamoto, K.; Itoh, H. J . Org. Chem. 1978, 43, 2320.
(10) Anderson, G. W.; Zimmerman, J . E.; Callahan, F. M. J . Am.
Chem. Soc. 1967, 89, 5012.
(11) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(12) (a) Hughes, A. D.; Simpkins, N. S. Synlett 1998, 967. (b) Hughes,
A. D.; Price, D. A.; Simpkins, N. S. J . Chem. Soc., Perkins Trans. 1
1999, 1295.

Antitumor Antibiotic Tetrazomine
J . Org. Chem., Vol. 66, No. 9, 2001 3135
Sch em e 4
Sch em e 5
radical deoxygenation provided the PMB-protected tetra-
zomine segment 15 in 54% yield over the two steps.
While only deprotection of the lactam remained to
convert 15 into the desired AB-ring segment of tetra-
zomine, we were unable to remove the PMB group despite
extensive experimentation (hydrogenolysis,13,14 dissolving
metal reduction,15 Pd(II),16 CAN-,17 and DDQ-oxidation,18
as well as acidic conditions,19 etc.). Several alternative
amide protective groups, including Boc, (trimethylsilyl)-
ethane sulfonyl (Ses),20 Ts, benzyl, and 3,4-dimethoxy-
benzyl, failed either because of premature cleavage or
substrate decomposition during forcing deprotection con-
ditions. In the absence of a protecting group, the second-
ary amide did not undergo cyclization to the isoquinoline.
We finally turned our attention to the N-allyl func-
tion.21 Primary amine 8 was allylated in 78% yield with
allyl bromide in the presence of CsOH (Scheme 4).22 Only
small amounts (∼5%) of diallylated amine were detected
under these conditions. The secondary amine 16 was
converted with acetoxyacetyl chloride in 86% yield into
the tertiary amide 17. Reduction of the aromatic nitro
group with Na2S2O4 and ethyl viologen dibromide (1,1′-
diethyl-4,4′-bipyridinium dibromide) in aqueous CH2Cl2,23
followed by aniline acetylation and ester saponification
provided alcohol 19 in 63% overall yield. It is noteworthy
that nitroarene reduction by the sodium dithionate/
viologen protocol was somewhat batch-dependent and
gave variable yields ranging from 45% to 75%.
Oxidation of alcohol 19 and acid-mediated cyclization
of the intermediate aldehyde 20 proceeded uneventfully
to give isoquinolinone 21 in 61% overall yield and as a
single diastereomer by 1H NMR (Scheme 5). The (S)-
configuration at C(4) of 21 was tentatively assigned based
on MM2 calculations which showed that the alternative
(4R)-stereoisomer was ca. 1.5 kcal/mol higher in energy.
Barton deoxygenation of 21 led to the bicyclic lactam 22
in 39% yield. The allyl group was stable to the radical
conditions used in the deoxygenation and also resisted
initial attempts for deprotection under Pd(II) reaction
conditions as well as treatment with trimethylalane in
the presence of Ni-catalysts.24,25 In contrast, isomerization
of the allyl amide to the enamide with Wilkinson’s
catalyst followed by cleavage of 23 under Weinreb’s
conditions with ozone and hydrolysis of the resulting
N-formyl compound gave the desired isoquinoline 24 in
45% yield from the allyl lactam, along with 20% of the
intermediate N-formyl derivative.26,27 In an attempt
to improve this sequence, we attempted a J ohnson-
Lemieux cleavage of enamide 23.28 The enamide was
treated with catalytic OsO4 in the presence of stoichio-
(13) Gigg, R.; Conant, R. Carbohydrate Res. 1982, 100, C5.
(14) (a) Rigby, J . H.; Maharoof, U. S. M.; Mateo, M. E. J . Am. Chem.
Soc. 2000, 122, 6624. (b) Bernotas, R. C.; Cube, R. V. Synth. Commun.
1990, 20, 1209. (c) Pearlman, W. M. Tetrahedron Lett. 1967, 17, 1663.
(15) (a) Ohgi, T.; Hecht, S. M. J . Org. Chem. 1981, 46, 1232. (b)
Kim, M. Y.; Starrett, J . E.; Weinreb, S. M. J . Org. Chem. 1981, 46,
5383. (c) Sugasawa, S.; Fujii, T. Chem. Pharm. Bull. 1958, 6, 587.
(16) (a) Rigby, J . H.; Gupta, V. Synlett 1995, 547. (b) Keck, G. E.;
Boden, E.; Sonnewald, U. Tetrahedron Lett. 1981, 22, 2615.
(17) (a) Yoshimura, J .; Yamaura, M.; Suzuki, T.; Hashimoto, H.
Chem. Lett. 1983, 1001. (b) Yamaura, M.; Suzuki, T.; Hashimoto, H.;
Yashimura, J .; Okamoto, T.; Shin, C.-g. Bull Chem. Soc. J pn. 1985,
58, 1413. (c) Morris, J .; Wishka, D. G. J . Org. Chem. 1991, 56, 3549.
(18) Mori, S.; Iwakura, H.; Takechi, S. Tetrahedron Lett. 1988, 29,
5391.
(19) TFA: (a) Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna,
L.; Fava, G. G.; Ferrari, M. B.; Pelosi, G. J . Chem. Soc., Perkin Trans.
1 1993, 2991. (b) Brooke, G. M.; Mohammed, S.; Whiting, M. C. J .
Chem. Soc., Chem. Commun. 1997, 1511. (c) Brooke, G. M.; Moham-
med, S.; Whiting, M. C. J . Chem. Soc., Perkin Trans. 1 1997, 3371.
Lewis acid: (a) Srikrishna, A.; Viswajanani, R.; Sattigeri, J . A.;
Vijaykumar, D. J . Org. Chem. 1995, 60, 5961. (b) Yu, W.; Su, M.; Gao,
X.; Yang, Z.; J in, Z. Tetrahedron Lett. 2000, 41, 4015. (c) Akiyama, T.;
Takesue, Y.; Kumegawa, M.; Nishimoto, H.; Ozaki, S. Bull. Chem. Soc.
J pn. 1991, 64, 2266.
(23) (a) Park, K. K.; Oh, C. H.; J oung, W. K. Tetrahedron Lett. 1993,
34, 7445. (b) Scheuerman, R. A.; Tumelty, D. Tetrahedron Lett. 2000,
41, 6531.
(24) Mori, M.; Ban, Y. Chem. Pharm. Bull. 1976, 24, 1992.
(25) Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4679.
(26) Osborn, J . A.; J ardine, F. H.; Young, J . F.; Wilkinson, G. J .
Chem. Soc. (A) 1966, 1711.
(27) (a) Lessen, T. A.; Demko, D. M.; Weinreb, S. M. Tetrahedron
Lett. 1990, 31, 2105. (b) Voigt, J .; Noltemeyer, M.; Reiser, O. Synlett
1997, 202.
(20) Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. Org.
Synth. 1997, 75, 161.
(21) Greene, T. W.; Wuts, P. G. M. Protective groups in organic
synthesis; 3rd ed.; Wiley: New York, 1999.
(22) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; J ung, K. W. Org.
Lett. 1999, 1, 1893.
(28) Uemura, D.; Hirata, Y.; Iwashita, T.; Naoki, H. Tetrahedron
1985, 41, 1007.

