Chiral aziridinyl radicals: An application to the synthesis of the core nucleus of FR-900482

Article abstract of DOI:10.1021/jo961992n

An asymmetric route to the core nucleus of the antitumor agent FR-900482 utilizes the cyclization of an aziridinyl radical into a functionalized indole nucleus. The route employs a selective Polonovski reaction and the Hootele-Dmitrienko rearrangement to install two oxygen atoms.

Full text of DOI:10.1021/jo961992n

J . Org. Chem. 1997, 62, 1083-1094
1083
Ch ir a l Azir id in yl Ra d ica ls: An Ap p lica tion to th e Syn th esis of th e
Cor e Nu cleu s of F R-900482
Frederick E. Ziegler* and Makonen Belema
Sterling Chemistry Laboratory, Yale University, New Haven, Connecticut 06520-8107
Received October 24, 1996X
An asymmetric route to the core nucleus of the antitumor agent FR-900482 utilizes the cyclization
of an aziridinyl radical into a functionalized indole nucleus. The route employs a selective Polonovski
reaction and the Hootele´-Dmitrienko rearrangement to install two oxygen atoms.
In 1987, FR-900482 (1a ), a mitomycin-like antitumor
agent,1,2 was isolated3 from Streptomyces sandaensis and
characterized4,5 by the Fujisawa Laboratories. FR-
900482, which is a 2:1 mixture (â:R ether bridge) of
stereoisomers at neutral pH and almost exclusively the
â-isomer in acidic medium, had its spectral properties
investigated as the product of triacetylation, FK-973 (2).
An X-ray analysis of FK-973 secured the relative stereo-
chemistry while biosynthetic studies demonstrated that
the nonaromatic portion of FR-900482 was derived from
D-glucosamine, thereby establishing the absolute stereo-
chemistry.6 Two years later, FR-66979 (1b) was isolated
from the same culture broth and was determined to have
similar activity to FR-900482.7 FR-66979 was prepared
from FR-900482 by catalytic hydrogenation. FK-973 was
found to be more effective than mitomycin C (3) in certain
tumor screens.8,9 FR-900482, FR-66979, and FK-973
Of these efforts, only Rapoport’s approach addressed the
preparation of chiral products derived from enantiomeri-
cally-pure starting material and Sulikowski’s recent
contribution explored the viability of a reagent-controlled
asymmetric synthesis. The total synthesis of (()-FR-
900482 was first accomplished by Fukuyama in 199224
and later by Danishefsky.25 More recently, Terashima
et al. reported the total synthesis of natural (+)-FR-
900482 using L-diethyl tartrate as the chiral pool.26-28
Our approach to FR-900482 is outlined in Scheme 1.
The late intermediate 4 was viewed as arising from
dihydroindole 5 by a double oxidation. To accomplish this
goal, oxidation of 5 to an indole would have to be avoided.
Drawing upon our earlier study29 involving the genera-
tion of carbon-centered aziridinyl radicals and their
intramolecular addition to an indole nucleus, indole 6 was
selected as a suitable substrate. Previous cyclizations
of this type had been conducted on indoles bearing
electron-withdrawing groups at the 3-position wherein
dimerization of the highly stabilized radical had
occurred.29-31 Two points were at issue: would an alkyl
behave similarly to mitomycin C in that they cross-link
DNA.10 The site of cross-linking has been determined
for FR-900482 and FR-66979 by the isolation of bis-
guanosine adducts derived from 5′-CpG sites.11-14
The unique structure of FR-900482 has prompted a
number of model studies directed toward its synthesis.15-23
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Shimomura, K.; Hirai, O.; Mizota, T.; Matsumoto, S.; Mori, J .;
Shibayama, F.; Kikuchi, H. J . Antibiot. 1987, 40, 600.
(2) Hirai, O.; Shimomura, K.; Mizota, T.; Matsumoto, S.; Mori, J .;
Kikuchi, H. J . Antibiot. 1987, 40, 607.
(3) Iwami, M.; Kiyoto, S.; Terano, H.; Kohsaka, M.; Aoki, H.;
Imanaka, H. J . Antibiot. 1987, 40, 589.
(4) Kiyoto, S.; Shibata, T.; Yamashita, M.; Komori, T.; Okuhara, M.;
Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J . Antibiot. 1987, 40,
594.
(5) Uchida, I.; Takase, S.; Kayakiri, H.; Kiyoto, S.; Hashimoto, M.;
Tada, T.; Koda, S.; Morimoto, Y. J . Am. Chem. Soc. 1987, 109, 4108.
(6) Fujita, T.; Takase, S.; Otsuka, T.; Terano, H.; Kohsaka, M. J .
Antibiot. 1988, 41, 392.
(7) Terano, H.; Takese, S.; Hosoda, J .; Kohsaka, M. J . Antibiot. 1989,
42, 145.
(8) Shimomura, K.; Manda, T.; Mukumoto, S.; Masuda, K.; Naka-
mura, T.; Mizota, T.; Matsumoto, S.; Nishigaki, F.; Oku, T.; Mori, J .;
Shibayama, F. Cancer Res. 1988, 48, 1166.
(9) Masuda, K.; Nakamura, T.; Mizota, T.; Mori, J .; Shimomura, K.
Cancer Res. 1988, 48, 5172.
(10) Masuda, K.; Nakamura, T.; Shimomura, K.; Shibata, T.; Terano,
H.; Kohsaka, M. J . Antibiot. 1988, 41, 1497.
(11) Woo, J .; Sigurdsson, S. T.; Hopkins, P. B. J . Am. Chem. Soc.
1993, 115, 1199.
(12) Williams, R. M.; Rajski, S. R. Tetrahedron Lett. 1993, 34, 7023.
(13) Huang, H.; Pratum, T. K.; Hopkins, P. B. J . Am. Chem. Soc.
1994, 116, 2703.
(14) Huang, H.; Rajski, S. R.; Williams, R. M.; Hopkins, P. B.
Tetrahedron Lett. 1994, 35, 9669.
(15) Yasuda, N.; Williams, R. M. Tetrahedron Lett. 1989, 30, 3397.
(16) J ones, R. J .; Rapoport, H. J . Org. Chem. 1990, 55, 1144.
(17) McClure, K. F.; Benbow, J . W.; Danishefsky, S. J . J . Am. Chem.
Soc. 1991, 113, 8185.
(18) McClure, K. F.; Danishefsky, S. J . J . Org. Chem. 1991, 56, 850.
(19) Dmitrienko, G. I.; Denhart, D.; Mithani, S.; Prasad, G. K. B.;
Taylor, N. J . Tetrahedron Lett. 1992, 33, 5705.
(20) McClure, K. F.; Danishefsky, S. J . J . Am. Chem. Soc. 1993, 115,
6094.
(21) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. 1995, 36, 1169.
(22) Miller, S. J .; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J . Am.
Chem. Soc. 1995, 117, 2108.
(23) Lim, H.-J .; Sulikowski, G. A. Tetrahedron Lett. 1996, 37, 5243.
(24) Fukuyama, T.; Xu, L.; Goto, S. J . Am. Chem. Soc. 1992, 114,
383.
(25) Schkeryantz, J . M.; Danishefsky, S. J . J . Am. Chem. Soc. 1995,
117, 4722.
(26) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron Lett.
1996, 37, 3471.
(27) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.;
Terashima, S. Tetrahedron Lett. 1996, 37, 3475.
(28) Katoh, T.; Yoshino, T.; Nagata, Y.; Nakatani, S.; Terashima,
S. Tetrahedron Lett. 1996, 37, 3479.
(29) Ziegler, F. E.; Belema, M. J . Org. Chem. 1994, 59, 7962.
(30) Ziegler, F. E.; Harran, P. G. J . Org. Chem. 1993, 58, 2768.
S0022-3263(96)01992-5 CCC: $14.00 © 1997 American Chemical Society

1084 J . Org. Chem., Vol. 62, No. 4, 1997
Ziegler and Belema
Sch em e 1
meier-Haack formylation afforded the target aldehyde
13 with the proviso that hydrolysis of the intermediate
iminium salt was conducted in water rather than aque-
ous alkali to minimize ester hydrolysis.35
To test whether or not reductive radical cyclization
could be conducted in the absence of an electron-
withdrawing group at the 3-position of the indole nucleus,
indole 12 was alkylated as previously described29 with
the triflate 14b, whose genesis was D-isoascorbic acid.36
The resultant ester 15a , prepared in 44% yield, was
saponified selectively to the monocarboxylic acid 15b with
excess LiOH without affecting the aromatic carbomethoxy
group (84%). Thiohydroxamate ester formation was
accomplished by the Barton-Samadi procedure37 which
utilizes 2,2′-dithiobis(pyridine N-oxide) and n-Bu3P.
Rather than employ a direct decarboxylation-cyclization
protocol whose shortcoming has been addressed previ-
ously,29 a two-step procedure was employed.
Sch em e 2
Visible light photolysis (W-lamp) of thiohydroxamic
acid anhydride 15c in neat BrCCl3 afforded a mixture of
cis and trans bromoaziridines 16a and16b (3.3:1, respec-
tively) in 53% yield. The presence of pyridine was
necessary to scavenge HBr, which is capable of cleaving
the aziridine ring.29 The major isomer was assigned the
cis stereochemistry based upon a coupling constant of 5.3
Hz for the vicinal aziridine hydrogens; the minor isomer
displayed J ) 1.7 Hz for the same signals. The isolation
of the bromoaziridines as a mixture was of little conse-
quence because both isomers were amenable to the
subsequent reductive cyclization. Accordingly, a toluene
solution of n-Bu3SnH and 1,1′-azobis(cyclohexylcarboni-
trile) (ACCN) was added via syringe pump to a mixture
of bromoaziridines 16a and 16b in refluxing toluene to
afford a 4:1 mixture of tetracycle 17 and uncyclized
aziridine 16c in 57% yield. The dilution technique was
required to maximize the 17:16c ratio. Rewardingly, the
benzylic radical obtained by cyclization was sufficiently
reactive to abstract a hydrogen atom from n-Bu3SnH and
sustain a chain process as opposed to dimerization, which
had been observed when an electron-withdrawing group
substituent at the 3-position of the indole ring permit
reductive cyclization and would the gramine-like struc-
ture of indole 6 survive the reaction conditions? Ready
access to 3-formylindoles and the availability of a suitable
electrophilic, enantiomerically-pure aziridine-2-carboxy-
late made this approach attractive. Moreover, the route
would flout conventional wisdom by incorporation of
“reactive” aziridine functionality at an early stage of the
synthetic scheme.
In their study directed toward an asymmetric synthesis
of FR-900482, J ones and Rapoport16 employed as a
starting material methyl 3-hydroxy-4-methyl-5-nitroben-
zoate (10) prepared from 3,5-dinitro-p-toluic acid by
successive sodium dithionite reduction, diazotization,32
and esterification. In our hands, the dithionite reduction
proved troublesome. Modification of the reported33 Zinin
reduction (ammonium sulfide) of toluic acid 9 provided
the intermediate m-anthranilic acid in 71% yield. o-
Nitrotoluene 11 was converted to the indole 12 in 56%
yield by the Batcho-Leimgruber procedure.34 Vils-
(31) Ziegler, F. E.; Harran, P. G. Tetrahedron Lett. 1993, 34, 4505.
(32) Nielson, O. B. T.; Bruun, H.; Bretting, C.; Feit, P. W. J . Med.
Chem. 1975, 18, 41.
(33) The molar ratio of ammonium sulfide to 3,5-dinitro-p-toluic acid
was increased from 1:1 to 3:1. Barben, I. K.; Suschitzky, H. J . Chem.
Soc. 1960, 672.
(34) Batcho, A. D.; Leimgruber, W. Organic Syntheses; J ohn Wiley:
New York, 1985; Vol. 63, p 214.
(35) J ames, P. N.; Snyder, H. R. Organic Syntheses; J ohn Wiley:
New York, 1963; Coll. Vol. IV, p 539.
(36) Dunigan, J .; Weigel, L. J . Org. Chem. 1991, 56, 6225.
(37) Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 48, 7083.

