Internal azomethine ylide cycloaddition methodology for access to the substitution pattern of aziridinomitosene A

Article abstract of DOI:10.1021/jo7013559

(Chemical Equation Presented) Highly substituted, tethered alkyne dipolarophiles participate in the internal 2 + 3 cycloaddition with azomethine ylides generated by treatment of oxazolium salts with cyanide ion. Starting from oxazole 26, a sequence of N-m

Full text of DOI:10.1021/jo7013559

Internal Azomethine Ylide Cycloaddition Methodology for Access to
the Substitution Pattern of Aziridinomitosene A
Drew R. Bobeck, Don L. Warner, and Edwin Vedejs*
Chemistry Department, UniVersity of Michigan, Ann Arbor, Michigan 48109
edVed@umich.edu
ReceiVed June 22, 2007
Highly substituted, tethered alkyne dipolarophiles participate in the internal 2 + 3 cycloaddition with
azomethine ylides generated by treatment of oxazolium salts with cyanide ion. Starting from oxazole 26,
a sequence of N-methylation, cyanide addition, and electrocyclic ring opening of a 4-oxazoline intermediate
affords the indoloquinone 31 in a one-pot process. A similar reaction from the protected alkynol derivative
25 affords the sensitive, but isolable, enone 32, and subsequent oxidation affords 31 and the deprotected
quinone alcohol 34. Related azomethine cycloaddition methodology via intramolecular oxazolium salt
formation from 43 or 46 is also demonstrated and allows the synthesis of quinone 45 and derived structures
having the substitution pattern of aziridinomitosene A. Removal of the N-trityl protecting group could
not be achieved without aziridine cleavage.
Introduction
to generate the transient azomethine ylide 8. Intramolecular
cycloaddition to 9 proceeds with yields of ca. 60% or better
when R1 ) H or Me and R2 ) trityl but becomes less efficient
when R2 ) Me (30-40% yield). Our continuing efforts to
prepare aziridinomitosene A (4) using similar methodology have
therefore focused on the N-trityl series to learn whether a late-
stage detritylation may be possible in the highly sensitive
environment. Although detritylation could not be accomplished
without aziridine cleavage, the studies described below dem-
onstrate access to relevant methoxy-substituted indoloquinones
and reveal reaction pathways not encountered previously. The
total synthesis of racemic 4 by Jiminez and Dong in 1999
remains the only route to the fully functionalized molecule.8
Enantiocontrolled synthesis of aziridinomitosenes has been
a challenging problem over many years.1-7 Prior reports from
our laboratory describe a potential solution, illustrated by the
synthesis of nonracemic quinones 1-3 related to aziridinomi-
tosene A (4), but lacking the C(7) methoxy group (Scheme 1).5c
The approach uses an intramolecular azomethine ylide cycload-
dition to assemble the tetracyclic aziridinomitosene core in a
sequence that begins with conversion of an oxazole 5 into the
oxazolium salt 6. Cyanide addition then forms a labile 4-ox-
azoline intermediate 7, and electrocyclic ring opening occurs
(1) Danishefsky, S. J.; Schkeryantz, J. M. Synlett 1995, 475.
(2) Shaw, K. J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515.
(3) Utsunomiya, I.; Fuji, M.; Sato, T.; Natsume, M. Chem. Pharm. Bull.
1993, 41, 854.
Results and Discussion
(4) Lee, S.; Lee, W. M.; Sulikowski, G. A. J. Org. Chem. 1999, 64,
4224.
Our azomethine ylide cycloaddition approach to 4 requires a
2,5-disubstituted oxazole intermediate 10. Introduction of the
acetylenic dipolarophile subunit via alkynyl anion addition to
the aldehyde 11 borrows from prior work, but the current route
features a more direct method for side-chain assembly from 12
based on lithiation at the oxazole C(5) position, metal exchange
via 13, and palladium-catalyzed coupling with enol triflate 14-
E. The latter was easily prepared by deprotonation of the â-keto
(5) (a) Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J. Org. Chem. 2000,
65, 5498. (b) Vedejs, E.; Little, J. J. Am. Chem. Soc. 2002, 124, 748. (c)
Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner, D. L.; Li, V. S.; Na, Y.;
Kohn, H. J. Am. Chem. Soc. 2003, 125, 15796. (d) Vedejs, E.; Little, J. D.;
Seaney, L. M. J. Org. Chem. 2004, 69, 1788. (e) Vedejs, E.; Little, J. D. J.
Org. Chem. 2004, 69, 1794. (f) Warner, D. L.; Hibberd, A. M.; Kalman,
M.; Klapars, A.; Vedejs, E. J. Org. Chem. 2007, 73, in press.
(6) Michael, J. P.; De Koning, C. B.; Petersen, R. L.; Stanbury, T. V.
Tetrahedron Lett. 2001, 42, 7513.
(7) Tsuboike, K.; Guerin, D. J.; Mennen, S. M.; Miller, S. J. Tetrahedron
2004, 60, 7367.
(8) Dong, W.; Jimenez, L. J. Org. Chem. 1999, 64, 2520.
10.1021/jo7013559 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
8506
J. Org. Chem. 2007, 72, 8506-8518

Internal Azomethine Ylide Cycloaddition Methodology
TABLE 1. Conversion of 15 to Enol Triflate 14a
SCHEME 1
entry
base
time
yield (%)
E:Z
1
2
3
4
5
6
KHMDS
NaHMDS
LiHMDS
NaH
MesLi
LiH
15 h
15 h
7 d
15 h
4 d
63
61
28
72
20
65
25:75
40:60
>95:5
54:46
>95:5
93:7
7 d
a Enolate generated in THF at -78 °C. N-Phenylbistriflimide was added,
and the mixture was warmed to rt and stirred (for time, see table).
SCHEME 2
7 days at rt for good conversion. The isomers were assigned
1
from the methyl H NMR chemical shifts, assuming a greater
downfield shift for 14-Z (δ ) 2.36 ppm) compared to
14-E (δ ) 2.18 ppm) due to proximity of the methyl and ester
groups.11
With access to the enol triflate 14-E established, the oxazole
coupling and azomethine ylide cycloaddition were investigated
in a model system (Scheme 2). Metalated oxazoles were
obtained from 2-phenyloxazole 1612 via deprotonation (BuLi/
TMEDA)13 or from the 5-bromo derivative 1714 by lithium
halogen exchange. The intermediate lithiooxazole 18 was then
quenched with Bu3SnCl to afford the stannane 19 (84%
isolated)15 or with anhydrous ZnCl2 to generate 20 in situ.
(10) (a) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972. (b)
Gibbs, R. A.; Krishnan, U.; Dolence, J. M.; Poulter, C. D. J. Org. Chem.
1995, 60, 7821. (c) Yokoyama, H.; Miyamoto, K.; Hirai, Y.; Takahashi, T.
Synlett 1997, 187. (d) Brummond, K. M.; Gesenberg, K. D.; Kent, J. L.;
Kerekes, A. D. Tetrahedron Lett. 1998, 39, 8613. (e) Furstner, A.; De Souza,
D.; Parra-Rapada, L.; Jensen, J. T. Angew. Chem., Int. Ed. 2003, 42, 5358.
(f) Movassaghi, M.; Ondrus, A. E. Org. Lett. 2005, 7, 4423. (g) Movassaghi,
M.; Ondrus, A. E. J. Org. Chem. 2005, 70, 8638.
(11) Larock, R. C.; Doty, M. J.; Han, X. J. J. Org. Chem. 1999, 64,
8770.
(12) Morwick, T.; Hrapchak, M.; Deturi, M.; Campbell, S. Org. Lett.
2002, 4, 2665.
ester 159 with various bases and enolate quenching with
N-phenylbistriflimide (Table 1).10 As expected, the E:Z ratio
of 14 increased with the coordinating ability of the enolate
counterion (Li > Na > K, entries 1-3), but enolate reactivity
decreased markedly. The best compromise of yield and E:Z
ratio was obtained using LiH as the base (entry 6; 65% yield,
93:7 E:Z), although the reaction was very slow and required
(9) (a) Brehm, W. J.; Levenson, T. J. Am. Chem. Soc. 1954, 76, 5389.
(b) Moriarty, R. M.; Vaid, R. K.; Ravikumar, V. T.; Vaid, B. K.; Hopkins,
T. E. Tetrahedron 1988, 44, 1603.
(13) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1998, 63, 551.
(14) Kashima, C.; Arao, H. Synthesis 1989, 873.
(15) Vedejs, E.; Monahan, S. D. J. Org. Chem. 1997, 62, 4763.
J. Org. Chem, Vol. 72, No. 22, 2007 8507