3136 J . Org. Chem., Vol. 66, No. 9, 2001
Wipf and Hopkins
an oil: [R]D +48.1 (c 1.1, CHCl3); IR (neat) 3381, 2938, 1602
cm-1; 1H NMR δ 7.41 (d, 1 H, J ) 7.2 Hz), 7.25 (t, 1 H, J ) 7.6
Hz), 6.96 (t, 1 H, J ) 7.5 Hz), 6.85 (d, 1 H, J ) 8.2 Hz), 5.11-
5.09 (m, 1 H), 3.94-3.92 (m, 1 H), 3.85 (bs, 4 H), 3.65-3.50
(m, 2 H); 13C NMR δ 156.4, 128.7, 127.2, 120.9, 110.3, 70.8,
66.7, 55.3; MS (EI) m/z (rel intensity)168 (M+, 42), 121 (66),
91 (100); HRMS (EI) m/z calcd for C9H12O3 168.0786, found
168.0793.
(S)-Acet ic Acid 2-Acet oxy-2-(2-Met h oxyp h en yl)et h yl
Ester . To a solution of 8.046 g (47.84 mmol) of diol 5 in 80.0
mL (0.989 mol) of pyridine was added at 0 °C 64.0 mL (69.2 g,
0.678 mol) of Ac2O. The reaction mixture was warmed to room
temperature, stirred for 8 h, poured onto ice, and stirred for 1
h. The solution was extracted with CH2Cl2, and the combined
organic extracts were washed with 3 N HCl, dried (MgSO4),
and concentrated. The residue was purified by chromatography
on SiO2 (hexanes/EtOAc; 7:3) to give 11.32 g (44.87 mmol, 94%)
of (S)-acetic acid 2-acetoxy-2-(2-methoxyphenyl)ethyl ester as
a light yellow liquid that solidified upon standing at -20 °C:
metric NaIO4 in aqueous THF to give the desired lactam
24 directly in 66% yield along with 30% of the intermedi-
ate N-formyl amide that was readily converted to the
lactam under basic conditions (NaHCO3, MeOH) and
provided an additional 26% of 24.
In conclusion, we have developed a scalable enantio-
selective synthesis of the AB-ring system of the novel
antitumor antibiotic tetrazomine. Key aspects of our
approach include the use of Sharpless asymmetric di-
hydroxylation conditions to install a benzylic stereocenter
in 94% ee in an o-methoxy styrene unit and an intramo-
lecular Friedel-Crafts hydroxyalkylation of an N-
allylated R-oxo acetamide to close the isoquinolinone ring.
Extensive experimentation was necessary to identify a
suitable amide protective group for this sequence. The
target heterocycle was obtained in an overall yield of 3%
over 18 synthetic steps; the only comparable literature
sequence proceeded in 15-16 steps and in comparable
overall yield to a racemic analogue of 21.2a Efforts to
elaborate key intermediate 24 toward the natural product
tetrazomine by a novel Heck annulation are ongoing in
our labs and will be disclosed in due course.
[R]D +40.0 (c 0.99, CHCl3); IR (neat) 2954, 1743, 1604 cm-1
;
1H NMR δ 7.35-7.27 (m, 2 H), 6.96 (t, 1 H, J ) 6.8 Hz), 6.87
(d, 1 H, J ) 8.1 Hz), 6.40 (dd, 1 H, J ) 7.1, 3.6 Hz), 4.36-4.24
(m, 2 H), 3.84 (s, 3 H), 2.13 (s, 3 H), 2.03 (s, 3 H); 13C NMR δ
170.8, 170.0, 156.3, 129.5, 126.9, 124.8, 120.6, 110.6, 68.7, 65.2,
55.5, 21.2, 20.9; MS (EI) m/z (rel intensity) 252 (M+, 52), 137
(100); HRMS (EI) m/z calcd for C13H16O5 252.0998, found
252.0997.
Exp er im en ta l Section
(S)-Acetic Acid 2-Acetoxy-2-(2-m eth oxy-3-n itr op h en -
yl)eth yl Ester (6). A solution of 19.91 g (78.94 mmol) of (S)-
acetic acid 2-acetoxy-2-(2-methoxyphenyl)ethyl ester in 100 mL
of CHCl3 was treated at -20 °C with 8.40 g (83.1 mmol) of
KNO3 and 39.0 mL (0.276 mol) of TFAA. The reaction mixture
was warmed to 0 °C, stirred for 2 d at 0 °C, quenched with
H2O, and warmed to room temperature. The aqueous layer
was extracted with CH2Cl2, and the combined organic extracts
were dried (Na2SO4) and concentrated to give a yellow oil that
was purified by chromatography on SiO2 (hexanes/EtOAc; 4:1)
to give 19.47 g (65.50 mmol, 83%) of 6 as a yellow oil: [R]D
Gen er a l. All moisture-sensitive reactions were performed
under an atmosphere of N2 or Ar and all glassware was dried
in an oven at 140 °C prior to use. THF and Et2O were dried
by distillation over Na/benzophenone and LAH under
a
nitrogen atmosphere, respectively. Dry CH2Cl2 and toluene
were obtained by distillation from CaH2. Unless otherwise
stated, solvents or reagents were used without further puri-
fication. NMR spectra were recorded at either 300 MHz/75
MHz (1H/13C NMR) or 500 MHz/125 MHz (1H/13C NMR) in
CDCl3 unless stated otherwise. Chemical shifts (δ) are reported
in parts per million and the residual solvent peak was used
as an internal standard. Data are reported as follows: chemi-
cal shift, multiplicity (s ) singlet, d ) doublet, t ) triplet, q )
quartet, m ) multiplet, b ) broad), integration, and coupling
constants.
1
-17.6 (c 1.62, CHCl3); IR (neat) 2956, 1747 cm-1; H NMR δ
7.82 (dd, 1 H, J ) 8.0, 1.5 Hz), 7.62 (dd, 1 H, J ) 7.9, 1.5 Hz),
7.24 (t, 1 H, J ) 8.0 Hz), 6.33 (t, 1 H, J ) 5.2 Hz), 4.31-4.27
(m, 2 H), 3.97 (s, 3 H), 2.11 (s, 3 H), 2.01 (s, 3 H); 13C NMR δ
170.6, 170.0, 151.2, 143.7, 133.5, 132.3, 125.9, 124.3, 68.0, 65.0,
63.1, 21.1, 20.9; MS (EI) m/z (rel intensity) 297 (7, M+), 182
(100), 166 (46); HRMS (EI) m/z calcd for C13H15NO7 297.0849,
found 297.0843.
1-Meth oxy-2-vin ylben zen e. A suspension of 44.4 g (124
mmol) of methyl triphenylphosphonium bromide in 250 mL
of dry THF was treated at room temperature with 84.0 mL of
n-BuLi (1.6 M solution in cyclohexane; 134 mmol). The
resulting orange solution was stirred for 4 h. Then, a solution
of 15.8 g (116 mmol) of o-anisaldehyde in 80 mL of dry THF
was added dropwise. Upon addition a white precipitate formed.