Chiral Aziridinyl Radicals
J . Org. Chem., Vol. 62, No. 4, 1997 1085
was present at the benzylic site.29 Although the stereo-
chemistry of tetracycle 17 was not readily derived from
1
the H NMR spectrum, the methine hydrogens are most
likely syn to one another as has been observed in previous
cyclizations of this type.29-31
Having established the viability of the reductive cy-
clization in the absence of an electron-withdrawing group,
the cyclization of a potentially labile indole-3-methanol
was explored. The alkylation of indole-3-carboxaldehyde
13 with triflate 14b was improved (66% yield) over the
alkylation of indole 12 by rapid isolation of the triflate,
which proved to be more stable than had been antici-
pated.38 Ester 18a was readily converted into a 3.8:1
mixture of aziridinyl bromides 19a and 19b in 69% yield
by the standard protocol. The cis stereoisomer again
prevailed over its trans counterpart. Not only did
coupling constants (J ) 4.9 and 1.8 Hz, respectively) of
the vicinal aziridine methine hydrogens support the
assignment, but also the cis isomer 19a displayed an
NOE between these two hydrogens (∼12%) while the
trans isomer 19b showed no NOE.
1
The H NMR spectrum of oxazolidinone 23, which is
the product of a net, nonreductive process, revealed an
exchangeable proton with a concentration dependent
chemical shift and a doublet at δ ) 6.13 (J ) 7.9 Hz)
corresponding to the methine hydrogen at C1.40 Although
the cyclization was run under a N2 atmosphere, no effort
was made to degas the solvent. Surrepticious oxygen
could oxidize radical 24 to the indole 25a followed by
nitrogen-assisted cleavage of the aziridine at the C1 site.
Readdition of the Boc carbonyl oxygen followed by loss
of the tert-butyl group would lead to oxazolidinone. This
mode of aziridine ring opening is critical in the nucleo-
philic attack on the reduced, activated forms of FR-
90048211 and mitomycin C.41 Alternatively, the appear-
ance of nonreduced products in the presence of n-Bu3SnH
in radical reactions is not uncommon. At least two
studies have invoked an SNR1 mechanism to explain the
oxidation of radicals in the absence of oxygen. The
stannane serves as a base in the formation of a radical
anion from the radical. Subsequent electron transfer
affords the nonreduced product.42-44
The stereochemistry of the major, cyclized alcohol 21b
and the minor, cyclized alcohol 22b were determined by
NOE difference experiments and coupling constants
obtained from their derived TBDMS ether 21a and
acetate 22c, respectively. Silyl ether 21a showed strong
enhancement of the C9-H (13.4%)45 and C1-H (9.3%) upon
irradiation of the C9a-H (Figure 1). This cis-cis arrange-
ment places the silyloxymethyl group and the aziridine
proximate to one another on the concave face of the
nitrogen-bearing [3.3.0] ring system. Irradiation of the
C1-H caused enhancement (4.9%) of one of the C10-H
hydrogens but no enhancement of C9-H. Although C1-H
and C9-H are cis to one another, they are remotely
situated on the convex face of the ring system. On the
Reduction of the mixture of aldehydes 19a and 19b was
readily achieved with NaBH4 in CH3OH to produce
indole-3-methanols 20a , which were directly silylated to
form the TBDMS ethers 20b. Attempts to purify silyl
ether 20b by SiO2 chromatography gave complex mix-
tures with only 6% recovery of the silyl ether. In spite
of the lability of the silyl ether toward chromatography,
reductive cyclization in toluene (bath temperature 116
°C) proved successful. No dimer was detected nor was
any reduced uncyclized product 20c isolated although it
had been detected spectroscopically. Chromatography
separated oxazolidinone 23 (2.2%) from the diastereo-
meric silyl ethers 21a and 22a . The latter silyl ethers
were separated as their alcohols 21b (51%) and 22b
(∼5%)39 after desilylation with tetra-n-butylammonium
fluoride (TBAF).
(40) Mitomycin numbering is used throughout the text for mitomy-
cin-like structures. FR-900482 numbering is employed for related
oxygen-bridged structures. These numbers may not agree with com-
pound names appearing in the Experimental Section.
(41) For leading references see, Tomasz, M.; Chawla, A. K.; Lipman,
R. Biochemistry 1988, 27, 3182.
(42) Antonio, Y.; De La Cruz, M. E.; Galeazzi, E.; Guzman, A.; Bray,
B. L.; Greenhouse, R.; Kurz, L. J .; Lustig, D. A.; Maddox, M. L.;
Muchowski, J . M. Can. J . Chem. 1994, 72, 15.
(43) Bowman, W. R.; Heaney, H.; J ordan, B. M. Tetrahedron 1991,
47, 10119.
(44) Moody, C. J .; Norton, C. L. Tetrahedron Lett. 1995, 36, 9051.
(45) The heads of arrows in Figure 1 are the observed hydrogen
atoms; the tails are irradiated.
(38) We thank Mr. Mikhail Berlin of this laboratory for this
observation.
(39) The yield of alcohol 22b is the average obtained by combining
the products of several runs.

1086 J . Org. Chem., Vol. 62, No. 4, 1997
Ziegler and Belema
A more efficient route to alcohol 21b may be imagined
by reductive cyclization of indole-3-methanol 20d . This
pathway resulted in the isolation of a mixture (5.5:1) of
the desired, cyclized alcohol 21b and reduced, uncyclized
alcohol 20a , respectively, in 53% yield. The inability to
separate effectively these alcohols established the longer
silylation route as the more prudent choice.
With the successful formation of the tetracyclic aziri-
dinol 21b, attention was directed toward the incorpora-
tion of the two oxygen atoms at C9a, which bears the basic
nitrogen. Any oxidation of 21b to a tetrasubstituted
iminium salt would result in facile aromatization to
indole 25bsa dead end. To preclude aromatization, a
formyl group was installed at C9 of tetracycle 21b to
permit controlled oxidation.47 The presence of the aziri-
dine ring would prohibit enamine formation by deproto-
nation of the iminium salt at C1.
To this end, oxidation of alcohol 21b to aldehyde 26
was explored. When Swern oxidation conditions48 were
employed, aldehyde 25c was a minor, but nonetheless,
undesirable byproduct. Tetra-n-butylammonium perru-
thenate49,50 oxidation gave aldehyde 25c as the major
product. Dess-Martin periodinane, particularly aged
samples,51,52 proved to be a satisfactory oxidant. Because
aldehyde 26 was also susceptible to aerial oxidation to
indole 25c, aldehyde 26 was directly condensed with
aqueous formalin53 in the presence of NaHCO3 to afford
a single aldol product in 86% yield after radial chroma-
1
tography. The H NMR spectrum of aldol 27a displayed
an exchangeable hydrogen at δ 2.77 (J ) 9.8 and 4.2 Hz)
that was coupled to each of the methylene hydrogen
atoms at δ 3.56 and 4.41, respectively. The resonance
at δ 3.56, in addition to being coupled to its geminal
partner, was also weakly coupled (J ) 1 Hz) to the
aldehyde hydrogen. This coupling pattern argued on
behalf of a hydrogen bond between the hydroxyl group
and the aldehyde group.
Although much effort would be expended in locating a
suitable protecting group for the hydroxyl group of aldol
27a , our initial choice was to prepare the TBDMS silyl
ether. From a practical viewpoint, the silylation was
conducted on the aldol product prior to its purification
by radial chromatography. In addition to the expected
silyl ether 27c, silyl ether 27d , which was higher in mass
F igu r e 1. NOE studies.
1
than 27c by 30 units, was also isolated. The H NMR
other hand, acetate 22c displayed a strong NOE (10.2%)
between these two hydrogen atoms that are cis but
proximately located on the concave face. No NOE is
observed between the trans hydrogens at C9 and C9a,
although the trans pair at C1 and C9a shows an enhance-
ment of 5.5%. The proximity of one of the C10 methylene
hydrogen atoms and the C9a-H is revealed by an 8.3%
NOE. These two structures, 21a and 22c, bear the same
relative stereochemistry between C1 and C9 and differ
only at the C9a center. The coupling constant for C9-H/
C9a-H (J ) 9.8 Hz) in silyl ether 21a and J ) 6.3 Hz in
acetate 22c supported the respective cis and trans
stereochemical assignments. The C1-H/C9a-H coupling
constant (J ) 1.8 Hz) in silyl ether 21a was consistent
with coupling constants of analogs in this series;29
however, the lack of coupling at this site in acetate 22c,
while consistent with a trans relationship, cannot be
construed as supporting evidence.46 Nonetheless, these
assignments would be supported by subsequent X-ray
and chemical correlation studies.
spectrum of 27d , with an additional AB pattern (δ 4.02,
4.76; J ) 5.2 Hz) revealed it to be a simple formaldehyde
homolog of 27c. The bis-formaldehyde adduct 27b was
never isolated upon radial chromatography. Its transient
stability may have been due to its existence as the
cyclized hemiacetal.
The stereochemistry of silyl ether 27c was revealed by
NOE difference studies (Figure 1). Irradiation of the
C1-H caused enhancement of the C2-H (8.2%), the C9a-H
(12.2%), and the aldehyde hydrogen (4.9%). The second
NOE placed the C2-H and C9a-H in a cis relationship as
(47) For an example of nucleophilic oxygen capture by an iminium
salt during oxidation see, Bartlett, M. F.; Lambert, B. F.; Taylor, W.
I. J . Am. Chem. Soc. 1964, 86, 729.
(48) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(49) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625.
(50) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(51) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 43, 4155.
(52) )For a recent modification of the original procedure and an
understanding of the mechanism see, Meyer, S. D.; Schreiber, S. L. J .
Org. Chem. 1994, 59, 7549.
(46) Harran, P. G., Ph. D. Thesis, Yale University, 1995.
(53) Ziegler, F. E.; Wallace, O. B. J . Org. Chem. 1995, 60, 3626.

Chiral Aziridinyl Radicals
J . Org. Chem., Vol. 62, No. 4, 1997 1087
was observed for silyl ether 21a . The C1-H/CHO NOE
(4.9%), the same magnitude as the C1-H/C10-H NOE in
silyl ether 21a , and the lack of an NOE between the
aldehyde hydrogen and C9a-H, set the trans relationship
between the C1-H and the aldehyde group. The C1-H/
aldehyde enhancement is not unusual; a similar NOE has
been observed5 between the C7-H and C9-H in FK-973
and the structurally related diastereomer of FR-900482.
From a mechanistic perspective, be it kinetic or thermo-
dynamic, the stereochemical arrangement at C9 in silyl
ether 27c is what would be expected from the aldol
condensation. Kinetic control would argue for the elec-
trophile formaldehyde to react with the enolate of alde-
hyde 26 on the uncongested convex R-face; thermody-
namically, the smaller, sp2-hybridized formyl group
would occupy the concave face of the tetracyclic ring
system of aldol 27a and the sp3-hybridized hydroxy-
methyl group would be favored on the convex face. The
relative stereochemistry of C1 and C9 would be confirmed
on a later substrate after introduction of the two oxygen
atoms.
position bore a hydrogen and an aziridine ring was not
present, Danishefsky and Feigelson58 observed that a
Polonovski reaction59 led to aromatization (via C9a imi-
nium salt) and C3 oxidation in near equal amounts. This
observation notwithstanding, treatment of silyl ether 27c
to m-CPBA provided amine oxide 28a as a single dia-
stereomer (1H NMR) presumably with the oxygen atom
cis to the C9a-H. Exposure of the amine oxide to acetic
anhydride in THF at 0 °C gave rise to a chromatographi-
cally inseparable 2.7:1 mixture (33%) of tert-carbinola-
mine 29a and the amine oxide precursor, amine 27c,
respectively, 40% yield of sec-carbinolamine 29b, and a
trace of aromatic substitution product 31a .60 As planned,
acetate added to the regioisomeric iminium salts and was
exchanged for a hydroxyl group during aqueous workup.
1
The H NMR spectrum of tert-carbinolamine 29a was
devoid of a C9a-H signal. The C1-H (δ ) 3.22, J ) 4.4
Hz) resonance was now coupled only to C2-H and no
longer coupled to two vicinal hydrogens as in amine 27c.
On the other hand, sec-carbinolamine 29b displayed a
C9a-H (δ ) 4.54, J ) 2.1 Hz) and a single C3-H (δ ) 4.91
(d, J ) 3.7 Hz)), coupled only to the exchangeable
hydroxyl proton at δ 1.96. Amine 27c was not present
due to incomplete oxidation but rather an undefined
reduction process. When the more reactive trifluoroacetic
anhydride was used, a complex reaction mixture was
produced; no carbinolamines were detected. The inter-
pretation of the selectivity in the Polonovski reaction at
the time was that the silyloxy group was providing
sufficient steric bulk to bias the formation of sec-carbino-
lamine over the tertiary isomer. Accordingly, the efficacy
of a seemingly smaller protecting group, acetyl, was
explored.
Acetate 27e, prepared from aldol 27a with Ac2O/
DMAP/pyr, was converted to amine oxide 28b with
m-CPBA in near quantitative yield. Rewardingly,
Polonovski rearrangement led to the formation of tert-
carbinolamine 29c (59%) and sec-carbinolamine 29d (8%).
1
The H NMR spectra of these isomers displayed similar
patterns to the products of the silyl series; combustion
analysis and/or mass spectroscopy confirmed the incor-
poration of a single oxygen in each isomer.
With the selectivity problem solved, interpolation of
oxygen in the C9a-N bond was required. This procedure
was first employed in FR-900482 studies by Dmitrienko19
and recently by Sulikowski.23 The process may involve
oxidation of a carbinolamine to its N-oxide61 followed by
spontaneous ring-opening and addition of the newly-
formed hydroxylamine oxygen to the resultant carbonyl
group. Ironically, an analogous sequence of events was
unknowingly uncovered by Polonovski in an investigation
of the N-oxides of Calabar bean alkaloids and correctly
interpreted by Hootele´62 as the rearrangement product.
Oxidation of carbinolamine 29c with m-CPBA led directly
to the ring-expanded acetate 30a , whose structure was
When the minor alcohol 22b was oxidized to an
aldehyde and subjected to an aldol condensation with
formalin, no trace of aldol product 27a could be isolated
1
or detected by H NMR. If major alcohol 21b and minor
alcohol 22b had the same relative stereochemistry at
C1-H and C9a-H, then the same aldol product, namely
alcohol 27a , would have been expected from both dia-
stereomers. This chemical experiment supported the
structural assignments for alcohols 21b and 22b that
were made through spectroscopic studies.
54-56
57
The oxidants Hg(OAc)2
and Pt/O2 proved unsuc-
cessful in the oxidation of silyl ether 27c. In a synthetic
study conducted in the mitomycin series, wherein the C9
(58) Danishefsky, S. J .; Feigelson, G. B. Heterocycles 1987, 25, 301.
(59) Grierson, D. In Organic Reactions; L. A. Paquette, Ed.; J ohn
Wiley: New York, 1990; Vol. 39, p 85.
(60) All the sec- and tert-carbinolamines encountered in this study
were mainly single stereoisomers, and no stereochemical assignments
were made.
(61) An alternative mechanism is the oxidation of the ring-opened
ketoamine intermediate that might exist in low concentration.
(62) Hootele´, C. Tetrahedron Lett. 1969, 2713.
(54) Leonard, N. J .; Miller, L. A.; Thomas, P. D. J . Am. Chem. Soc.
1956, 78, 3463.
(55) Stork, G.; Guthikonda, R. N. J . Am. Chem. Soc. 1972, 94, 5109.
(56) Magnus, P.; Giles, M.; Bonnert, R.; J ohnson, G.; McQuire, L.;
Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J . Am. Chem. Soc. 1993,
115, 8116.
(57) Ziegler, F. E.; Bennett, G. B. J . Am. Chem. Soc. 1973, 95, 7458.

