Synthesis of the first photo-triggered pro-mitosene based on FR-900482

Article abstract of DOI:10.1016/S0040-4020(99)01046-7

A stereocontrolled synthesis of an eight-membered ring precursor to a photo-triggered mitosene is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01046-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 521–532
Synthesis of the First Photo-Triggered Pro-mitosene
Based on FR-900482
*
Robert M. Williams, Samuel B. Rollins and Ted C. Judd
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 26 October 1999; revised 28 November 1999; accepted 2 December 1999
Abstract—A stereocontrolled synthesis of an eight-membered ring precursor to a photo-triggered mitosene is described. ᭧ 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
(SW-480 and SW-620) but requires deacetylation in vivo
and in vitro to FR-70496 (5), for the expression of bio-
chemical and cytotoxic activity.5 In contrast to mitomycin
C, FK-973 and FK-317 do not cause oxidative single strand
scission of DNA.6–9 The Fujisawa drugs have been shown to
be a significantly less host toxic than mitomycin C and are
approximately three-fold more potent. In addition, FK-317
has recently been shown to be more cytotoxic than
adriamycin and cis-platin, drugs that are frequently used
in the clinic.
FR-900482 (1), and FR-66979 (2) are anti-tumor antibiotics
that were obtained from the fermentation harvest of
Streptomyces sandaensis No. 6897 at the Fujisawa Pharma-
ceutical Co. in Japan.1–3 The triacetate derivative FK-973
(3)4 and the recently disclosed drug candidate FK-317 (4),5
both semi-synthetically derived from FR-900482, have
shown highly promising anti-tumor activity in human
clinical trials. FK-317, now in phase II clinical trials holds
considerable promise to replace the structurally related and
widely used anti-tumor drug mitomycin C (MMC, 6).2 In
initial phase I clinical trials, patients treated with FK-973
exhibited vascular leak syndrome and this substance was
subsequently withdrawn from clinical development.
FK-317, on the other hand, was found not to induce vascular
leak syndrome in patients and recently passed phase I
clinical trials.5
It is well established that MMC is reductively activated to
provide an electrophilic mitosene via the in situ bio-
reductive formation of a semi-quinone radical anion.9
Non-specific oxidative damage to DNA and other cellular
macromolecules mediated by MMC is a manifestation of
superoxide production resulting from the reduction of
molecular oxygen by the semi-quinone radical anion inter-
mediates; subsequent Haber–Weiss/Fenton cycling
produces hydroxyl radical and related highly reactive and
diffusable oxidants capable of causing non-selective tissue
damage.10 The relatively low host toxicity of FK-973 and
FK-317 in clinical trials relative to MMC may be correlated
to the incapacity of these agents to cause indiscriminate
oxidative damage to DNA and other healthy cellular targets.
Since FK-973 and MMC both share the ability to cross-link
DNA, it is very clear that the lack of oxidation chemistry
inherent in FK-973 has not at all compromised its efficacy as
an anti-tumor drug relative to MMC.
Previous reports from the Fujisawa group have shown that
FK-973 forms DNA–DNA interstrand cross-links and
DNA–protein cross links in L1210 cells.6 Similarly, FK-
317 was shown to lead to the formation of DNA–DNA
and DNA–protein cross-links in human non-small cell
lung cancer cells (A549) and human colon cancer cells
It has been demonstrated that FR-900482 (and by analogy,
FR-66979, FK-973 and FK-317) undergo reductive acti-
vation in vitro to form the reactive mitosene derivative 9
(Scheme 1) which preferentially cross-links duplex DNA at
0
0
5 CpG3 steps.7,8 The mechanism of reductive activation
involves the thiol-mediated two-electron reduction of the
N–O bond11 in the presence of trace Fe(II) salts8c generating
the transient ketone 7 which rapidly cyclizes to the
Keywords: mitosene; photochemical trigger; aziridine; FR-900482; anti-
tumor antibiotic.
* Corresponding author. Fax: ϩ1-970-491-5610;
e-mail: rmw@chem.colostate.edu
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01046-7

522
R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
Scheme 1.
carbinolamines 8. Expulsion of water has been inferred as
the rate-determining step enroute to the electrophilic mito-
sene.8d
of FR-900482.13 In an attempt to design and synthesize
molecules that mimic or combine the cross-linking activity
of FR-900482, synthetic efforts in our labs have been
focused on constructing a suitably masked activation
cascade intermediate corresponding to 11 (Scheme 1) that
is not reductively activated but that could, in principle, be
triggered photochemically, oxidatively, or hydrolytically to
form a reactive mitosene. As a first step toward testing
this hypothesis, the synthesis of the first light-activated
pro-mitosene is described herein.14
It can thus be seen that MMC, FR-900482 and congeners are
actually naturally occurring clever ‘pro-drugs’ that must be
reductively activated in vivo to expose the highly reactive
electrophilic mitosene derivatives that are responsible for
the biological activity displayed by these substances.10
Our objectives in this area are aimed at exploiting the
concept of latent triggering of pro-mitosenes by designing
and synthesizing new masked mitosenes of the general
structure 11 that can be triggered by alternative chemical
and/or biochemical means. The ultimate goals of these stra-
tegies are to improve the tumor selectivity of such agents.
Since many anti-tumor drugs display multiple modes of
action such as, intercalation, oxidative scission of double-
and single-stranded DNA, cross-linking, alkylation and
membrane effects amongst others, the issue of chemical
and biological selectivity is of paramount, fundamental
importance to provide the next generation of highly effec-
tive and selective anti-tumor drugs.
Results and Discussion
The aliphatic portion of the pro-drug model system was
prepared from commercially available cis-2-butene-1,4-
diol (12) (Scheme 2). Formation of the cyclic acetal with
p-anisaldehyde and sodium cyanoborohydride reduction of
the acetal gave the mono protected cis-diol in 60% yield
over two steps. Sharpless epoxidation of the allylic alcohol
gave epoxide 13 (75%) in approximately 94:6 er. Non-
selective ring opening of 13 with sodium azide gave a
mixture of the corresponding azido alcohols in a ϳ3:2
ratio (the mixture was not purified except for characteriza-
tion purposes). Selective protection of the primary alcohols
of gave a mixture of the corresponding O-TBS ethers 14 and
15 (83%, for the two steps).15 Reduction of the azides with
Raney Nickel and carbomethoxylation of the resulting
The unique structure of the Fujisawa drugs and their
extraordinary anti-tumor activities have made these
substances attractive synthetic targets. Several different
approaches to the core nucleus of 1 have been published,12
and three groups have successfully completed the syntheses
Scheme 2.

R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
523
Scheme 3.
aziridine afforded 16 (88%, for the three steps). Removal of
the O-TBS ether from 16 with tetra-n-butyl ammonium
fluoride gave the corresponding alcohol (86% yield)
which was converted to the corresponding aldehyde (17)
with Dess–Martin periodinane16 in 95% yield.
Acylation of 23 with 6-nitroveratryl chloroformate
(NVocCl) produced the corresponding carbamate (88%) as
a mixture of conformational isomers (1H NMR analysis).20
Reduction of the methyl ester and removal of the
carbomethoxy group in one step with DIBAH gave 24
(61%).13b It was observed that the TBS ether of 24 could
be removed only via prior deprotection of the aziridine
nitrogen atom. Thus, following decarbomethoxylation of
the aziridine, the O-TBS ether was smoothly removed
with TBAF to afford the corresponding diol. Selective
re-protection of the aziridine gave 25 in 89% overall yield
from 24.13b Finally, Dess–Martin oxidation16 of the primary
and secondary alcohols produced keto-aldehyde 26 in 83%
yield (Scheme 3).
Following literature procedures, commercially available
3,5-dinitro-p-toluic acid was transformed into methyl
3-methoxymethyloxy-4-methyl-5-nitrobenzoate (18).12b,12f,17
Deprotonation of nitro toluene 18 and nucleophilic
addition12a to aldehyde 17 afforded the secondary alcohol
19 as a 4:1 mixture of diastereomers (85%) which were
separated by chromatography and subsequently processed
individually. The secondary alcohol was protected as the
corresponding O-TBS ether (96%). The oxidative removal
of the O-p-methoxybenzyl group18 gave the primary alcohol
(93%) which was subjected to Dess–Martin oxidation16 to
afford aldehyde 20 (82%) with an overall yield from 19 to
20 of 73%. Reduction of the nitro group was accomplished
by catalytic hydrogenation to afford the labile aniline 21.
With the ‘pro-mitosene’ model system (26) in hand, we
examined removal of the NVOC group photochemically
under various conditions to explore the proof-of-principle
for the photochemical generation of a mitosene (Scheme 4).
This was best effected by subjecting 26 (lmaxˆ345 nm,
eˆ6800; 295 nm, eˆ7740; 238 nm, eˆ17 300; 217 nm,
eˆ18 500, CH3CN) to 350 nm irradiation for 24 h at
room temperature in a 3:1 solution of CH3CN/H2O.19 The
sole isolable product was the ring-opened mitosene 30 as a
1:1 mixture of secondary alcohol diastereomers (38%). This
substance must have arisen by the stepwise trans-annular
cyclization of the secondary amine (27) on the ketone to
give the tetracyclic carbinolamine 28 followed by dehy-
dration to the mitosene 29. This substance (29) proved too
reactive to isolate from the aqueous milieu and we were
As expected, cyclization of 21 to the eight-membered ring
substance 23 proved difficult. It was found that cyclization
was best accomplished by prior dehydration to the imine in
˚
the presence of MgSO4 and 4 A molecular sieves under
dilute conditions (ϳ0.002 M). After 24 h, the crude imine
was reduced with NaCNBH3 to give 23 in 60% overall yield
from 20. It should be noted that the imine-forming
cyclization reaction is somewhat capricious with variable
amounts of dimer derived from 22 being observed.

524
R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
Scheme 4.
only able to obtain and characterize the water trapping
adducts 30.
recorded on a Perkin–Elmer 1600 series FTIR as thin
films from dichloromethane and are reported as lmax in
wavenumbers (cmϪ1). Optical rotations were obtained on
a Rudolph Research Autopol III automatic polarimeter at
a wave length of 589 nm (sodium ‘D’ line) with a 1.0 dm
cell with a volume of 1 mL. Specific rotations, [a]2D5 are
reported at the specified temperature and concentration (c)
given in grams per 100 mL in the specified solvent.