The suspension was stirred for 1 h and concentrated in vacuo
to give a viscous orange oil that was purified by passing
through a short column of SiO2 (hexanes) to yield 12.7 g (94.6
mmol, 82%) of 1-methoxy-2-vinyl-benzene as a faint yellow
(S)-1-(2-Meth oxy-3-n itr op h en yl)eth a n e-1,2-d iol. To a
solution of 19.47 g (65.50 mmol) of diacetate 6 in 300 mL of
MeOH was added a solution of 18.34 g (132.7 mmol) of K2CO3
in 100 mL H2O. After 30 min, the reaction mixture was diluted
with EtOAc and H2O, and the aqueous layer was extracted
with EtOAc. The combined organic extracts were dried (Mg-
SO4) and concentrated to afford 12.97 g (60.85 mmol, 93%) of
(S)-1-(2-methoxy-3-nitrophenyl)ethane-1,2-diol as an orange
liquid: IR (neat) 3003, 1625, 1598 cm-1; H NMR δ 7.41 (dd,
oil: [R]D +10.8 (c 1.21, CHCl3); IR (neat) 3384, 1604, 1529 cm-1
;
1
1 H, J ) 7.6, 1.5 Hz), 7.17 (td, 1 H, J ) 8.2, 1.6 Hz), 7.00 (dd,
1 H, J ) 17.7, 11.1 Hz), 6.87 (t, 1 H, J ) 7.5 Hz), 6.80 (d, 1 H,
J ) 8.2 Hz), 5.68 (dd, 1 H, J ) 17.9, 1.6 Hz), 5.20 (dd, 1 H, J
) 11.1, 1.5 Hz), 3.77 (s, 3 H); 13C NMR δ 156.9, 131.8, 129.0,
126.9, 126.7, 120.8, 114.6, 111.0, 55.6; MS (EI) m/z (rel
intensity) 134 (M+, 27), 91 (100), 65 (26); HRMS (EI) m/z calcd
for C9H10O 134.0732, found 134.0727.
1H NMR δ 7.76-7.73 (m, 2 H), 7.21 (t, 1 H, J ) 7.6 Hz), 5.20-
5.10 (m, 1 H), 3.90-3.80 (m, 5 H), 3.57 (br t, 1 H, J ) 9.8 Hz),
3.30 (br s, 1 H); 13C NMR δ 150.7, 143.3, 136.8, 132.5, 125.2,
124.4, 69.2, 66.9, 63.0; MS (EI) m/z (rel intensity) 182 (100);
HRMS (EI) m/z calcd for C8H8NO4 (M-CH3O) 182.0453, found
182.0449;
(R)-2-(ter t-Bu t yld ip h en ylsila n yloxy)-1-(2-m et h oxy-3-
n itr op h en yl)eth a n ol (7). To a solution of 4.324 g (20.29
mmol) of (S)-1-(2-methoxy-3-nitrophenyl)ethane-1,2-diol in 25
mL of dry DMF was added 2.78 g (40.8 mmol) of imidazole
followed by 5.30 mL (5.56 g, 20.2 mmol) of TBDPSCl. The
reaction mixture was stirred at room temperature for 4 h,
poured onto H2O, and extracted with Et2O. The combined ether
extracts were washed with brine, dried (MgSO4), and concen-
trated in vacuo to give a yellow oil that was purified by
chromatography on SiO2 (hexanes/EtOAc; 9:1) to afford 1.611
g (2.338 mmol, 12%) of the di-TBDPS-protected compound and
6.684 g (14.81 mmol, 73%) of 7 as a viscous yellow oil: [R]D
(S)-1-(2-Meth oxyp h en yl)eth a n e-1,2-d iol (5). To a sus-
pension of 72.2 g of AD-Mix-R [37.5 mg (0.101 mmol) of K2-
OsO2(OH)4, 398 mg (0.555 mmol) of (DHQ)2PHAL, 50.5 g (154
mmol) of K3Fe(CN)6, 21.2 g (155 mmol) of K2CO3] in 250 mL
of t-BuOH and 250 mL of H2O was added at 0 °C 7.00 g (52.2
mmol) of 2-vinylanisole. The reaction mixture was stirred
vigorously for 3 h, treated with 76.5 g (0.607 mmol) of sodium
sulfite, warmed to room temperature, and stirred for an
additional 45 min. After addition of EtOAc, the aqueous layer
was extracted with EtOAc, and the combined organic layers
were dried (MgSO4), filtered, and concentrated to give a yellow
oil that was purified by chromatography on SiO2 (hexanes/
EtOAc; 3:7) to afford 8.198 g (48.74 mmol, 93%) of diol 5 as
+38.5 (c 1.31, CHCl3); IR (neat) 3566, 3073, 2253 cm-1
;
1H
NMR δ 7.83-7.76 (m, 2 H), 7.69-7.66 (m, 2 H), 7.59-7.57 (m,

Antitumor Antibiotic Tetrazomine
J . Org. Chem., Vol. 66, No. 9, 2001 3137
2 H), 7.46-7.38 (m, 6 H), 7.25 (t, 1 H, J ) 8.0 Hz), 5.19-5.12
(m, 1 H), 3.97 (dd, 1 H, J ) 10.3, 6.7 Hz), 3.69 (s, 3 H), 3.63
(dd, 1 H, J ) 10.2, 7.7 Hz), 3.24 (d, 1 H, J ) 3.4 Hz), 1.10 (s,
9 H); 13C NMR δ 136.6, 135.7, 135.6, 132.7, 130.2, 130.1, 128.1,
128.0, 125.0, 124.1, 69.0, 68.0, 62.7, 27.0, 19.4; MS (EI) m/z
(rel intensity) 434 (6), 394 (26), 199 (100); HRMS (EI) m/z calcd
for C21H20NO5Si (M - C4H9) 394.1111, found 394.1119.
(S)-2-[2-(ter t-Bu tyld ip h en ylsila n yloxy)-1-(2-m eth oxy-
3-n itr op h en yl)eth yl]isoin d ole-1,3-d ion e. To a solution of
6.658 g (14.76 mmol) of alcohol 7 in 90 mL of dry THF were
added 4.66 g (17.8 mmol) of Ph3P, 2.607 g (17.69 mmol) of
phthalimide, and 2.80 mL (3.10 g, 17.8 mmol) of DEAD. The
reaction mixture was stirred for 90 min, concentrated in vacuo
to give a viscous orange oil, and purified by chromatography
on SiO2 (hexanes/EtOAc; 4:1) to afford 7.663 g (13.20 mmol,
89%) of (S)-2-[2-(tert-butyl-diphenylsilanyloxy)-1-(2-methoxy-
3-nitrophenyl)ethyl]isoindole-1,3-dione as a viscous oil: [R]D
mL (1.75 g; 12.8 mmol) of isobutyl chloroformate. After 15 min,
a solution of 5.324 g (9.336 mmol) of amine 9 in 15 mL of dry
CH2Cl2 was added dropwise via cannula. The reaction mixture
was warmed to room temperature, stirred for 12 h, diluted
with CH2Cl2, and washed with 1 N NaH2PO4 and brine. The
organic layer was dried (MgSO4) and concentrated to give a
yellow oil that was purified by chromatography on SiO2
(hexanes/EtOAc; 7:3) to afford 4.660 g (6.952 mmol, 74%) of
10 as a viscous oil: [R]D +38.0 (c 0.9, CHCl3); IR (neat) 3016,
1
2859, 1750, 1667 cm-1; H NMR δ 7.76 (d, 1 H, J ) 8.0 Hz),
7.61-7.27 (m, 12 H), 7.17-7.09 (m, 2 H), 6.85-6.75 (m, 2 H),
6.63 (d, 1 H, J ) 8.1 Hz), 5.75-5.65 (m, 0.4 H); 5.26-5.13 (m,
1 H), 4.90-3.90 (m, 6 H), 3.85, 3.80, 3.73, 3.62 (4 s, 6 H), 2.24,
2.16 (2 s, 3 H), 1.02, 0.93 (2 s, 9 H); 13C NMR δ 170.8, 170.7,
168.0, 167.8, 159.2, 158.7, 135.8, 135.6, 134.9, 134.3, 132.8,
132.6, 130.3, 130.0, 129.4, 128.4, 128.2, 127.9, 127.4, 126.2,
125.1, 123.7, 123.1, 114.5, 114.2, 113.7, 62.9, 62.7, 62.1, 61.7,
55.7, 55.5, 55.4, 54.9, 48.7, 44.9, 26.9, 20.9, 20.8, 19.2; MS (EI)
m/z (rel intensity) 671 ([M + H]+, 10), 613 (40), 121 (100);
HRMS (EI) m/z calcd for C33H33N2O8Si (M - C4H9) 613.2006,
found 613.2025.