1088 J . Org. Chem., Vol. 62, No. 4, 1997
Ziegler and Belema
confirmed by single crystal X-ray analysis.63 The 1H
NMR of the acetate indicated a single stereoisomer unlike
the 2:1 mixture present in FR-900482. The solution and
solid state structures need not be the same stereoisomer
in respect to the ether bridge. The X-ray structure
confirmed the relative stereochemistry at C1 and C9 of
acetate 27e. This evidence, along with the NOE studies
conducted on silyl ether 27c, confirmed the stereochem-
istry of aldol product 27a .
Although the acetyl protecting group proved beneficial
for the Polonovski reaction, the group could not be
removed effectively from acetate 30a under a variety of
conditions. Reagents as diverse as Na2CO3/MeOH,
n-Bu3SnOMe,64 Otera’s catalyst,65 and p-TsOH/MeOH
caused decomposition of the substrate. When acetate 30a
1
was dissolved in MeOH-d4/Na2CO3 and monitored by H
NMR, only the resonance of sodium acetate (δ 1.89) could
be identified! In light of the sensitivity of acetate 30a
toward these varied conditions, a protecting group that
could be removed under neutral or weakly acidic condi-
tions was considered. The carbobenzoxy protecting group
was chosen, in spite of its seemingly greater bulk than
the acetyl group.
Direct acylation of alcohol 27c with carbobenzoxy
chloride (CbzCl) in the presence of i-Pr2NEt failed to
effect acylation, and the addition of DMAP to the reaction
mixture did not improve matters. However, treatment
of the alcohol with 1,1′-carbonyldiimidazole in CH3CN
afforded the imidazolide which, in situ, was solvolyzed
by the addition of benzyl alcohol and DMAP to provide
benzyl carbonate 27f in 68% yield. Amine oxide forma-
tion occurred without incident (98% yield), and subse-
quent rearrangement afforded a separable mixture of
carbinolamines 29e and 29f in a 13:1 ratio (68%).66
Rewardingly, the Polonovski reaction conducted on ben-
zyl carbonate 27f proved more selective than the reaction
performed on acetate 27e.
During the course of this investigation, we also had
the opportunity to explore the Polonovski reaction on the
silyloxymethyl ether 27d , methoxymethyl ether 27g, and
carbomethoxy derivative 27h . The tert:sec-carbinolamine
ratio for the nonacyl protected substrates, 27c (1.0:1.8),
27d (1.4:1.0), and 27g (1.2:1.0), was not selective. In
addition, trace amounts of the acetoxy, aromatic substi-
tution products 31a -c67 were also produced from their
respective substrates. However, the amine oxide of
carbomethoxy derivative 27h gave a 6:1 ratio (tertiary:
secondary) in 70% yield. None of the acyl derivatives
gave products of aromatic substitution. These data do
not support a steric argument for the regioselectivity in
the Polonovski reaction. A possible explanation for the
selectivity observed with the acyl series is that the
carbonyl of the protecting group, which is situated cis to
the C9a-H, is participating as an internal base, albeit
through a seven-membered transition state, in the elimi-
nation process and thereby accelerating the formation of
the tetrasubstituted iminium ion at the expense of its
regioisomer and aromatic substitution products. This
argument implies kinetic formation of the iminium salts.
Hootele´-Dmitrienko rearrangement of carbinolamine
29e was performed in the usual way without incident to
afford hemiketal 30b. Hydrogenolysis of both benzyl
groups of 30b proceeded in high yield to afford triol 32.
The reduction was conducted in the presence of HOAc
(10% Pd/C, EtOH, rt) to maintain the pH below 7.
Although the triol was stable and could be purified by
flash chromatography, prolonged exposure to SiO2 caused
decomposition. No attempt was made to effect selective
debenzylation; however, hydrogenation of a sample of
30b obtained directly from ring expansion did indicate
that carbonate debenzylation was faster than liberation
of the phenol. The 1H NMR spectrum of the triol revealed
the three hydroxyl protons at δ 8.26, 7.61, and 4.42 (dd,
J ) 11.2, 1.4 Hz) upon exchange with CH3OH-d4. The
hydroxyl of the hydroxymethyl group (δ 4.42) was coupled
to each of the adjacent methylene protons, one of which
(δ 4.10) appeared as a triplet of doublets (J ) 11.2, 1.9
Hz). The deuterium exchange reduced this pattern to a
doublet of doublets with the same coupling constants,
indicating that geminal coupling and W-coupling re-
mained. These data support intramolecular hydrogen
bonding of the aldol structure. At this juncture there was
no direct evidence to permit the assignment of the
stereochemistry of the ether bridge. Because the triol is
a single isomer, its stereochemistry was assumed to be
the same as that of the acetate 30a , upon which the X-ray
determination was conducted.
Triol 32 was readily converted to its acetonide 33a
which provided stability and rigidity to the molecule. The
geometry of the ether bridge in the acetonide need not
be the same as is present in the triol. However, the
rigidity imparted to the molecule by the dioxane ring
permitted an extensive NOE study that mapped the
hydrogen atom contiguity (Figure 1) and consequently
(63) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(64) Farina, V.; Huang, S. Tetrahedron Lett. 1992, 33, 3979.
(65) Otera, J .; Dan-oh, N.; Nozaki, H. J . Org. Chem. 1991, 56, 5307.
(66) This ratio varied between 8:1 and 13:1.
(67) The site of substitution, C5 or C7, was not determined.

Chiral Aziridinyl Radicals
J . Org. Chem., Vol. 62, No. 4, 1997 1089
permitted the assignment of the stereochemistry of the
ether bridge. Irradiation of the phenolic hydrogen en-
hanced the C4 aromatic hydrogen, the equatorial C13-H
of the dioxane ring, and the aldehyde hydrogen. The
issue of the ether bridge was resolved in favor of the
R-configuration when irradiation of the aldehyde hydro-
gen gave an enhancement (5.7%) of the aziridine hydro-
gen at C9. This is the same relationship that exists
between one of the side chain methylene hydrogens and
the C1 aziridine hydrogen in silyl ether 21a and aldehyde
27c. If the ether bridge of 33a were of the â-configura-
tion (34), then the aldehyde hydrogen would be remote
from the C9-H and an NOE would not be expected. On
the other hand, an NOE would have been anticipated
between the proximate C9-H and the axial C13-H of the
dioxane ring; however, no enhancement was observed.
The aldehyde hydrogen showed W-coupling (J ) 1.2 Hz)
to the axial dioxane hydrogen, C13-H, although the
observation did not assist in distinguishing between
structures 33a and 34. The lack of coupling of C11-Ha to
C10-H distinguished this signal from C11-Hb. A subse-
quent irradiation related the proximity of C11-Ha to C2-
H.
ingly, the desired decarbonylated product 33b was ob-
tained; unfortunately, the reaction proved to be capri-
cious. No seemingly identical set of reaction conditions
in regard to sample or reagent source, solvent prepara-
tion, atmosphere, concentration, or reaction time gave
the same result. Changes in reaction temperature, the
use of oxygen-free or oxygen-containing atmospheres and
degassed or non-degassed solvent, addition of the reagent
at reflux, or addition of incremental Ph3P failed to give
consistent results.73
The mass spectrum of decarbonylation product 33b
indicated the loss of 28 mass units relative to aldehyde
33a . The 1H NMR spectrum of 33b was devoid of an
aldehyde signal, and the appearance of the new methine
hydrogen at δ 3.46 that was coupled to the C13 equatorial
proton at δ 4.43 (J ) 6.0 Hz) and the obscured C13 axial
proton at δ 3.81-3.89 (11.1 Hz) supported the assign-
ment. Amongst the NOEs present in acetal 33b (Figure
1), the 3.7% enhancement between C7-H and C9-H
confirmed that decarbonylation occurred with retention
of configuration. A similar NOE was observed between
these hydrogens in the isomer of FR-900842 that has the
same R-bridge as acetal 33b.5
This study has demonstrated that aziridinyl radicals
may be employed as reactive intermediates in an asym-
metric synthesis of the core nucleus of FR-900482. We
are currently exploring alternative decarbonylation routes
to the synthesis of the core nucleus 33b whose remaining
functionality should be able to be manipulated to lead to
the synthesis of FR-900482 itself.24,25,27
With the structure of aldehyde 33a established, atten-
tion was directed toward its decarbonylation in anticipa-
tion of the remaining functional group manipulations.
The only stereochemical issue in FR-900482 is the trans
relationship between the side chain and the aziridine
ring. This relationship is present in aldehyde 33a , which
requires decarbonylation to occur with retention of con-
figuration. Two procedures meet this requirement.
Schaffner68 has shown that photodecarbonylation of
chiral â,γ-unsaturated aldehydes proceeds with retention
of configuration.69 Likewise, the seminal studies of
Walborsky70 demonstrated that stoichiometric decarbo-
nylation with Wilkinson’s catalyst, (Ph3P)3RhCl, also
meets this requirement.71,72
The substrates reported by Schaffner contained limited
functionality although one of them, R-naphthylisobu-
tyraldehyde, was structurally related to aldehyde 33a .
The aldehyde was converted to its TBDMS derivative 33c
to minimize any adverse effects of the free phenolic group
during photolysis. A degassed methanol solution of the
silyl ether was photolyzed (450-W Hanovia Hg lamp,
Pyrex filter) for 2 h. 1H NMR analysis of the reaction
mixture was not encouraging because, in addition to the
presence of starting material, four additional aldehyde
hydrogen signals were observed; no evidence of decarbon-
ylation products could be detected. Owing to the com-
plexity of the reaction mixture, attention was directed
to the use of (Ph3P)3RhCl.
Exp er im en ta l Section
Unless otherwise noted, all anhydrous reactions were
conducted in oven-dried glassware under N2. THF was
distilled from sodium benzophenone ketyl; CH2Cl2, benzene,
toluene, triethylamine, pyridine, and CBrCl3 were distilled
from CaH2. Other solvents and reagents were used as
received. 1,1′-Azobis(cyclohexanecarbonitrile) (ACCN), ob-
tained from Polysciences, Inc., was recrystallized from etha-
nol-water. (Ph3P)3RhCl (98%) was obtained from Acros.
Thiohydroxamic acid anhydrides were prepared in aluminum
foil-covered flasks and were degassed (freeze-pump-thaw, 3×)
in the dark. Photolyses were conducted in Pyrex tubes with
a 500-W tungsten halogen lamp (Norelco or Sylvania). Work-
up means the organic phase was dried over MgSO4, filtered,
and evaporated in vacuo. All reactions were conducted at room
temperature unless stated otherwise.
Flash chromatography (SiO2) was conducted as described
by Still.74 CH2Cl2 prep means that CH2Cl2 was used for
preparing the column and for loading the sample; elution was
conducted with the respective solvent systems. Since some of
the advanced intermediates were unstable to extended contact
with silica gel, their purification was conducted on short
columns that allowed rapid elution. Radial chromatography
was conducted on a Chromatotron 7924 T.
The rate of stoichiometric decarbonylation with Wilkin-
son’s “catalyst” decreases in the order primary > second-
ary > tertiary. These data argue that steric factors are
important. Accordingly, studies were conducted on the
free phenol 33a in either xylene or benzonitrile at 130
°C in the presence of 2.2 equiv of (Ph3P)3RhCl. Reward-
Melting points are uncorrected. Optical rotations and IR
spectra were recorded in CHCl3 (1% EtOH). Unless stated
1
otherwise, product ratio were obtained by H NMR. 1H NMR
(300 MHz, 7.24 ppm) and 13C NMR (75.5 MHz, 77.0 ppm) were
recorded in CDCl3.
J is used to indicate an average coupling
constant from chemically nonequivalent hydrogens with com-
parable coupling constants. 13C NMR* indicates that the
number of observed signals due to signal overlap is less than
the number of chemically nonequivalent carbons present in
the compound.
(68) Baggiolini, E.; Hamlow, H. P.; Schaffner, K. J . Am. Chem. Soc.
1970, 92, 4906.
(69) For a recent synthetic application of photodecarbonylation see,
MacMillan, D. W. C.; Overman, L. E. J . Am. Chem. Soc. 1995, 117,
10391.
(70) Walborsky, H. M.; Allen, L. E. J . Am. Chem. Soc. 1971, 93, 5465.
(71) Regeneration of (Ph3P)3RhCl from (Ph3P)2RhCl(CO), the product
of decarbonylation, has been described: O'Connor, J . M.; Ma, J . Inorg.
Chem. 1993, 32, 1866.
(72) For a review on decarbonylation with (Ph3P)3RhCl see, Tsuji,
J .; Ohno, K. Synthesis 1969, 157.
Meth yl 3-(Ben zyloxy)-4-m eth yl-5-n itr oben zoa te (11).
To a solution of phenol 10 (25.27 g, 0.1197 mol) in DMF (200
(73) The decarbonylation conditions reported in the Experimental
Section were inconsistently reproducible.
(74) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