Bobeck et al.
TABLE 2. Oxidation of 32 to Quinones 31 and 34
yield
SCHEME 3
entry
[O]
T (°C)
time
(%)
products
1
2
3
4
5
6
7
8
DDQ
rt
rt
rt
-78
0-rt
rt
2 h
15 h
15 h
10 min
1 h
95a
88a
99b
72b
84b
56b
74b
69b
7:1 31:34
4:1 31:34
3:2 31:34
31
31
31
31
31
TBAF, O2, Pd/C
HF-pyr, O2, NEt3
KHMDS; then NCS
DBU and NCS
phosphazene,c NCS
KHMDS; PhSeCl
15 h
-78 to rt 10 min
KHMDS; PhI(OAc)2 -78 to rt
1 h
a Isolated combined yield of 31 and 34 from crude 32. b Purified 32 used.
c Phosphazene base P1-t-Bu.
oxazolium salt 27 was added to excess BnMe3N+CN- at 0 °C
to form the transient 4-oxazoline 28, followed by electrocyclic
ring opening to the azomethine ylide 29 and subsequent [3 +
2] cycloaddition to 30.5a,c,15 Spontaneous elimination of HCN
then produced the indoloquinone 31, isolated in 40% overall
yield from the oxazole 26.
Focus then turned to the protected diol oxazole 25 as the
cycloaddition precursor (Scheme 3). Alkylation of 25 with
MeOTf as before and the usual treatment with cyanide ion
initiated the cycloaddition sequence. Despite initial concerns
about the stability of the desired cycloadduct 32, the substance
could be purified by chromatography on silica gel (47% yield),
although some decomposition was noted. Structure 32 was
1
confirmed, and the aromatic tautomer 33 was ruled out by H
and 13C NMR evidence, including the characteristic enone 13
C
signal at δ 179.5 ppm.
Starting from 16, a preliminary test of the Negishi coupling16
of 20 was performed using Pd2(dba)3/PPh3 with 1.1 equiv of a
1:1 mixture of the enol triflates 14-E and 14-Z. After 15 h at rt,
the enoate 21 was obtained in a modest 36% overall yield, but
with a promising 9:1 ratio of E:Z isomers suggesting higher
reactivity for the E-isomer. Enoate 21 was also prepared by Stille
coupling.17 Thus, 20 was heated at 65 °C with 1.1 equiv of 14
(57:43 E:Z mixture) in the presence of Pd2(dba)3 and trifu-
rylphosphine.18 This gave 21 in 84% yield, but with a lower
E:Z ratio (3:1). On the other hand, when enriched 14-E (>95:5
E:Z, 1.3 equiv) was used, the desired enoate 21 was obtained
in >95% yield as the sole product.
Next, the tethered alkyne required for the cycloaddition was
installed. Enoate 21 was converted to the enal 23 (71% overall)
by DIBAL reduction to the allylic alcohol 22 and oxidation with
TPAP-NMO.19 Installation of the alkyne dipolarophile was then
accomplished by addition of LiCtCCH2OTBS to give an
intermediate alcohol 24 and protection afforded the TBS ether
25 (73% from 23). Alternatively, oxidation of 24 gave the ynone
26 (57% from 23).
Oxidation of 32 proceeded smoothly using 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ)15 and allowed conversion of the
crude cycloaddition product to the more stable quinone oxidation
state. Partial deprotection occurred as well, and the product was
obtained as a 7:1 mixture of 31:34 (95% combined from oxazole
25 without purification of 32). Several other oxidations20 were
also effective (Table 2), although partial deprotection of the
primary OTBS ether occurred in entries 1-3. On the other hand,
the combination of various oxidants with stronger bases for the
oxidation step5c resulted in conversion to the protected quinone
31, although in somewhat lower yield. Presumably, these
reactions proceed via the phenoxide anion derived from 33.
As shown in Scheme 3, the methoxy enone substitution
pattern corresponding to the aziridinomitosene A quinone is fully
compatible with the azomethine ylide cycloaddition step. Indeed,
better yields were obtained from 25 and from 26 compared to
related cycloadditions studied previously in our laboratory.
Furthermore, the potentially troublesome nonaromatized inter-
mediate 32 could be handled with minimal complications using
the in situ oxidation approach. With these encouraging results
in hand, we sought to apply similar methodology to the synthesis
of aziridinomitosene A (4) according to the retrosynthesis shown
in Scheme 1.
With cycloaddition precursors 25 and 26 in hand, generation
of the azomethine ylide and subsequent [3 + 2] cycloaddition
could be explored (Scheme 3). Enone 26 was studied first
because the expected cycloadduct would be at the desired
quinone oxidation state. Thus, the oxazole nitrogen of 26 was
alkylated selectively with MeOTf (CH3CN, 48 h). The resulting
The aziridinyl oxazole 12 was prepared starting with the
addition of lithiated oxazole borane 3521 to N-trityl-O-allylserinal
365c (Scheme 4). This gave 37 as an inseparable 6:1 diastere-
omer mixture (84%), but the major isomer could be purified
after aziridine formation under Mitsunobu conditions. Based on
the vicinal coupling constant J ) 6.1 Hz for the aziridine
methine protons, the major aziridine (65%) was assigned the
(16) (a) Negishi, E. I. Acc. Chem. Res. 1982, 15, 340. (b) Russell, C. E.;
Hegedus, L. S. J. Am. Chem. Soc. 1983, 105, 943. (c) Knochel, P.; Singer,
R. D. Chem. ReV. 1993, 93, 2117.
(17) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1.
(18) Andersen, N. G.; Keay, B. A. Chem. ReV. 2001, 101, 997.
(19) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P Synthesis
1994, 639.
(20) Feigelson, G. B.; Egbertson, M.; Danishefsky, S. J.; Schulte, G. J.
Org. Chem. 1988, 53, 3390.
(21) Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192.
8508 J. Org. Chem., Vol. 72, No. 22, 2007

Internal Azomethine Ylide Cycloaddition Methodology
SCHEME 4
SCHEME 5
pared to the model system. The resulting anion 13 was stirred
with freshly fused ZnCl2 to generate 39, followed by Negishi
coupling16 with triflate 14 (1.1 equiv of 14-E) to give ester 40
in 70% overall yield from oxazole 12. The corresponding Stille
coupling17 was investigated briefly, but 40 was obtained in a
lower 56% yield from 12.
To install the alkyne necessary for [3 + 2] cycloaddition,
ester 40 was converted to aldehyde 11 by the usual two-step
reduction/oxidation procedure via alcohol 41 (65%). Addition
of LiCtCCH2OTBS to 11 then gave an intermediate alcohol
42 that was oxidized to ketone 43 in 70% overall yield.
The key [3 + 2] cycloaddition could now be explored starting
with ketone 43. This approach is the most direct route to the
tetracyclic aziridinomitosene core, and it is also the safest route
because it avoids the hydroquinone oxidation state corresponding
to solvolytically reactive leucoaziridinomitosenes. Best results
were obtained using the crystallized benzene complex of
AgOTf24 for iodine activation and intramolecular N-alkylation.
Conversion of 43 to the oxazolium salt 44 was monitored by
1H NMR spectroscopy in C6D6 and was complete after 3 h.
Subsequent azomethine ylide generation was then performed
by addition of 44 to excess BnMe3N+CN- in CH3CN at rt, the
same procedure used in the model study. A transient yellow
color was observed that faded within seconds, presumably due
to the formation and subsequent reactions of the azomethine
ylide. After 2 h at rt, the desired tetracyclic aziridinomitosene
45 was indeed isolated. A single experiment gave 45 in 33%
yield, but this result was never reproduced despite much effort.
The crucial variables could not be identified, yields in the 10-
27% range were more typical, and unknown byproducts were
formed that could not be isolated.
cis stereochemistry 38. This result was expected from previous
studies using 5-substituted oxazoles5c and provides the basis
for assigning the stereochemistry of 37. Allyl deprotection using
zirconocene generated in situ22 followed by iodide formation
following a modified Mitsunobu procedure23 then gave the
desired 12.
Compared to the lithiation of oxazole 16 used in the model
system (Scheme 2), the corresponding reaction of 12 must
contend with the potentially sensitive iodomethylaziridine
subunit. Although lithium-iodine exchange or oligomerization
of 16 were potential concerns, it was anticipated that steric
shielding in the cis-fused, trityl-substituted aziridine would
discourage intermolecular events involving either the primary
iodide or the aziridine moieties and that sp2 hybridization and
adjacent heteroatoms would favor the lithiated oxazole. Fortu-
nately, 12 was deprotonated cleanly with LDA/TMEDA13 at
-78 °C (Scheme 4) without any additional precautions com-
Because the cycloaddition from ketone 43 was too unpredict-
able for scaleup, an alternative route from alcohol 42 was
explored after protection as the TBS ether 46 (78% over the
two steps from 11; Scheme 5). Intramolecular alkylation and
ylide generation were then performed as before using the
purified AgOTf-benzene complex.24 Following the same
procedure used in Scheme 4 and in prior studies, the intermedi-
(22) Ito, H.; Taguchi, T.; Hanzawa, Y. J. Org. Chem. 1993, 58, 774.
(23) Kunz, H.; Schmidt, P. Liebigs Ann. Chem. 1982, 1245.
(24) Dines, M. B. J. Organomet. Chem. 1974, 67, C55.
J. Org. Chem, Vol. 72, No. 22, 2007 8509

Bobeck et al.
SCHEME 6
difficult. Eventually, partially enriched fractions of two new
products were obtained by chromatography on NEt3-buffered
silica gel that proved to be two diastereomers 53 resulting from
the desired [2 + 3] cycloaddition of azomethine ylide 52, but
without the usual elimination of HCN. Varying amounts of
decomposition products were also observed during attempts to
purify 53 by chromatography, including a structure that is
tentatively assigned as the expected adduct 49 from MS and
NMR evidence. However, enriched samples of 49 were never
obtained, nor could either isomer of 53 be isolated without
contamination. Structure 53 is consistent with the upfield
chemical shift of the aziridine protons (δ ) 2.15, 2.59 ppm
and δ ) 2.34, 2.79 ppm) compared to δ ) 2.89 and 3.03 ppm
for the analogous protons of 45. However, decisive evidence
for 53 proved elusive until yet another unexpected product was
isolated during attempts to aromatize 53 to 45.
Oxidation of 53 using base/NCS, DDQ, or TBAF/Pd-C/O2
gave extensive degradation along with traces of 45. However,
20
treatment of crude 53 with HF-pyridine/O2 and added NEt3
to prevent aziridine cleavage produced a separable mixture of
highly colored quinones (Scheme 6), including quinone alcohol
54 as well as the silyl ether 45. A deep red quinone was also
isolated, and was assigned structure 55, corresponding to
oxidation without HCN elimination. The high field chemical
shifts of the aziridine protons at δ ) 2.64 and 2.96 ppm
suggested the same sp3 environment at C(9a) as seen in 53.
With a mass corresponding to 54 + CN + OH and strong NMR
evidence for the HO and CH2OH subunits (one exchangeable
proton, singlet at δ ) 4.03 ppm; a second exchangeable proton
at δ ) 4.65 ppm as a doublet of doublets coupled to the C(10)
methylene protons). Eventually, X-ray quality crystals were
obtained, and the structure was confirmed.
ate oxazolium salt 47 was added to BnMe3N+CN- (4 equiv) in
CH3CN at rt and the transient color of ylide 48 appeared as
usual. However, the isolated product proved to be 50 (33%,
2:1 dr) and not the expected enone 49. The formula of 50 was
deduced using ESMS (m/z ) 49 + HCN), and the connectivity
was established by NMR spectroscopy. Furthermore, the 13C
NMR spectrum showed CN peaks at δ ) 117.0 and 117.1 ppm
for the two diastereomers and the 1H NMR spectrum contained
two signals for the C(6) methine hydrogens at δ ) 3.30 ppm
and δ ) 3.26 ppm as quartets, consistent with structure 50.
Analogous cyanide adducts were not observed starting from the
ketone 44, nor in the model study from either 25 or 26.
Furthermore, nucleophilic addition at C(7) in mitomycin-derived
quinones is reported to follow an addition/elimination pathway.25
On the other hand, simple addition of cyanide to a vinylogous
ester has been reported in an unrelated substrate.26
Even though the product was not the desired vinylogous ester
49, oxidation of the cycloaddition product mixture containing
50 was nonetheless attempted in the hope that elimination of
HCN might generate 49 in situ and that enolization and
subsequent oxidation would afford the desired quinone 45.
However, treatment with KHMDS/NCS at -78 °C gave 45 in
a marginal 17% yield from 46.
For preparative purposes, it was best to oxidize the crude
cycloaddition mixture obtained from 46 by activation with
AgOTf-benzenecomplex24 followedby1.0equivofBnMe3N+CN-.
Without separation, the resulting mixture was treated with HF-
20
pyridine/O2 and NEt3 to give 34% of 45 + 54 combined,
together with 14% of 55. Similar experiments with partially
purified 53 were less efficient overall, but did provide evidence
that only one of the two diastereomers of 53 undergoes
elimination of HCN while the other oxidizes to 55. The
combined 48% yield of tetracyclic adducts is not far from the
range of yields obtained using simpler cycloaddition substrates,
but the 34% recovery of useful quinones (45 + 54) was less
than desired. Some solace was taken by considering the dramatic
change in structure and the number of transformations to 45 in
the one-pot procedure starting from oxazole 46.
The last steps potentially leading to aziridinomitosene A
require introduction of the carbamate and removal of the trityl
protecting group. When tetracycle 45 was subjected to reductive
detritylation conditions with Et3SiH/MsOH at -40 °C desily-
lation to 54 proved faster than detritylation.27 The TBS ether in
45 was therefore removed with NEt3/HF-pyr, and the alcohol
54 was converted to carbamates 56 and 57 using standard
methods (Scheme 7).28 Treatment of 56 with Et3SiH/MsOH at
0 °C followed by cleavage of the trichloroacyl group with K2-
CO3 afforded a product mixture having a major ESMS peak at
m/z ) 358 amu corresponding to the ring opened amino alcohol
In an attempt to prevent formation of the cyanide adduct 50,
azomethine ylide generation was performed with 1.0 equiv of
BnMe3N+CN- instead of the excess used earlier (Scheme 6).
This experiment gave a low yield (<10%) of the quinone 45,
but neither 49 nor 50 was detected by NMR. On the other hand,
a mass corresponding to 50 (m/z ) 49 + HCN) did appear in
the electrospray mass spectrum of the crude product, suggesting
that isomers of 50 had been formed. Structure 51 resulting from
simple iodide-cyanide exchange was ruled out based on
disappearance of the oxazole proton in the NMR spectrum, but
further characterization of the sensitive product mixture was
(25) Iyengar, B. S.; Remers, W. A.; Bradner, W. T. J. Med. Chem. 1986,
29, 1864.
(26) Tatsuta, K.; Hayakawa, J.; Tatsuzawa, Y. Bull. Chem. Soc. Jpn.
1989, 62, 490.
(27) (a) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org.
Chem. 2001, 66, 7542. (b) Kim, M.; Vedejs, E. J. Org. Chem. 2004, 69,
7262.
(28) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
8510 J. Org. Chem., Vol. 72, No. 22, 2007