+32.4 (c 0.96, CHCl3); IR (neat) 3071, 2858, 1776, 1713 cm-1
;
1H NMR δ 7.96-7.60 (m, 11 H), 7.40-7.20 (m, 6 H), 7.18 (t, 1
H, J ) 7.7 Hz), 6.01-5.92 (m, 1 H), 4.67 (t, 1 H, J ) 9.8 Hz),
4.20-4.15 (m, 1 H), 3.89 (s, 3 H), 0.93 (s, 9 H); 13C NMR δ
168.6, 152.1, 143.7, 135.7, 135.6, 134.9, 134.3, 133.0, 131.9,
130.1, 130.0, 127.9, 125.6, 123.9, 123.5, 63.2, 62.0, 50.4, 26.7,
19.1; MS (EI) m/z (rel intensity) 565 (16), 523 (100), 328 (55);
HRMS (EI) m/z calcd for C29H23N2O6Si (M - C4H9) 523.1325,
found 523.1318.
(R)-Acetic Acid [[1-(3-Acetyla m in o-2-m eth oxyp h en yl)-
2-(ter t-bu tyldiph en ylsilan yloxy)eth yl]-(4-m eth oxyben zyl)-
ca r ba m oyl]m eth yl Ester (11). To a solution of 4.511 g (6.279
mmol) of nitroarene 10 in 50 mL of n-PrOH was added 843.2
mg of 10% Pd/C. The suspension was stirred under H2 (1 atm)
for 4 h, filtered through Celite (EtOAc), and concentrated to
give the crude aniline as a maroon, amorphous solid. A solution
of this aniline in 30 mL of dry CH2Cl2 was treated with 1.88
mL (1.36 g, 13.5 mmol) of Et3N followed by 718 µL (793 mg,
10.1 mmol) of AcCl. The reaction mixture was stirred at room
temperature for 12 h, diluted with CH2Cl2, and washed with
H2O and brine. The organic layer was dried (MgSO4) and
chromatographed on SiO2 (hexanes/EtOAc; 1:1) to afford 2.432
g (3.565 mmol, 53%) of 11 as a light tan, viscous oil in addition
to 1.450 g (2.264 mmol, 34%) of the intermediate aniline which
was resubjected to acetylation to yield at total of 3.732 g (5.470
mmol, 81%) of amide 11: [R]D -34.4 (c 1.08, CHCl3); IR (neat)
(S)-2-(ter t-Bu t yld ip h en ylsila n yloxy)-1-(2-m et h oxy-3-
n it r op h en yl)et h yla m in e (8). A solution of 7.663 g (13.20
mmol) of (S)-2-[2-(tert-butyldiphenylsilanyloxy)-1-(2-methoxy-
3-nitrophenyl)ethyl]isoindole-1,3-dione and 2.3 mL (40 mmol)
of hydrazine mono hydrate in 70 mL of EtOH was heated at
reflux for 3 h. The reaction mixture was cooled to room
temperature, diluted with Et2O, and filtered. The solid was
washed with Et2O, and the filtrate was concentrated in vacuo,
redissolved in Et2O, and washed with 1 N HCl. The organic
layer was dried (Na2SO4) and concentrated to afford 5.940 g
(13.19 mmol, 100%) of 8 as an orange, amorphous solid: mp
59-60 °C; [R]D -6.6 (c 1.06, CHCl3); IR (CHCl3) 2932, 2860
cm-1; 1H NMR δ 9.27 (bs, 1 H) 7.90 (d, 1 H, J ) 7.2 Hz), 7.74
(d, 1 H, J ) 7.8 Hz), 7.55 (d, 2 H, J ) 6.6 Hz), 7.40-7.25 (m,
8 H), 6.95 (t, 1 H, J ) 8.0 Hz), 4.82 (br s, 1 H), 4.10 (dd, 1 H,
J ) 10.8, 4.2 Hz), 3.88 (dd, 1 H, J ) 10.6, 4.5 Hz), 3.58 (s, 3
H), 1.0 (s, 9 H); 13C NMR δ 151.4, 143.1, 136.0, 135.7, 135.6,
133.5, 132.2, 130.4, 130.3, 130.2, 128.1, 128.0, 126.3, 123.9,
64.3, 62.8, 51.0, 26.9, 19.3; MS (EI) m/z (rel intensity) 393 (15),
198 (100), 181 (91); HRMS (EI) m/z calcd for C21H21N2O4Si (M
- C4H9) 393.1271, found 393.1253.
(S)-[2-(ter t-Bu tyld ip h en ylsila n yloxy)-1-(2-m eth oxy-3-
n itr op h en yl)eth yl]-(4-m eth oxyben zyl)a m in e (9). To a so-
lution of 5.031 g (11.17 mmol) of amine 8 in 13 mL of MeOH
was added at 0 °C 712.7 mg (11.34 mmol) of NaBH3CN
followed by 1.50 mL (1.68 g, 12.3 mmol) of p-anisaldehyde and
0.5 mL of AcOH. The reaction mixture was warmed to room
temperature, stirred overnight, and quenched with H2O and
solid Na2CO3. The viscous suspension was transferred to a
separatory funnel and extracted with CH2Cl2. The combined
organic extracts were dried (Na2SO4) and concentrated in
vacuo to give a bright yellow oil that was purified by chroma-
tography on SiO2 (hexanes/EtOAc; 9:1) to afford 5.324 g (9.336
mmol, 84%) of amine 9 as a light yellow oil: [R]D -37.3 (c 0.74,
CHCl3); IR (neat) 2859, 1611 cm-1; 1H NMR δ 7.91 (dd, 1 H, J
) 7.7, 1.6 Hz), 7.73 (dd, 1 H, J ) 8.1, 1.6 Hz), 7.63-7.55 (m,
4 H), 7.45-7.30 (m, 6 H), 7.25-7.15 (m, 3 H), 6.89 (d, 2 H, J
) 8.5 Hz), 4.33 (dd, 1 H, J ) 8.1, 3.9 Hz), 3.83-3.79 (m, 4 H),
3.68-3.56 (m, 6 H), 2.50 (bs, 1 H), 1.06 (s, 9 H); 13C NMR δ
158.8, 152.2, 143.9, 137.2, 135.8, 135.7, 133.8, 133.3, 133.2,
132.5, 130.0, 129.4, 127.9, 124.5, 124.1, 114.0, 67.5, 62.9, 56.7,
55.5, 51.0, 27.0, 19.4; MS (EI) m/z (rel intensity) 513 (36), 121
(100); HRMS (EI) m/z calcd for C29H29N2O5Si (M - C4H9)
513.1846, found 513.1844.