Elemental analyses were performed by M-H-W
Laboratories, Phoenix, AZ, and are accurate to within
^0.4% of the calculated values. High resolution mass
spectra were obtained on a Fisons VG-7070 at University
of California Riverside. Nuclear Magnetic Resonance
(NMR) spectra were acquired using a Bruker AC-300 or
JS-300 spectrometer.
Synthesis of 26 and the selective production of 30 from this
material by photochemical activation demonstrates the
viability of constructing novel ‘pro-mitosene’ derivatives
which may find utility as new and selectively activated
DNA–DNA and DNA–protein cross-linking agents and
probes. Studies towards the synthesis of fully funtionalized
photoactivated mitosenes and other non-reductively
activated ‘pro-mitosene’ and related derivatives are under
investigation in these laboratories and will be reported on in
due course.
Experimental
4,7-Dihydro-2-(4-methoxyphenyl)-1,3-dioxepin. A mixture
of p-anisaldehyde (136 g, 1.0 mol, 1.0 equiv.), cis-2-butene-
1,4-diol (12) (105 g, 1.2 mol, 1.2 equiv.), and p-TsOH
(0.20 g, 1.1 mmol, 0.11 mol%) in 450 mL of benzene was
refluxed with azeotropic removal of water. After 1.5 days,
the dark brown mixture was cooled to room temperature,
diluted with 500 mL of benzene, washed sequentially with
3×125 mL H2O and 1×200 mL sat. NaCl(aq). The organic
solution was concentrated in vacuo, and the resulting oil was
fractionally distilled under vacuum (1 mmHg, ϳ160ЊC) to
yield 120 g (58% yield) of 4,7-dihydro-2-(4-methoxy-
phenyl)-1,3-dioxepin as a clear, colorless, viscous oil
(Ͼ95% pure). Rfˆ0.50 (5:1 Hex/EtOAc). 1H NMR
(300 MHz, CDCl3) d TMS: 3.79 (3H, s); 4.23 (2H, dd,
Jˆ1.7, 15.0 Hz); 4.36 (2H, dd, Jˆ1.7, 15.0 Hz); 5.74 (2H,
t, Jˆ1.7 Hz); 5.81 (1H, s); 6.88 (2H, d, Jˆ8.8 Hz); 7.43 (2H,
d, Jˆ8.8 Hz). 13C NMR (75 MHz, CDCl3) d TMS: 55.2 (q),
64.3 (t), 101.9 (d), 113.4 (d), 127.6 (d), 129.9 (d), 131.1 (s),
159.6 (s). IR (NaCl, neat): 3030, 2938, 2855, 1613, 1586,
1513, 1445 cmϪ1. Anal. calcd for C12H14O3: C, 69.88; H,
6.84. Found: C, 69.68; H, 6.69.
General procedures
Unless otherwise noted materials were obtained from
commercially available sources and used without further
purification. Diethyl ether (Et2O) and THF were distilled
from sodium benzophenone ketyl under a nitrogen atmos-
phere. Methylene chloride, triethylamine, pyridine, aceto-
nitrile, and methanol were distilled under a nitrogen
atmosphere from calcium hydride. Dimethyl formamide
˚
was dried over activated 4 A molecular sieves. All reactions
involving hygroscopic substances were conducted with
flame or oven dried glassware under an inert atmosphere
(Ar) dried by passage of atmospheric gases through a
column packed with CaSO4. Filtrations of organic extracts
were conducted with a cotton plug using gravity, and
concentration of the resultant filtrate was performed under
reduced pressure (aspirator) using a rotary evaporator.
Chromatographic separations were performed with EM
Science TLC plates (silica-gel 60, F254, 20×20 cm×250 mm)
or with EM Science 230–400 mesh silica gel using positive
air pressure. Reactions and chromatographic fractions were
monitored and analyzed with EM Science TLC plates.
Visualization on TLC was achieved with ultraviolet light
or heating of TLC plates submerged in a 5% solution of
phosphomolybdic acid in 95% ethanol. Radial chroma-
tography employed a Chromatotron Model 7954 using 2
or 4 mm silica plates as needed. Melting points were
determined in open-ended capillary tubes with a Mel-Temp
apparatus and are uncorrected. Infrared spectra were
(Z)-4-[(4-Methoxyyphenyl)methoxy]-2-buten-1-ol. The ace-
tal (4,7-dihydro-2-(4-methoxyphenyl)-1,3-dioxepin)prepared
as described above (11.8 g, 57.2 mmol, 1 equiv.) and
180 mL of dry DMF were added to a 1 L flask. A solution
of NaCNBH3 (10.6 g, 168.7 mmol, 3 equiv.) and TFA
(22.7 mL, 294.6 mmol, 5 equiv.) in 90 mL of dry DMF
(prepared at 0ЊC) was transferred via cannula into the
flask under negative pressure at ambient temperature. The

R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
525
resulting solution was stirred 2.0 h until TLC analysis (1:1
EtOAc/Hex) showed the reaction to be complete. The reac-
tion was quenched by dropwise addition of 1 M NaOH(aq)
until the solution reached a pH equal to 7. Following
concentration in vacuo, the resulting oil was redissolved
in 200 mL of CH2Cl2 and washed with 2×100 mL H2O
and 1×150 mL sat. NaCl(aq). The solution was dried over
MgSO4, filtered, concentrated, and dried under vacuum
for 12 h. The crude oil was purified by distillation using a
kugelrohr apparatus (ϳ1 mmHg, 160ЊC) to yield 10.0 g of
the allylic alcohol (85% yield) as a clear colorless oil
(Ͼ95% pure). Rfˆ0.40 1:1 Hex/EtOAc. 1H NMR (300
MHz, CDCl3) d TMS: 2.04 (1H, br, D2O exch.); 3.78
(3H, s); 4.04 (2H, d, Jˆ6.0 Hz); 4.14 (2H, d, Jˆ6.0 Hz);
4.44 (2H, s); 5.76 (2H, m); 6.86 (2H, d, Jˆ8.6 Hz); 7.23
(2H, d, Jˆ8.6 Hz). 13C NMR (75 MHz, CDCl3) d TMS:
55.2 (q), 58.7 (t), 65.3 (t), 72.1 (t), 113.8 (d), 128.4 (d),
129.5 (d), 129.9 (s), 132.3 (d), 159.3 (s). IR (NaCl, neat):
(75 MHz, CDCl3) d TMS: 54.7 (d); 55.2 (q); 55.6 (d);
60.7 (t); 67.7 (t); 73.1 (t); 113.9 (d); 129.4 (s); 129.5 (d);
159.4 (s). IR (NaCl, neat): 3424, 2935, 1612, 1585, 1513,
1463 cmϪ1. Anal. calcd for C12H16 O4: C, 64.27; H, 7.19.
Found: C, 64.49; H, 7.10.
Mosher ester of epoxide 13. Alcohol 13 (ϳ0.10 mmol,
1.0 equiv.) and 500 mL of CH2Cl2 were added to a 10 mL
conical flask. The solution was stirred until the alcohol had
completely dissolved, and DMAP (1.0 equiv.) and Et3N
(4.0 equiv.) were added. After stirring for another 2 min,
(ϩ)-MTPA-Cl (1.2 equiv.) was added to the solution. An
immediate change to orange was seen, and the reaction was
stirred until the reaction was complete by TLC analysis (4:1
Hex/EtOAc). The excess acid chloride was quenched by the
addition of dimethylaminopropylamine (5.0 equiv.), and the
mixture was stirred for another 15 min. The mixture was
concentrated and passed through a short plug of silica gel
(4:1 Hex/EtOAc). The crude oil was analyzed by 19F NMR
3406, 3022, 2934, 2860, 1613, 1586, 1513, 1464 cmϪ1
.
Anal. calcd for C12H16O3: C, 69.21; H, 7.74. Found: C,
68.94; H, 7.56.
without further purification. Rfˆ0.60 (4:1 Hex/EtOAc). 19
F
NMR (282 MHz, CDCl3) (ref CF3CH2OH Ϫ80 ppm) d
TMS: Ϫ74.54 (CF3); Ϫ74.60 (CF3). 87% ee (^2% ee).
(2S-cis)-3-[[(4-Methoxyphenyl)methoxy]methyl]-oxirane-
methanol (13). Freshly distilled CH2Cl2 (200 mL) was
added to a 1 L three-neck round bottom flask and cooled
[S-(R,S)]-2-Azido-4-[(4-methoxyphenyl)methoxy]-1,3-
butanediol and [R-(R,S)]-3-azido-4-[(4-methoxyphenyl)-
methoxy]-1,2-butanediol. Epoxide 13 (1.52 g, 6.78 mmol,
1.0 equiv.), NH4Cl (0.72 g, 13.5 mmol, 2.0 equiv.), NaN3
(2.20 g, 33.9 mmol, 5.0 equiv.), 40 mL CH3OCH2CH2OH,
and 5 mL distilled H2O were added to a 100 mL flask. The
stirred reaction mixture was heated at reflux for 4 h when
TLC analysis (EtOAc) showed complete loss of starting
material. The cooled mixture was concentrated in vacuo.
The resulting orange solid was dissolved in EtOAc, passed
through a short plug of silica gel using EtOAc as eluant,
concentrated, and dried overnight under vacuum. The
cloudy orange oil was used without further purification.
For analytical purposes, the mixture of regioisomers was
further purified (Ͼ95% pure) by silica gel column chroma-
tography (EtOAc). Rfˆ0.56; 0.47 (EtOAc). Mixture of
isomers: 1H NMR (300 MHz, CDCl3) d TMS: 2.1–2.3
(1H, br, D2O exch.); 2.4–2.7 (1H, br, D2O exch.); 3.52
(1H, d, Jˆ1.8 Hz); 3.53 (1H, d, Jˆ2.3 Hz); 3.59 (1/2H,
m); 3.64 (1/2H, d, Jˆ5.0 Hz); 3.71 (1/2H, d, Jˆ5.1 Hz);
3.77 (3/2H, m); 3.79 (3H, s); 3.82 (1/2H, d, Jˆ4.8 Hz);
3.94 (1/2H, q, Jˆ4.3 Hz); 4.47 (1H, s); 4.49 (1H, s); 6.87
(2H, d, Jˆ8.6 Hz); 7.24 (2H, d, Jˆ8.6 Hz). 13C NMR
(75 MHz, CDCl3) d TMS: Major isomer, 55.2 (q), 62.6
(t), 64.1 (d), 70.6 (d), 70.7 (t), 73.2 (t), 113.9 (d), 129.3
(s), 129.5 (d), 159.4 (s). Minor isomer, 55.2 (q), 62.2 (d),
63.6 (t), 69.8 (t), 71.8 (d), 73.2 (t), 113.9 (d), 129.3 (s), 129.4
(d), 159.4 (s). IR (NaCl, neat): 3410, 2935, 2865, 2104,
1612, 1586, 1514, 1464 cmϪ1. Anal. calcd for the mixture
C12H17N3O4: C, 53.92; H, 6.41; N, 15.72. Found: C, 53.71;
H, 6.36; N, 15.49.