1090 J . Org. Chem., Vol. 62, No. 4, 1997
Ziegler and Belema
mL) were added K2CO3 (16.57 g, 0.1198 mol) and benzyl
chloride (16.0 mL, 0.139 mol). The deep-red reaction mixture
was heated at 100 °C for 5.5 h. The majority of the DMF was
removed in vacuo at 70 °C. The residue was partitioned
between EtOAc (200 mL) and water (150 mL), and the aqueous
phase was extracted with EtOAc (200 mL, 2x). The combined
organic extracts were washed with brine and worked up.
Baseline material was removed with a short SiO2 column
(CH2Cl2). Recrystallization (EtOAc, hexanes) afforded 24.76
137.1, 136.8, 132.7, 128.5, 128.0, 127.6, 124.7, 119.5, 118.2,
108.5, 103.2, 69.7, 52.1; LRMS (CI) m/ z (M + H)+ ) 310.15.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53.
Found: C, 69.90; H, 4.93; N, 4.49.
Meth yl (2R,3S)-1-(ter t-Bu tyloxyca r bon yl)-3-[1-[4-(ben -
zyloxy)-6-(m eth oxycar bon yl)-1H-in dolyl]m eth yl]azir idin e-
2-ca r boxyla te (15a ). Alkylation of indole 12 (2.50 g, 8.89
mmol) with aziridinol 14a (1.03 g, 4.45 mmol) was conducted
as previously described for 3-cyanoindole.29 The crude mate-
rial was purified by flash chromatography (30-40% ether/
hexanes) to afford an impure white solid (0.96 g, 44% yield).
The impurity was removed by a second flash chromatography
(CH2Cl2) to afford diester 15a : mp 120.0-121.0 °C (ether,
hexanes); [R]20D ) +19.9 (c, 0.476, CHCl3); IR 1745, 1724, 1711
cm-1; 1H NMR δ 7.79 (s, 1 H), 7.50 (d, J ) 7.5 Hz, 2 H), 7.43-
7.30 (m, 3 H), 7.30 (s, 1 H), 7.25 (d, J ) 3.0 Hz, 1 H), 6.70 (d,
J ) 3.0 Hz, 1 H), 5.24 (s, 2 H), 4.36 (dd, J ) 15.0, 4.0 Hz, 1 H),
4.19 (dd, J ) 15.0, 6.0 Hz, 1 H), 3.92 (s, 3 H), 3.72 (s, 3 H),
1
g of a pale yellow solid: mp 83.7-84.2 °C; IR 1724 cm-1; H
NMR δ 8.07 (d, J ) 1.1 Hz, 1H), 7.76 (d, J ) 1.1 Hz, 1 H),
7.47-7.32 (m, 5 H), 5.17 (s, 2 H), 3.93 (s, 3 H), 2.45 (s, 3 H);
13C NMR δ 165.1, 157.5, 150.9, 135.6, 129.0, 128.7, 128.4,
127.5, 127.3, 117.3, 115.1, 71.1, 52.6, 12.3; LRMS (CI) m/ z
(M + H)+ ) 302.20. Anal. Calcd for C16H15NO5: C, 63.78; H,
5.02; N, 4.65. Found: C, 63.56; H, 5.01; N, 4.62. A second
crop provided 5.74 g. The mother liquor was concentrated and
purified by flash chromatography (4% EtOAc/hexanes) followed
by recrystallization to afford an additional material (1.86 g;
90% combined yield).
Meth yl 4-(Ben zyloxy)-1H-in d ole-6-ca r boxyla te (12). To
a solution of nitrotoluene 11 (29.00 g, 0.0962 mol) in DMF (60.0
mL) was added freshly distilled pyrrolidine (12.0 mL, 0.144
mol) and N,N-dimethylformamide dimethyl acetal (19.0 mL
of 94% purity, 0.134 mol). The dark, red-colored reaction
mixture was heated at 110 °C for 3.5 h followed by concentra-
tion of the solution with a rotary evaporator. CH3OH (350
mL) and CH2Cl2 (15 mL) were added to the residue, and the
solution was stored at 6 °C for 12 h. The garnet-colored
precipitate was filtered, carefully washed with cold CH3OH,
and freed of solvent under high vacuum. A 10:1 mixture of
pyrrolidino styrene and N,N-dimethylamino styrene was
obtained (23.24 g, 64%): 1H NMR (pyrrolidino styrene) δ 8.08
(d, J ) 13.2 Hz, 1 H), 7.97 (d, J ) 1.6 Hz, 1 H), 7.56 (d, J )
1.6 Hz, 1 H), 7.50-7.35 (m, 5 H), 5.44 (d, J ) 13.2 Hz, 1 H),
5.16 (s, 2 H), 3.88 (s, 3 H), 3.18-3.14 (m, 4 H), 1.90-1.85 (m,
4 H).
Raney nickel (1 mL of 50% slurry in pH 9.0 water) was
added to a 1:1 THF/CH3OH (300 mL) solution of nitrostyrenes
(21.50 g, 0.0566 mol) at room temperature. Hydrazine hydrate
(5 mL, 55%) was added dropwise as the exothermic reaction
mixture, accompanied by vigorous evolution of gas, was stirred.
When the evolution of gas subsided (1.3 h), an additional 5
mL of hydrazine hydrate was added, and the reaction mixture
was warmed to 43 °C. Over the next 3 h two additional
portions of hydrazine hydrate (4 mL, 1 mL) were added, and
the reaction mixture was stirred until gas evolution ceased.
The Raney nickel was filtered on a pad of Celite and washed
with CH2Cl2. The filtrate was worked up. Flash chromatog-
raphy of the residue (30% EtOAc/hexanes) afforded indole 12
as a white solid (14.06 g, 88%): mp 165.0-166.8 °C (THF,
hexanes); IR 3479, 1709 cm-1; 1H NMR δ 8.42 (br s, 1 H), 7.84
(s, 1 H), 7.52 (d, J ) 7.03 Hz, 2 H), 7.45-7.24 (m, 5 H), 6.75
(br s, 1 H), 5.26 (s, 2 H), 3.92 (s, 3 H); 13C NMR (CD2Cl2, δ )
53.80) 168.2, 152.2, 137.6, 136.7, 128.8, 128.2, 127.9, 126.5,
125.0, 122.9, 108.0, 101.5, 100.5, 70.3, 52.2; LRMS (CI) m/ z
(M + H)+ ) 282.20. Anal. Calcd for C17H15NO3: C, 72.58; H,
5.37; N, 4.98. Found: C, 72.77; H, 5.42; N, 4.99.
3.22-3.17 (m, 1 H), 2.86 (d, J ) 2.3 Hz, 1 H), 1.34 (s, 9 H); 13
C
NMR δ 167.9, 167.5, 157.6, 152.0, 137.0, 136.7, 129.5, 128.4,
127.8, 127.4, 124.4, 123.2, 105.7, 101.4, 100.2, 82.2, 69.9, 52.6,
51.9, 46.7, 41.9, 38.9, 27.6; LRMS (CI) m/ z (M + H)+ ) 495.30.
Anal. Calcd for C27H30N2O7: C, 65.58; H, 6.11; N, 5.66.
Found: C, 65.67; H, 6.15; N, 5.57.
(2R,3S)-1-(ter t-Bu tyloxyca r bon yl)-3-[1-[4-(ben zyloxy)-
6-(m eth oxyca r bon yl)-1H-in d olyl]m eth yl]a zir id in e-2-ca r -
boxylic Acid (15b). Ester 15a (503.7 mg, 1.018 mmol) was
saponified as previously reported (ester 5a 29) except that the
basic aqueous solution was not washed with CH2Cl2 to avoid
formation of an emulsion. The acid was obtained as a white
solid (412.0 mg, 84%): mp 155.5-158.0 °C dec (EtOAc/
hexanes); [R]27D ) +22.6 (c, 0.860, CHCl3); IR 2745-3413 (br),
1733, 1713 cm-1; 1H NMR δ 7.79 (s, 1 H), 7.50 (d, J ) 7.5 Hz,
2 H), 7.42-7.26 (m, 4 H), 7.23 (d, J ) 3.1 Hz, 1 H), 6.70 (d, J
) 3.1 Hz, 1 H), 5.24 (s, 2 H), 4.39 (dd, J ) 15.0, 4.0 Hz, 1 H),
4.24 (dd, J ) 15.0, 5.8 Hz, 1 H), 3.91 (s, 3 H), 3.20-3.16 (m, 1
H), 2.86 (d, J ) 2.5 Hz, 1 H), 1.33 (s, 9 H); 13C NMR δ 171.8,
168.1, 157.7, 152.1, 137.1, 136.8, 129.5, 128.5, 127.9, 127.4,
124.5, 123.4, 105.9, 101.7, 100.4, 82.8, 70.1, 52.1, 46.7, 42.6,
38.6, 27.7; LRMS (CI) m/ z (M + H)+ ) 481.40. Anal. Calcd
for C26H28N2O7: C, 64.99; H, 5.87; N, 5.83. Found: C, 64.90;
H, 5.89; N, 5.76.
(2R,3S)- a n d (2S,3S)-1-(ter t-Bu tyloxyca r bon yl)-3-[1-[4-
(ben zyloxy)-6-(m eth oxyca r bon yl)-1H-in d olyl]m eth yl]-2-
br om oa zir id in e (16a ; 16b). The decarboxylative bromina-
tion of acid 15b (690.0 mg, 1.436 mmol) was conducted
according to the procedure described (acid 5b29). Without
removing the CBrCl3, the reaction mixture was submitted to
flash chromatography (5-10% EtOAc/hexanes) to afford a
mixture of cis-bromoaziridine 16a and trans-bromoaziridine
16b (16a /16b ) 3.3). An additional flash chromatography
(CHCl3) removed 2,2′-dipyridyl disulfide along with partial
separation of the two diastereomers (390.0 mg, 53% combined
yield). 16a (white solid): mp 83.0-86.0 °C (ether/hexanes);
[R]22
D ) +29.4 (c, 0.850, CHCl3); IR 1732, 1710 cm-1; 1H NMR
δ 7.88 (s, 1 H), 7.50 (d, J ) 7.8 Hz, 2 H), 7.42-7.31 (m, 5 H),
6.72 (d, J ) 3.3 Hz, 1 H), 5.26 (s, 2 H), 4.67 (d, J ) 5.3 Hz, 1
H), 4.47 (dd, J ) 15.1, 5.3 Hz, 1 H), 4.39 (dd, J ) 15.1, 5.9 Hz,
1 H), 3.93 (s, 3 H), 2.86-2.80 (m, 1 H), 1.36 (s, 9 H); 13C NMR
δ 167.9, 158.2, 152.1, 137.1, 136.8, 129.5, 128.5, 127.8, 127.4,
124.5, 123.5, 105.9, 101.7, 100.4, 83.3, 70.1, 51.9, 46.4, 41.2,
40.4, 27.6; LRMS (EI) m/ z (M)+ ) 514.45, 516.45. Anal. Calcd
for C25H27N2O5Br: C, 58.26; H, 5.28; N, 5.44. Found: C, 58.34;
H, 5.33; N, 5.39. 16b (colorless oil): IR 1712 (br) cm-1; 1H NMR
δ 7.77 (s, 1 H), 7.50 (d, J ) 7.9 Hz, 2 H), 7.42-7.30 (m, 4 H),
7.18 (d, J ) 3.5 Hz, 1 H), 6.70 (d, J ) 3.5 Hz, 1 H), 5.25 (s, 2
H), 4.34 (app d, J ) 4.8 Hz, 2 H), 4.04 (d, J ) 1.7 Hz, 1 H),
3.93 (s, 3 H), 3.05 (app td, J ) 4.8, 1.7 Hz, 1 H), 1.42 (s, 9 H);
13C NMR δ 167.9, 156.4, 152.2, 137.1, 136.9, 129.5, 128.5,
127.9, 127.5, 124.8, 123.4, 105.6, 101.8, 100.5, 83.4, 70.1, 52.0,
46.1, 44.1, 36.8, 27.9; HRMS (EI) calcd for M+ C25H27N2O5Br:
514.1103, found 514.1097.
Meth yl 4-(Ben zyloxy)-3-for m yl-1H-in d ole-6-ca r boxy-
la te (13). POCl3 (6.00 mL, 64.4 mmol) was added dropwise
to stirred DMF (50 mL, 0 °C). After the addition was complete,
the mixture was stirred for an additional 45 min. To the
vigorously stirred solution was cannulated a THF (300 mL)
solution of indole 12 (14.79 g, 52.57 mmol) over 7 min. The
reaction mixture attained a yellow color, and within minutes
a heavy precipitate formed. The cooling bath was removed,
and the reaction mixture was stirred for 3 h at room temper-
ature. Addition of water dissolved the precipitate. After 5 h
of stirring, the solution was diluted with EtOAc and washed
with water (3×), 1% NaHCO3 solution, and brine and then
worked up. Recrystallization of the crude material from THF/
ether afforded a pale yellow solid (15.01 g, 92%): mp 221.4-
1
222.0 °C; IR 3455, 1713, 1662 cm-1; H NMR (DMSO-d6, δ )
Met h yl (1a S,8b R)-1,1a ,2,8,8a ,8b -H exa h yd r o-7-(b en -
zyloxy)-1-(ter t-bu tyloxyca r bon yl)a zir in o[2′,3′:3,4]p yr r o-
lo[1,2-a ]in d ole-5-ca r b oxyla t e (17) a n d (2S)-1-(ter t-Bu -
t y lo x y c a r b o n y l)-2-[1-[4-(b e n zy lo x y )-6-(m e t h o x y c a r -
2.47) 12.57 (br s, 1 H), 10.30 (s, 1 H), 8.25 (s, 1 H), 7.79 (s, 1
H), 7.54 (d, J ) 7.7 Hz, 2 H), 7.43-7.32 (m, 4 H), 5.30 (s, 2 H),
3.84 (s, 3 H); 13C NMR (DMSO-d6, δ ) 39.5) 186.0, 166.5, 152.4,