1
3305, 2859, 2250, 1748, 1663 cm-1; H NMR δ 8.29-8.15 (m,
1 H), 7.75-7.20 (m, 11 H), 7.12-6.88 (m, 3 H), 6.82-6.61 (m,
2 H), 6.09-5.99 (m, 0.3 H), 5.37 (d, 0.6 H, J ) 14.8 Hz), 5.15-
5.06 (m, 0.5 H), 5.00 (d, 0.5 H, J ) 14.3 Hz), 4.63-4.39 (m, 2
H), 4.07-3.61 (m, 8 H), 2.26-2.05 (m, 6 H), 1.01, 0.96 (2 s, 9
H); 13C NMR δ 171.0, 168.5, 167.9, 167.7, 158.6, 148.4, 135.7,
135.6, 132.7, 132.5, 132.0, 130.6, 130.1, 129.8, 129.4, 128.9,
128.8, 128.1, 127.8, 127.4, 124.8, 123.2, 122.5, 120.7, 114.2,
113.6, 63.1, 62.2, 61.7, 61.5, 61.2, 55.3, 54.2, 47.2, 44.7, 26.9,
25.0, 24.9, 21.0, 20.8, 19.2; MS (EI) m/z (rel intensity) 651 (28),
625 (11), 121 (100); HRMS (EI) m/z calcd for C35H37N2O7Si (M
- C4H9) 625.2370, found 625.2375.
(R)-N-[1-(3-Acetyla m in o-2-m eth oxyp h en yl)-2-(ter t-bu -
t yld ip h en ylsila n yloxy)et h yl]-2-h yd r oxy-N-(4-m et h oxy-
ben zyl)a ceta m id e (12). To a solution of 2.432 g (3.565 mmol)
of diacetate 11 in 25 mL of MeOH was added 655.0 mg (4.739
mmol) of K2CO3 in 5 mL of H2O. After 90 min, the mixture
was diluted with EtOAc and H2O, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated to give
an orange oil that was purified by chromatography on SiO2
(CH2Cl2/EtOAc; 7:3) to afford 2.024 g (3.177 mmol, 89%) of 12
as a viscous oil: [R]D -28.3 (c 1.24, CHCl3); IR (neat) 3420,
1
3313, 2859, 2250, 1683, 1643 cm-1; H NMR δ 8.26-8.20 (m,
1 H), 7.69-7.27 (m, 11 H), 7.11-6.63 (m, 6 H), 6.07 (bt, 0.3 H,
J ) 6.1 Hz), 4.99 (dd, 0.6 H, J ) 8.3, 5.1 Hz), 4.68, 4.54 (2 d,
1 H, J ) 14.8 Hz), 4.40-3.68 (m, 9 H), 3.46 (s, 3 H), 2.22, 2.21
(2s, 3 H), 1.02, 1.00 (2 s, 9 H); 13C NMR δ 173.5, 173.3, 168.6,
159.1, 158.6, 148.2, 135.8, 135.7, 135.6, 132.7, 132.5, 132.1,
129.9, 129.3, 128.6, 128.5, 128.0, 127.8, 127.5, 124.9, 124.8,
123.2, 122.6, 114.2, 113.6, 62.8, 61.5, 60.9, 60.3, 55.4, 55.3, 54.6,
46.5, 45.2, 26.9, 25.0, 24.9, 19.2, 19.1; MS (EI) m/z (rel
intensity) 640 (M+, 7), 583 (12), 121 (100); HRMS (EI) m/z calcd
for C33H35N2O6Si (M-C4H9) 583.2264, found 583.2258.
(R)-Acet ic Acid [[2-(ter t-Bu t yld ip h en ylsila n yloxy)-1-
(2-m eth oxy-3-n itr op h en yl)eth yl]-(4-m eth oxyben zyl)ca r -
ba m oyl]m eth yl Ester (10). To a solution of 1.439 g (12.19
mmol) of acetoxyacetic acid and 2.00 mL (1.84 g; 18.2 mmol)
of NMM in 25 mL of dry CH2Cl2 was added at -20 °C 1.66
(R)-N-[1-(ter t-Bu t yld ip h en ylsila n yloxym et h yl)-4-h y-
d r oxy-8-m eth oxy-2-(4-m eth oxyben zyl)-3-oxo-1,2,3,4-tet-
r a h yd r oisoqu in olin -7-yl]a ceta m id e (14). A solution of 157

3138 J . Org. Chem., Vol. 66, No. 9, 2001
Wipf and Hopkins
µL (1.70 mmol) of oxalyl chloride in 5 mL of dry CH2Cl2 was
treated at -60 to -50 °C with a solution of 272 µL (3.34 mmol)
of DMSO in 2 mL of CH2Cl2 followed by a solution of 1.020 g
(1.593 mmol) of 12 in 2 mL of CH2Cl2. After 45 min, 1.09 mL
(791 mg, 7.80 mmol) of Et3N were added, and the reaction
mixture was warmed to room temperature, stirred for 2 h, and
quenched with H2O. The aqueous layer was extracted with
CH2Cl2. The combined organic extracts were dried (MgSO4)
and concentrated in vacuo to give 953.7 mg (1.494 mmol, 94%)
of crude aldehyde 13. A solution of this compound in 14 mL of
dioxane was treated with 340.5 mg (1.987 mmol) of anhydrous
pTsOH, heated at reflux for 90 min, cooled to room tempera-
ture, diluted with H2O, and extracted with Et2O. The combined
organic extracts were dried (MgSO4) and purified by chroma-
tography on SiO2 (CH2Cl2/EtOAc; 7:3) to afford 760.5 mg (1.191
mmol, 75%) of 14 as a light yellow glass: [R]D -41.0 (c 1.03,
CHCl3); IR (neat) 3422, 2859, 2250, 1651 cm-1; 1H NMR δ 8.26
(d, 1 H, J ) 8.2 Hz), 7.60-7.27 (m, 13 H), 7.09 (d, 2 H, J ) 7.8
Hz), 6.78 (d, 2 H, J ) 7.8 Hz), 5.60 (d, 1 H, J ) 14.6 Hz), 5.06
(s, 1 H), 4.70 (bs, 1 H), 4.30 (d, 1 H, J ) 14.5 Hz), 4.21 (s, 1 H),
3.85-3.66 (m, 5 H), 3.12 (s, 3 H), 2.17 (s, 3 H), 1.05 (s, 9 H);
13C NMR δ 172.1, 168.3, 159.3, 144.4, 135.7, 135.6, 133.1,
132.6, 132.5, 130.3, 130.1, 129.7, 128.5, 128.0, 123.8, 121.7,
121.3, 114.2, 66.6, 65.5, 60.7, 55.9, 55.4, 49.4, 27.0, 24.9, 19.2;
MS (EI) m/z (rel intensity) 581 (21), 121 (100); HRMS (EI) m/z
calcd for C33H33N2O6Si (M - C4H9) 581.2108, found 581.2105.