˚
to Ϫ24ЊC before addition of 5 g of powdered 4 A molecular
sieves. Next, freshly distilled (ϩ)-diethyl-l-tartrate (8.2 mL,
48.5 mmol, 1.3 equiv.), freshly distilled titanium isopro-
poxide (12.2 mL, 41.0 mmol, 1.1 equiv.), and 3.0 M tert-
butyl hydroperoxide in toluene (25 mL, 74.6 mmol, 2.0
equiv.) were added to the flask. The mixture was stirred
for 30 min to let the catalyst age. The allylic alcohol ((Z)-
4-[(4-methoxyyphenyl)methoxy]-2-buten-1-ol) prepared as
described above (7.5 g, 36.0 mmol, 1.0 equiv.) in ϳ10 mL
˚
of CH2Cl2 (dried over 4 A molecular sieves) was added
dropwise to the mixture over 20 min. The reaction was
stirred at Ϫ24ЊC for 2 days. After TLC analysis (1:1 Hex/
EtOAc) showed no sign of starting material, the reaction
was placed on a Ϫ45ЊC acetonitrile/CO2 bath and quenched
with 100 mL of 10% aqueous tartaric acid. The two-phase
solution was stirred with a mechanical stirrer for 30 min and
then allowed to warm to room temp over 1 h. Approxi-
mately 200 mL of water was added to the mixture, and the
aqueous solution was extracted. During the extraction, the
emulsion due to the molecular sieves was removed by filter-
ing the aqueous solution through a cotton plug. The
combined organic extracts were dried over MgSO4 and
immediately passed through a Celite pad. The concentrated
oil was dissolved in 150 mL Et2O and cooled to 0ЊC on an
ice bath. Next, 50 mL of 1 M NaOH(aq), pre-cooled to 0ЊC,
was added to the organic solution. The biphasic mixture was
stirred vigorously for 1.5 h. The organic layer was
separated, washed with 1×H2O, and 1×sat. NaCl(aq), and
dried over Na2SO4. The resulting oil was dried overnight
under vacuum. Crystalization of the product from Et2O at
Ϫ33ЊC afforded 6.05 g (75% yield) of epoxide 13 as a white
solid (Ͼ95% pure). Rfˆ0.31 (1:1 Hex/EtOAc) [a]2D5ˆ
Ϫ25.5 (cˆ1.0, CHCl3). Rfˆ0.31 (1:1 Hex/EtOAc). 1H
NMR (300 MHz, CDCl3) d TMS: 2.04 (1H, br, D2O
exch.); 3.22–3.28 (2H, m); 3.62 (1H, dd, Jˆ5.0, 11.0 Hz);
3.71 (1H, dd, Jˆ5.9, 11.0 Hz); 3.65–3.80 (2H, m); 3.80 (3H,
s); 4.46 (1H, d, Jˆ11.4 Hz); 4.55 (1H, d, Jˆ11.4 Hz); 6.87
(2H, d, Jˆ8.6 Hz); 7.26 (2H, d, Jˆ8.6 Hz). 13C NMR
[S-(R,S)]-3-Azido-4-[[(1,1-dimethlethyl)dimethylsilyl]oxy]-
1-[(4-methoxyphenyl)methoxy]-2-butanol (14) and [R-
(R,S)]-3-azido-1-[[(1,1-dimethlethyl)dimethylsilyl]oxy]-
4-[(4-methoxyphenyl)methoxy]-2-butanol (15). The diol
(as a mixture of isomers) from the previous reaction
(1.15 g, 4.31 mmol, 1.0 equiv.), and 17 mL of CH2Cl2
were added to a 50 mL conical flask. The stirred mixture
was cooled on an ice bath for 10 min when Et3N (1.20 mL,

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R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
8.62 mmol, 2.0 equiv.), TBSCl (943 mg, 6.25 mmol,
1.4 equiv.), and DMAP (53 mg, 0.43 mmol, 0.1 equiv.)
were added. After stirring for 1 h, the mixture was placed
in the refrigerator at 4ЊC. After 15.5 h, TLC analysis of the
crude reaction mixture (EtOAc) showed complete loss of
starting material. The reaction mixture was concentrated in
vacuo and passed through a short plug of silica gel using 4:1
Hex/EtOAc as eluant to yield 1.60 g (90% from 13) of 14
and 15 as a cloudy orange oil which was used without
further purification. For analytical purposes, the mixture
was further purified (Ͼ95% pure) by silica gel column
chromatography (4:1 Hex/EtOAc). Mixture of isomers:
Rfˆ0.34; 0.27 (1:1 Hex/ EtOAc). 1H NMR (300 MHz,
CDCl3) d TMS: 0.05 (1.5H, s); 0.06 (1.5H, s); 0.08 (3H,
s); 0.88 (4.5 H, s); 0.89 (4.5H, s); 2.5 (1H, br, D2O exch.);
3.78 (3H, s); 3.46–3.92 (6H, m); 4.47 (1H, s); 4.50 (1H, s);
6.87 (2H, d, Jˆ8.6 Hz); 7.23 (1H, d, Jˆ8.6 Hz); 7.26
(1H, d, Jˆ8.6 Hz). IR (NaCl, neat): 3424, 3005, 2935,
2838, 2103, 1613, 1586, 1514 cmϪ1. Anal. calcd for
C18H31N3O4Si: C, 56.66; H, 8.19; N, 11.01. Found: C,
56.48; H, 7.89; N, 10.79.
17.1 equiv.) followed by approximately 3 g of Raney
Nickel. The reaction mixture was stirred for 3 h under
argon atmosphere when TLC analysis (1:1 EtOAc/Hex)
showed the reaction to be complete. The reaction was
filtered through a pad of Celite with EtOH and concentrated.
The resulting oil was dissolved in 400 mL of EtOAc and
washed with 1×NaCl(aq) and dried over Na2SO4. The
mixture was filtered, concentrated, and placed under
vacuum for 12 h. The clear yellow oil was dissolved in
300 mL of CH2Cl2 and cooled on an ice bath for ϳ15 min
while stirring. Pyridine (10.0 mL, 20.8 mmol, 3.1 equiv.)
was added to the mixture, and the mixture was stirred for
another 5 min when methyl chloroformate (6.4 mL,
82.8 mmol, 2.0 equiv.) was added dropwise over 2 min.
The reaction was stirred for 20 min when TLC analysis
showed a complete loss of the unprotected aziridine
(Rfˆ0.73 10:1 CH2Cl2/MeOH). To the reaction mixture
was added 300 mL sat NaHCO3(aq), and the bilayer was
stirred vigorously for 10 min. The two layers were
separated. The aqueous layer was extracted with
2×150 mL EtOAc, and the combined organic layers were
washed 1×200 mL sat NaCl(aq). The organic layer was dried
over Na2SO4, filtered, and concentrated. The crude oil was
purified by column chromatography (4:1 Hex/EtOAc) to
yield 15.0 g (88% overall yield from 14 and 15) of 16 as a
light yellow oil (Ͼ95% pure). [a]2D5ˆϩ9.6 (cˆ2.1, CHCl3).
Rfˆ0.50 (2:1 hexane/EtOAc). 1H NMR (500 MHz, CDCl3)
d TMS: 0.03 (3H, s); 0.05 (3H, s); 0.86 (9H, s); 2.69 (1H,
dd, Jˆ6.0, 6.0 Hz); 2.77 (1H, dd, Jˆ6.0, 6.0 Hz); 3.55 (1H,
dd, Jˆ5.5, 11.2 Hz); 3.58 (1H, dd, Jˆ6.3, 11.2 Hz); 3.60
(1H, dd, Jˆ6.1, 11.4 Hz); 3.71 (3H, s); 3.77 (1H, dd, Jˆ5.9,
11.4 Hz); 3.78 (3H, s); 4.46 (1H, d, Jˆ11.5 Hz); 4.59 (1H, d,
Jˆ11.5 Hz); 6.85 (2H, d, Jˆ8.6 Hz); 7.26 (2H, d,
Jˆ8.6 Hz). 13C NMR (75 MHz, CDCl3) d TMS: Ϫ5.4 (q);
Ϫ5.3 (q); 18.2 (s); 25.7 (q); 40.4 (d); 41.8 (d); 53.5 (q); 55.1
(q); 61.2 (t); 67.1 (t); 72.4 (t); 113.7 (d); 129.4 (d); 129.9 (s);
159.2 (s); 163.5 (s). IR (NaCl, neat): 3436, 3001, 2954,
2931, 1732, 1613, 1514, 1464, 1439 cmϪ1. Anal. calcd for
C20H33NO5Si: C, 60.73; H, 8.41; N, 3.54. Found: C, 60.60;
H, 8.62; N, 3.45.
[S-(R,S)]-3-Azido-4-[[(1,1-dimethlethyl)dimethylsilyl]oxy]-
1-[(4-methoxyphenyl)methoxy]-methanesulfonate-2-buta-
nol and [R-(R,S)]-3-azido-1-[[(1,1-dimethlethyl)di-
methylsilyl]oxy]-4-[(4-methoxyphenyl)methoxy]-methane-
sulfonate-2-butanol. Alcohols 14 and 15 (15.8 g, 41.4
mmol, 1.0 equiv.) and 414 mL of CH2Cl2 were added to a
1 L conical flask. The stirred solution was placed on an ice
bath for 15 min when Et3N (17.3 mL, 124.1 mmol,
3.0 equiv.) was added. The mixture was stirred for another
5 min when methanesulfonyl chloride (4.8 mL, 62.0 mmol,
1.5 equiv.) was added to the flask dropwise over a minute.
After 30 min, TLC analysis (2:1:2 CH2Cl2/Et2O/Hex) of the
reaction showed complete loss of the starting material. To
the reaction mixture was added 200 mL of sat NaHCO3(aq)
,
and the bilayer solution was stirred vigorously for 10 min.
Following the addition of 100 mL of H2O, the two layers
were separated. The aqueous layer was extracted with
2×150 mL EtOAc, and the combined organic layers were
washed with 1×200 mL sat NaCl(aq), and dried over Na2SO4.