Internal Azomethine Ylide Cycloaddition Methodology
SCHEME 7
alcohol 59 was recovered (ca. 5:1 dr by NMR), and the structure
was confirmed by comparison with literature MS and NMR
data.29,30
The deprotection studies of 57 are consistent with rapid
C(1)-N heterolysis due to the activating effect of the indolo-
quinone nitrogen. This was no surprise given the long history
of DNA alkylation involving similar events, and in particular,
the studies by Kohn et al. with aziridinomitosenes B-D.31
Nevertheless, there was reason to think that deprotection might
be possible. Thus, earlier efforts in our laboratory had succeeded
in the detritylation of 61 to 62 using iPr3SiH/MsOH.27b
Evidently, the vinylogous carbamate C)O group of the ester
substituent in 62 is an important stabilizing factor, but we had
imagined (hoped) that the vinylogous amide (quinone) carbonyls
of 57 would be at least as effective. This has proven not to be
the case.
Conclusions
Indoloquinone 31 was obtained in excellent yield using
internal azomethine ylide cycloaddition methodology starting
from the oxazole 25 when the sensitive intermediate cycloadduct
32 was oxidized without isolation. The ketone substrate 26 gave
lower yields of 31 using the analogous oxazolium salt activation
with cyanide ion. Similar routes to the tetracyclic quinone 45
encountered complications due to cyanide addition at the stage
of the vinylogous ketone 49. Furthermore, two unexpectedly
stable cycloadduct diastereomers 53 were encountered, and only
one diastereomer could be converted into the desired quinone
45 after oxidation. The presence of a sensitive aziridine in all
of the tetracyclic intermediates raises complications throughout
the late stages of this sequence, but the challenge was met until
the very last stage, the reductive N-trityl cleavage. This
transformation has been achieved in a related system (61), but
could not be demonstrated on a preparative scale with 57 due
to aziridine ring opening.
We were well aware that N-trityl cleavage as the last step
would be exceptionally challenging. This risk was accepted for
two reasons. First, one of the goals of the study was to better
define the limits of what chemistry is possible in the presence
of the solvolytically sensitive aziridines. Second, the bulky
N-trityl group is helpful at the stage of oxazolium salt formation
using AgOTf. When smaller substituents are present at the
aziridine nitrogen, activation of the iodide results in competing
internal alkylation of oxazole nitrogen and intermolecular
displacement by the same cyanide ion that is necessary to
generate the azomethine ylide for the cycloaddition. At this
point, it is clear that a different protecting group for aziridine
nitrogen will be needed that is compatible with the internal
oxazole alkylation/cyanide activation sequence.
59 + Na. Another peak at m/z ) 275 amu was assigned to the
cation 60 resulting from heterolysis of the carbamate, identical
to ESMS data reported previously for 59.29 A small peak at
m/z ) 340 amu, the mass expected for aziridinomitosene A (4)
+ Na, was also observed in samples of the crude product
mixture. However, 4 was not detected by NMR comparison with
a spectrum of authentic material, and was not present above
the detection threshold level of ca. 2-3%. Treatment of the
carbamate 57 with Et3SiH/MsOH also gave the amino alcohol
59 according to ESMS assay, although the mass corresponding
to 4 was not detected in this case.29
In view of the above results, the reductive detritylation
procedure was reoptimized in an attempt to lower the temper-
ature threshold. Using the stronger acid TfOH together with
the more potent hydride source triphenylsilane allowed detri-
tylation of simpler model structures (for example, (R)-benzyl
1-tritylaziridine-2-carboxylate) as low as -40 °C with 1.0 equiv
of each reagent over a time scale of 0.5-15 h. However, when
the new procedure (15 h at -40 °C and workup with pH 10.3
buffer) was applied to 57, ESMS assay (m/z ) 600 amu, 58 +
Na) indicated formation of the N-tritylamino alcohol 58 as the
main component in a 3:1 mixture with the amino alcohol 59.
The N-tritylamino alcohol was not purified, but structure 58 is
Experimental Section
(E)-Methyl 2-Methoxy-3-(trifluoromethylsulfonyloxy)but-2-
enoate (14). To a suspension of LiH (81.0 mg, 10.2 mmol) in THF
(28 mL) at -78 °C was added a solution of 159 in THF (1 mL)
dropwise over 5 min. After the mixture was stirred at -78 °C for
1 h, a solution of N-phenylbis(trifluoromethanesulfonimide) (2.43
g, 6.80 mmol) in THF (6 mL) was added dropwise over 5 min.
The resulting solution was stirred at -78 °C for 1 h and then
1
consistent with the ESMS data and H NMR evidence for the
intact N-trityl group, new C(6) methyl signals at δ ) 1.94 and
δ ) 1.90 ppm in a 3:1 ratio, as well as new downfield methine
signals. Tentatively, we interpret the methyl signals as evidence
for diastereomeric amino alcohols from aziridine cleavage as
reported for 59.30 When 2 equiv of TfOH and 2 equiv of HSiPh3
were used for the deprotection of 57 at -40 °C, only the amino
(30) Taylor, W. G.; Remers, W. A. J. Med. Chem. 1975, 18, 307.
(31) (a) Han, I.; Kohn, H. J. Org. Chem. 1991, 56, 4648. (b) Schiltz, P.;
Kohn, H. J. Am. Chem. Soc. 1993, 115, 10510. (c) Li, V. S.; Choi, D.;
Tang, M. S.; Kohn, H. J. Am. Chem. Soc. 1996, 118, 3765.
(29) Paz, M. M.; Tomasz, M. Org. Lett. 2001, 3, 2789.
J. Org. Chem, Vol. 72, No. 22, 2007 8511