(R)-N-[1-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-8-m eth -
oxy-2-(4-m eth oxyben zyl)-3-oxo-1,2,3,4-tetr ah ydr oisoqu in -
olin -7-yl]a ceta m id e (15). To a solution of 358.7 mg (0.5619
mmol) of alcohol 14 in 6 mL of dry CH2Cl2 were added 4.2 mg
(0.034 mmol) of DMAP, 79.0 µL (77.3 mg, 0.976 mmol) of
pyridine, and 135 µL (168 mg, 0.972 mmol) of phenyl thion-
ochloroformate. The reaction mixture was stirred for 6 h,
concentrated, and passed through a short plug of SiO2 (CH2-
Cl2/EtOAc; 9:1) to give 305.6 mg (0.3946 mmol) of the crude
thiocarbonate as a light yellow, sticky solid. A solution of this
compound in 30 mL of dry, degassed benzene was heated at
reflux and treated over a 2.5 h period with a solution of 7.1
mg (0.043 mmol) of AIBN and 138 µL (0.512 mmol) of Bu3-
SnH in 5 mL of dry, degassed benzene. After 24 h, an
additional solution of 7.1 mg (0.043 mmol) of AIBN in 5 mL of
benzene was added. The reaction mixture was heated at reflux
for an additional 36 h, cooled to room temperature, and
concentrated in vacuo. The residue was purified by chroma-
tography on SiO2 (CH2Cl2/EtOAc; 3:1) through a plug of KF
to afford 190.2 mg (0.3056 mmol, 54%) of 15 as a light yellow,
viscous oil: [R]D -19.2 (c 1.09, CHCl3); IR (neat) 3421, 3289,
4 H), 3.21 (dd, 1 H, J ) 14.3, 4.9 Hz), 3.09 (dd, 1 H, J ) 14.3,
5.9 Hz), 2.20 (bs, 1 H), 1.07 (s, 9 H); 13C NMR δ 152.2, 143.9,
137.3, 136.9, 135.8, 135.7, 133.7, 133.3, 133.2, 130.1, 130.0,
128.0, 124.5, 124.1, 116.1, 67.4, 63.0, 56.9, 50.2, 27.0, 19.4; MS
(EI) m/z (rel intensity) 433 (82), 221 (100); HRMS (EI) m/z calcd
for C24H25N2O4Si (M - C4H9) 433.1584, found 433.1576.
(R)-Acetic Acid {Allyl-[2-(ter t-bu tyldiph en ylsilan yloxy)-
1-(2-m eth oxy-3-n itr op h en yl)eth yl]ca r ba m oyl}m eth yl Es-
ter (17). To a solution of 838.7 mg (1.711 mmol) of allylamine
16 in 10 mL of dry Et2O were added at 0 °C 430 µL (312 mg,
3.09 mmol) of Et3N and 276 µL (351 mg, 2.57 mmol) of
acetoxyacetyl chloride. The reaction mixture was slowly
warmed to room temperature, stirred overnight, and filtered.
The residue was washed with Et2O, and the filtrate was
concentrated and purified by chromatography on SiO2 (hex-
anes/EtOAc; 3:2) to yield 864.1 mg (1.464 mmol, 86%) of the
desired amide 17 as a yellow oil: [R]D +33.8 (c 1.29, CHCl3);
1
IR (neat) 3073, 2251, 1751, 1668 cm-1; H NMR δ 7.80 (bt, 1
H, J ) 9.2 Hz), 7.68-7.55 (m, 3 H), 7.50-7.27 (m, 8 H), 7.16
(bt, 1 H, J ) 7.9 Hz), 5.73-5.50 (m, 1.5 H), 5.20-5.10 (m, 2
H), 4.83-4.56 (m, 2.5 H), 4.20-3.50 (m, 7 H), 2.21, 2.17 (2 s,
3 H), 1.03, 0.99 (2 s, 9 H); 13C NMR δ 170.7, 170.6, 167.6, 167.2,
152.9, 152.2, 143.8, 142.8, 135.7, 135.6, 135.3, 134.7, 134.5,
134.1, 133.7, 132.8, 132.7, 132.4, 132.3, 131.9, 130.3, 130.2,
130.0, 128.1, 127.9, 126.1, 125.0, 123.6, 123.1, 117.3, 116.7,
62.9, 62.8, 62.6, 62.5, 61.7, 60.4, 55.3, 54.5, 47.9, 45.1, 26.8,
20.7, 19.1; MS (EI) m/z (rel intensity) 533 (70), 199 (100);
HRMS (EI) m/z calcd for C28H29N2O7Si (M - C4H9) 533.1744,
found 533.1743.
(R)-Acetic Acid {[1-(3-Acetyla m in o-2-m eth oxyp h en yl)-
2-(ter t-b u t yld ip h en ylsila n yloxy)et h yl]a llylca r b a m oyl}-
m eth yl Ester (18). To a solution of 586.3 mg (0.9932 mmol)
of allyl amide 17 and 18.6 mg (0.0497 mmol) of ethyl viologen
dibromide in 7.5 mL of CH2Cl2/H2O (8:1) was added dropwise
a solution of 685 mg (4.95 mmol) of K2CO3 and 808 mg (4.59
mmol) Na2S2O4 in 3.5 mL of H2O. The reaction mixture was
stirred for 24 h, diluted with H2O, and extracted with CH2-
Cl2, EtOAc, and Et2O. The combined organic extracts were
dried (Na2SO4), concentrated, and passed through a short plug
of SiO2 (hexanes/EtOAc, 1:1) to yield 420.3 mg (0.7500 mmol,
76%) of the desired aniline as a yellow, sticky solid. A solution
of this aniline was then dissolved in 7 mL of dry CH2Cl2 was
treated with 210 µL (152 mg, 1.51 mmol) of Et3N and 93.0 µL
(103 mg, 1.31 mmol) of acetyl chloride. The reaction mixture
was stirred at room temperature for 12 h, concentrated in
vacuo, and purified by chromatography on SiO2 (hexanes/
EtOAc; 1:1) to yield 402.1 mg (0.6675 mmol, 67% from 17) of
18 as a viscous oil: [R]D -45.0 (c 1.02, CHCl3); IR (neat) 3302,
1
2247, 1642 cm-1; H NMR δ 8.15 (d, 1 H, J ) 8.3 Hz), 7.57-
1
7.52 (m, 2 H), 7.46-7.27 (m, 10 H), 7.12 (d, 2 H, J ) 8.5 Hz),
6.92 (d, 1 H, J ) 8.2 Hz), 6.79 (d, 2 H, J ) 8.6 Hz), 5.66 (d, 1
H, J ) 14.8 Hz), 4.66-4.61 (m, 1 H), 4.18 (d, 1 H, J ) 14.8
Hz), 3.84-3.61 (m, 7 H), 3.18 (s, 3 H), 2.18 (s, 3 H), 1.03 (s, 9
H); 13C NMR δ 169.8, 168.4, 159.2, 144.9, 135.7, 135.6, 132.8,
132.7, 130.5, 130.0, 129.7, 129.6, 129.4, 128.0, 126.1, 123.7,
121.3, 114.2, 65.9, 60.7, 56.4, 55.4, 48.2, 37.5, 27.0, 24.9, 19.2;
MS (EI) m/z (rel intensity) 622 (M+, 10), 565 (30), 121 (100);
3072, 2248, 1750, 1664 cm-1; H NMR δ 8.28-8.19 (m, 1 H),
7.75-7.55 (m, 5 H), 7.45-7.27 (m, 6 H), 7.09-7.02 (m, 1.5 H),
6.78 (d, 0.5 H, J ) 7.4 Hz), 6.07 (t, 0.4 H, J ) 5.9 Hz), 5.58-
5.45 (m, 1 H), 5.33 (d, 0.6 H, J ) 14.6 Hz), 5.10-5.00 (m, 1.5
H), 4.95-4.68 (m, 3 H), 4.14-3.97 (m, 2 H), 3.82-3.64 (m, 5
H), 2.23-2.16 (m, 6 H), 1.05, 1.00 (2 s, 9 H); 13C NMR δ 170.9,
170.6, 168.6, 168.5, 167.4, 167.1, 148.4, 147.9, 135.7, 135.6,
134.0, 133.9, 133.1, 130.2, 130.1, 129.9, 128.0, 127.8, 124.7,
124.6, 123.7, 123.0, 122.4, 120.8, 117.1, 116.8, 62.8, 62.7, 61.8,
61.5, 61.3, 54.9, 53.3, 46.4, 44.8, 26.8, 24.9, 24.8, 20.8, 19.1;
MS (EI) m/z (rel intensity) 545 (100), 388 (54); HRMS (EI) m/z
calcd for C30H33N2O6Si (M - C4H9) 545.2108, found 545.2104.