The reaction mixture was concentrated in vacuo and passed
through a short plug of silica gel using 4:1 Hex/EtOAc as
eluant to yield 19.0 g (96% yield) of the product as a light
yellow oil which was used without further purification. For
analytical purposes, the mixture was further purified (Ͼ95%
pure) by column chromatography (10:1:10 CH2Cl2/Et2O/
Hex). Mixture of isomers: Rfˆ0.44 (2:1:2 CH2Cl2/Et2O/
(2S-cis)-Methyl ester 2-(hydroxymethyl)-3-[(4-methoxy-
pheny)methoxylmethyl]-1-aziridinecarboxylic acid. Aziri-
dine 16 (2.02 g, 5.1 mmol, 1.0 equiv.) and 50 mL of THF
were added to a 200 mL flask. The stirred solution was
cooled on an ice bath for 15 min, and 1 M TBAF in THF
(6.1 mL, 6.1 mmol, 1.2 equiv.) was added. After 30 min, the
reaction was complete by TLC analysis (4:1 Hex/EtOAc).
The reaction mixture was removed from the ice bath,
quenched by the addition of 25 mL sat NH4Cl(aq), and stirred
vigorously for 5 min. The THF was evaporated, and the
aqueous solution was diluted with 25 mL H2O and extracted
with Et2O (5×30 mL). The combined organic layers were
dried over Na2SO4 overnight. The filtered solution was
concentrated, and the resulting oil was purified by column
chromatography (2:1 CH2Cl2/Et2O) to yield 1.24 g (86%
yield) of the alcohol as light yellow oil (Ͼ95% pure).
[a]2D5ˆϩ36.6 (cˆ1.3, CHCl3). Rfˆ0.21 (2:1 CH2Cl2/
1
Hex). H NMR (300 MHz, CDCl3) d TMS: 0.03, 0.05,
0.06 (6H, s); 0.86, 0.87 (9H, s); 3.04, 3.05 (3H, s); 3.79
(3H, s); 3.64-3.88 (6H, m); 4.47, 4.48 (2H, ABq,
Jˆ11.4 Hz); 4.70, 4.80 (1H, q, Jˆ5 Hz); 6.86, 6.87 (2H,
d, Jˆ8.6 Hz); 7.22, 7.25 (2H, d, Jˆ8.6 Hz). IR (NaCl,
neat): 2955, 2932, 2108, 1613, 1515, 1465 cmϪ1. Anal.
calcd for C19H33N3O6SSi: C, 49.65; H, 7.24; N, 9.14.
Found: C, 49.86; H, 7.06; N, 8.98.
(2S-cis)-Methyl ester 2-[[[(1,1-dimethylethyl)dimethyl-
silyl]oxy]methyl]-3-[(4-methoxypheny)methoxylmethyl]-
1-aziridinecarboxylic acid (16). The mesylate compound
described above (19.0 g, 41.3 mmol, 1 equiv.) and 440 mL
of EtOH were added to a 1 L flask. To the resulting solution
was added hydrazine monohydrate (34.3 mL, 707.1 mmol,
1
Et2O). H NMR (300 MHz, CDCl3) d TMS: 2.37 (1H, br,
D2O exch.); 2.81 (2H, m); 3.40 (1H, dd, Jˆ7.2, 10.7 Hz);
3.51 (1H, m); 3.70 (3H, s); 3.78 (3H, s); 3.82 (1H, m); 3.84
(1H, dd, Jˆ5.5, 10.7 Hz); 4.44 (1H, d, Jˆ11.4 Hz); 4.52
(1H, d, Jˆ11.4 Hz); 6.86 (2H, d, Jˆ8.7 Hz); 7.23 (2H, d,

R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
527
Jˆ8.7 Hz). 13C NMR (75 MHz, CDCl3) d TMS: 39.5 (d);
41.5 (d); 53.7 (q); 55.2 (q); 60.5 (t); 67.4 (t); 73.0 (t); 113.9
(d); 129.2 (s); 129.6 (d); 159.5 (s); 163.2 (s). IR (NaCl,
neat): 3430, 3003, 2955, 1728, 1613, 1586, 1514,
1440 cmϪ1. Anal. calcd for C14H19NO5: C, 59.78; H, 6.81;
N, 4.98. Found: C, 59.80; H, 7.02; N, 4.82.
Major diastereomer 19: [a]2D5ˆϪ38.4 (cˆ1.3, CHCl3).
1
Rfˆ0.50 (2:1 CH2Cl2/Et2O). H NMR (300 MHz, CDCl3)
d TMS: 2.65 (1H, dd, Jˆ6.5, 8.4 Hz); 2.80 (1H, ddd,
Jˆ5.7, 6.5, 7.9 Hz); 2.98 (1H, br, D2O exch.); 3.33 (1H,
dd, Jˆ7.9, 10.5 Hz); 3.40 (2H, m); 3.42 (3H, s); 3.60 (1H,
m); 3.64 (3H, s); 3.76 (3H, s); 3.85 (1H, dd, Jˆ5.7,
10.5 Hz); 3.92 (3H, s); 4.41 (1H, d, Jˆ11.5 Hz); 4.46 (1H,
d, Jˆ11.5 Hz); 5.25 (2H, app. sing.); 6.79 (2H, d,
Jˆ8.6 Hz); 7.17 (2H, d, Jˆ8.6 Hz); 7.91 (1H, d,
Jˆ1.5 Hz); 8.10 (1H, d, Jˆ1.5 Hz). 13C NMR (75 MHz,
CDCl3) d TMS: 30.4 (t), 39.2 (d), 44.8 (d), 52.4 (q), 53.5
(q), 54.9 (q), 56.3 (q), 67.3 (t), 69.1 (d), 72.7 (t), 94.7 (t),
113.6 (d), 117.6 (d), 118.1 (d), 126.8 (s), 128.8 (s), 129.4
(d), 129.7 (s), 151.5 (s), 156.0 (s), 159.2 (s), 162.7 (s), 164.7
(s). IR (NaCl, neat): 3509, 2956, 2923, 2854, 1728, 1613,
1538, 1514, 1438 cmϪ1. Anal. for the mixture of diastereo-
mers: calcd for C25H30N2O11: C, 56.18; H, 5.66; N, 5.24.
Found: C, 55.93; H, 5.83; N, 5.04.
(2S-cis)-Methyl ester 2-formyl-3-[(4-methoxypheny)-
methoxylmethyl]-1-aziridinecarboxylic acid (17). The
alcohol described above (1.29 g, 4.58 mmol, 1.0 equiv.)
and 45 mL CH2Cl2 were added to a 200 mL flask. The
mixture was stirred for 5 min when Dess–Martin reagent16
(3.5 g, 7.3 mmol, 1.6 equiv.) was added to the flask in one
portion. The mixture was stirred for 2.5 h when TLC
analysis (2:1 CH2Cl2/Et2O) showed complete loss of starting
material. The reaction mixture was dissolved in 150 mL
Et2O and poured into a solution of 150 mL sat NaHCO3(aq)
with seven-fold excess of Na2S2O3·5H2O (9.0 g). The
biphasic mixture was vigorously stirred for 15 min while
the milky color of the organic layer slowly disappeared
The two layers were separated. The organic layer was
washed with 1×25 mL sat NaHCO3(aq) and 1×25 mL H2O.
The combined aqueous layers were back extracted with
5×30 mL Et2O. The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The crude oil was
purified by column chromatography (1.5:1 Hex/EtOAc) to
yield 1.20 g (92% yield) of 17 as a clear colorless oil (Ͼ95%
pure). [a]2D5ˆϪ80.6 (cˆ1.3, CHCl3). Rfˆ0.60 (2:1 CH2Cl2/
Et2O). 1H NMR (300 MHz, CDCl3) d TMS: 3.04 (1H, ddd,
Jˆ4.3, 4.4, 6.9 Hz); 3.10 (1H, dd, Jˆ4.5, 6.9 Hz); 3.64 (1H,
dd, Jˆ4.3, 11.2 Hz); 3.73 (1H, dd, Jˆ4.4, 11.2 Hz); 3.75
(3H, s); 3.78 (3H, s); 4.45 (1H, d, Jˆ11.5 Hz); 4.47 (1H, d,
Jˆ11.5 Hz); 6.85 (2H, d, Jˆ8.7 Hz); 7.19 (2H, d,
Jˆ8.7 Hz); 9.31 (1H, d, Jˆ4.5 Hz). 13C NMR (75 MHz,
CDCl3) d TMS: 43.5 (d); 44.7 (d); 54.1 (q); 55.2 (q); 65.8
(q); 73.0 (q); 113.9 (d); 129.2 (s); 129.5 (d); 159.4 (s); 161.8
(s); 196.3 (d). IR (NaCl, neat): 3006, 2953, 2834, 1719,
1612, 1586, 1513, 1438 cmϪ1. Anal. calcd for C14H17NO5:
C, 60.21; H, 6.14; N, 5.02. Found: C, 60.45; H, 6.21; N,
4.96.
Minor diastereomer 19: [a]2D5ˆϩ14.2 (cˆ1.3, CHCl3).
1
Rfˆ0.45 (2:1 CH2Cl2/Et2O). H NMR (300 MHz, CDCl3)
d TMS: 2.33 (1H, br, D2O exch.); 2.66 (1H, dd, Jˆ6.8,
6.8 Hz); 2.81 (1H, ddd, Jˆ5.2, 6.5, 6.8 Hz); 3.20 (1H, dd,
Jˆ5.2, 13.4 Hz); 3.36 (2H, m); 3.41 (3H, s); 3.50 (1H, dd,
Jˆ6.5, 11.0 Hz); 3.73 (3H, s); 3.78 (3H, s); 3.84 (1H,
m); 3.92 (3H, s); 4.43 (1H, d, Jˆ11.4 Hz); 4.50 (1H,
d, Jˆ11.4 Hz); 5.21 (2H, app. sing.); 6.84 (2H, d,
Jˆ8.6 Hz); 7.21 (2H, d, Jˆ8.6 Hz); 7.92 (1H, d,
Jˆ1.5 Hz); 8.08 (1H, d, Jˆ1.5 Hz). 13C NMR (75 MHz,
CDCl3) d TMS: 30.9 (t), 41.3 (d), 45.8 (d), 52.7 (q), 53.9
(q), 55.2 (q), 56.6 (q), 66.9 (t), 68.9 (d), 72.6 (t), 95.0 (t),
113.8 (d), 118.0 (d), 118.5 (d), 126.3 (s), 129.4 (d), 129.7
(s), 130.3 (s), 151.5 (s), 156.3 (s), 159.3 (s), 163.3 (s), 164.7
(s). IR (NaCl, neat): 3509, 2956, 2855, 1728, 1613, 1538,
1514, 1438 cmϪ1
.