Bobeck et al.
warmed to rt and stirred for 7 d. The yellow solution was poured
into H2O (100 mL) and extracted with Et2O. The combined organic
extracts were washed with a 10% citric acid solution, dried
(MgSO4), and filtered, and solvents were removed (aspirator). The
residue was purified by flash chromatography on silica gel (50 mm
× 15 cm, 10% Et2O/hexanes, 50 mL fractions) to yield 1.23 g (65%)
of triflate 14 as a volatile clear oil as an inseparable 93:7 ratio of
E:Z isomers (1H NMR analysis), analytical TLC on silica gel 60
F254, 10% Et2O/hexanes, Rf ) 0.3: molecular ion (M + Na) calcd
for C7H9F3NaO6S 300.9970, found m/z ) 300.9963, error ) 2 ppm;
Preparation of 21 by Stille Coupling of 19 and 14. To a
suspension of Pd2(dba)3 (123 mg, 0.134 mmol) and trifurylphos-
phine (125 mg, 0.537 mmol) in DMF (4 mL) that was stirred at rt
20 min was added a solution of triflate 14 (478 mg, 1.48 mmol of
a >95:5 ratio of E/Z-14) in DMF (4 mL, including cannula and
flask washings) via cannula dropwise. The dark purple solution
was allowed to stir at rt 20 min, and then a solution of stannane
1915 (583 mg, 1.34 mmol) in DMF (5 mL, including cannula and
flask washings) was added via cannula dropwise. The reaction was
heated to 65 °C and stirred for 15 h. After being cooled to rt, the
green solution was poured into saturated aqueous NH4Cl (30 mL)
and extracted with Et2O. The combined organic extracts were
washed with H2O and brine and dried (MgSO4), and the solvents
were removed (aspirator). The yellow oil was purified by flash
column chromatography on silica gel (40 mm × 15 cm, 15%
EtOAc/hexanes, 40 mL fractions) to yield 0.367 g (>99%) of ester
21 as a light yellow oil in a >95:5 ratio of E:Z isomers identical to
previously made material.
1
IR (neat, cm-1) 1735, CdO, 1424; 500 MHz H NMR (CDCl3,
ppm) major E-isomer δ 3.87 (3H, s) 3.70 (3H, s) 2.18 (3H, s); the
presence of the minor Z-isomer was deduced from methyl integrals
at δ 3.88 (0.07H, s) 3.71 (0.07H, s) 2.36 (0.07H, s); 13C NMR
(125 MHz, CDCl3, ppm) E-isomer δ 161.5, 146.8, 142.4, 118.5
(q, 318 Hz), 60.5, 52.5, 15.8; Z-isomer δ 163.2, 147.1, 142.5, 118.5
(q, 318 Hz), 60.4, 52.7, 17.2.
Preparation of (E)-Methyl 2-Methoxy-3-(2-phenyloxazol-5-
yl)but-2-enoate (21) by Negishi Coupling between 17 and 14.
5-Bromo-2-phenyloxazole14 (17) (151 mg, 0.673 mmol) in THF
(3 mL) was cooled to -78 °C, and nBuLi (1.67 M solution in
hexanes, 0.50 mL, 0.84 mmol) was added dropwise over 2 min.
After the mixture was stirred at -78 °C for 10 min, ZnCl2 (1.0 M
solution in THF, 2.7 mL, 2.7 mmol) was added, and the yellow
solution was allowed to warm to rt over 25 min. In a separate flask,
Pd2(dba)3 (60.0 mg, 0.0655 mmol) and PPh3 (38.0 mg, 0.0145
mmol) were dissolved in THF (2 mL) and stirred at rt 20 min.
Triflate 14 (205 mg, 0.737 mmol of a 1:1 ratio of E/Z-14) in THF
(1 mL) was added dropwise at rt and the resulting green solution
was stirred at rt for 10 min. The previously made organozinc was
added via cannula dropwise over 5 min followed by a THF rinse
(1 mL). After being stirred at rt for 15 h, the solution was poured
into saturated aqueous NH4Cl (10 mL) and extracted with Et2O.
The combined organic extracts were dried (MgSO4) and filtered,
and solvents were removed (aspirator). The yellow oil was purified
by flash column chromatography on silica gel (30 mm × 16 cm,
15% EtOAc/hexanes, 30 mL fractions) to yield 66 mg (36%) of
ester 21 as a light yellow oil in an inseparable 93:7 ratio of E:Z
isomers, analytical TLC on silica gel 60 F254, 15% EtOAc/hexanes,
Rf ) 0.2: molecular ion (M + H) calcd for C15H16NO4 274.1079,
found m/z ) 274.1070, error ) 3 ppm; IR (neat, cm-1) 1729, Cd
(E)-2-Methoxy-3-(2-phenyloxazol-5-yl)but-2-en-1-ol (22). To
a solution of ester 21 (158 mg, 0.578 mmol) in toluene (6 mL) at
-78 °C was added DIBAL-H (20 wt % solution in toluene, 1.80
mL, 2.17 mmol) dropwise over 5 min. After being stirred at -78 °C
for 2 h, the cooling bath was removed and 6 mL of Et2O was added
followed by 6 mL of saturated aqueous sodium potassium tartrate
(Rochelle’s salt). The biphasic solution was vigorously stirred at rt
for 1 h, and then the mixture was extracted with Et2O. The
combined organic extracts were dried (MgSO4) and filtered, and
solvents were removed (aspirator). The off-white solid was purified
by flash column chromatography on silica gel (20 mm × 15 cm,
3:1 Et2O/hexanes, 11 mL fractions) to yield 0.134 g (94%) of
alcohol 22 as a white solid, analytical TLC on silica gel 60 F254,
3:1 Et2O/hexanes, Rf ) 0.3. Pure material was obtained by
crystallization in EtOAc/hexanes as white rods: mp ) 97 - 99 °C;
molecular ion (M + H) calcd for C14H16NO3 246.1130, found m/z
) 246.1119, error ) 4 ppm; IR (neat, cm-1) 3263, OH, 1642; 400
MHz 1H NMR (CDCl3, ppm) δ 7.98-7.93 (2H, m) 7.44-7.41 (3H,
m) 6.97 (1H, s) 4.59 (2H, d, J ) 5.9 Hz) 3.83 (3H, s) 2.93 (1H, t,
J ) 5.9 Hz) 1.93 (3H, s); 13C NMR (100 MHz, CDCl3, ppm) δ
160.8, 153.5, 151.1, 130.4, 129.0, 127.3, 126.2, 125.3, 107.8, 58.3,
56.9, 13.4.
(E)-2-Methoxy-3-(2-phenyloxazol-5-yl)but-2-enal (23). A solu-
tion of alcohol 22 (268 mg, 1.09 mmol), N-methylmorpholine
N-oxide (NMO) (269 mg, 2.30 mmol), and molecular sieves
(activated powder, 4 Å, 1.34 g) in CH2Cl2 (14 mL) was stirred at
rt for 30 min. Tetrapropylammonium perruthenate (TPAP) (77.0
mg, 0.219 mmol) was then added, and the resulting black solution
was stirred at rt for 1 h and then filtered through a silica gel plug
eluting with 250 mL of a 1:1 acetone/hexanes solution. Solvents
were removed (aspirator), and the light yellow solid was purified
by flash column chromatography on silica gel (30 mm × 16 cm,
40% Et2O/hexanes, 12 mL fractions) to yield 0.200 g (75%) of
aldehyde 23 as a light yellow solid, analytical TLC on silica gel
60 F254, 40% Et2O/hexanes, Rf ) 0.3. Pure material was obtained
by crystallization in hexanes as light yellow needles: mp ) 77
-80 °C; molecular ion (M + H) calcd for C14H14NO3 244.0974,
found m/z ) 244.0966, error ) 3 ppm; IR (neat, cm-1) 1665 Cd
1
O, 1644; for major E-21: 400 MHz H NMR (CDCl3, ppm) δ
8.01-7.95 (2H, m) 7.48-7.43 (3H, m) 7.18 (1H, s) 3.82 (3H, s)
3.71 (3H, s) 2.10 (3H, s); the presence of the minor Z-isomer was
deduced from methyl integrals at δ 3.88 (0.24H, s) 3.72 (0.24H, s)
2.46 (0.24H, s); 13C NMR of the major E-21 (100 MHz, CDCl3,
ppm) δ 165.1, 161.2, 149.1, 144.6, 130.6, 129.0, 127.4, 127.0,
126.4, 112.9, 58.6, 52.6, 13.7.
Preparation of 21 by Negishi Coupling between 16 and 14.
To a solution of 2-phenyloxazole 1612 (32.0 mg, 0.220 mmol) in
THF (1.5 mL) at -78 °C were added TMEDA (0.33 mL, 2.20
mmol, distilled over solid Na) and nBuLi (1.30 M solution in
hexanes, 0.19 mL, 0.242 mmol) dropwise over 5 min. After the
mixture was stirred at -78 °C for 1 h, ZnCl2 (1.12 M in THF,
0.79 mL, 0.880 mmol) was added dropwise and then the cooling
bath was removed and the organozinc solution was allowed to warm
to rt. In a separate flask, Pd2(dba)3 (20.1 mg, 0.0220 mmol) and
PPh3 (23.0 mg, 0.0880 mmol) were dissolved in THF (0.5 mL)
and stirred at rt 20 min. Triflate 14 (71.1 mg, 0.255 mmol of a
>95:5 ratio of E/Z-14) in THF (0.5 mL) was added dropwise, and
the resulting green solution was stirred at rt for 25 min. The
previously made organozinc was added via cannula dropwise over
5 min followed by a THF rinse (0.5 mL). After being stirred at rt
for 15 h, the solution was poured into saturated aqueous NH4Cl
and extracted with Et2O. The combined organic extracts were dried
(MgSO4) and filtered, and solvents were removed (aspirator). The
yellow oil was purified by preparatory TLC on silica gel (20 cm ×
20 cm × 1000 µm, 15% EtOAc/hexanes eluent) to give 28.3 mg
(47%) of 21 as a light yellow oil in a >95:5 ratio of E:Z isomers.
1
O; 500 MHz H NMR (CDCl3, ppm) δ 10.19 (1H, s) 8.06-8.02
(2H, m) 7.52-7.47 (3H, m) 7.34 (1H, s) 3.83 (3H, s) 2.29 (3H, s);
13C NMR (125 MHz, CDCl3, ppm) δ 187.1, 163.6, 151.9, 148.2,
131.4, 131.3, 129.4, 129.2, 126.9, 126.8, 60.3, 13.4.
(E)-7-(tert-Butyldimethylsilyloxy)-3-methoxy-2-(2-phenylox-
azol-5-yl)hept-2-en-5-yn-4-one (26). To a solution of tert-bu-
tyldimethylsilyl propargyl ether32 (33.0 mg, 0.193 mmol) in THF
(1.0 mL) at -42 °C was added nBuLi (0.374 M solution in hexanes,
0.52 mL, 0.193 mmol) dropwise over 5 min. After the solution
was stirred at -42 °C for 1 h, a solution of aldehyde 23 (26.0 mg,
0.107 mmol) in THF (1.0 mL, including cannula and flask
(32) Araki, Y.; Konoike, T. J. Org. Chem. 1997, 62, 5299.
8512 J. Org. Chem., Vol. 72, No. 22, 2007