Chiral Aziridinyl Radicals
J . Org. Chem., Vol. 62, No. 4, 1997 1091
bon yl)1H-in d olyl]m eth yl]a zir id in e (16c). A toluene (6.7
mL) solution of 1,1′-azo(biscyclohexylcarbonitrile) (ACCN)
(37.2 mg, 0.152 mmol) and n-Bu3SnH (272 µL, 0.981 mmol)
was added dropwise to a refluxing toluene (23.0 mL) solution
of bromoaziridines 16a and 16b (390.0 mg, 0.757 mmol) over
30 min. The reaction mixture was heated for 2.25 h, cooled
to room temperature and directly submitted to flash chroma-
tography (0-20% EtOAc/hexanes) to give a mixture (4:1) of
tetracycle 17 and reduced, uncyclized aziridine 16c (188.7 mg,
57% combined yield). The two compounds were separated by
flash chromatography (CH2Cl2). 16c (white foam): IR 1711
d6, δ ) 2.49) 13.52 (br s, 1 H), 10.31 (s, 1 H), 8.34 (s, 1 H), 8.00
(s, 1 H), 7.54 (d, J ) 7.0 Hz, 2 H), 7.44-7.32 (m, 4 H), 5.35 (s,
2 H), 4.74 (dd, J ) 14.7, 3.2 Hz, 1 H), 4.26 (dd, J ) 14.7, 7.5
Hz, 1 H), 3.87 (s, 3 H), 3.12-3.06 (m, 2 H), 1.19 (s, 9 H); 13C
NMR* (DMSO-d6, δ ) 39.5) 185.7, 168.4, 166.5, 157.5, 152.4,
137.4, 136.7, 135.3, 128.5, 128.0, 127.6, 124.9, 119.8, 117.5,
107.5, 103.8, 80.9, 69.9, 52.2, 47.2, 41.3, 27.3; HRMS (FAB)
calcd for (M + H)+ C27H29N2O8: 509.1924, found 509.1925.
(2R,3S)- a n d (2S,3S)-1-(ter t-Bu tyloxyca r bon yl)-3-[1-[4-
(b en zyloxy)-3-for m yl-6-(m et h oxyca r b on yl)-1H -in d olyl-
]m eth yl]-2-br om oa zir id in e (19a ; 19b). Decarboxylative
bromination of thiohydroxamate 18c (1.10 g, 2.16 mmol) was
conducted as described except that the thiohydroxamic acid
anhydride formation was conducted for 3.5 h.29 Without
removing the CBrCl3, the reaction mixture was submitted to
flash chromatography (10-30% EtOAC/hexanes) to afford a
mixture of bromoaziridines 19a and 19b (3.8:1.0, 853.7 mg,
73%). An additional flash chromatography of the mixture (4%
EtOAc/CHCl3) effected the partial separation of the two
diastereomers wherein early and late fractions afforded pure
1
(br) cm-1; H NMR δ 7.81 (s, 1 H), 7.51 (d, J ) 7.0 Hz, 2 H),
7.42-7.29 (m, 5 H), 6.70 (d, J ) 3.3 Hz, 1 H), 5.25 (s, 2 H),
4.34 (dd, J ) 14.8, 4.1 Hz, 1 H), 4.13 (dd, J ) 14.8, 6.4 Hz, 1
H), 3.92 (s, 3 H), 2.78-2.74 (m, 1 H), 2.34 (d, J ) 6.2 Hz, 1 H,
CH2NBOC), 2.00 (d, J ) 3.6 Hz, 1 H, CH2NBOC), 1.36 (s, 9
H); 13C NMR δ 168.0, 161.5, 152.1, 137.2, 136.9, 129.7, 128.5,
127.8, 127.4, 124.3, 123.4, 106.0, 101.5, 99.9, 81.6, 70.1, 51.9,
48.2, 36.4, 29.8, 27.7; LRMS (EI) m/ z M+ ) 436.40; HRMS
(EI) calcd for M+ C25H28N2O5: 436.1998, found 436.1995. 17
(white foam): [R]24 ) +67.8 (c, 0.545, CHCl3); IR 1713 cm-1
;
material. 19a (white foam): [R]23 ) +9.8 (c, 1.63, CHCl3);
D
D
1H NMR δ 7.46-7.30 (m, 5 H), 7.07 (d, J ) 0.8 Hz, 1 H), 6.81
(d, J ) 0.8 Hz, 1 H), 5.12 (d, J ) 11.9 Hz, 1 H), 5.07 (d, J )
11.9 Hz, 1 H), 4.20 (ddd, J ) 10.3, 4.7, 1.5 Hz, 1 H,
CH2NCHCH2), 3.86 (s, 3 H), 3.60 (d, J ) 12.4 Hz, 1 H), 3.38-
3.30 (m, 2 H), 3.19-3.10 (m, 3 H), 1.37 (s, 9 H); 13C NMR δ
167.4, 161.1, 155.5, 154.5, 137.1, 131.0, 128.4, 127.8, 127.3,
122.9, 105.4, 104.4, 81.2, 69.9, 64.5, 52.6, 51.9, 45.5, 43.3, 28.5,
27.9; HRMS (EI) calcd for M+ C25H28N2O5: 436.1998, found
436.1991.
IR 1733, 1714 cm-1; H NMR δ 10.45 (s, 1 H), 8.13 (s, 1 H),
1
7.91 (s, 1 H), 7.50 (s, 1 H), 7.47 (dd, J ) 8.0, 1.2 Hz, 2 H),
7.45-7.33 (m, 3 H), 5.28 (s, 2 H), 4.70 (d, J ) 4.9 Hz, 1 H),
4.53 (dd, J ) 14.9, 4.9 Hz, 1 H), 4.38 (dd, J ) 14.9, 6.7 Hz, 1
H), 3.94 (s, 3 H), 2.90-2.84 (m, 1 H), 1.32 (s, 9 H); 13C NMR δ
187.4, 167.1, 157.8, 153.2, 137.5, 136.1, 133.6, 128.7, 128.2,
127.6, 125.9, 120.5, 119.0, 106.5, 104.2, 83.7, 70.6, 52.3, 47.3,
40.7, 39.8, 27.6; LRMS (CI) m/ z (M + H)+ ) 543.25, 545.25.
Anal. Calcd for C26H27N2O6Br: C, 57.47; H, 5.01; N, 5.16.
Found: C, 57.58; H, 5.04; N, 5.12. 19b: mp 114.8-116.8 °C
Meth yl (2R,3S)-1-(ter t-Bu tyloxyca r bon yl)-3-[1-[4-(ben -
zyloxy)-3-for m yl-6-(m eth oxyca r bon yl)-1H-in d olyl]m eth -
yl]a zir id in e-2-ca r boxyla te (18a ). To a DMF (38.0 mL)
solution of indole 13 (1.96 g, 6.34 mmol) was added dropwise
NaN(TMS)2 (6.41 mL of 1.0 M/THF, 6.41 mmol), and then the
reaction mixture was stirred for 1.5 h at room temperature.
Meanwhile, freshly distilled trifluoromethanesulfonic acid
anhydride (1.25 mL, 7.43 mmol) was added dropwise over a
few minutes to a cooled (-30 °C) CH2Cl2 (22.0 mL) solution of
aziridinol 14a (1.555 g, 6.721 mmol) and pyridine (0.60 mL,
7.41 mmol). The reaction mixture was stirred for 50 min at
-30 °C, and the cold bath was removed. The reaction mixture
was partitioned between CH2Cl2 and water (150 mL each), and
the organic phase was thoroughly dried over MgSO4 (7 min),
filtered, and evaporated in vacuo (room temperature). The
crude triflate was dissolved in CH2Cl2 (26.0 mL), cooled to -30
°C, and cannulated into the indole anion solution that had been
cooled to -30 °C. The reaction mixture was stirred for 1 h
and quenched with saturated NH4Cl solution. The mixture
was diluted with EtOAc (200 mL) and washed with water (50
mL, 6×) to remove the DMF. The aqueous phase was back-
extracted with EtOAc (50 mL), and the combined organic
extracts were washed with brine and worked up. Flash
chromatography of the crude solid (preabsorbed on SiO2; 2%
CH3OH/CHCl3) afforded recovered indole 13 (278.0 mg, 14%)
and impure alkylated indole which was resubmitted to flash
chromatography (30-40% EtOAc/hexanes) to afford ester 18a
(CH2Cl2/hexanes); IR (CDCl3) 1727, 1717 cm-1 1H NMR δ
;
10.44 (s, 1 H), 7.96 (s, 1 H), 7.82 (s, 1 H), 7.51 (s, 1 H), 7.49-
7.34 (m, 6 H), 5.29 (s, 1 H), 4.49 (dd, J ) 15.0, 3.7 Hz, 1 H),
4.29 (dd, J ) 15.0, 5.9 Hz, 1 H), 4.05 (d, J ) 1.8 Hz, 1 H), 3.96
(s, 3 H), 3.09-3.05 (m, 1 H), 1.39 (s, 9 H); 13C NMR δ 187.4,
167.1, 156.0, 153.2, 137.4, 136.1, 133.7, 128.7, 128.2, 127.6,
126.1, 120.4, 118.9, 106.2, 104.2, 83.7, 70.6, 52.3, 47.0, 43.2,
36.3, 27.8; HRMS (EI) calcd for (M)+ C26H27N2O6Br: 542.1052,
found 542.1051.
Meth yl (1aS,8R,8aS,8bR)- an d Meth yl (1aS,8R,8aR,8bR)-
1,1a ,2,8,8a ,8b -H e xa h y d r o-7-(b e n zylo xy)-8-(h y d r o x y -
m eth yl)-1-(ter t-bu tyloxyca r bon yl)a zir in o[2′,3′:3,4]p yr r o-
lo[1,2-a ]in d ole-5-ca r b oxyla t e (21b ; 22b ), a n d Met h yl
(3aS,10bS)-2,3,3a,10b- Tetr ah ydr o-9-(ben zyloxy)-10-[[(ter t-
b u t yld im et h ylsilyl)oxy]m et h yl]-2-oxo-4H -oxa zolo[3′,4′:
5,4]p yr r olo[1,2-a ]in d ole-7-ca r boxyla te (23). Sodium boro-
hydride (98.0 mg, 2.59 mmol) was added to a MeOH solution
(18.0 mL, 0 °C) of bromoaziridines 19a and 19b (4:1, 1.023 g,
2.193 mmol). The reaction mixture was stirred for 15 min,
quenched with acetone, and partitioned between EtOAc (50
mL) and water (20 mL) containing 2 mL of saturated NH4Cl
solution. The organic phase was washed with water, and the
combined aqueous phase was back extracted with EtOAc. The
combined organic extracts were then washed with brine and
worked up: 1H NMR (major isomer) δ 7.88 (s, 1 H), 7.50-
7.38 (m, 5H), 7.36 (s, 1 H), 7.30 (s, 1 H), 5.27 (s, 2 H), 4.74 (br
s, 2 H), 4.66 (d, J ) 5.3 Hz, 1 H, CHBr), 4.44-4.32 (m, 2 H,
NCH2), 3.94 (s, 3 H), 2.86-2.80 (m, 2 H, CH2CH, OH), 1.37 (s,
9 H).
Imidazole (178.7 mg, 2.625 mmol) and TBDMSCl (363.0 mg,
2.336 mmol) were added to a CH2Cl2 (18 mL) solution of the
crude indole methanols 20a . The reaction mixture was stirred
for 40 min, the white suspension was filtered, and the filtrate
was diluted with CH2Cl2 and washed with water. The organic
phase was dried over Na2SO4, filtered, and evaporated in
vacuo.
To a toluene (42.0 mL) solution of the crude silyloxy ethers
20b and ACCN (98.0 mg, 0.401 mmol) was added 1 mL of a
toluene (6 mL) solution of n-Bu3SnH (640 µL, 2.37 mmol). The
silyloxy ether solution was heated in an oil bath (116 °C), and
the rest of the n-Bu3SnH solution was added via a syringe
pump over 65 min. The reaction mixture was heated for an
additional 1 h, cooled to room temperature, and submitted to
flash chromatography (0-10% EtOAc/hexanes) to give an
impure silyloxy ethers 21a . Further elution with ether fol-
as a white solid (2.20 g, 66%): mp 118.0-119.5 °C (ether);
1
[R]25 ) +27.4 (c, 2.00, CHCl3); IR 1746, 1727 cm-1; H NMR
D
δ 10.42 (s, 1 H), 8.02 (s, 1 H), 7.81 (s, 1 H), 7.48-7.31 (m, 6
H), 5.26 (d, 2 H), 4.47 (dd, J ) 14.9, 3.6 Hz, 1 H), 4.15 (dd, J
) 14.9, 6.6 Hz, 1 H), 3.92 (s, 3 H), 3.72 (s, 3 H), 3.23-3.18 (m,
1 H), 2.89 (d, J ) 2.7 Hz, 1 H), 1.32 (s, 9 H); 13C NMR δ 187.4,
167.2, 167.1, 157.2, 153.1, 137.5, 136.1, 133.6, 128.7, 128.2,
127.6, 125.9, 120.4, 118.9, 106.4, 104.2, 82.6, 70.5, 52.8, 52.2,
47.6, 41.2, 38.8, 27.6; LRMS (CI) m/ z (M + H)+ ) 523.25. Anal.
Calcd for C28H30N2O8: C, 64.36; H, 5.79; N, 5.36. Found: C,
64.42; H, 5.84; N, 5.43.
(2R,3S)-1-(ter t-Bu tyloxyca r bon yl)-3-[1-[4-(ben zyloxy)-
3-for m yl-6-(m eth oxyca r bon yl)-1H-in d olyl]m eth yl]a zir i-
d in e-2-ca r boxylic Acid (18b). Ester 18a (6.38 g, 12.2 mmol)
was saponified as described except that less LiOH (0.536 g,
22.0 mmol) was used, and the basic aqueous solution was not
washed with CH2Cl2 to avoid formation of emulsion.29 Acid
18b was obtained as a white solid (5.94 g, 96%): mp 194-195
°C dec (EtOAc/ hexanes); IR 1729, 1716 cm-1; 1H NMR (DMSO-