[2S-(2a,3a)]-Methyl ester 2-[1-[[(1,1-dimethylethyl)di-
methylsilyl]oxy]-2-[4-(methoxycarbonyl)-2-(methoxy-
methoxy)-6-nitrophenyl]ethyl]-3-[[(4-methoxyphenyl)-
methoxy]methyl]-1-aziridinecarboxylic acid. Compound
19 (337 mg, 0.70 mmol, 1.0 equiv.), and 350 mL of DMF
were added to a 10 mL conical flask. Once 19 had
completely dissolved, imidazole (167 mg, 2.46 mmol,
3.5 equiv.), and TBSCl (212 mg, 1.41 mmol, 2.0 equiv.)
were added to the flask. After stirring for 24 h, TLC analysis
(1:1 Hex/EtOAc) of the crude reaction showed complete
loss of starting material, and the reaction was diluted with
15 mL Et2O. The organic solution was washed with 10 mL
water, and the two layers were separated. The aqueous layer
was back extracted with 6×15 mL Et2O. The combined
organic layers were washed with 15 mL sat NaCl(aq), dried
over Na2SO4, filtered, and concentrated. The crude oil was
purified by column chromatography (1.5:1 Hex/EtOAc) to
give 437 mg (96% yield) of product as a clear yellow oil
(Ͼ95% pure).
[2S-(2a,3a)]-Methyl ester 2-[1-hydroxy-2-[4-(methoxy-
carbonyl)-2-(methoxymethoxy)-6-nitrophenyl]ethyl]-3-
[[(4-methoxyphenyl)methoxy]methyl]-1-aziridinecar-
boxylic acid (19). Compound 18 (4.69 g, 18.4 mmol,
2.0 equiv.) and 20 mL of DMF were added to a 50 mL
flask. The stirred mixture was cooled on an ice bath for
20 min when 0.5 M NaOMe in MeOH (1.8 mL, 0.9 mmol,
0.1 equiv.) was added. The clear solution immediately
turned dark purple. After the addition of base, 17 (2.58 g,
9.2 mmol, 1.0 equiv.) in 10 mL of DMF was added to the
reaction mixture in 1 mL aliquots every 5 min. After the
additions were complete (50 min), the reaction was stirred
for another 3.5 h and quenched with 35 mL of sat NH4Cl(aq)
.
After 10 min, the reaction was diluted with 20 mL water,
and the aqueous mixture was extracted with 6×50 mL Et2O,
1×25 mL CH2Cl2, and 1×25 mL EtOAc. The combined
organic extracts were washed with 1×45 mL sat
NaCl(aq), dried over Na2SO4, filtered and concentrated.
The crude oil was purified by column chromatography
(1:1 Hex/EtOAc) to yield 4.2 g (85–90% yield) of 19 as
a yellow oil (4:1 mixture of separable diastereomers)
(Ͼ95% pure).
Major diastereomer: [a]2D5ˆϪ27.6 (cˆ1.6, CHCl3).
1
Rfˆ0.50 (1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d
TMS: Ϫ0.40 (3H, s); Ϫ0.11 (3H, s); 0.69 (9H, s); 2.59 (1H,
dd, Jˆ5.5, 6.3 Hz); 2.74 (1H, ddd, Jˆ4.6, 6.3, 6.8 Hz); 3.22
(1H, dd, Jˆ4.8, 13.5 Hz); 3.41 (1H, dd, Jˆ9.0, 13.5 Hz);
3.43 (3H, s); 3.60 (1H, dd, Jˆ6.8, 11.0 Hz); 3.68 (3H, s);
3.68 (1H, dd, Jˆ4.6, 11.0 Hz); 3.77 (3H, s); 3.91 (3H, s);

528
R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
4.12 (1H, ddd, Jˆ4.8, 5.5, 9.0 Hz); 4.50 (1H, d, Jˆ11.4 Hz);
4.60 (1H, d, Jˆ11.4 Hz); 5.21 (2H, app. sing.); 6.85 (2H, d,
Jˆ8.5 Hz); 7.27 (2H, d, Jˆ8.5 Hz); 7.90 (1H, d, Jˆ1.5 Hz);
8.06 (1H, d, Jˆ1.5 Hz). 13C NMR (75 MHz, CDCl3) d
TMS: Ϫ0.53 (q), Ϫ0.48 (q), 17.8 (s), 25.6 (q), 32.2 (t),
41.1 (d), 45.1 (d), 52.6 (q), 53.6 (q), 55.2 (q), 56.6 (q),
67.3 (t), 68.0 (d), 72.5 (t), 94.9 (t), 113.7 (d), 117.6 (d),
118.4 (d), 127.3 (s), 129.5 (d), 129.9 (s), 130.0 (s), 151.7
(s), 156.6 (s), 159.2 (s), 163.5 (s), 164.9 (s). IR (NaCl, neat):
mixture of diastereomers: calcd for C23H36N2O10Si: C,
52.26; H, 6.86; N, 5.30. Found: C, 52.22; H, 6.66; N, 5.19.
Minor diastereomer: [a]2D5ˆϩ8.8 (cˆ2.8, CH2Cl2). Rfˆ0.30
1
(1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d TMS:
Ϫ0.24 (3H, s); 0.02 (3H, s); 0.82 (9H, s); 1.78 (1H, br,
D2O exch.); 2.56 (1H, ddd, Jˆ4.4, 6.6, 6.7 Hz); 2.74 (1H,
dd, Jˆ6.6, 8.7 Hz); 3.13 (3H, m); 3.25 (1H, dd, Jˆ7.2,
13.2 Hz); 3.47 (3H, s); 3.68 (3H, s); 3.90 (1H, m); 3.92
(3H, s); 5.27 (1H, d, Jˆ7.0 Hz); 5.29 (1H, d, Jˆ7.0 Hz);
7.92 (1H, d, Jˆ1.5 Hz); 8.05 (1H, d, Jˆ1.5 Hz). 13C NMR
(75 MHz, CDCl3) d TMS: Ϫ5.3 (q), Ϫ4.8 (q), 17.7 (s), 25.5
(q), 31.9 (t), 42.8 (d), 46.9 (d), 52.6 (q), 53.4 (q), 56.6 (q),
60.0 (t), 70.0 (d), 94.9 (t), 117.4 (d), 118.1 (d), 125.9 (s),
130.2 (s), 151.5 (s), 156.6 (s), 163.3 (s), 164.6 (s). IR (NaCl,
3001, 2954, 2856, 1731, 1613, 1537, 1514, 1438 cmϪ1
.
Anal. for the mixture of diastereomers: calcd for
C31H44N2O11Si: C, 57.39; H, 6.84; N, 4.32. Found: C,
57.50; H, 6.91; N, 4.50.
Minor diastereomer: [a]2D5ˆϩ10.5 (cˆ1.1, CHCl3). Rfˆ0.5
1
(1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d TMS:
neat): 3503, 2954, 2857, 1732, 1538, 1438 cmϪ1
.
Ϫ0.31 (3H, s); 0.03 (3H, s); 0.80 (9H, s); 2.61 (1H, ddd,
Jˆ4.4, 6.7, 7.1 Hz); 2.69 (1H, dd, Jˆ6.7, 8.5 Hz); 2.98 (1H,
dd, Jˆ4.4, 11.1 Hz); 3.11 (1H, dd, Jˆ6.6, 13.2 Hz); 3.19
(1H, dd, Jˆ7.1, 11.1 Hz); 3.23 (1H, dd, Jˆ7.6, 13.2 Hz);
3.39 (3H, s); 3.69 (3H, s); 3.77 (3H, s); 3.79 (1H, m); 3.91
(3H, s); 4.40 (1H, d, Jˆ11.5 Hz); 4.50 (1H, d, Jˆ11.5 Hz);
5.17 (2H, apparent singlet); 6.82 (2H, d, Jˆ8.6 Hz); 7.18
(2H, d, Jˆ8.6 Hz); 7.87 (1H, d, Jˆ1.5 Hz); 8.01 (1H, d,
Jˆ1.5 Hz). 13C NMR (75 MHz, CDCl3) d TMS: Ϫ5.3 (q),
Ϫ4.8 (q), 17.7 (s), 25.6 (q), 31.8 (t), 40.9 (d), 46.0 (d), 52.6
(q), 53.4 (q), 55.1 (q), 56.5 (q), 66.9 (t), 70.3 (d), 72.1 (t),
94.7 (t), 113.6 (d), 117.4 (d), 118.2 (d), 126.1 (s), 129.4 (d),
129.6 (s), 130.1 (s), 151.5 (s), 156.6 (s), 159.1 (s), 163.2 (s),
164.6 (s). IR (NaCl, neat): 2964, 1732, 1614, 1538, 1514,
[2S-(2a,3a)]-Methyl ester 2-[1-[[(1,1-dimethylethyl)di-
methylsilyl]oxy]-2-[4-(methoxycarbonyl)-2-(methoxy-
methoxy)-6-nitrophenyl]ethyl]-3-formyl-1-aziridinecar-
boxylic acid (20). The alcohol described in the previous
experiment (98 mg, 0.18 mmol, 1.0 equiv.), and 1.5 mL of
CH2Cl2 were added to a 25 mL flask. The mixture was
stirred for 5 min and Dess–Martin reagent16 (118 mg,
0.32 mmol, 1.8 equiv.) was added to the flask in one portion.
After stirring for 2.5 h, the cloudy white mixture was diluted
in 10 mL Et2O and poured into a solution of 20 mL sat
NaHCO3(aq) with 8.0 equiv. of Na2S2O3·5H2O (435 mg).
The milky biphasic mixture turned clear after 15 min of
vigorous stirring. The two layers were separated, and the
organic layer was washed with 1×10 mL NaHCO3(aq), and
1×10 mL H2O. The combined aqueous layers were
extracted with 3×15 mL Et2O. The combined organic layers
were dried over Na2SO4, filtered, and concentrated. The
crude oil was purified by flash chromatography (2:1 Hex/
EtOAc) to give 81 mg (82% yield) of 20 as a clear colorless
oil (Ͼ95% pure).
1438 cmϪ1
.