Internal Azomethine Ylide Cycloaddition Methodology
washings) was added dropwise via cannula, the reaction mixture
was stirred for an additional 2 h at -42 °C, and then the cooling
bath was removed and 2 mL of saturated aqueous sodium
bicarbonate was added. After being stirred at rt 10 min, the solution
was poured into brine and extracted with CH2Cl2. The combined
organic extracts were dried (Na2SO4) and filtered, and solvents were
removed (aspirator). To the crude alcohol from above in CH2Cl2
(2 mL) were added NMO (26.0 mg, 0.225 mmol) and molecular
sieves (activated powder, 4 Å,120 mg), and the mixture was stirred
at rt for 20 min. TPAP (8.0 mg, 0.021 mmol) was added in one
portion, and the black solution was stirred an additional 1 h at rt
then filtered through a silica gel plug (2 cm × 5 cm) and eluted
with 50 mL of a 1:1 hexanes/acetone solution. Solvents were
removed (aspirator), and the yellow foam was purified by prepara-
tory TLC on silica gel (20 cm × 20 cm × 1000 µm, 20% EtOAc/
hexanes eluent) to give 25.0 mg (57%) of 26 as a yellow foam,
analytical TLC on silica gel 60 F254, 20% EtOAc/hexanes: Rf )
0.3; molecular ion (M + H) calcd for C23H30NO4Si 412.1944, found
m/z ) 412.1935, error ) 2 ppm; IR (neat, cm-1) 1640 CdO; 500
BnMe3N+CN- (9.0 mg, 0.054 mmol) in freshly distilled CH3CH2-
CN (2.0 mL, including cannula and flask washings, stirred over
activated 4 Å molecular sieves, distilled over CaH2, and distilled
again over P2O5) at 0 °C via cannula dropwise over 5 min. The
reaction was stirred at 0 °C for 10 min, and then the cooling bath
was removed and the light orange solution was stirred at rt for 15
h. The orange solution was poured into brine and extracted with
Et2O. The combined organic extracts were dried (MgSO4) and
filtered, and solvents were removed (aspirator) to yield a light
orange oil. The orange oil was purified by preparative TLC on silica
gel (20 cm × 20 cm × 1000 µm, 15% EtOAc/hexanes eluent) to
give 4.0 mg (40%) of 31 as an orange oil: molecular ion (M +
Na) calcd for C24H31NNaO4Si 448.1920, found m/z ) 448.1922,
error ) 1 ppm; IR (neat, cm-1) 1661 CdO, 1640 CdO, 1609; UV
(CH3OH, nm) 266 (ꢀ 33000), 347 (ꢀ 8500), 448 (ꢀ 4400); 500 MHz
1H NMR (CDCl3, ppm) δ 7.50-7.42 (5H, m) 4.67 (2H, s) 4.00
(3H, s) 3.80 (3H, s) 2.00 (3H, s) 0.86 (9H, s) 0.05 (3H, s); 13C
NMR (125 MHz, CDCl3, ppm) δ 179.9, 179.6, 156.9, 141.9, 130.8,
129.4, 129.3, 129.3, 129.3, 128.7, 122.5, 121.9, 61.3, 55.6, 34.4,
26.2, 18.8, 9.0, -5.1.
1
MHz H NMR (CDCl3, ppm) δ 8.05-8.01 (2H, m) 7.49 (1H, s)
7.47-7.44 (3H, m) 4.33 (2H, s) 3.75 (3H, s) 2.22 (3H, s) 0.84
(9H, s) 0.03 (6H, s); 13C NMR (125 MHz, CDCl3, ppm) δ 174.8,
162.1, 151.0, 148.4, 130.9, 130.5, 129.1, 127.2, 126.8, 120.3, 92.4,
84.3, 59.9, 51.7, 25.9, 18.4, 15.4, -5.2.
Cycloaddition from Protected Akynol 25 to Pyrroloenone 32.
A solution of oxazole 25 (48.0 mg, 0.0909 mmol) and molecular
sieves (activated 4 Å, 200 mg) in CH3CN (2 mL, stirred over
activated 4 Å molecular sieves, distilled over CaH2, and distilled
again over P2O5) was stirred at rt for 15 min. MeOTf (15 µL, 0.136
mmol) was added, and the solution was allowed to stir at rt for 15
h. MeOTf (15 µL, 0.136 mmol) again was added and the solution
stirred at rt for an additional 15 h. Salt formation was indicated by
TLC analysis of reaction mixture, Rf ) 0.0, and by mass
spectroscopy with molecular ion (M+) calcd for C30H48NO4Si2 542,
found m/z ) 542. The newly formed oxazolium salt was added to
a solution of BnMe3N+CN- (35.0 mg, 0.200 mmol) in CH3CN (2
mL, including cannula and flask washings), stirred over activated
4 Å molecular sieves, distilled over CaH2, and distilled again over
P2O5) at 0 °C via cannula dropwise over 5 min. The reaction was
stirred at 0 °C for 10 min and then warmed to rt and stirred for 2
h. The orange solution was poured into pH 5.8 buffer (15 mL) and
extracted with Et2O. The combined organic extracts were dried
(MgSO4) and filtered, and solvents were removed (aspirator). The
orange oil was purified by preparative TLC on silica gel (20 cm ×
20 cm × 1000 µm, 20% EtOAc/hexanes eluent) to give 23.0 mg
(47%) of 32 as a white solid, analytical TLC on silica gel 60 F254,
20% EtOAc/hexanes, Rf ) 0.6. Pure material was obtained by
crystallization in hexanes as off-white rods: mp ) 72-74 °C;
molecular ion (M + Na) calcd for C30H47NNaO4Si2 564.2941, found
m/z ) 564.2939, error ) 0 ppm; IR (neat, cm-1) 1638; 500 MHz
1H NMR (CDCl3, ppm) δ 7.48-7.40 (3H, m) 7.38-7.36 (2H, m)
5.81 (1H, s) 4.86 (1H, AB, J)11.2 Hz) 4.26 (1H, AB, J ) 11.2
Hz) 4.08 (3H, s) 3.84 (3H, s) 1.86 (3H, s) 0.90 (9H, s) 0.86 (9H,
s) 0.05 (3H, s) 0.04 (3H, s) -0.08 (3H, s) -0.46 (3H, s); 13C NMR
(125 MHz, CDCl3, ppm) δ 179.5, 165.9, 139.7, 130.7, 130.5, 128.7,
128.6, 128.5, 125.3, 120.4, 116.1, 61.7, 56.9, 56.4, 33.9, 26.2, 25.9,
18.7, 18.5, 7.9, -4.0, -4.1, -5.1, -5.2.
Preparation of 31 and 3-(Hydroxymethyl)-5-methoxy-1,6-
dimethyl-2-phenyl-1H-indole-4,7-dione (34) from 25. To a solu-
tion of oxazole 25 (25.0 mg, 0.0474 mmol) in CH3CN (0.6 mL,
stirred over activated 4 Å molecular sieves, distilled over CaH2,
and distilled again over P2O5) and molecular sieves (activated 4
Å, 150 mg) was added MeOTf (14 µL, 0.0592 mmol). The clear
solution was allowed to stir at rt 15 h. MeOTf (7 µL, 0.0592 mmol)
was added, and the light brown solution was stirred for an additional
15 h at rt. The oxazolium salt was transferred to a solution of
BnMe3N+CN- (18.0 mg, 0.104 mmol) in CH3CN (4.5 mL,
including cannula and flask washings, stirred over activated 4 Å
molecular sieves, distilled over CaH2, and distilled again over P2O5)
at 0 °C via cannula dropwise over 5 min. The reaction was stirred
at 0 °C for 10 min, and then the cooling bath was removed and the
light orange solution was stirred at rt for 2 h. The orange solution
was poured into pH 5.8 buffer (15 mL) and extracted with Et2O.
(E)-5-(4,7-Bis(tert-butyldimethylsilyloxy)-3-methoxyhept-2-en-
5-yn-2-yl)-2-phenyloxazole (25). To a solution of tert-butyldim-
ethylsilyl propargyl ether32 (252 mg, 1.48 mmol) in THF (1.5 mL)
at -78 °C was added nBuLi (1.47 M solution in hexanes, 1.01
mL, 1.48 mmol) dropwise over 5 min. The solution was allowed
to stir at -78 °C for 1 h, and then a solution of aldehyde 23 (200
mg, 0.822 mmol) in THF (0.5 mL, including cannula and flask
washings) was added dropwise via cannula and the reaction was
allowed to slowly warm to -42 °C over 20 min. The light yellow
solution was stirred at -42 °C for 2 h, and then the cooling bath
was removed and 2 mL of saturated aqueous sodium bicarbonate
was added. After being stirred at rt for 10 min, the solution was
poured into brine and extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4) and filtered, and solvents were
removed (aspirator). The crude alcohol from above was dissolved
in CH2Cl2 (2 mL), and tert-butyldimethylsilyl chloride (151 mg,
1.00 mmol) was added followed by imidazole (84.0 mg, 1.23
mmol). The suspension was stirred for 15 h at rt and then poured
into brine and extracted with CH2Cl2. The combined organic extracts
were dried (Na2SO4) and filtered, and solvents were removed
(aspirator). The clear oil was purified by flash column chromatog-
raphy on silica gel (40 mm × 15 cm, 20% Et2O/hexanes, 15 mL
fractions) to yield 0.318 g (73%) of oxazole 23 as a clear oil,
analytical TLC on silica gel 60 F254, 20% Et2O/hexanes, Rf )
0.5: molecular ion (M + Na) calcd for C29H45NNaO4Si2 550.2785,
found m/z ) 550.2777, error ) 1 ppm; IR (neat, cm-1) 1638; 400
MHz 1H NMR (CDCl3, ppm) δ 8.09-8.02 (2H, m) 7.49-7.42 (3H,
m) 7.07 (1H, s) 5.80 (1H, t, J ) 1.8 Hz) 4.38 (2H, d, J ) 1.8 Hz)
3.99 (3H, s) 2.03 (3H, s) 0.89 (9H, s) 0.88 (9H, s) 0.11 (6H, s)
0.09 (3H, s) 0.05 (3H, s); 13C NMR (100 MHz, CDCl3, ppm) δ
161.2, 152.7, 150.6, 130.4, 129.0, 127.7, 126.4, 126.3, 107.5, 84.3,
83.8, 61.2, 59.9, 52.0, 26.0, 25.9, 18.4, 14.1, -4.6, -4.8, -5.0.
Azomethine Ylide Cycloaddition To Form 4-(tert-Butyldim-
ethylsilyloxy)-3-((tert-butyldimethylsilyloxy)methyl)-5-methoxy-
1,6-dimethyl-2-phenyl-1H-indol-7(4H)-one (31). To a solution of
ynone oxazole 26 (10.0 mg, 0.0243 mmol) in freshly distilled CH3-
CH2CN (0.5 mL, stirred over activated 4 Å molecular sieves,
distilled over CaH2, and distilled again over P2O5) and molecular
sieves (activated 4 Å, 7 beads) was added MeOTf (4 µL, 0.0365
mmol). The clear solution was allowed to stir at rt for 15 h. MeOTf
(4 µL, 0.0592 mmol) was added, and the light brown solution was
stirred for an additional 15 h at rt. Salt formation was indicated by
TLC analysis of reaction mixture, Rf ) 0.0 and by mass spectros-
copy with molecular ion (M+) calcd for C24H32NO4Si 426, found
m/z ) 426. The oxazolium salt was transferred to a solution of
J. Org. Chem, Vol. 72, No. 22, 2007 8513