(R )-N -[1-(3-Ace t yla m in o-2-m e t h oxyp h e n yl)-2-(t er t -
b u t y ld ip h e n y ls ila n y lo x y )e t h y l]-N -a lly l-2-h y d r o x y -
a ceta m id e (19). To a solution of 2.369 g (3.933 mmol) of the
diacetate 18 in 30 mL of MeOH was added a solution of 761
mg (5.51 mmol) of K2CO3 in 5 mL of H2O. After 2 h, the
reaction mixture was diluted with H2O and extracted with
EtOAc. The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to yield 2.080 g (3.713 mmol, 94%) of
the primary alcohol 19 as a viscous oil: [R]D -47.8 (c 1.14,
CHCl3); IR (neat) 3422, 3308, 3073, 2250, 1644 cm-1; 1H NMR
δ 8.30-8.23 (m, 1 H), 7.66-7.29 (m, 11 H), 7.10-6.97 (m, 1.6
H), 6.80 (bd, 0.5 H, J ) 7.5 Hz), 6.08 (bt, 0.4 H, J ) 6.4 Hz),
5.52-5.32 (m, 1 H), 5.04-4.79 (m, 2.5 H), 4.52 (dq, 1 H, J )
10.5, 3.7 Hz), 4.17-3.95 (m, 3 H), 3.82-3.56 (m, 7 H), 2.24,
2.22 (2 s, 3 H), 1.04, 1.02 (2 s, 9 H); 13C NMR δ 172.8, 172.7,
HRMS (EI) m/z calcd for
C37H42N2O5Si 622.2863, found
622.2842.
(R)-Allyl-[2-(ter t-bu tyld ip h en ylsila n yloxy)-1-(2-m eth -
oxy-3-n itr op h en yl)eth yl]a m in e (16). A suspension of 980
mg of 4 Å MS in 16 mL of dry DMF was treated with 553 mg
(3.36 mmol) of CsOH‚H2O. After 10 min of vigorous stirring,
a solution of 1.513 g (3.360 mmol) of amine 8 in 5 mL of dry
DMF was added. The reaction mixture was stirred for 30 min,
treated with 344 µL (478 mg, 3.95 mmol) of allyl bromide, and
stirred overnight. The suspension was filtered, and the filtrate
was diluted with H2O and extracted with Et2O. The combined
organic extracts were dried (Na2SO4) and purified by chroma-
tography on SiO2 (hexanes/EtOAc; 85:15) to yield 1.293 g
(2.636 mmol, 78%) of amine 16 as an orange oil: [R]D -45.1 (c
1.06, CHCl3); IR (neat) 3073, 2254 cm-1; 1H NMR δ 7.82 (d, 1
H, J ) 7.7 Hz), 7.72 (d, 1 H, J ) 8.1 Hz), 7.68-7.64 (m, 2 H),
7.60-7.55 (m, 2 H), 7.46-7.34 (m, 6 H), 7.19 (t, 1 H, J ) 7.7
Hz), 5.98-5.85 (m, 1 H), 5.31-5.12 (m, 2 H), 4.35 (dd, 1 H, J
) 7.5, 3.9 Hz), 3.84 (dd, 1 H, J ) 10.0, 3.2 Hz), 3.69-3.60 (m,

Antitumor Antibiotic Tetrazomine
J . Org. Chem., Vol. 66, No. 9, 2001 3139
168.8, 168.6, 148.4, 148.0, 135.8, 135.7, 135.6, 133.6, 133.1,
132.7, 132.5, 132.0, 130.3, 130.2, 129.9, 128.6, 128.0, 127.9,
124.8, 124.7, 123.0, 122.7, 117.3, 116.9, 62.5, 61.4, 61.1, 60.5,
60.1, 54.2, 53.8, 45.8, 45.0, 26.8, 24.9, 24.7, 19.2, 19.1; MS (EI)
m/z (rel intensity) 503 (42), 388 (24), 295 (100); HRMS (EI)
m/z calcd for C28H31N2O5Si (M-C4H9) 503.2002, found 503.2021.
N -[(1R ,4S )-2-Allyl-1-(t er t -b u t yld ip h e n ylsila n yloxy-
m et h yl)-4-h yd r oxy-8-m et h oxy-3-oxo-1,2,3,4-t et r a h yd r o-
isoqu in olin -7-yl]a ceta m id e (21). A solution of 387 µL (4.01
mmol) of oxalyl chloride in 8 mL of dry CH2Cl2 was treated at
-50 to -60 °C with a solution of 671 µL (8.44 mmol) of DMSO
in 8 mL CH2Cl2 followed by a solution of 2.080 g (3.713 mmol)
of 19 in 8 mL of CH2Cl2. After 45 min, 2.69 mL (1.95 g, 19.3
mmol) of Et3N was added, and the reaction mixture was
allowed to warm to room temperature, stirred for 2 h, and
diluted with H2O. The aqueous layer was extracted with CH2-
Cl2. The combined organic layers were dried (MgSO4) and
concentrated in vacuo to give crude aldehyde 20. A solution of
this compound in 30 mL of dioxane was treated with 833.1
mg (4.837 mmol) of anhydrous pTsOH and heated at reflux.
After 90 min, the reaction mixture was cooled to room
temperature, diluted with H2O, and extracted with Et2O. The
combined organic extracts were dried (MgSO4) and purified
by chromatography on SiO2 (hexanes/EtOAc; 45:55) to afford
1.269 g (2.273 mmol, 61%) of 21 as a light yellow glass: [R]D
-34.6 (c 1.00, CHCl3); IR (CHCl3) 3422, 3311, 3072, 2250, 1658
(m, 3 H), 4.80-4.75 (m, 1 H), 3.87 (dd, 1 H, J ) 10.5, 3.3 Hz),
3.78-3.64 (m, 6 H), 3.51 (d, 1 H, J ) 19.2 Hz), 2.22 (s, 3 H),
1.00 (s, 9 H); 13C NMR δ 169.5, 168.4, 145.0, 135.6, 135.5,
133.3, 132.8, 132.7, 130.5, 130.0, 129.8, 128.0, 126.0, 123.7,
121.5, 117.1, 66.0, 61.2, 57.3, 48.3, 37.3, 27.0, 24.9, 19.2; MS
(EI) m/z (rel intensity) 542 (M+, 17), 485 (11), 273 (100); HRMS
(EI) m/z calcd for C32H38N2O4Si 542.2601, found 542.2578.