[2S-(2a,3a)]-Methyl ester 2-[1-[[(1,1-dimethylethyl)di-
methylsilyl]oxy]-2-[4-(methoxycarbonyl)-2-(methoxy-
methoxy)-6-nitrophenyl]ethyl]-3-(hydroxymethyl)-1-
aziridinecarboxylic acid. The silyl ether described above
(205 mg, 0.32 mmol, 1.0 equiv.), 2.7 mL of CH2Cl2, and
150 mL of H2O were added to a 25 mL flask. After stirring
for 5 min, DDQ (93 mg, 0.41 mmol, 1.3 equiv.) was added
to the mixture in one portion. The reaction mixture
immediately turned dark green, and over the course of the
next 1.5 h, the mixture slowly turned bright orange. After
1.5 h, the crude reaction mixture was passed through a short
plug of activated alumina using 10:1 CH2Cl2/MeOH as
eluant. After concentration in vacuo, the crude oil was
purified by column chromatography (1:1 Hex/EtOAc) to
give 160 mg (93% yield) of product as a clear orange oil
(Ͼ95% pure).
Major diastereomer 20: [a]2D5ˆϩ5.4 (cˆ1.1, CH2Cl2).
1
Rfˆ0.42 (1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d
TMS: Ϫ0.18 (3H, s); 0.00 (3H, s); 0.76 (9H, s); 2.79 (1H,
dd, Jˆ3.5, 6.8 Hz); 3.00 (1H, dd, Jˆ4.6, 6.8 Hz); 3.14 (1H,
dd, Jˆ6.8, 13.2 Hz); 3.23 (1H, dd, Jˆ7.4, 13.2 Hz); 3.49
(3H, s); 3.68 (3H, s); 3.92 (3H, s); 4.50 (1H, ddd, Jˆ3.5, 6.8,
7.4 Hz); 5.30 (2H, s); 7.94 (1H, d, Jˆ1.5 Hz); 8.12 (1H, d,
Jˆ1.5 Hz); 9.50 (1H, d, Jˆ4.6 Hz). 13C NMR (75 MHz,
CDCl3) d TMS: Ϫ5.3 (q), Ϫ4.7 (q), 17.9 (s), 25.6 (q),
32.1 (t), 45.1 (d), 48.7 (d), 52.7 (q), 53.9 (q), 56.7 (q),
67.7 (d), 94.9 (t), 118.0 (d), 118.4 (d), 125.8 (s), 130.4 (s),
151.2 (s), 156.7 (s), 161.9 (s), 164.6 (s), 196.9 (d). IR (NaCl,
neat): 2962, 2863, 1730, 1537, 1437 cmϪ1. Anal. for the
mixture of diastereomers: calcd for C23H34N2O10Si: C,
52.46; H, 6.51; N, 5.32. Found: C, 52.64; H, 6.61; N, 5.30.
Major diastereomer: [a]2D5ˆϪ55.6 (cˆ1.2, CH2Cl2).
1
Rfˆ0.30 (1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d
TMS: Ϫ0.34 (3H, s); Ϫ0.06 (3H, s); 0.73 (9H, s); 1.95 (1H,
br, D2O exch.); 2.61 (1H, dd, Jˆ5.7, 6.2 Hz); 2.72 (1H, ddd,
Jˆ4.5, 6.4, 6.4 Hz); 3.26 (1H, dd, Jˆ5.1, 13.4 Hz); 3.42
(1H, dd, Jˆ8.8, 13.4 Hz); 3.49 (3H, s); 3.67 (3H, s); 3.90
(2H, m); 3.92 (3H, s); 4.25 (1H, ddd, Jˆ5.1, 5.7, 8.8 Hz);
5.27 (1H, d, Jˆ6.9 Hz); 5.29 (1H, d, Jˆ6.9 Hz); 7.92 (1H, d,
Jˆ1.5 Hz); 8.09 (1H, d, Jˆ1.5 Hz). 13C NMR (75 MHz,
CDCl3) d TMS: Ϫ5.2 (q), Ϫ4.9 (q), 17.8 (s); 25.5 (q);
32.3 (t); 42.9 (d)45.9 (d); 52.6 (q); 53.7 (q); 56.6 (q); 60.2
(t); 68.1 (d); 95.0 (t); 117.6 (d); 118.4 (d); 127.0 (s); 129.9
(s); 151.6 (s); 156.6 (s); 163.5 (s); 164.8 (s). IR (NaCl, neat):
3510, 2955, 2856, 1730, 1540, 1438 cmϪ1. Anal. for the
Minor diastereomer 20: [a]2D5ˆϩ112 (cˆ2.0, CH2Cl2).
1
Rfˆ0.42 (1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d
TMS: Ϫ0.23 (3H, s); 0.08 (3H, s); 0.85 (9H, s); 3.01 (2H,
m); 3.05 (1H, dd, Jˆ6.7, 13.3 Hz); 3.23 (1H, dd, Jˆ7.3,
13.3 Hz); 3.47 (3H, s); 3.72 (3H, s); 3.93 (3H, s); 3.96
(1H, m); 5.26 (1H, d, Jˆ7.0 Hz); 5.28 (1H, d, Jˆ7.0 Hz);
7.91 (1H, d, Jˆ1.5 Hz); 8.06 (1H, d, Jˆ1.5 Hz); 8.95 (1H, d,
Jˆ5.5 Hz). 13C NMR (75 MHz, CDCl3) d TMS: Ϫ5.3 (q),
Ϫ4.8 (q), 17.7 (s), 25.5 (q), 31.7 (t), 45.6 (d), 48.7 (d), 52.6

R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
529
(q), 53.8 (q), 56.6 (q), 69.7 (d), 94.8 (t), 117.6 (d), 118.3 (d),
125.1 (s), 130.5 (s), 151.4 (s), 156.3 (s), 161.4 (s), 164.5 (s),
195.0 (d). IR (NaCl, neat): 2956, 2858, 1732, 1538,
7.36 (1H, d, Jˆ1.4 Hz); 7.50 (1H, d, Jˆ1.4 Hz); 8.09
(1H, s).
1439 cmϪ1
.
(1aS,9aS)-Dimethyl ester 9-[[(1,1-dimethylethyl)dimethyl-
silyl]oxy]-1a,2,3,8,9,9a-hexahydro-7-(methoxymethoxy)-
1H-azirino[2,3-c][1]benzazocine-1,5-dicarboxylic acid (23).
Major diastereomer 23: [a]2D5ˆϩ48.9 (cˆ0.9, CH2Cl2).
(1aS,9aS)-Dimethyl ester 9-[[(1,1-dimethylethyl)dimethyl-
silyl]oxy]-1a,2,3,8,9,9a-hexahydro-7-(methoxymethoxy)-
1H-azirino[2,3-c][1]benzazocine-1,5-dicarboxylic acid (23).
40 mL of MeOH, freshly distilled from CaH2, was added to
a 100 mL flask. The stirred solution was degassed with H2
for 30 min using a 20 gauge needle connected directly to a
H2 cylinder. The flask was then flushed with argon, and 5%
Pd/C (200 mg, 0.095 mmol, 0.25 equiv.) was added in one
portion. The mixture was degassed with H2 for another
30 min and then kept under H2 for another 30 min. Nitro-
aldehyde 20 (200 mg, 0.38 mmol, 1.0 equiv.) in 2 mL of
MeOH was added to the mixture dropwise over 1 min.
After 8 min, TLC analysis (1:1 Hex/EtOAc) of the reaction
showed complete loss of 20. The reaction was diluted with
MeOH and passed through a short pad of Celite using
MeOH, and the filtrate was concentrated in vacuo. The
residue was filtered through a short plug of Celite using
CH2Cl2, and the filtrate was concentrated again. The residue
1
Rfˆ0.42 (1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d
TMS: 0.15 (3H, s); 0.17 (3H, s); 0.94 (9H, s); 2.52 (2H, m);
2.84 (1H, dd, Jˆ10.5, 13.9 Hz); 3.18 (1H, dd, Jˆ5.3,
13.9 Hz); 3.46 (3H, s); 3.59 (1H, m); 3.67 (3H, s); 3.78
(1H, m); 3.84 (3H, s); 4.06 (1H, br, D2O exch.); 4.47 (1H,
ddd, Jˆ5.3, 5.3, 5.3 Hz); 5.19 (1H, d, Jˆ6.6 Hz); 5.23 (1H,
d, Jˆ6.6 Hz); 7.04 (1H, d, Jˆ1.5 Hz); 7.18 (1H, d,
Jˆ1.5 Hz). 13C NMR (75 MHz, CDCl3) d TMS: Ϫ5.1 (q),
Ϫ4.9 (q), 18.4 (s), 25.8 (q), 31.0 (t), 41.4 (d), 43.0 (d), 47.3
(t), 52.0 (q), 53.3 (q), 56.3 (q), 69.0 (d), 94.3 (t), 105.3 (d),
114.3 (d), 118.3 (s), 129.4 (s), 148.3 (s), 156.2 (s), 163.9 (s),
166.8 (s). IR (NaCl, neat): 3394, 2952, 2855, 1724, 1587,
1438 cmϪ1. Mass spectrum (ESϩ) m/z: 481 (MϩH). Anal.
for the mixture of diastereomers: calcd for C23H36N2O7Si:
C, 57.48; H, 7.55; N, 5.83. Found: C, 57.77; H, 7.86; N 5.64.
was dissolved in 200 mL of CH2Cl2. Activated 4 A
Minor diastereomer 23: [a]2D5ˆϩ127 (cˆ0.9, CH2Cl2).
˚
1
molecular sieves (ϳ30 pieces) and MgSO4 (2 g) were
added to the solution. The stirred mixture was heated to
reflux for 24–36 h. The cooled mixture was filtered through
a pad of Celite using 10:1 CH2Cl2/MeOH (500 mL). The
filtrate was concentrated, and the residue was immediately
dissolved in solution of 2:1 CH2Cl2/MeOH (12 mL). After
the mixture was cooled on an ice bath for 10 min, NaCNBH3
(23 mg, 0.38 mmol, 1.0 equiv.) and TFA (29 mL,
0.38 mmol, 1.0 equiv.) were added in one portion. After
4 min, TLC analysis of the reaction (1:1 Hex/EtOAc)
showed no signs of the starting material, and the reaction
was quenched with 30 mL sat NaHCO3(aq). The two layers
were separated, and the aqueous layer was extracted with
3×CH2Cl2. The combined organic layers were washed with
1×sat NaCl(aq), dried over Na2SO4, filtered, concentrated,
and purified by radial silica PTLC (4 mm plate, 2:1 Hex/
EtOAc) to give 110 mg (40–60% yield from 20) of 23 as a
clear yellow oil (Ͼ95% pure).