1092 J . Org. Chem., Vol. 62, No. 4, 1997
Ziegler and Belema
lowed by EtOAc gave a yellow solid, which upon trituration
with ether, afforded oxazolidone 23 as a white solid (25.4 mg,
2.2%): mp 279.0-280.5 °C dec (CH2Cl2/ether); [R]26D ) +138.8
(c, 0.640, CHCl3); IR 3461, 3251 (br), 1757, 1710 cm-1; 1H NMR
δ 7.60 (d, J ) 0.9 Hz, 1 H), 7.47 (d, J ) 8.1 Hz, 2 H), 7.41-
7.32 (m, 3 H), 7.22 (d, J ) 0.9 Hz, 1 H), 6.40 (br s, 1 H,
exchangeable), 6.13 (d, J ) 7.9 Hz, 1 H, CHOCONH), 5.30-
5.05 (m, 5 H), 4.24 (dd, J ) 11.0, 5.9 Hz, 1 H), 4.17 (dd, J )
11.0, 2.4 Hz, 1 H), 3.90 (s, 3 H), 0.91 (s, 9 H), 0.11 (s, 3 H),
0.09 (s, 3 H); 13C NMR δ 167.6, 159.1, 153.5, 137.5, 136.8,
133.0, 128.5, 127.9, 127.3, 125.2, 124.0, 113.0, 106.7, 101.3,
75.8, 70.1, 59.5, 58.8, 52.0, 51.2, 26.1, 18.6, -5.4, -5.7; HRMS
(FAB) calcd for (M - H)+ C28H33N2O6Si: 521.2104, found
521.2108. Anal. Calcd for C28H34N2O6Si: C, 64.34; H, 6.56;
N, 5.36. Found: C, 64.41; H, 6.52; N, 5.40.
with CH2Cl2, and washed with 3% NH4Cl. The organic layer
was dried over Na2SO4, and the solvent was removed in vacuo.
The residue was passed through a small amount of SiO2 to
remove any trace of baseline material and then purified by
radial chromatography (CHCl3 for loading sample; 35% EtOAc/
hexanes) to afford aldol 27a as a white foam (324.0 mg, 86%):
[R]25D ) +66.5 (c, 0.480, CHCl3); IR 3565, 1715 cm-1; 1H NMR
δ 10.11 (d, J ) 1.0 Hz, 1 H), 7.39-7.29 (m, 5 H), 7.11 (s, 1 H),
6.89 (s, 1 H), 5.10 (d, J ) 12.1 Hz, 1 H), 5.05 (d, J ) 12.1 Hz,
1 H), 4.41 (dd, J ) 11.4, 4.2 Hz, 1 H, CH2OH), 4.37 (d, J ) 1.9
Hz, 1 H, CH2NCH), 3.87 (s, 3 H), 3.68 (d, J ) 12.5 Hz, 1 H),
3.56 (app td, J ) 10.4, 1.0 Hz, 1 H, CH2OH), 3.31 (dd, J )
12.5, 1.7 Hz, 1 H), 3.26 (dd, J ) 4.7, 1.7 Hz, 1 H), 3.05 (dd, J
) 4.7, 1.9 Hz, 1 H, CHCHN-BOC), 2.77 (dd, J ) 9.8, 4.2 Hz,
1 H, OH), 1.36 (s, 9 H); 13C NMR δ 203.9, 166.8, 160.1, 157.7,
155.1, 136.0, 133.4, 128.6, 128.0, 127.0, 118.8, 104.9, 104.7,
81.9, 70.9, 70.0, 64.4, 61.3, 52.2, 51.7, 42.9, 42.4, 27.7; LRMS
(CI) m/ z (M)+ ) 495.15. Anal. Calcd for C27H30N2O7: C,
65.58; H, 6.11; N, 5.66. Found: C, 65.49; H, 6.14; N, 5.61.
Meth yl (1a S,8R,8a S,8bR)-1,1a ,2,8,8a ,8b-Hexa h yd r o-7-
(b en zyloxy)-8-[[(ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-1-
(ter t-bu tyloxyca r bon yl)-8-for m yla zir in o[2′,3′:3,4]p yr r o-
To a THF (12.0 mL) solution of crude silyl ether 21a 75 was
added tetra-n-butylammonium fluoride (TBAF, 1.3 mL of 1.0
M/THF). The mixture was stirred 12 h and then poured into
a mixture of EtOAc (80 mL), H2O (40 mL), and saturated
NH4Cl (20 mL). The organic layer was washed with brine and
worked up. Flash chromatography (30-50% EtOAc/hexanes)
afforded diastereomeric alcohols 22b (∼5%)39 and 21b (450 mg,
51% for four steps). Additional flash chromatography of 22b
(Florisil; CH2Cl2 prep; 20-30% EtOAc/hexanes) afforded a
white foam: [R]27D ) -47.5 (c, 1.05, CHCl3); IR 3512 (br), 1713
lo[1,2-a ]in d ole-5-ca r b oxyla t e
(27c)
a n d
Met h yl
(1aS,8R,8aS,8bR)-1,1a,2,8,8a,8b-Hexah ydr o-7-(ben zyloxy)-
8-[[[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]oxy]m eth yl]-1-
(ter t-bu tyloxyca r bon yl)-8-for m yla zir in o[2′,3′:3,4]p yr r o-
lo[1,2-a ]in d ole-5-ca r boxyla te (27d ). Imidazole (92.6 mg,
1.36 mmol), TBDMSCl (206.3 mg, 1.369 mmol), and DMAP
(19.4 mg, 0.159 mmol) were added to a CH2Cl2 (5.2 mL)
solution of crude (prior to chromatography) aldol 27a that was
prepared from alcohol 21b (175.9 mg, 0.3770 mmol) by the
procedure described above. The reaction mixture was stirred
for 3 h, filtered, and concentrated. The residue was submitted
to flash chromatography (7-15% EtOAc/hexanes) to obtain
silyl ethers 27c (white foam; 158.6 mg, 69%) and 27d (white
1
cm-1; H NMR δ 7.41-7.32 (m, 5 H), 7.19 (s, 1 H), 6.99 (s, 1
H), 5.12 (d, J ) 11.2 Hz, 1 H), 5.06 (d, J ) 11.2 Hz, 1 H), 4.00-
3.58 (m, 5 H), 3.87 (s, 3 H), 3.30-3.17 (m, 3 H), 2.71 (dd, J )
7.6, 4.2 Hz, 1 H), 1.44 (s, 9 H); 13C NMR δ 166.8, 160.1, 156.7,
154.8, 135.9, 132.3, 128.7, 128.4, 127.7, 124.4, 108.5, 106.3,
81.7, 70.6, 70.3, 64.8, 55.2, 52.1, 48.1, 47.7, 45.3, 27.9; HRMS
(EI) calcd for (M)+ C26H30N2O6: 466.2104, found 466.2102.
21b: mp 177.3-177.7 °C (EtOAc); [R]25 ) +86.8 (c, 0.644,
D
CHCl3); IR 3504 (br), 1714 cm-1; H NMR δ 7.43-7.29 (m, 5
1
H), 7.07 (s, 1 H), 6.80 (s, 1 H), 5.09 (d, J ) 11.3 Hz, 1 H), 5.04
(d, J ) 11.3 Hz, 1 H), 4.41-4.34 (m, 1 H), 4.28 (dd, J ) 10.2,
2.0 Hz, 1 H), 4.11-4.00 (m, 1 H), 3.85 (s, 3 H), 3.85-3.77 (m,
1 H), 3.61 (d, J ) 12.4 Hz, 1 H), 3.36-3.27 (m, 3 H), 3.17 (dd,
J ) 4.7, 1.9 Hz, 1 H), 1.38 (s, 9 H); 13C NMR δ 167.1, 161.3,
155.5, 154.9, 136.3, 131.4, 128.6, 128.1, 127.7, 122.3, 104.8,
104.0, 82.0, 70.3, 67.0, 61.0, 52.0, 51.8, 44.4, 43.0, 42.5, 27.8;
LRMS (EI) m/ z (M)+ ) 466.50. Anal. Calcd for C26H30N2O6:
C, 66.94; H, 6.48; N, 6.00. Found: C, 66.83; H, 6.54; N, 5.94.
Meth yl (1a S,8R,8a S,8bR)-1,1a ,2,8,8a ,8b-Hexa h yd r o-7-
(b en zyloxy)-1-(ter t-b u t yloxyca r b on yl)-8-for m yl-8-(h y-
d r oxym eth yl)a zir in o[2′,3′:3,4]p yr r olo[1,2-a ]in d ole-5-ca r -
boxyla te (27a ). A CH2Cl2 (17.0 mL) solution of Dess-Martin
periodinane (430.0 mg, 1.014 mmol) was rapidly added to a
CH2Cl2 (10.0 mL) solution of alcohol 21b (362.0 mg, 0.7759
mmol). The reaction mixture was stirred for 45 min and
diluted with ether (150 mL), and the resulting cloudy solution
was washed with a mixture of H2O (15 mL), saturated aqueous
NaHCO3 (15 mL), and saturated aqueous Na2S2O3 (1.5 mL)
to give a clear solution. The solvent was removed in vacuo,
and the residue was used in the next reaction. For the purpose
of identification, a sample of the ether solution was worked
up to give crude aldehyde 26: 1H NMR δ 9.97 (d, J ) 3.1 Hz,
1 H), 7.40-7.30 (m, 5 H), 7.14 (s, 1 H), 6.88 (s, 1 H), 5.14 (d,
J ) 11.9 Hz, 1 H), 5.07 (d, J ) 11.9 Hz, 1 H), 4.38 (dd, J )
11.1, 1.8 Hz, 1 H, CH2NCH), 4.10 (dd, J ) 11.1, 3.1 Hz, 1 H),
3.87 (s, 3 H), 3.66 (d, J ) 12.5 Hz, 1 H), 3.31 (dd, J ) 12.5, 1.7
Hz, 1 H), 3.23 (dd, J ) 4.7, 1.7 Hz, 1 H, CH2CH) 3.13 (dd, J )
4.7, 1.8 Hz, 1 H), 1.35 (s, 9 H).
foam; 33.8 mg, 14%). 27c: [R]26 ) +90.0 (c, 0.690, CHCl3);
D
IR 1716 cm-1; H NMR δ 10.06 (s, 1 H), 7.39-7.26 (m, 5 H),
1
7.09 (s, 1 H), 6.85 (s, 1 H), 5.10 (d, J ) 11.8 Hz, 1 H), 5.04 (d,
J ) 11.8 Hz, 1 H), 4.26 (d, J ) 1.9 Hz, 1 H), 3.22 (d, J ) 9.9
Hz, 1 H), 3.94 (d, J ) 9.9 Hz, 1 H), 3.87 (s, 3 H), 3.64 (d, J )
12.4 Hz, 1 H), 3.31 (dd, J ) 12.4, 1.8 Hz, 1 H), 3.22 (dd, J )
4.6, 1.8 Hz, 1 H), 3.12 (dd, J ) 4.6, 1.9 Hz, 1 H), 1.35 (s, 9 H),
0.72 (s, 9 H), -0.08 (s, 3 H), -0.21 (s, 3 H); 13C NMR δ 200.8,
167.0, 160.4, 157.9, 155.1, 136.4, 132.8, 128.5, 127.9, 127.0,
119.8, 104.4, 104.3, 81.6, 71.3, 69.8, 63.7, 62.7, 52.1, 51.7, 43.0,
42.7, 27.7, 25.6, 18.0, -5.6, -5.8; HRMS (CI) calcd for (M)+
C33H44N2O7Si: 608.2918, found 608.2929. 27d : IR 1717 cm-1
;
1H NMR δ 10.04 (s, 1 H), 7.38-7.28 (m, 5 H), 7.12 (s, 1 H),
6.88 (s, 1 H), 5.11 (d, J ) 12.2 Hz, 1 H), 5.06 (d, J ) 12.2 Hz,
1 H), 4.80 (d, J ) 5.2 Hz, 1 H), 4.76 (d, J ) 5.2 Hz, 1 H), 4.23
(d, J ) 1.8 Hz, 1 H), 4.12 (d, J ) 9.8 Hz, 1 H), 4.02 (d, J ) 9.8
Hz, 1 H), 3.87 (s, 3 H), 3.66 (d, J ) 12.5 Hz, 1 H), 3.32 (dd, J
) 12.5, 1.2 Hz, 1 H), 3.23 (dd, J ) 4.2, 1.2 Hz, 1 H), 3.10 (dd,
J ) 4.2, 1.8 Hz, 1 H), 1.35 (s, 9 H), 0.80 (s, 9 H), -0.03 (s, 3
H), -0.06 (s, 3 H); 13C NMR δ 200.6, 167.0, 160.3, 157.7, 155.0,
136.3, 133.0, 128.5, 127.9, 127.0, 119.8, 104.9, 104.5, 90.4, 81.8,
71.8, 69.9, 68.5, 60.7, 52.2, 51.9, 42.9, 42.6, 27.8, 25.6, 18.0,
-5.16; HRMS (CI) calcd for (M)+ C34H46N2O8Si: 638.3023,
found 638.3031.
Meth yl (1a S,8R,8a S,8bR)-1,1a ,2,8,8a ,8b-Hexa h yd r o-7-
(ben zyloxy)-8-[(a cetyloxy)m eth yl]-1-(ter t-bu tyloxyca r bo-
n yl)-8-for m yla zir in o[2′,3′:3,4]p yr r olo[1,2- a ]in d ole-5-ca r -
boxyla te (27e). Pyridine (36 µL, 0.44 mmol), acetic anhydride
(43 µL, 0.46 mmol), and DMAP (2.0 mg, 0.016 mmol) were
added to a CH2Cl2 (2 mL) solution of alcohol 27a (110.0 mg,
0.2224 mmol). The reaction mixture was stirred for 1 h and
then partitioned between CH2Cl2 and 3% NH4Cl solution. The
organic phase was dried over Na2SO4, filtered, and evaporated
in vacuo. Flash chromatography of the residue (20-30%
EtOAc/hexanes) afforded acetate 27e as a white foam (110.0
mg, 92%): mp 128.8-129.0 °C (EtOAc/hexanes; white chunky
solid); [R]19D ) +68.0 (c, 0.550, CHCl3); IR 1720 cm-1; 1H NMR
δ 10.04 (s, 1 H), 7.37-7.25 (m, 5 H), 7.12 (s, 1 H), 6.88 (s, 1
H), 5.12 (d, J ) 11.9 Hz, 1 H), 5.07 (d, J ) 11.9 Hz, 1 H), 4.70
(d, J ) 11.2 Hz, 1 H, CH2OAc), 4.50 (d, J ) 11.2 Hz, 1 H),
4.07 (d, J ) 1.9 Hz, 1 H), 3.88 (s, 3 H), 3.67 (d, J ) 12.5 Hz,
The resulting undried, crude aldehyde 26 was dissolved in
CH2Cl2/MeOH (1:1; 16.0 mL) and treated with 37% aqueous
formaldehyde (2.2 mL, 27.1 mmol) and NaHCO3 (32.0 mg,
0.381 mmol). The reaction mixture was stirred for 2 h, diluted
(75) A sample of the silyl ether mixture was purified by radial
chromatography (CH2Cl2) to afford 21a upon which the NOE studies
were conducted: 1H NMR (500.1 MHz; C6D6, δ ) 7.19) 7.25-7.16 (m,
7H), 4.93 (dd, J ) 10.0, 4.7 Hz, 1 H, CH2O), 4.69 (dd, J ) 11.2, 10.0
Hz, 1 H, CH2O), 4.55 (d, J ) 10.8 Hz, 1 H), 4.51 (d, J ) 10.8 Hz, 1 H),
4.02 (dd, J ) 9.8, 1.8 Hz, 1 H, CH2NCH), 3.82-3.77 (m, 1 H, CHCH2O),
3.59 (s, 3 H), 3.45 (d, J ) 12.4 Hz, 1 H), 3.32 (dd, J ) 4.4, 1.8 Hz, 1 H,
NCHCHNBoc), 2.78-2.74 (m, 2 H), 1.22 (s, 9 H), 1.04 (s, 9 H), 0.20 (s,
3 H), 0.15 (s, 3 H).