(R)-N-[1-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-8-m eth -
oxy-3-oxo-2-p r op en yl-1,2,3,4-tetr a h yd r oisoqu in olin -7-yl]-
a ceta m id e (23). To a solution of 329.2 mg (0.6070 mmol) of
the allyl amide 22 in 1.2 mL of dry toluene was added 44.6
mg (0.0482 mmol; 8 mol %) of ClRh(PPh3)3. The reaction
mixture was heated at reflux for 14 h, cooled to room
temperature, concentrated, and passed through a short plug
of SiO2 (CH2Cl2/EtOAc; 4:1) to yield 242.3 mg (0.4467 mmol,
74%) of enamide 23 as a light tan, viscous oil that was carried
on without further purification: 1H NMR δ 8.22 (d, 1 H, J )
8.3 Hz), 7.49-7.27 (m, 12 H), 6.93 (d, 1 H, J ) 8.3 Hz), 5.27-
5.18 (m, 2 H), 4.01 (dd, 1 H, J ) 10.4, 3.6 Hz), 3.86 (d, 1 H, J
) 19.5 Hz), 3.74-3.68 (m, 4 H), 3.53 (d, 1 H, J ) 19.6 Hz),
2.24 (s, 3 H), 1.76 (dd, 3 H, J ) 6.6, 1.4 Hz), 0.94 (s, 9 H); 13
C
NMR δ 168.4, 168.2, 145.3, 135.6, 135.5, 132.7, 129.9, 129.8,
127.9, 126.4, 125.8, 123.5, 121.6, 107.2, 65.1, 61.3, 55.1, 37.6,
26.8, 24.9, 19.1, 15.7.
(R)-N-[1-(ter t-Bu tyld ip h en ylsila n yloxym eth yl)-8-m eth -
oxy-3-oxo-1,2,3,4-tetr a h yd r oisoqu in olin -7-yl]a ceta m id e
(24). To a solution of 58.4 mg (0.108 mmol) of enamide 23 in
1 mL of THF was added 1.8 mg (0.0071 mmol) of OsO4 followed
by a solution of 36.5 mg (0.171 mmol) of NaIO4 in 1 mL of
H2O. The reaction mixture was stirred at room-temperature
overnight, diluted with H2O, and extracted with CH2Cl2. The
combined organic extracts were dried (MgSO4) and concen-
trated in vacuo. The residue was purified by chromatography
on SiO2 (CH2Cl2/EtOAc; 1:1) to afford 17.2 mg (0.0324 mmol,
30%) of N-formyl amide and 35.6 mg (0.0709 mmol, 66%) of
24 as a light yellow glass: [R]D +9.2 (c 1.0, CHCl3); IR (CHCl3)
1
cm-1; H NMR δ 8.27 (d, 1 H, J ) 8.4 Hz), 7.70-7.25 (m, 12
H), 5.80-5.65 (m, 1 H, 5.16-5.03 (m, 3 H), 4.92-4.79 (m, 1
H), 4.13 (s, 1 H), 3.90-3.80 (m, 2 H), 3.73-3.63 (m, 7 H), 2.21
(s, 3 H), 1.01 (s, 9 H); 13C NMR δ 171.8, 168.5, 144.7, 135.6,
135.5, 135.0, 133.2, 132.6, 132.4, 130.4, 130.1, 128.0, 127.7,
123.8, 122.0, 121.3, 117.8, 67.2, 66.6, 65.6, 61.2, 56.9, 49.4, 26.9,
24.8, 19.2; MS (EI) m/z (rel intensity) 558 (M+, 9), 199 (100);
HRMS (EI) m/z calcd for
C32H38N2O5Si 558.2550, found
558.2555.
(R)-N-[2-Allyl-1-(ter t-bu tyld ip h en ylsila n yloxym eth yl)-
8-m eth oxy-3-oxo-1,2,3,4-tetr a h yd r oisoqu in olin -7-yl]a cet-
a m id e (22). To a solution of 200.2 mg (0.3586 mmol) of alcohol
21 in 2.7 mL of dry CH2Cl2 was added 12.1 mg (0.0990 mmol)
of DMAP, 51.0 µL (50.0 mg, 0.630 mmol) of pyridine, and 86.0
µL (108 mg, 0.613 mmol) of PhOC(S)Cl. The reaction flask was
wrapped in aluminum foil, and the solution was stirred at
room temperature. After 1 h, 12.1 mg (0.0990 mmol) of DMAP
and 24.0 µL (30.1 mg, 0.171 mmol) of PhOC(S)Cl were added.
The reaction mixture was stirred for an additional 16 h,
concentrated, and passed through a short plug of SiO2 (hex-
anes/EtOAc; 1:1) to yield 181.3 mg (0.2611 mmol) of the crude
thionocarbonate as a yellow, sticky solid. A solution of this
compound in 15 mL of dry, degassed benzene was treated with
a solution of 3 mg (0.02 mmol) of AIBN and 91.0 µL (99.1 mg,
0.338 mmol) of Bu3SnH in 3 mL of dry, degassed benzene over
a 2.5 h period. After 24 h, an additional 3 mg (0.02 mmol) of
AIBN in 3 mL of benzene was added. The reaction mixture
was heated at reflux for an additional 36 h, cooled to room
temperature, and concentrated in vacuo. The residue was
purified by chromatography on SiO2 (CH2Cl2/EtOAc; 4:1)
through a plug of KF to afford 76.4 mg (0.141 mmol, 39%) of
lactam 22 as a white, amorphous solid: mp 170.5-172.1 °C;
[R]D -10.9 (c 1.17, CHCl3); IR (CHCl3) 3423, 2860, 1685, 1638
1
3253, 3072, 2247, 1669 cm-1; H NMR δ 8.15 (d, 1 H, J ) 8.2
Hz), 7.62-7.55 (m, 3 H), 7.45-7.28 (m, 8 H), 7.13 (bs, 1 H),
6.88 (d, 1 H, J ) 8.2 Hz), 4.75 (bs, 1 H); 3.88 (d, 1 H, J ) 9.7
Hz), 3.72-3.60 (m, 5 H), 3.45 (d, 1 H, J ) 20.1 Hz), 2.21 (s, 3
H), 1.02 (s, 9 H); 13C NMR δ 171.7, 168.5, 145.7, 135.6, 135.4,
133.0, 132.9, 130.0, 129.9, 129.5, 127.9, 127.8, 124.4, 124.1,
121.7, 67.8, 61.1, 54.4, 35.9, 26.9, 26.6; 24.8, 19.2; MS (EI) m/z
(rel intensity) 445 (95), 233 (100), 199 (91); HRMS (EI) m/z
calcd for C25H25N2O4Si (M - C4H9) 445.1584, found 445.1587.
To a solution of 73.3 mg (0.138 mmol) of the N-formyl amide
side product in 3 mL of MeOH was added 15.5 mg (0.185
mmol) of NaHCO3. After 2 h, the solution was diluted with
H2O and extracted with CH2Cl2. The combined organic extracts
were dried (MgSO4) and concentrated in vacuo to give 60.4
mg (87%) of 24.
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (CA 78039).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
cm-1; H NMR δ 8.18 (d, 1 H, J ) 8.3 Hz), 7.56-7.26 (m, 11
H), 6.91 (d, 1 H, J ) 8.3 Hz), 5.84-5.72 (m, 1 H), 5.15-4.95
J O015512Q