Rfˆ0.50 (1:1 Hex/EtOAc). H NMR (300 MHz, CDCl3) d
TMS: 0.10 (3H, s); 0.11 (3H, s); 0.92 (9H, s); 2.58 (1H, m);
2.66 (1H, dd, Jˆ5.1, 6.9 Hz); 3.06 (1H, dd, Jˆ8.7, 15.0 Hz);
3.12 (1H, d, Jˆ4.5 Hz); 3.13 (1H, d, Jˆ4.5 Hz); 3.45 (3H,
s); 3.62 (1H, dd, Jˆ3.6, 8.1 Hz); 3.66 (3H, s); 3.83 (1H, br,
D2O exch.); 3.84 (3H, s); 4.23 (1H, ddd, Jˆ4.5, 4.5, 4.5 Hz);
5.16 (1H, d, Jˆ6.6 Hz); 5.19 (1H, d, Jˆ6.6 Hz); 7.07 (1H, d,
Jˆ1.5 Hz); 7.30 (1H, d, Jˆ1.5 Hz). 13C NMR (75 MHz,
CDCl3) d TMS: Ϫ5.0 (q), Ϫ4.9 (q), 18.2 (s), 25.7 (q),
33.5 (t), 40.2 (d), 48.2 (t), 48.4 (d), 52.0 (q), 53.4 (q), 56.2
(q), 72.9 (d), 94.6 (t), 107.7 (d), 115.6 (d), 123.3 (s), 129.0
(s), 149.3 (s), 156.4 (s), 163.3 (s), 166.8 (s). IR (NaCl, neat):
3387, 2953, 2856, 1724, 1585, 1437 cmϪ1. Mass spectrum
(ESϩ) m/z: 481 (MϩH).
(1aS,9aS)-3-[(4,5-Dimethoxy-2-nitrophenyl)methyl] 1,5
dimethyl ester 9-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
1a,2,3,8,9,9a-hexahydro-7-(methoxymethoxy)-1H-
azirino[2,3-c][1]benzazocine-1,3,5(2H)-tricarboxylic acid.
Compound 23 (140 mg, 290 mmol, 1.0 equiv.) and 3.5 mL
of CH2Cl2 were added to a 25 mL conical flask. The solution
was stirred for 3 min when N,N-diisopropylethylamine
(152 mL, 870 mmol, 3.0 equiv.), 6-nitroveratryl chloro-
formate (200 mg, 730 mmol, 2.5 equiv.), and DMAP
(36 mg, 290 mmol, 1.0 equiv.) were added. After 4 h, TLC
analysis (1:1 Hex/EtOAc) of the reaction showed no starting
material. The reaction was diluted with 15 mL sat
NaHCO3(aq) and extracted with 3×EtOAc. The combined
organic layers were washed with 1×sat NaCl(aq), dried
over Na2SO4, filtered, concentrated, and purified using
radial silica gel PTLC (2:1 Hex/EtOAc, 2 mm plate) to
give 185 mg (88% yield) of product as a clear yellow oil.
[2S-(2a,3a)]-Methyl ester 2-[2-[2-amino-4-(methoxycar-
bonyl)-6-(methoxymethoxy)phenyl]-1-[[(1,1-dimethyl-
ethyl)dimethylsilyl]oxy]ethyl]-3-formyl-1-aziridinecar-
boxylic acid (21). Major diastereomer 21: Rfˆ0.43 (1:1
1
Hex/EtOAc). H NMR (300 MHz, CDCl3) d TMS: Ϫ0.13
(3H, s); 0.10 (3H, s); 0.82 (9H, s); 2.69 (1H, dd, Jˆ6.5,
13.8 Hz); 2.82 (1H, dd, Jˆ7.8, 13.7 Hz); 2.88 (1H, dd,
Jˆ2.6, 6.9 Hz); 3.05 (1H, dd, Jˆ4.0, 6.9 Hz); 3.47 (3H,
s); 3.73 (3H, s); 3.84 (3H, s); 3.89 (2H, br, D2O exch.);
4.44 (1H, m); 5.21 (2H, s); 7.03 (1H, d, Jˆ1.4 Hz); 7.11
(1H, d, Jˆ1.4 Hz); 9.54 (1H, d, Jˆ4.0 Hz). IR (NaCl, neat):
3466, 3381, 2954, 2857, 1718, 1586, 1437 cmϪ1
.
Intermediate imine (22). Major diastereomer 22: Rfˆ0.49
(1:1 Hex/EtOAc). 1H NMR (300 MHz, CDCl3) d TMS: 0.07
(3H, s); 0.18 (3H, s); 0.96 (9H, s); 2.29 (1H, dd, Jˆ11.0,
12.9 Hz); 2.56 (1H, dd, Jˆ5.9, 5.9 Hz); 2.86 (1H, d,
Jˆ6.0 Hz); 3.00 (1H, dd, Jˆ4.3, 12.9 Hz); 3.46 (3H, s);
3.73 (3H, s); 3.87 (3H, s); 4.28 (1H, ddd, Jˆ4.5, 6.0,
10.7 Hz); 5.22 (1H, d, Jˆ6.9 Hz); 5.28 (1H, d, Jˆ6.9 Hz);
Major diastereomer: [a]2D5ˆϩ26.9 (cˆ1.2, CH2Cl2).
Rfˆ0.40 (1:1 Hex/EtOAc). 1H NMR (300 MHz,
d6-DMSO, 383 K) d TMS: 0.12 (3H, s); 0.14 (3H, s); 0.88
(9H, s); 2.68 (2H, br); 2.88 (2H, s); 2.93 (1H, br); 3.07 (1H,
br); 3.46 (3H, s); 3.62 (3H, s); 3.80 (3H, br); 3.86 (3H, s);
3.87 (3H, s); 4.34 (1H, br); 5.29 (2H, s); 5.41 (2H, s); 6.92

530
R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
(1H, s); 7.46 (1H, d, Jˆ1.5 Hz); 7.63 (1H, d, Jˆ1.5 Hz);
7.65 (1H, s). IR (NaCl, neat): 2953, 2856, 1726, 1581, 1522,
1440 cmϪ1. Mass spectrum (ESϩ) m/z (relative intensity):
720 (MϩH) (100%). Exact mass: (FAB) calcd for
C33H46N3O13Si 720.2799. Found: 720.2786. Anal. calcd
for C33H45N3O13Si: C, 55.06; H, 6.30; N, 5.84. Found: C,
54.93; H, 6.48; N, 5.66.
(NaCl, neat): 3429 br, 3314 br, 2928, 2854, 1704, 1581,
1524, 1440 cmϪ1. Mass spectrum (ESϩ) m/z (relative inten-
sity): 520 (MϩH, 100%).
(1aS,9aS)-3-[(4,5-Dimethoxy-2-nitrophenyl)methyl] 1-
methyl ester 5-methanol-1a,2,3,8,9,9a-hexahydro-7-
(methoxymethoxy)-9-hydroxy-1H-azirino[2,3-c][1]benza-
zocine-1,3(2H)-dicarboxylic acid (25). The diol described
above (15 mg, 29 mmol, 1.0 equiv.) and 300 mL pyridine
were added to a 10 mL flask. After stirring for 5 min,
N-((methoxy)carbonyloxy)succinimide (5 mg, 29 mmol,
1.0 equiv.) was added in one portion. After 2.5 h, TLC
analysis (10:1 CH2Cl2/MeOH) showed complete loss of
starting material, and the reaction was diluted with water
and sat NH4Cl(aq). The aqueous solution was extracted with
3×EtOAc. The combined organic layers were washed with
1×sat NaHCO3(aq) and 1×sat NaCl(aq), dried over Na2SO4,
filtered, concentrated, and purified by radial silica gel PTLC
(10:1 CH2Cl2/MeOH, 2 mm plate) to give 14 mg (89% yield
from 24) of 25 as a foamy yellow oil.
(1aS,9aS)-3-[(4,5-Dimethoxy-2-nitrophenyl)methyl] 5-meth-
anol-9-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1a,2,3,8,
9,9a-hexahydro-7-(methoxymethoxy)-1H-azirino[2,3-
c][1]benzazocine-3-carboxylic acid (24). Nitroveratryl car-
bamate described above (76 mg, 0.105 mmol, 1.0 equiv.) and
1.5 mL CH2Cl2 were added to a 25 mL round bottom flask. The
stirred solution was cooled to Ϫ78ЊC on a CO2/acetone bath for
10 min when 1.0 M DIBAL in hexane (528 mL, 0.528 mmol,
5.5 equiv.) was added in dropwise portions with 5 min between
each addition. After 5 h, the reaction was quenched at Ϫ78ЊC
by the addition of one drop of MeOH and two drops of sat
NaCl(aq). After removing from the bath and coming to room
temperature, the solution was filtered through a short plug of
Celite with CH2Cl2. The two layers were separated, and the
aqueous layer was extracted with 3×CH2Cl2. The combined
organic layers were dried over Na2SO4. The solution was
filtered, concentrated, and purified by radial silica gel PTLC
(2 mm plate, 22:1 CH2Cl2/MeOH) to give 39 mg (61% yield) of
aziridine 24 as a clear yellow oil.
Major diastereomer: [a]2D5ˆϩ30.6 (cˆ1.5, CH2Cl2).
Rfˆ0.38 (10:1 CH2Cl2/MeOH). 1H NMR (300 MHz,
d6-DMSO, 378 K) d TMS: 2.64 (2H, s); 2.84 (2H, s); 2.91
(2H, s); 3.44 (3H, s); 3.62 (3H, s); 3.78 (3H, s); 3.85 (3H, s);
4.06 (1H, s); 4.41 (1H, br, D2O exch.); 4.45 (2H, s); 4.72
(1H, D2O exch.); 5.21 (2H, s); 5.37 (2H, s); 6.81 (1H, s);
6.90 (1H, s); 7.03 (1H, s); 7.65 (1H, s). IR (NaCl, neat):
3741, 2954, 2852, 1731, 1715, 1614, 1582, 1520,
1442 cmϪ1. Mass spectrum (ESϩ) m/z (relative intensity):
578 (MϩH, 100%). Exact mass: (FAB) calcd for
C26H32N3O12: 578.1986. Found: 578.1954. Anal. calcd for
C26H32N3O12·0.6H2O: C, 53.07; H, 5.51; N, 7.14. Found: C,
53.39; H, 5.71; N, 6.75.
Major diastereomer: [a]2D5ˆϩ25.4 (cˆ2.6, CH2Cl2).