Chiral Aziridinyl Radicals
J . Org. Chem., Vol. 62, No. 4, 1997 1093
1 H), 3.30 (dd, J ) 12.5, 1.8 Hz, 1 H), 3.24 (dd, J ) 4.7, 1.8, 1
H), 3.09 (dd, J ) 4.7, 1.9 Hz, 1 H), 1.90 (s, 3 H), 1.35 (s, 9 H);
13C NMR δ 199.6, 170.8, 166.8, 160.1, 157.8, 155.2, 136.1,
133.4, 128.6, 127.9, 127.0, 118.5, 104.9, 104.4, 81.9, 71.7, 70.0,
64.4, 59.7, 52.2, 51.8, 42.7, 42.2, 27.7, 20.8; LRMS (EI) m/ z
(M)+ ) 536.55. Anal. Calcd for C29H32N2O8: C, 64.91; H, 6.01;
N, 5.22. Found: C, 64.87; H, 6.01; N, 5.24.
hexanes) to give a faint yellow solid. Recrystallization from
EtOAc/hexanes gave white plates (50.0 mg, 69%) upon which
a single crystal X-ray analysis was conducted. 30a : mp
(darkens at 175 °C, tarry through 235 °C, no distinct dec pt);
1
[R]20 ) -44.9 (c, 0.356, CHCl3); IR 3289 (br), 1720 cm-1; H
D
NMR δ 9.84 (s, 1 H), 7.39-7.30 (m, 6 H), 7.15 (d, J ) 1.2 Hz,
1 H), 6.35 (s, 1 H, OH), 5.50 (d, J ) 12.8 Hz, 1 H), 5.17 (s, 2
H), 4.48 (d, J ) 12.8 Hz, 1 H), 3.90 (s, 3 H), 3.89 (dd, J ) 14.6,
2.1 Hz, 1 H), 3.76 (d, J ) 14.6 Hz, 1 H), 2.98 (d, J ) 6.8 Hz, 1
H), 2.75 (dd, J ) 6.8, 2.1 Hz, 1 H), 1.91 (s, 3 H), 1.32 (s, 9 H);
13C NMR δ 198.8, 174.4, 166.3, 159.8, 155.4, 150.0, 135.2,
131.1, 128.7, 128.4, 127.5, 116.7, 113.1, 107.3, 93.3, 82.6, 70.9,
61.1, 58.0, 52.4, 52.0, 42.5, 32.0, 27.7, 21.1.
Meth yl (1a S,8R,8a S,8b S)-1,1a ,2,8,8a ,8b-Hexa h yd r o-8-
[(a cet yloxy)m et h yl]-7-(b en zyloxy)-1-(ter t-b u t yloxyca r -
b on yl)-8-for m yla zir in o[2′,3′:3,4]p yr r olo[1,2- a ]in d ole-5-
ca r boxyla te 3-Oxid e (28b). To a CH2Cl2 (3.0 mL) solution
of amine 27e (148.0 mg, 0.2758 mmol) at 0 °C was added
m-chloroperbenzoic acid (m-CPBA, 96% pure, 54.5 mg, 0.303
mmol), and the reaction mixture was stirred vigorously for 1.8
h. Additional m-CPBA (2.8 mg, 0.016 mmol) was added, and
10 min later the solution was submitted directly to flash
chromatography (CH2Cl2 prep; EtOAc; 30% CH3OH/EtOAc) to
give amine oxide 28b as a white foam, containing a trace of
impurity believed to be its diastereomer (149.4 mg, 98%): IR
Meth yl (1a S,8R,8a S,8bR)-1,1a ,2,8,8a ,8b-Hexa h yd r o-7-
(ben zyloxy)-8-[[(ben zyloxyca r bon yl)oxy]m eth yl]-1-(ter t-
bu tyloxyca r bon yl)-8-for m yla zir in o[2′,3′:3,4]p yr r olo[1,2-
a ]in dole-5-car boxylate (27f). 1,1′-Carbonyldiimidazole (150.0
mg, 0.9251 mmol) was added to an CH3CN (12.0 mL) solution
of alcohol 27a (385.0 mg, 0.7785 mmol), and the reaction
mixture was stirred for 3.5 h. Benzyl alcohol (600 µL, 5.80
mmol) and DMAP (60.0 mg, 0.491 mmol) were added, and the
reaction mixture was heated at 63 °C for 3.0 h. The solvent
was removed, and the residue was submitted to flash chro-
matography (CH2Cl2 prep; 10-25% EtOAc/hexanes) to give a
pale yellow foam containing traces of an impurity (349.0 mg,
71%). This material was suitable for further experiments. A
sample of 27f was purified by radial chromatography (3%
1
1727 cm-1; H NMR δ 10.09 (s, 1 H), 7.82 (s, 1 H), 7.65 (s, 1
H), 7.40-7.30 (m, 5 H), 5.20 (s, 1 H), 5.09 (d, J ) 11.2 Hz, 1
H, CH2OAc), 4.79 (d, J ) 2.8 Hz, 1 H), 4.72 (d, J ) 13.3 Hz, 1
H), 4.47 (d, J ) 11.2 Hz, 1 H), 4.30 (dd, J ) 13.3, 2.9 Hz, 1 H),
3.90 (s, 3 H), 3.64 (dd, J ) 5.5, 2.9 Hz, 1 H), 3.55 (dd, J ) 5.5,
2.8 Hz, 1 H), 1.96 (s, 3 H), 1.32 (s, 9 H); 13C NMR* δ 196.4,
170.4, 165.0, 158.9, 155.4, 155.2, 134.9, 128.8, 128.5, 127.2,
122.8, 113.5, 111.6, 88.9, 83.1, 73.3, 70.9, 62.9, 60.1, 52.6, 42.5,
41.2, 27.6, 20.8; HRMS (FAB) calcd for (M + H)+ C29H33N2O9:
553.2186, found 553.2187.
EtOAc/CH2Cl2) for characterization purposes: [R]23 ) +36.0
D
(c, 0.540, CHCl3); IR 1742, 1720 cm-1; H NMR δ 10.02 (s, 1
1
H), 7.38-7.26 (m, 10 H), 7.10 (s, 1 H), 6.87 (s, 1 H), 5.11-5.02
(m, 4 H), 4.78 (d, J ) 10.9 Hz, 1 H), 4.58 (d, J ) 10.9 Hz, 1 H),
4.13 (d, J ) 1.9 Hz, 1 H), 3.88 (s, 3 H), 3.66 (d, J ) 12.6 Hz,
1 H), 3.29 (dd, J ) 12.6, 1.8 Hz, 1 H), 3.23 (dd, J ) 4.7, 1.8
Hz, 1 H), 3.08 (dd, J ) 4.7, 1.9 Hz, 1 H), 1.35 (s, 9 H); 13C
NMR* δ 199.2, 166.8, 160.1, 157.8, 155.3, 154.8, 136.1, 135.0,
133.6, 128.6, 128.4, 128.3, 127.9, 127.0, 117.9, 105.0, 104.5,
82.0, 71.4, 70.0, 69.7, 67.8, 59.6, 52.2, 51.7, 42.7, 42.1, 27.7;
LRMS (EI) m/ z (M)+ ) 628.60. Anal. Calcd for C35H36N2O9:
C, 66.87; H, 5.77; N, 4.46. Found: C, 66.90; H, 5.83; N, 4.40.
Meth yl (1a S,8R,8a S,8b S)-1,1a ,2,8,8a ,8b-Hexa h yd r o-7-
(ben zyloxy)-8-[[(ben zyloxyca r bon yl)oxy]m eth yl]-1-(ter t-
bu tyloxyca r bon yl)-8-for m yla zir in o[2′,3′:3,4]p yr r olo[1,2-
a ]in d ole-5-ca r boxyla te 3-Oxid e (28c). The oxidation of
amine 27f (408.0 mg, 0.6490 mmol) was conducted according
to the procedure described for amine 27e to afford slightly
impure amine oxide as a white foam (410.9 mg, ∼98%), which
Meth yl (1a S,8S,8bS)-1,1a ,2,8,8a ,8b-Hexa h yd r o-8-[(a ce-
tyloxy)m eth yl]-7-(ben zyloxy)-1-(ter t-bu tyloxyca r bon yl)-
8-for m yl-8a-h ydr oxyazir in o[2′,3′:3,4]pyr r olo[1,2-a ]in dole-
5-ca r b oxyla t e (29c) a n d Met h yl (1a R,8R,8a S,8b R)-
1,1a ,2,8,8a ,8b -H e x a h y d r o -8-[(a c e t y lo x y )m e t h y l]-7-
(b e n zyloxy)-1-(t er t -b u t yloxyca r b on yl)-8-for m yl-2-h y-
d r oxya zir in o[2′,3′:3,4]p yr r olo[1,2-a ]in d ole-5-ca r b oxy-
la te (29d ). Acetic anhydride (65 µL, 0.69 mmol) was added
to a THF (3.6 mL) solution of amine oxide 28b (112.0 mg,
0.2027 mmol) at 0 °C, and the reaction mixture was stored at
0 °C for 40 h. Water (1.0 mL) was added, and the solution
was stirred for 20 min. The reaction mixture was partitioned
between CH2Cl2 and 3% NH4Cl solution. The organic phase
was dried over Na2SO4, filtered, and evaporated in vacuo.
Flash chromatography (CH2Cl2 prep; 20-30% EtOAc/hexanes)
afforded a mixture of regioisomeric alcohols. Radial chroma-
tography of the mixture gave tert-carbinolamine 29c (66.4 mg,
59%) and sec-carbinolamine 29d (8.4 mg, 8%) containing a
was suitable for the next reaction. 28c: IR 1728 cm-1 1H
;
trace of what might be its C2 anomer. 29c: [R]21 ) -8.1 (c,
NMR δ 10.10 (s, 1 H), 7.82 (s, 1 H), 7.63 (s, 1 H), 7.36-7.32
(m, 10 H), 5.17-5.09 (m, 5 H), 4.80 (d, J ) 2.7 Hz, 1 H), 4.73
(d, J ) 13.3 Hz, 1 H), 4.61 (d, J ) 10.6 Hz, 1 H), 4.29 (dd, J )
13.3, 2.8 Hz, 1 H), 3.90 (s, 3 H), 3.63 (dd, J ) 5.4, 2.8 Hz, 1 H),
3.54 (dd, J ) 5.4, 2.7 Hz, 1 H), 1.32 (s, 9 H); 13C NMR* δ 195.6,
165.0, 158.9, 155.5, 155.3, 154.3, 135.1, 134.93, 134.86, 128.8,
128.5, 128.4, 127.2, 122.2, 113.7, 111.4, 88.2, 83.2, 72.7, 70.9,
70.0, 66.4, 59.5, 52.7, 42.1, 40.9, 27.6; HRMS (FAB) calcd for
(M + H)+ C35H37N2O10: 645.2448, found 645.2449.
D
1
0.552, CHCl3); IR 3568, 3328 (br), 1749, 1718 cm-1; H NMR
δ 9.93 (s, 1 H), 7.36-7.29 (m, 5 H), 7.15 (s, 1 H), 6.83 (s, 1 H),
5.13-5.09 (m, 3 H), 4.74 (d, J ) 11.7 Hz, 1 H), 3.94 (s, 1 H,
OH), 3.87 (s, 3 H), 3.66 (d, J ) 12.5 Hz, 1 H), 3.45 (dd, J )
12.5, 1.5 Hz, 1 H), 3.31 (dd, J ) 4.4, 1.5 Hz, 1 H), 3.17 (d, J )
4.4 Hz, 1 H), 1.78 (s, 3 H), 1.35 (s, 9 H); 13C NMR δ 199.2,
170.4, 166.8, 159.4, 155.0, 154.5, 136.1, 133.3, 128.6, 128.0,
127.2, 117.5, 105.4, 103.8, 102.4, 82.2, 70.2, 62.8, 61.6, 52.3,
50.8, 45.7, 41.2, 27.7, 20.7; LRMS (CI) m/ z (M + H)+ ) 553.65.
Anal. Calcd for C29H32N2O9: C, 63.03; H, 5.84; N, 5.07.
Found: C, 62.96; H, 5.87; N, 5.00. 29d : IR (CCl4) 3612, 1749,
Meth yl (1a S,8S,8bS)-1,1a ,2,8,8a ,8b-Hexa h yd r o-7-(ben -
zyloxy)-8-[[(b en zyloxyca r b on yl)oxy]m et h yl]-1-(ter t-b u -
tyloxycar bon yl)-8-for m yl-8a-h ydr oxyazir in o[2′,3′:3,4]pyr -
r olo[1,2-a ]in d ole-5-ca r b oxyla t e (29e) a n d Met h yl
(1aR,8R,8aS,8bR)-1,1a,2,8,8a,8b-Hexah ydr o-7-(ben zyloxy)-
8-[[(ben zyloxyca r bon yl)oxy]m eth yl]-1-(ter t-bu tyloxyca r -
b on yl)-8-for m yl-2-h yd r oxya zir in o[2′,3′:3,4]p yr r olo[1,2-
a ]in d ole-5-ca r boxyla te (29f). Acetic anhydride (210 µL, 2.23
mmol) was added to a THF (12.0 mL) solution of amine oxide
28c (410.9 mg, 0.6374 mmol) at 0 °C and was stored for 24 h
(0 °C). Water (1 mL) was added, and the mixture was stirred
for 10 min. The solution was partitioned between CH2Cl2 and
3% NH4Cl solution, and the organic phase was dried with
Na2SO4, filtered, and evaporated in vacuo. Flash chromatog-
raphy (20-30% EtOAc/hexanes; for the first 30 min, the
column was eluted by gravity to allow the hydrolysis of the
intermediate acetate on silica gel) gave a mixture of isomeric
carbinolamines 29e and 29f as a white foam (29e:29f )13:1
1
1726 cm-1; H NMR (CD2Cl2, δ ) 5.32) 10.01 (s, 1 H), 7.42-
7.33 (m, 5 H), 7.18 (s, 1 H), 7.08 (s, 1 H), 5.26 (d, J ) 3.4 Hz,
1 H, NCHOH), 5.10 (s, 2 H, OCH2Ph), 4.68 (d, J ) 11.2 Hz, 1
H), 4.48 (d, J ) 11.2 Hz, 1 H), 4.42 (d, J ) 1.9 Hz, 1 H), 3.87
(s, 3 H), 3.39 (d, J ) 4.4 Hz, 1 H), 3.25 (dd, J ) 4.4, 1.9 Hz, 1
H), 2.63 (d, J ) 3.4 Hz, 1 H, OH), 1.91 (s, 3 H), 1.37 (s, 9 H);
HRMS (CI) calcd for (M + H)+ C29H33N2O9: 553.2186, found
553.2194.
Met h yl (1a S,8R,9S,9a S)-1,1a ,2,8,9,9a -H exa h yd r o-8-
[(a cet yloxy)m et h yl]-7-(b en zyloxy)-1-(ter t-b u t yloxyca r -
b on yl)-8-for m yl-9-h yd r oxy-3,9-e p oxy-3H -a zir in o[2,3-
c][1]ben za zocin -5-ca r boxyla te (30a ). To a CH2Cl2 (3 mL)
solution of tert-carbinolamine 29c (70.0 mg, 0.127 mmol) at 0
°C was added m-CPBA (75% pure, 35.7 mg, 0.155 mmol) over
0.5 min, and the reaction mixture was stirred vigorously for
1.5 h. The resulting orange solution was submitted directly
to rapid flash chromatography (CH2Cl2 prep; 20-33% EtOAc/
1
by H NMR; 302.0 mg, 73%) which was submitted to the ring
expansion step without further purification. For the purpose