Bobeck et al.
The combined organic extracts were dried (MgSO4) and filtered,
and solvents were removed (aspirator) to yield a light orange oil.
The crude oil from above was dissolved in benzene (1.0 mL) and
DDQ (22.0 mg, 0.0948 mmol) was added in one portion. The dark
black solution was stirred at rt for 2 h then poured into Et2O/H2O/1
M NaOH (10 mL:10 mL:1 mL) and extracted with Et2O. The
combined organic extracts were dried (MgSO4) and filtered, and
solvents were removed (aspirator). The orange oil was purified by
preparative TLC on silica gel (20 cm × 20 cm × 1000 µm, 15%
EtOAc/hexanes eluent) to give 16.8 mg of 31 as an orange oil and
1.7 mg of 34 as an orange solid (95% combined yield), analytical
TLC on silica gel 60 F254, 15% EtOAc/hexanes, Rf ) 0.5 (silyl
ether) and Rf ) 0.2 (alcohol). For alcohol 34: Pure material was
obtained by crystallization in EtOAc/hexanes as orange needles:
mp ) 119-121 °C; molecular ion (M + Na) calcd for C18H17-
NNaO4 334.1055, found m/z ) 334.1055, error ) 0 ppm; IR (neat,
cm-1) 3425 OH, 1731 CdO, 1638 CdO; 500 MHz 1H NMR
(CDCl3, ppm) δ 7.52-7.46 (3H, m) 7.31-7.29 (2H, m) 4.51 (2H,
d, J)7.1 Hz) 4.19 (1H, t, J)7.1 Hz) 4.03 (3H, s) 3.79 (3H, s) 2.02
(3H, s); 13C NMR (125 MHz, CDCl3, ppm) δ 181.2, 179.5, 156.6,
139.5, 130.7, 130.2, 129.9, 129.6, 129.1, 128.6, 124.1, 122.8, 61.4,
56.4, 34.3, 9.2.
chromatography on silica gel (5 × 20 cm, 2:1 hexane/Et2O eluent,
1 × 300 mL then 20 mL fractions). Fractions 14-24 were
concentrated to yield product. Fractions 25-63 were concentrated
by rotary evaporation, and the residue was purified by another flash
chromatography on silica gel under the same conditions. Fractions
18-36 were combined with the original 14-24 to give 5.7 g (65%)
of 38 with >95% dr (NMR analysis) as a white foam, analytical
TLC on silica gel 60 F254, 5:1 hexane/EtOAc, Rf ) 0.1: molecular
ion (M + Na+) calcd for C28H26N2NaO2 445.18920, found m/z )
445.1880, error ) 3 ppm; base peak ) 243 amu; IR (neat, cm-1
)
1596, 1574; 300 MHz NMR (CDCl3, ppm) δ 7.66 (1H, d, J ) 0.8
Hz) 7.56-7.48 (6H, m) 7.30-7.17 (9H, m) 7.15 (1H, d, J ) 0.8
Hz) 5.71 (1H, dddd, J ) 17.0, 10.4, 5.5, 5.5 Hz) 5.14-5.04 (2H,
m) 4.01 (1H, dd, J ) 10.4, 4.9 Hz) 3.78 (2H, ddd, J ) 5.5, 1.4, 1.4
Hz) 3.72 (1H, dd, J ) 10.4, 7.1 Hz) 2.56 (1H, d, J ) 6.1 Hz) 1.98
(1H, ddd, J ) 7.1, 6.0, 4.9 Hz); 13C NMR (100 MHz, CDCl3, ppm)
δ 161.7, 143.5, 138.6, 134.4, 129.4, 127.7, 127.5, 126.9, 116.9,
75.0, 71.8, 68.1, 38.6, 32.2.
Allyl Ether Cleavage from 38: (2S,3R)-2-(Oxazol-2-yl)-3-
hydroxymethyl-1-tritylaziridine. A solution of zirconocene dichlo-
ride (2.63 g, 8.99 mmol) in 40 mL of anhydrous THF was cooled
to -78 °C, and nBuLi (1.56 M solution in hexanes, 11.5 mL, 17.9
mmol) was added dropwise over 30 min. After the resulting yellow
solution was stirred at -78 °C for 1 h, a solution of the allyl ether
38 (2.48 g, 5.87 mmol) in anhydrous THF (30 mL, including
cannula and flask washings) was added dropwise via cannula. The
yellow solution was stirred at -78 °C for 5 min, the cooling bath
was removed, and the reaction mixture was allowed to warm to rt.
After 1 h at rt, the resulting dark brown solution was cooled to
0 °C, and 30 mL of saturated aqueous NH4Cl was added. The pale
yellow suspension was stirred at rt for 3 h and then filtered through
Celite (35 cm) with ether (200 mL). The filtrate was washed with
brine, dried (Na2SO4), and concentrated by rotary evaporation.
The residue was purified by flash chromatography on silica gel
(5 × 20 cm, 3:2 hexane/EtOAc eluent, 20 mL fractions). Fractions
16-46 gave 2.22 g (98%) of the product as a colorless foam,
analytical TLC on silica gel 60, 1:1 hexane/EtOAc, Rf ) 0.3:
molecular ion (M + Na+) calcd for C25H22N2NaO2 405.15790,
found m/z ) 405.1582, error ) 1 ppm; IR (neat, cm-1) 3379, O-H;
1574; 300 MHz NMR (CDCl3, ppm) δ 7.67 (1H, d, J ) 0.8 Hz)
7.58-7.51 (6H, m) 7.34-7.20 (9H, m) 7.15 (1H, d, J ) 0.8 Hz)
4.13 (1H, ddd, J ) 12.1, 6.3, 4.1 Hz) 4.01-3.83 (2H, m) 2.38
(1H, d, J ) 6.0 Hz) 2.02-1.94 (1H, m); 13C NMR (100 MHz,
CDCl3, ppm) δ 162.4, 143.6, 139.2, 129.3, 127.8, 127.0, 127.0,
74.9, 61.1, 39.4, 31.6.
(2S,3R)-2-(Oxazol-2-yl)-3-iodomethyl-1-tritylaziridine (12). A
solution of Ph3P (2.28 g, 8.7 mmol) in 40 mL of anhydrous toluene
was cooled to 0 °C, and diethyl azodicarboxylate (1.3 mL, 8.12
mmol) was added, followed by a solution of the alcohol prepared
above (2.22 g, 5.8 mmol) in anhydrous toluene (40 mL, including
cannula and flask washings), followed by MeI (0.54 mL, 8.7 mmol).
After the resulting white suspension was stirred at 0 °C for 5 min,
the cooling bath was removed, and the reaction mixture was heated
at 70 °C for 2 h. The precipitate gradually dissolved forming a
mixture of a pale yellow solution and a few drops of brown oil,
which was concentrated by rotary evaporation. The residue was
dissolved in 5 mL of CH2Cl2 and purified by flash chromatography
on silica gel (4.5 × 15 cm, 5:1 hexane/ethyl acetate, 20 mL
fractions). Fractions 9-31 were concentrated by rotary evaporation
and purified by another flash chromatography on silica gel (4.5 ×
15 cm, 10:1 hexane/ethyl acetate, 20 mL fractions). Fractions 9-22
gave 2.78 g (97%, 95% for two steps) of the pure product as a
colorless foam, analytical TLC on silica gel 60, 5:1 hexane/ethyl
acetate eluent, Rf ) 0.3. Molecular ion (M + Na+) calcd for C25H21-
IN2NaO 515.05990, found m/z ) 515.0600, error ) 0 ppm; IR
(neat, cm-1) 1574; 300 MHz NMR (CDCl3, ppm) δ 7.70 (1H, d, J
) 0.8 Hz) 7.55-7.48 (6H, m) 7.32-7.20 (9H, m) 7.19 (1H, d, J
) 0.8 Hz) 3.68 (1H, dd, J ) 9.9, 4.7 Hz) 3.55 (1H, dd, J ) 9.9,
9.4 Hz) 2.60 (1H, d, J ) 6.0 Hz) 2.11 (1H, ddd, J ) 9.4, 6.0, 4.7
Amino Alcohol 37. To a solution of oxazole (1.74 g, 25.2 mmol)
in 100 mL of anhydrous THF at rt was added BH3-THF (1.0 M
solution in THF, Aldrich, fresh bottle, 26.5 mL, 26.5 mmol). After
being stirred at rt for 1 h, the colorless solution was cooled to -78
°C, and nBuLi (1.52 M solution in hexanes, 17.4 mL, 26.5 mmol)
was added dropwise over 30 min. The colorless solution was stirred
at -78 °C for 1.5 h, and then a solution of the aldehyde 365c (9.36
g, 25.2 mmol) in anhydrous THF (75 mL, including cannula and
flask washings) was added via cannula dropwise over 30 min. The
resulting pale yellow solution was stirred at -78 °C for 1.5 h and
then quenched with 200 mL of 5% AcOH in EtOH. The cooling
bath was removed, and the reaction mixture was allowed to warm
to rt. After being stirred at rt for 24 h, the colorless solution was
concentrated by rotary evaporation, poured into ether, and washed
with saturated aqueous NaHCO3. The aqueous layer was extracted
with ether, and all organic extracts were combined, dried (Na2-
SO4), and concentrated by rotary evaporation. The crude material
1
contained a 6:1 dr ratio, as determined by H NMR assay. The
residue was purified by flash chromatography on silica gel (5.5 ×
20 cm, 900 mL of 1:1 hexane/ether then 900 mL of 2:1 hexane/
acetone eluent, 20 mL fractions). Fractions 52-67 gave 9.21 g
(84%) of the alcohol 37 with 12:1 dr (NMR analysis) as a white
foam, analytical TLC on silica gel 60 F254, 2:1 hexane/EtOAc, Rf
) 0.2: molecular ion (M + Na+) calcd for C28H28N2NaO3
463.19980, found (electrospray) m/z ) 463.2019, error ) 5 ppm;
base peak ) 243 amu; IR (neat, cm-1) 3342, OH; 1571; 400 MHz
NMR (CDCl3, ppm), major diastereomer, δ 7.62 (1H, d, J ) 0.7
Hz) 7.56-7.51 (6H, m) 7.30-7.24 (6H, m) 7.22-7.16 (3H, m)
7.07 (1H, s) 5.77-5.62 (1H, m) 5.16-5.03 (2H, m) 4.58 (2H, d, J
) 5.1 Hz) 3.60-3.50 (2H, m) 3.36-3.29 (1H, m) 2.85 (1H, dd, J
) 9.5, 2.9 Hz) 2.82-2.50 (1H, s) 2.41 (1H, dd, J ) 9.5, 6.6 Hz).
In addition, signals for the minor (8%) diastereomer were resolved
at 7.62-7.58 (1H, m) 6.99 (1H, s), 4.02 (1H, dd, J) 8.8, 3.7 Hz)
3.91 (1H, d, J ) 8.8 Hz) 3.68-3.65 (2H, m) 3.26-3.19 (1H, s)
3.18 (1H, dd, J) 9.5, 2.6 Hz); 13C NMR (100 MHz, CDCl3, ppm),
major diastereomer, δ 164.3, 146.4, 138.8, 134.1, 128.6, 128.0,
126.9, 126.6, 117.0, 71.8, 70.9, 69.3, 69.1, 54.9.
2-[(2S,3R)-3-Allyloxymethyl-1-trityl-aziridin-2-yl] oxazole 38
from Amino Alcohol 37. To a solution of alcohol 37 (9.21 g, 20.9
mmol) and Ph3P (8.22 g, 31.3 mmol) in 150 mL of anhydrous THF
was added diethyl azodicarboxylate (4.8 mL, 30.7 mmol) dropwise
over 10 min. The cooling bath was removed, and the reaction
mixture was allowed to warm to rt. After being stirred at rt for 14
h, the yellow solution was concentrated to approximately 10 mL
by rotary evaporation and then passed through a 5 × 10 cm2 plug
of silica and the plug was washed with 1:1 hexane/EtOAc. The
filtrate was concentrated by rotary evaporation and purified by flash
8514 J. Org. Chem., Vol. 72, No. 22, 2007