1
Rfˆ0.41 (10:1 CH2Cl2/MeOH). H NMR (300 MHz, d6-
DMSO, 373 K) d TMS: 0.12 (3H, s); 0.13 (3H, s); 0.91
(9H, s); 2.02 (2H, s); 2.86 (2H, s); 2.93 (2H, s); 3.45 (3H,
s); 3.83 (3H, s); 3.87 (3H, s); 4.28 (1H, s); 4.46 (2H, s); 4.71
(1H, s, D2O exch.); 5.19 (1H, d, Jˆ6.6 Hz); 5.22 (1H, d,
Jˆ6.6 Hz); 5.41 (2H, s); 6.81 (1H, s); 7.03 (2H, s); 7.66 (1H,
s). IR (NaCl, neat): 3368, 2954, 2856, 1713, 1582, 1524,
1441 cmϪ1. Mass spectrum (ESϩ) m/z (relative intensity):
634 (MϩH, 100%). Exact mass: (FAB) calcd for
C30H44N3O10Si: 634.2796. Found: 634.2760. Anal. calcd
for C30H43N3O10Si: C, 56.85; H, 6.84; N, 6.63. Found: C,
56.53; H, 7.07; N, 6.37.
(1aS-cis)-3-[(4,5-Dimethoxy-2-nitrophenyl)methyl] 1-methyl
ester 5-formyl-1a,8,9,9a-tetrahydro-7-(methoxymethoxy)-
9-oxo-1H-azirino[2,3-c][1]benzazocine-1,3(2H)-dicarboxy-
lic acid (26). Diol 25 (35 mg, 62 mmol, 1.0 equiv.) and
600 mL CH2Cl2 were added to a 10 mL conical flask. The
solution was stirred for 5 min when Dess–Martin period-
inane16 (68 mg, 160 mmol, 2.6 equiv.) was added in one
portion. The reaction immediately became cloudy and
white. After 1.5 h, additional amounts of Dess–Martin
reagent (55 mg) and 150 mL CH2Cl2 were added to the reac-
tion. After another 0.5 h, TLC analysis (10:1 CH2Cl2/
MeOH) showed no sign of staring material. The reaction
was diluted with Et2O and added to a solution of sat
NaHCO3(aq) and NaS2O3·5H2O (123 mg, 8 equiv.). The
biphasic mixture was vigorously stirred for 15 min. The
organic layer was diluted with EtOAc and separated from
the aqueous layer. The organic layer was washed with 1×sat
NaHCO3(aq) and 1×H2O. The combined aqueous layers were
back extracted with 2×EtOAc. The combined organic layers
were dried over Na2SO4, filtered, concentrated, and purified
using radial silica gel PTLC (2 mm plate, 2:1 CH2Cl2/Et2O)
to give 28 mg (83% yield) of ketone 26 as a clear foamy oil.
(1aS,9aS)-3-[(4,5-Dimethoxy-2-nitrophenyl)methyl] 5-meth-
anol-1a,2,3,8,9,9a-hexahydro-7-(methoxymethoxy)-9-
hydroxy-1H-azirino[2,3-c][1]benzazocine-3-carboxylic
acid. Compound 24 (50 mg, 0.079 mol, 1.0 equiv.) and
1 mL THF were added to a 10 mL conical flask. The
solution was stirred for 5 min on an ice bath when 1.0 M
TBAF in THF (135 mL, 0.135 mmol, 1.65 equiv.) was
added dropwise over 1 min. After the addition was
complete, the reaction was allowed to warm to room
temp. After 4 h, TLC analysis (10:1 CH2Cl2/MeOH)
showed no sign of starting material. The reaction was
diluted with water, and the THF was removed in vacuo.
The aqueous solution was extracted with 3×EtOAc. The
combined organic layers were dried over Na2SO4, filtered,
concentrated, and purified by radial silica gel PTLC (2 mm
plate, 10:1 CH2Cl2/MeOH) to give 35 mg (85% yield) of the
diol as a foamy yellow oil. The unstable diol was
immediately taken on to the next step without further puri-
fication.
Major diastereomer: [a]2D5ˆϪ40.3 (cˆ1.3, CH2Cl2).
Rfˆ0.80 (10:1 CH2Cl2/MeOH). 1H NMR (300 MHz,
d6-DMSO, 378 K) d TMS: 2.91 (4H, s); 3.37 (1H, s); 3.38
(1H, s); 3.44 (3H, s); 3.60 (3H, s); 3.76 (3H, s); 3.85 (3H, s);
5.34 (4H, m); 6.82 (1H, s); 7.27 (1H, s); 7.58 (1H, s); 7.63
Major diastereomer: Rfˆ0.23 (10:1 CH2Cl2/MeOH). IR

R. M. Williams et al. / Tetrahedron 56 (2000) 521–532
531
(1H, s); 9.93 (1H, s). IR (NaCl, neat): 2954, 2847, 1729,
References
1702, 1581, 1521, 1443 cmϪ1. UV lmax (CH3CN) nm (e):
345 (6800), 298 (7740), 238 (18 500). Mass spectrum
(FAB) m/z (relative intensity): 574 (MϩH, 100%). Exact
mass: (FAB) calcd for C26H28N3O12: 574.1673. Found:
574.1702.
1. (a) Iwami, M.; Kiyoto, S.; Terano, H.; Kohsaka, M.; Aoki, H.;
Imanaka, H. J. Antibiotics 1987, 40, 589–593. (b) Kiyoto, S.;
Shibata, T.; Yamashita, M.; Komori, T.; Okuhara, M.; Terano,
H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiotics 1987, 40,
594–599. (c) Uchida, I.; Takase, S.; Kayakiri, H.; Kiyoto, S.;
Hashimoto, M.; Tada, T.; Koda, S.; Morimoto, Y. J. Am. Chem.
Soc. 1987, 109, 4108–4109.
2. (a) Shimomura, K.; Hirai, O.; Mizota, T.; Matsumoto, S.; Mori,
J.; Shibayama, F.; Kikuchi, H. J. Antibiotics 1987, 40, 600–606.
(b) Hirai, O.; Shimomura, K.; Mizota, T.; Matsumoto, S.; Mori, J.;
Kikuchi, H. J. Antibiotics 1987, 40, 607–611.
(2S)-Methyl ester [6-formyl-2,3-dihydro-1-hydroxy-8-
(methoxymethoxy)-1H-pyrrolo[1,2-a]indol-2-yl]-carbamic
acid (30). Ketone 26 (15 mg, 26 mmol, 1.0 equiv.), 3 mL
CH3CN, and 1 mL H2O were added to a 5 mL pyrex tube.
The test tube was placed in a 50 mL pyrex test tube. The
௣
50 mL tube was stoppered and placed in a Rayonet photo-
chemical reactor and exposed to 350 nm light. Over the
course of the reaction, the solution slowly turned dark
orange. After 24 h, the reaction mixture was removed
from the photo reactor, and the CH3CN was removed in
vacuo. The resulting aqueous solution was diluted with
water and extracted with 3×EtOAc. The combined organic
extracts were dried over Na2SO4, filtered, and concentrated.
The orange residue was purified by PTLC to yield 3.0 mg of
30 (38% yield) as brown solids in a 1:1 mixture of isomers.
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1
The stereochemistry was tentatively assigned by H NMR
correlation with similar diastereomers.21
trans-Diastereomer: [a]2D5ˆϩ15.2 (cˆ0.25, CH2Cl2).
Rfˆ0.42 (20:20:1 CH2Cl2/Et2O/MeOH). 1H NMR
(300 MHz, CDCl3) d TMS: 2.34 (1H, br, D2O exch.); 3.52
(3H, s); 3.74 (3H, s); 3.92 (1H, dd, Jˆ8.0, 10.0 Hz); 4.55
(1H, dd, Jˆ8.0, 10.0 Hz); 4.88 (1H, m); 5.19 (1H, d,
Jˆ4.8 Hz); 5.34 (1H, d, Jˆ6.6 Hz); 5.37 (1H, d,
Jˆ6.6 Hz); 5.70 (1H, d, Jˆ7.2 Hz); 6.65 (1H, s); 7.23
(1H, d, Jˆ1.2 Hz); 7.41 (1H, d, Jˆ1.2 Hz); 9.88 (1H, s).
IR (NaCl, neat): 3354, 2956, 2923, 1716, 1682, 1558, 1538,
1456 cmϪ1 13C NMR (75 MHz, CDCl3) d TMS: 47.9 (t),
.
52.6 (d), 56.3 (q), 56.5 (q), 66.6 (d), 77.1 (s), 94.1 (d), 94.5
(t), 102.2 (d), 109.4 (d), 127.8 (s), 132.3 (s), 133.5 (s), 144.9
(s), 151.2 (s), 192.0 (d). Mass spectrum (ESϩ) m/z (relative
intensity): 335 (MϩH, 100%). Exact mass: (FAB) calcd for
C16H19N2O6: 335.1243. Found: 335.1229.
cis-Diastereomer: [a]2D5ˆϪ21.6 (cˆ0.25, CH2Cl2). Rfˆ0.27
(20:20:1 CH2Cl2/Et2O/MeOH). 1H NMR (300 MHz,
CDCl3) d TMS: 2.81 (1H, br, D2O exch.); 3.53 (3H, s);
3.73 (3H, s); 3.93 (1H, m); 4.61 (2H, m); 5.06 (1H, br,
D2O exch.); 5.22 (1H, d, Jˆ3.9 Hz); 5.35 (2H, s); 6.64
(1H, s); 7.25 (1H, d, Jˆ1.2 Hz); 7.45 (1H, d, Jˆ1.2 Hz);
9.93 (1H, s). IR (NaCl, neat): 3332, 2923, 2852, 1704, 1682,
1568, 1532, 1455 cmϪ1 13C NMR (75 MHz, CDCl3) d
.
TMS: 48.4 (t), 52.7 (d), 56.3 (q), 63.3 (q), 74.2 (d), 77.1
(s), 94.0 (d), 94.9 (t), 103.3 (d), 108.5 (d), 128.7 (s), 132.4
(s), 133.6 (s), 145.2 (s), 151.2 (s), 191.8 (d). Mass spectrum
(ESϩ) m/z (relative intensity): 335 (MϩH, 100%). Exact
mass: (FAB) calcd for C16H19N2O6: 335.1243. Found:
335.1244.
10. Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98,
2723–2796.
Acknowledgements
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6491–6494.
This work was supported by the National Institutes of
Health (Grant CA51875). Mass spectra were obtained on
instruments supported by the NIH Shared Instrumentation
Grant GM49631.
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loss of the starting material.
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was carried through.
21. The stereochemistry of tetraacetates i and ii has previously
been determined: Egbertson, M. S. PhD Dissertation, Yale Uni-
versity, 1989.
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