1094 J . Org. Chem., Vol. 62, No. 4, 1997
Ziegler and Belema
of characterization, the isomers were separated by radial
d im e t h y l-9,11b -e p o x y a zir in o [2,3-c]-1,3-d io x in o [4,5-
e][1]ben za zocin e-7-ca r boxyla te (33a ). To a CH2Cl2 (3 mL)
solution of triol 32 (65 mg, 0.15 mmol) was added 2,2-
dimethoxypropane (70 µL, 0.57 mmol) and p-TsOH‚H2O (2.6
mg, 0.014 mmol). The mixture was stirred for 20 min, diluted
with CH2Cl2, and washed with water. The organic layer was
dried over Na2SO4, filtered, and concentrated. Flash chroma-
tography (CH2Cl2 prep; 20-25% EtOAc/hexanes) of the residue
chromatography (10% acetone/CHCl3). 29e: IR 3566, 1752
1
cm-1; H NMR δ 9.89 (s, 1 H), 7.35-7.25 (m, 8 H), 7.16-7.14
(m, 2 H), 7.13 (s, 1 H), 6.81 (s, 1 H), 5.12 (d, J ) 11.3 Hz, 1 H),
5.09 (d, J ) 11.6 Hz, 1 H), 5.03 (d, J ) 11.6 Hz, 1 H), 4.96 (s,
2 H), 4.86 (d, J ) 11.3 Hz, 1 H), 3.89 (s, 3 H), 3.64 (d, J ) 12.5
Hz, 1 H), 3.61 (s, 1 H, OH), 3.44 (dd, J ) 12.5, 1.7 Hz, 1 H),
3.30 (dd, J ) 4.4, 1.7 Hz, 1 H), 3.16 (dd, J ) 4.4 Hz, 1 H), 1.35
(s, 9 H); 13C NMR* δ 199.0, 166.7, 159.4, 155.1, 154.5, 136.1,
134.8, 133.4, 128.6, 128.5, 128.2, 128.0, 127.2, 117.1, 105.5,
103.9, 102.3, 82.3, 70.2, 69.8, 65.2, 62.8, 52.2, 50.7, 45.8, 41.2,
afforded acetonide 33a as a colorless oil (50.0 mg, 70%): [R]19
D
) +45.7 (c, 1.224, CHCl3); IR 3235 (br), 1721cm-1; 1H NMR δ
10.11 (d, J ) 1.2 Hz, 1 H), 8.15 (s, 1 H, OH), 7.16 (d, J ) 1.4
Hz, 1 H), 7.03 (d, J ) 1.4 Hz, 1 H), 4.72 (d, J ) 12.0 Hz, 1 H),
4.09 (dd, J ) 12.0, 1.2 Hz, 1 H, CH2O), 3.96 (dd, J ) 14.7, 2.1
Hz, 1 H), 3.89 (s, 3 H), 3.79 (d, J ) 14.7 Hz, 1 H), 3.08 (d, J )
6.7 Hz, 1 H), 2.80 (dd, J ) 6.7, 2.1 Hz, 1 H), 1.58 (s, 3 H), 1.54
(s, 3 H), 1.34 (s, 9 H); 13C NMR δ 201.6, 166.9, 160.0, 154.4,
148.7, 130.5, 116.4, 111.9, 111.4, 100.8, 93.4, 83.0, 60.5, 52.5,
51.8, 50.3, 43.4, 32.3, 29.3, 27.6, 24.9; LRMS (CI) m/ z (M +
H)+ ) 477.45; HRMS (FAB) calcd for (M + H)+ C20H23N2O9:
477.1873, found 477.1876.
27.7; HRMS (FAB) calcd for (M)+ C35H36N2O10
:
644.2370,
found 644.2370. 29f: IR (CCl4) 3609, 1751, 1726 cm-1
;
1H
NMR (500 MHz; CD2Cl2, δ ) 5.30) 9.97 (s, 1 H), 7.38-7.26
(m, 10 H), 7.16 (d, J ) 0.9 Hz, 1 H), 7.09 (d, J ) 0.9 Hz, 1 H),
5.22 (d, J ) 3.5 Hz, 1 H, HOCH), 5.08 (d, J ) 11.5 Hz, 1 H),
5.05 (d, J ) 11.5 Hz, 1 H), 5.69 (d, J ) 11.5 Hz, 2 H), 4.70 (d,
J ) 10.9 Hz, 1 H), 4.60 (d, J ) 10.9 Hz, 1 H), 4.42 (d, J ) 2.1
Hz, 1 H, HOCHNCH), 3.86 (s, 3 H), 3.36 (d, J ) 4.3 Hz, 1 H),
3.21 (dd, J ) 4.3, 2.1 Hz, 1 H), 2.54 (d, J ) 3.5 Hz, 1 H, OH),
1.35 (s, 9 H); 13C NMR (125.7 MHz; CD2Cl2, δ ) 54.00)* 199.6,
166.9, 159.9, 156.3, 155.3, 155.0, 136.8, 135.8, 134.5, 129.1,
129.0, 128.6, 127.7, 118.9, 106.4, 105.3, 87.7, 82.9, 71.4, 70.7,
70.4, 68.5, 60.0, 52.8, 47.4, 41.5, 38.7; HRMS (EI) calcd for
(M)+ C35H36N2O10: 644.2370, found 644.2366.
Meth yl (1aS,8R,9S,9aS)-1,1a,2,8,9,9a-Hexah ydr o-7-(ben -
zyloxy)-8-[[(b en zyloxyca r b on yl)oxy]m et h yl]-1-(ter t-b u -
tyloxyca r bon yl)-8-for m yl-9-h yd r oxy-3,9-ep oxy-3H-a zir i-
n o[2,3-c][1]ben za zocin e-5-ca r boxyla te (30b). A mixture
of carbinolamines 29e and 29f (29e:29f ) 13:1, 145.0 mg,
0.2089 mmol) was oxidized according to the procedure de-
scribed for carbinolamine 29c. The resulting orange solution
was directly submitted to rapid flash chromatography on a
short column (CH2Cl2 prep; 25-33% EtOAc/hexanes) to give
30b as a yellow foam (112.0 mg, 81%): [R]23D ) -75.2 (c, 0.770,
CHCl3); IR 3309 (br), 1719 cm-1; 1H NMR δ 9.84 (s, 1 H), 7.38-
7.25 (m, 11 H), 7.15 (d, J ) 1.0 Hz, 1 H), 6.30 (s, 1 H, OH),
5.40 (d, J ) 12.9 Hz, 1 H), 5.15 (d, J ) 12.1 Hz, 1 H), 5.14 (s,
2 H), 5.07 (d, J ) 12.1 Hz, 1 H), 4.68 (d, J ) 12.9 Hz, 1 H),
3.90 (dd, J ) 14.6, 2.0 Hz, 1 H), 3.89 (s, 3 H), 3.78 (d, J ) 14.6
Hz, 1 H), 3.00 (d, J ) 6.8 Hz, 1 H), 2.76 (dd, J ) 6.8, 2.0 Hz,
1 H), 1.33 (s, 9 H); 13C NMR* δ 198.6, 166.2, 159.7, 157.0,
155.5, 150.0, 135.3, 134.6, 131.2, 128.7, 128.4, 128.3, 128.0,
127.5, 116.3, 113.1, 107.3, 93.3, 82.6, 71.0, 70.3, 64.9, 58.1, 52.3,
52.0, 42.5, 32.0, 27.7; HRMS (FAB) calcd for (M + H)+
C35H37N2O11: 661.1397, found 661.2406.
Meth yl (4aR,10aS,11aS,11bS)-4,4a,10,10a,11,11b-Hexah y-
d r o-11-(ter t-bu tyloxyca r bon yl)-5-h yd r oxy-2,2-d im eth yl-
9,11b-epoxyazir in o[2,3-c]-1,3-dioxin o[4,5-e][1]ben zazocin e-
7-ca r b oxyla t e (33b ). Tris(triphenylphosphine)rhodium
chloride (20.4 mg, 0.0220 mmol; stored under nitrogen but
weighed in the air) and xylene (1.7 mL, reagent grade, used
as received) were added to aldehyde 33a (5.1 mg, 0.011 mmol).
The heterogeneous mixture was purged with N2 for 3 min and
lowered into a preheated oil-bath (130 °C). After heating
began, the mixture became homogeneous, and within a few
minutes a precipitate appeared. The dark-red heterogeneous
reaction mixture was heated for 3.75 h and cooled, and the
solvent was removed in vacuo. Flash chromatography of the
residue (0-10% EtOAc/hexanes) afforded the decarbonylated
product 33b containing Ph3P-derived impurities. An ad-
ditional flash chromatography (CH2Cl2 prep; 15-25% EtOAc/
hexanes) gave pure 33b as a colorless oil film (3.7 mg, 77%):
1
IR 3295 (br), 1717 cm-1; H NMR δ 7.04 (d, J ) 1.2 Hz, 1 H,
C6-H), 6.97 (d, J ) 1.2 Hz, 1 H), 6.23 (br s, 1 H, OH), 4.43 (dd,
J ) 11.7, 6.0 Hz, 1 H, CH2O(C13-Heq)), 3.89-3.81 (m, 2 H),
3.85 (s, 3 H), 3.65 (d, J ) 14.6 Hz, 1 H, NCH2), 3.46 (dd, J )
11.1, 6.0 Hz, 1 H, CHCH2O), 3.07 (d, J ) 6.6 Hz, 1 H), 2.70
(dd, J ) 6.6, 1.8 Hz, 1 H), 1.58 (s, 3 H), 1.50 (s, 3 H), 1.33 (s,
9 H); 13C NMR (125.7 MHz) δ 166.7, 160.7, 154.0, 149.0, 129.2,
118.4, 112.1, 110.7, 100.1, 92.5, 82.1, 58.8, 52.3, 52.2, 44.4, 33.5,
32.3, 30.2, 27.8, 24.4; HRMS (FAB) calcd for (M + H)+
C22H29N2O8: 449.1924, found 449.1925.
Meth yl (1aS,8R,9S,9aS)-1,1a,2,8,9,9a-Hexah ydr o-1-(ter t-
b u t yloxyca r b on yl)-8-for m yl-7,9-d ih yd r oxy-8-(h yd r oxy-
m eth yl)-3,9-epoxy-3 H-azir in o[2,3-c][1]ben zazocin e-5-car -
boxyla te (32). A mixture of HOAc (60 µL), 10% Pd/C (43.8
mg), and benzyl carbonate 30b (112.0 mg, 0.1695 mmol) in
EtOH (8.0 mL) was stirred under a hydrogen atmosphere for
30 min. The catalyst was filtered, and the solvent was
removed in vacuo. Flash chromatography of the residue
(CH2Cl2 prep; 30-40% EtOAc/hexanes) on a short column with
rapid elution afforded triol 32 as an off-white foam (68.0 mg,
92%): [R]23D ) +10.8 (c, 0.460, CHCl3); IR 3257 (br), 1720, 1706
Ack n ow led gm en t. This research was supported by
PHS grant GM-54499, NSF Grant CHE-9520250, and
NSF Instrumentation Grant CHE-9121109. The X-ray
analysis was conducted by Susan de Gala of the The
Yale Chemical Instrumentation Center (YCIC), Sterling
Chemistry Laboratory, to whom all inquires regarding
X-ray data should be addressed. M.B. expresses his
gratitude for Dox and Kent Fellowships.
1
cm-1; H NMR δ 10.19 (d, J ) 1.9 Hz, 1 H), 8.26 (br s, 1 H,
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
OH), 7.61 (br s, 1 H, OH), 7.14 (d, J ) 1.1 Hz, 1 H), 7.03 (d, J
) 1.1 Hz, 1 H), 4.66 (dd, J ) 11.2, 1.4 Hz, 1 H, CH2OH), 4.42
(dd, J ) 11.2, 1.4 Hz, 1 H, CH2OH), 4.10 (app td, J ) 11.2,
1.9 Hz, 1 H, CH2OH), 3.97 (dd, J ) 14.7, 1.9 Hz, 1 H), 3.90 (s,
3 H), 3.78 (d, J ) 14.7 Hz, 1 H), 3.07 (d, J ) 6.7 Hz, 1 H), 2.81
(dd, J ) 6.7, 1.9 Hz, 1 H), 1.33 (s, 9 H); 13C NMR δ 206.2,
166.8, 160.1, 153.4, 149.4, 130.9, 114.9, 112.1, 110.9, 94.5, 83.0,
64.5, 55.6, 52.7, 52.3, 42.9, 32.7, 27.7; HRMS (FAB) calcd for
(M + H)+ C20H25N2O9: 437.1560, found 437.1561.
spectra of compounds 16b, 16c, 17, 18b, 19b, 22b, 27c, 27d ,
27g, 27h , 28b, 28c, 29a /27c mixture, 29b, 29d , 29e, 29f, 30a ,
30b, 31a , 32, 33a , and 33b, and 13C NMR spectra for
compounds 28b , 28c, and 33b are provided. Experimental
procedures are available for compounds 27g, 27h , 29a , 29b,
and 31a (31 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead for ordering information.
Meth yl (4aR,10aS,11aS,11bS)-4,4a,10,10a,11,11b-Hexah y-
d r o-11-(ter t-bu tyloxyca r bon yl)-4a -for m yl-5-h yd r oxy-2,2-
J O961992N