Internal Azomethine Ylide Cycloaddition Methodology
Hz); 13C NMR (100 MHz, CDCl3, ppm) δ 160.5, 143.3, 139.0,
129.2, 127.8, 127.8, 127.1, 75.4, 41.5, 34.9, 3.2.
ppm) δ 187.0, 162.4, 152.2, 148.6, 143.3, 130.2, 129.5, 129.4,
128.1, 127.4, 75.7, 60.1, 42.0, 35.1, 15.3, 3.2.
Preparation of (E)-Methyl 3-(2-((2S,3R)-3-(Iodomethyl)-1-
tritylaziridin-2-yl)oxazol-5-yl)-2-methoxybut-2-enoate (40) from
12. To a solution of diisopropylamine (153 µL, 1.09 mmol) in THF
(3 mL) at 0 °C was added nBuLi (1.53 M solution in hexanes,
0.69 mL, 1.04 mmol) dropwise over 5 min. After being stirred at
0 °C for 30 min, the LDA solution was transferred via cannula
dropwise over 20 min to a stirred solution of oxazole 12 (0.466 g,
0.946 mmol) and TMEDA (1.43 mL, 9.46 mmol, distilled over
solid Na) in THF (3 mL) at -78 °C. After the resulting yellow
solution was stirred at -78 °C for 1 h, ZnCl2 (1.5 M in THF, 2.52
mL, 3.78 mmol) was added dropwise, the cooling bath was
removed, and the organozinc solution was allowed to warm to rt.
In a separate flask, Pd2(dba)3 (87.0 mg, 0.0946 mmol) and PPh3
(99.0 mg, 0.378 mmol) were dissolved in THF (2.5 mL) and stirred
at rt 25 min. Triflate 14 (305 mg, 1.10 mmol of a >95:5 ratio of
E/Z-14) in THF (2.5 mL) was added dropwise, and the resulting
green solution was stirred at rt for 25 min. The previously made
organozinc was added via cannula dropwise over 5 min. After being
stirred at rt for 15 h, the solution was poured into saturated aqueous
NH4Cl (20 mL) and extracted with Et2O (3 × 40 mL). The
combined organic extracts were dried (MgSO4) and filtered, and
solvents were removed (aspirator). The yellow oil was purified by
flash column chromatography on silica gel (40 mm × 16 cm, 5:1
hexanes/EtOAc, 30 mL fractions) to yield 0.408 g (70%) of ester
40 as a colorless solid, analytical TLC on silica gel 60 F254, 5:1
EtOAc/hexanes, Rf ) 0.3. Pure material was obtained by crystal-
lization in EtOAc/hexanes as clear rods: mp ) 125-127 °C;
molecular ion (M + Na) calcd for C31H29IN2NaO4 643.1070, found
m/z ) 643.1077, error ) 1 ppm; IR (neat, cm-1) 1729 CdO; 400
MHz 1H NMR (CDCl3, ppm) δ 7.50-7.49 (6H, m) 7.30-7.21 (9H,
m) 7.10 (1H, s) 3.75 (3H, s) 3.69 (3H, s) 3.70-3.66 (1H, m) 3.53
(1H, dd, J ) 9.9 Hz, 9.2 Hz) 2.53 (1H, d, J ) 5.9 Hz) 2.13-2.07
(1H, m) 2.07 (3H, s); 13C NMR (125 MHz, CDCl3, ppm) δ 165.0,
160.0, 149.7, 144.6, 143.5, 129.5, 128.0, 127.4, 126.2, 112.9, 75.6,
58.6, 52.6, 41.9, 35.3, 13.8, 3.3.
(E)-7-(tert-Butyldimethylsilyloxy)-2-(2-((2S,3R)-3-(iodomethyl)-
1-tritylaziridin-2-yl)oxazol-5-yl)-3-methoxyhept-2-en-5-yn-4-
one (43). To a solution of tert-butyldimethylsilyl propargyl ether32
(213 mg, 1.25 mmol) in THF (8 mL) at -78 °C was added nBuLi
(1.53 M solution in hexanes, 0.82 mL, 1.25 mmol) dropwise over
5 min. The clear solution was stirred for 1 h at -78 °C, and then
a solution of aldehyde 11 (370 mg, 0.627 mmol) in THF (5 mL
including flask and cannula washings) was added via cannula
dropwise over 5 min. The resulting yellow solution was warmed
to -42 °C and stirred for 2 h at -42 °C. The cooling bath was
then removed, and 10 mL of saturated aqueous sodium bicarbonate
was added. After being stirred at rt 10 min, the solution was poured
into H2O and extracted with Et2O. The combined organic extracts
were dried (MgSO4) and filtered, and solvents were removed
(aspirator).
The crude alcohol 42 from above, N-methylmorpholine N-oxide
(154 mg, 1.32 mmol), and molecular sieves (activated powder, 4
Å, 1.40 g) in CH2Cl2 (13 mL) were stirred at rt for 30 min. TPAP
(44.0 mg, 0.125 mmol) was then added in one portion, and the
black solution was stirred at rt for 1 h. The black solution was
then filtered through a silica gel plug eluting with 100 mL of a 1:1
acetone/hexanes solution. Solvents were removed (aspirator), and
the light yellow solid was purified by flash column chromatography
on silica gel (40 mm × 17 cm, 20% EtOAc/hexanes, 25 mL
fractions) to yield 0.335 g (70%) of ketone 43 as a light yellow
foam, analytical TLC on silica gel 60 F254, 20% EtOAc/hexanes,
Rf ) 0.4: molecular ion (M + Na) calcd for C39H43IN2NaO4Si
781.1934, found m/z ) 781.1932, error ) 0 ppm; IR (neat, cm-1
)
1648 CdO; 500 MHz 1H NMR (CDCl3, ppm) δ 7.57 (1H, s) 7.53-
7.51 (6H, m) 7.29-7.26 (6H, m) 7.23-7.22 (3H, m) 4.38 (1H,
AB, J ) 17.6 Hz) 4.36 (1H, AB, J ) 17.6 Hz) 3.75 (3H, s) 3.66
(1H, dd, J ) 9.8 Hz, 4.9 Hz) 3.50 (1H, dd, J ) 9.8 Hz, 9.0 Hz)
2.56 (1H, d, J ) 5.9 Hz) 2.19 (3H, s) 2.13-2.09 (1H, m) 0.89
(9H, s) 0.10 (6H, s); 13C NMR (125 MHz, CDCl3, ppm) δ 174.7,
161.1, 150.5, 148.9, 143.5, 129.9, 129.5, 128.0, 127.3, 120.0, 92.7,
84.3, 75.6, 60.1, 51.9, 41.9, 35.2, 25.9, 18.4, 15.3, 3.4, -5.0.
(E)-3-(2-((2S,3R)-3-(Iodomethyl)-1-tritylaziridin-2-yl)oxazol-
5-yl)-2-methoxybut-2-enal (11). To a solution of ester 40 (0.958
g, 1.54 mmol) in toluene (25 mL) at -78 °C was added DIBAL-H
(20 wt % solution, 4.8 mL, 5.79 mmol) dropwise. After the resulting
yellow solution was stirred for 2 h at -78 °C, the cooling bath
was removed and 25 mL of Et2O was added followed by 25 mL of
saturated aqueous sodium potassium tartrate (Rochelle’s salt). The
mixture was vigorously stirred for 1 h, and then the mixture was
extracted with Et2O. The combined organic extracts were dried
(MgSO4) and filtered, and solvents were removed (aspirator) to
give 0.719 g (79%) of 41 as a white foam that was sufficiently
pure for the next reaction without further purification, analytical
TLC on silica gel 60 F254, 30% EtOAc/hexanes, Rf ) 0.2. A
solution of the alcohol from above (185 mg, 0.312 mmol),
N-methylmorpholine N-oxide (77.0 mg, 0.655 mmol), and molecular
sieves (activated powder, 4 Å, 360 mg) in CH2Cl2 (5 mL) was
stirred at rt. After the solution was stirred at rt 30 min, TPAP (22.0
mg, 0.0624 mmol) was added in one portion. After being stirred at
rt for 1 h, the black solution was filtered through a silica gel plug
eluting with 150 mL of a 1:1 acetone/hexanes solution. Solvents
were removed (aspirator), and the light yellow solid was purified
by flash column chromatography on silica gel (30 mm × 15 cm,
2:1 hexanes/Et2O, 20 mL fractions) to yield 0.150 g (82%) of
aldehyde 11 as a light yellow foam, analytical TLC on silica gel
60 F254, 2:1 hexanes/Et2O, Rf ) 0.3: molecular ion (M + Na)
calcd for C30H27IN2NaO3 613.0964, found m/z ) 613.0959, error
) 1 ppm; IR (neat, cm-1) 1673 CdO; 500 MHz 1H NMR (CDCl3,
ppm) δ 9.99 (1H, s) 7.53-7.51 (6H, m) 7.30-7.27 (6H, m) 7.27
(1H, s) 7.25-7.22 (3H, m) 3.80 (3H, s) 3.68 (1H, dd, J ) 9.8 Hz,
4.4 Hz) 3.50 (1H, dd, J ) 9.8 Hz, 9.8 Hz) 2.57 (1H, d, J ) 5.9
Hz) 2.24 (3H, s) 2.19-2.15 (1H, m); 13C NMR (125 MHz, CDCl3,
Cycloaddition from Ketone 43: Isolation of 45. To a nitrogen-
flushed dry NMR tube were added AgOTf‚1/2benzene24 (10.0 mg,
0.0343 mmol) and C6D6 (0.25 mL) and then ketone 43 (20.0 mg,
0.0264 mmol) in C6D6 (0.2 mL including cannula and flask
washings) via cannula, and the tube was set in the dark. After 3 h,
1H NMR showed no starting oxazole 43, and oxazolium salt
formation was indicated by characteristic changes in the chemical
shift of the oxazole hydrogen from δ ) 7.67 ppm (C6D6) to 8.55
ppm (C6D6), and this solution was transferred via syringe equipped
with a syringe filter to a solution of BnMe3N+CN- (19.0 mg, 0.106
mmol) in freshly distilled CH3CN (1.0 mL including NMR tube
washings, stirred over activated 4 Å molecular sieves, distilled over
CaH2, and distilled again over P2O5) at rt over 5 min. The dark
orange solution was stirred at rt for 2 h and then poured into H2O/
brine and extracted with Et2O. The combined organic extracts were
dried (MgSO4) and filtered, and solvents were removed (aspirator).
The orange oil was purified by preparative TLC on silica gel (20
cm × 20 cm × 1000 µm pretreated with NEt3 vapor for 30 min,
5:1 hexanes/EtOAc with 2% NEt3 eluent) to give 5.4 mg (33%) of
tetracycle 45 as an orange oil, analytical TLC on silica gel 60 F254,
40% EtOAc/hexanes, Rf ) 0.7: [R]23 -12.5 (c 0.04, EtOAc).
D
Molecular ion (M + Na) calculated for C39H42N2NaO4Si: 653.2812,
found m/z ) 653.2808, error ) 1 ppm; IR (neat, cm-1) 1657 Cd
O, 1642 CdO; UV (CH3OH, nm) 286 (ꢀ 1100) 350 (ꢀ 600) 433 (ꢀ
450); 500 MHz 1H NMR (CDCl3, ppm) δ 7.45-7.44 (6H, m) 7.31-
7.22 (9H, m) 5.14 (1H, AB, J ) 14.2 Hz) 4.92 (1H, AB, J ) 14.2
Hz) 4.55 (1H, d, J ) 13.8 Hz) 4.10 (1H, dd, J ) 13.8 Hz, 3.9 Hz)
4.00 (3H, s) 3.03 (1H, d, J ) 4.9 Hz) 2.89 (1H, dd, J ) 4.9 Hz,
3.9 Hz) 1.97 (3H, s) 0.81 (9H, s) 0.01 (3H, s) -0.05 (3H, s); 13C
NMR (125 MHz, CDCl3, ppm) δ 179.9, 179.0, 157.4, 141.7, 129.4,
J. Org. Chem, Vol. 72, No. 22, 2007 8515

Bobeck et al.
128.4, 128.1, 128.0, 127.3, 127.2, 123.0, 120.3, 74.4, 61.4, 58.9,
50.2, 41.9, 35.4, 26.3, 18.7, 8.7, -5.2, -5.2.
796.3962, error ) 3 ppm; IR (neat, cm-1) 1659 CdO; 500 MHz
1H NMR (CDCl3, ppm) overlapping diastereomer signals given as
a sum of individual isomer values, δ 7.48-7.44 (10H, m) 7.30-
7.21 (15H, m) 5.36 (1H, s) 5.36 (0.6H, s) 4.77 (1H, AB, J ) 12.0
Hz) 4.74 (0.6H, AB, J ) 12.5 Hz) 4.68 (0.6H, AB, J ) 12.5 Hz)
4.64 (1H, AB, J ) 12.0 Hz) 4.63 (0.6H, d, J ) 13.2 Hz) 4.56 (1H,
d, J ) 13.2 Hz) 4.18-4.13 (1.6H, m) 3.59 (3H, s) 3.57 (2H, s)
3.30 (0.6H, q, J ) 7.1 Hz) 3.26 (1H, q, J ) 6.8 Hz) 2.91-2.88
(2.6H, m) 2.81 (0.6H, d, J ) 4.9 Hz) 1.44 (3H, d, J ) 6.8 Hz)
1.42 (2H, d, J ) 7.1 Hz) 0.89 (6H, s) 0.86 (9H, s) 0.84 (6H, s)
0.80 (9H, s) 0.25 (1.8H, s) 0.17 (3H, s) 0.06 (1.8H, s) 0.05 (3H, s)
5-((E)-4,7-Bis(tert-butyldimethylsilyloxy)-3-methoxyhept-2-en-
5-yn-2-yl)-2-((2S,3R)-3-(iodomethyl)-1-tritylaziridin-2-yl)ox-
azole (46). To a solution of tert-butyldimethylsilyl propargyl ether32
(251 mg, 1.47 mmol) in THF (10 mL) at -78 °C was added nBuLi
(1.47 M solution in hexanes, 1.0 mL, 1.47 mmol) dropwise over 5
min. After the clear solution was stirred for 1 h at -78 °C, a solution
of aldehyde 11 (435 mg, 0.737 mmol) in THF (5 mL including
cannula washings) was added via cannula dropwise over 5 min.
The resulting yellow solution was warmed to -42 °C and stirred
for 2 h. The cooling bath was then removed, 10 mL of saturated
aqueous sodium bicarbonate was added, and the solution was stirred
at rt 10 min. The resulting light yellow solution was poured into
brine and extracted with Et2O. The combined organic extracts were
dried (MgSO4) and filtered, and solvents were removed (aspirator).
The crude alcohol from above was dissolved in CH2Cl2 (15 mL),
and tert-butyldimethylsilyl chloride (222 mg, 1.47 mmol) was added
followed by imidazole (125 mg, 1.84 mmol). After being stirred
for 15 h at rt, the reaction mixture was poured into H2O (20 mL)
and extracted wth CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried (Na2SO4) and filtered, and solvents were
removed (aspirator). The clear oil was purified by flash column
chromatography on silica gel (50 mm × 16 cm, 10% EtOAc/
hexanes, 40 mL fractions) to yield 0.500 g (78%) of oxazole 46 as
an inseparable 1:1 mixture of diastereomers as a white foam,
analytical TLC on silica gel 60 F254, 10% EtOAc/hexanes, Rf )
0.2: molecular ion (M + Na) calcd for C45H59IN2NaO4Si2 897.2956,
found m/z ) 897.2947, error ) 1 ppm; IR (neat, cm-1) 1638; 400
MHz 1H NMR (CDCl3, ppm) overlapping diastereomer signals
given as a sum of individual isomer values, δ 7.53-7.51 (12H, m)
7.29-7.19 (18H, m) 7.02 (1H, s) 7.00 (1H, s) 5.69 (1H, t, J ) 1.8
Hz) 5.67 (1H, t, J ) 1.8 Hz) 4.38 (2H, d, J ) 1.8 Hz) 4.34 (2H,
2, J ) 1.8 Hz) 3.98 (3H, s) 3.97 (3H, s) 3.70-3.66 (2H, m) 3.59-
3.53 (2H, m) 2.57-2.54 (2H, m) 2.16-2.06 (2H, m) 2.00 (3H, s)
1.99 (3H, s) 0.90 (9H, s) 0.89 (9H, s) 0.88 (18H, s) 0.11 (3H, s)
0.11 (3H, s) 0.09 (6H, s) 0.08 (3H, s) 0.07 (3H, s) 0.03 (3H, s)
0.02 (3H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 159.9, 159.7,
152.5, 152.5, 151.0, 151.0, 143.5, 143.5, 129.5, 129.5, 128.0, 128.0,
127.3, 127.3, 125.6, 125.5, 107.4, 107.2, 84.4, 84.4, 83.7, 83.7,
75.7, 75.6, 61.1, 61.0, 59.9, 59.8, 52.0, 52.0, 41.8, 41.7, 35.3, 35.2,
26.0, 26.0, 18.4, 18.4, 18.3, 14.2, 14.1, 3.5, 3.5, -4.4, -4.5, -4.7,
-4.7, -4.9, -4.9.
-0.01 (1.8H, s) -0.05 (1.8H, s) -0.06 (3H, s) -0.16 (3H, s); 13
C
NMR (100 MHz, CDCl3, ppm) δ 184.6, 184.5, 144.1, 143.9, 132.3,
132.3, 129.4, 129.3, 128.0, 127.3, 127.3, 123.8, 123.3, 117.1, 117.0,
116.3, 116.3, 83.9, 83.8, 77.4, 74.5, 74.2, 63.0, 62.7, 57.5, 56.9,
53.1, 50.8, 50.6, 45.1, 45.0, 43.1, 41.9, 35.1, 34.7, 29.9, 29.9, 26.2,
26.1, 25.7, 25.7, 18.5, 18.4, 8.9, 8.8, -4.2, -4.3, -4.7, -4.8, -5.0,
-5.1, -5.2, -5.4.
NCS Oxidation of 50 to Indoloquinone 45. To a solution of
AgOTf‚1/2benzene24 (23.0 mg, 0.0778 mmol) in CH2Cl2 (0.25 mL)
in a dry, nitrogen-flushed NMR tube was added a solution of
oxazole 46 (34.0 mg, 0.0389 mmol) in CD2Cl2 (0.45 mL including
cannula and flask washings) via cannula. After 1 h at rt, shielded
from light, 1H NMR showed no starting oxazole 46, and the brown
solution was transferred via syringe equipped with a syringe filter
to a solution of BnMe3N+CN- (27.0 mg, 0.156 mmol) in CD3CN
(2.0 mL including NMR tube washings) at 0 °C over 5 min. The
orange solution was warmed to rt over 5 min and then stirred an
addition 1 h at rt. The dark solution was poured into H2O/brine
(20 mL, 1:1 v:v) and extracted with EtOAc (3 × 15 mL). The
combined organic extracts were dried (MgSO4) and filtered, and
solvents were removed (aspirator). To the crude product obtained
above in THF (0.6 mL) at -78 °C was added KHMDS (0.30 mL
of a 0.258 M solution in THF, 0.0778 mmol) and the solution stirred
at -78 °C for 30 min. NCS (0.34 mL of a 0.232 M solution in
THF, 0.0778 mmol) was added and the solution stirred for an
additional 25 min at -78 °C. After being warmed to rt over 15
min, the orange solution was poured into H2O and extracted with
EtOAc. The combined organic extracts were dried (MgSO4) and
filtered, and solvents were removed. The orange oil was purified
by preparative TLC on silica gel (20 cm × 20 cm × 1000 µm
pretreated with NEt3 vapor for 30 min, 5:1 hexanes/EtOAc with
2% NEt3 eluent) to give 4.1 mg (17% over two steps) of tetracycle
45 as an orange oil identical to the material described above by 1H
NMR.
Cyanide Adduct 50 via Azomethine Ylide Generation from
46. To a solution of AgOTf‚1/2benzene24 (8.0 mg, 0.026 mmol) in
C6D6 (0.2 mL) in a dry, nitrogen flushed NMR tube was added a
solution of oxazole 46 (24 mg, 0.027 mmol) in C6D6 (0.4 mL
including cannula and flask washings) via cannula. After sitting in
Azomethine Ylide Cycloaddition from Bis-TBS-Protected
Diol 46: Isolation of 54 and 55 and Detection of 53. To a solution
of AgOTf‚1/2benzene24 (13.5 mg, 0.0457 mmol) in CD2Cl2 (0.2 mL)
in a dry, nitrogen-flushed NMR tube was added a solution of
oxazole 46 (40.0 mg, 0.0457 mmol) in CD2Cl2 (0.4 mL including
cannula and flask washings) via cannula. After the tube sat in the
1
the dark for 3.5 h at rt, H NMR showed no starting oxazole 46
and oxazolium salt formation was indicated by characteristic
changes in the chemical shift of the oxazole hydrogens from δ )
7.01 and 6.99 ppm (CD2Cl2) to 7.77 and 7.73 ppm (CD2Cl2), and
the brown solution was transferred via syringe equipped with a
syringe filter to a solution of BnMe3N+CN- (19 mg, 0.11 mmol)
in freshly distilled CH3CN (1.0 mL including NMR tube washings,
stirred over activated 4 Å molecular sieves, distilled over CaH2,
and distilled again over P2O5) at 0 °C over 5 min. After the orange
solution was stirred at 0 °C for 30 min, the reaction was warmed
to rt over 10 min and stirred for an additional 30 min. The dark
solution was poured into H2O/brine and extracted with EtOAc. The
combined organic extracts were dried (MgSO4) and filtered, and
solvents were removed (aspirator). The brown oil was purified by
preparative TLC on silica gel (20 cm × 20 cm × 1000 µm
pretreated with NEt3 vapor for 30 min, 5:1 hexanes/EtOAc with
2% NEt3 eluent) to give 6.9 mg (33%) of tetracycle 50 as a white
solid in a 3:2 mixture (1H NMR analysis) of inseparable diaster-
eomers, analytical TLC on silica gel 60 F254 pretreated with NEt3
vapor, 5:1 hexanes/EtOAc with 2% NEt3, Rf ) 0.6: molecular ion
(M + Na) calcd for C46H59N3NaO4Si2 796.3942, found m/z )
1
dark for 1 h at rt, H NMR showed no starting oxazole 46 and
oxazolium salt formation was indicated by characteristic changes
in the chemical shift of the oxazole hydrogens from δ ) 7.01 and
6.99 ppm (CD2Cl2) to 7.77 and 7.73 ppm (CD2Cl2), and this solution
was transferred via syringe equipped with a syringe filter to a
solution of BnMe3N+CN- (8.0 mg, 0.0457 mmol) in CH2Cl2 (2.0
mL including NMR tube washings) at 0 °C over 5 min. After the
orange solution was stirred at 0 °C for 1 h, H2O (2 mL) was added
and the solution was poured into H2O and extracted with CH2Cl2.
The combined organic extracts were dried (Na2SO4) and filtered,
and solvents were removed (aspirator) to yield crude 53 as a 1:1
ratio of diastereomers. In preparative work, this mixture was used
without further purification to minimize decomposition, but chro-
matography allowed isolation of small amounts of partially purified
material for spectroscopy. Preparative TLC on silica gel 60 F254,
5:1 hexanes/EtOAc 2% NEt3, Rf ) 0.4 (20 cm × 20 cm × 1000
µm, 5:1 hexanes/EtOAc 2% NEt3 eluent) gave the less polar
diastereomer of 53; ESMS molecular ion (M + Na) calcd for
8516 J. Org. Chem., Vol. 72, No. 22, 2007

Internal Azomethine Ylide Cycloaddition Methodology
1
C46H59N3NaO4Si2 796.4, found m/z ) 796.4; partial 500 MHz H
NMR (CDCl3, ppm) δ 7.41-7.40 (6H, m) and 7.31-7.20 (9H, m)
for the N-Tr group, 5.77 (1H, s) for the CH-OTBS hydrogen, 4.60
(1H, dd, J ) 14.6 Hz, 2.0 Hz) and 4.48 (1H, dd, J ) 14.6 Hz, 2.7
Hz) for the CH2OTBS hydrogens, 3.98 (3H, s) for the OCH3
hydrogens, 3.60 (1H, d, J ) 13.4 Hz) and 3.49 (1H, dd, J ) 13.4
Hz, 2.2 Hz) for the N-CH2-CHNTr hydrogens, 2.59 (1H, d, J )
4.6 Hz) and 2.15 (1H, dd, J ) 4.6 Hz, 2.2 Hz) for the aziridine
hydrogens, 1.79 (3H, s) for the C-6 CH3 hydrogens; 13C NMR (125
MHz, CDCl3, ppm) δ 117.4 for the CN. For the more polar
diastereomer, Rf ) 0.2, partial purification by preparative TLC on
0.039 mmol) was added dropwise and the mixture stirred at rt for
15 h. The dark orange solution was poured into brine (20 mL) and
extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts
were dried (Na2SO4) and filtered, and solvents were removed
(aspirator). The orange oil was was purified by preparative TLC
on silica gel (20 cm × 20 cm × 1000 µm pretreated with NEt3
vapor for 30 min, 30% EtOAc/hexanes with 2% NEt3 eluent) to
give 4.9 mg (75%) of alcohol 54 as an orange solid identical to the
1
material described above by H NMR.
Carbamoylation of 54 and Analytical Scale Detritylation. To
a solution of alcohol 54 (3.8 mg, 0.0074 mmol) in CH2Cl2 (0.5
mL) cooled to -78 °C was added trichloroacetyl isocyanate (18
µL of a 0.42 M solution in CH2Cl2, 0.0076 mmol) dropwise. After
being stirred at -78 °C for 1 h, the reaction was warmed to rt over
20 min and then stirred for an additional 1 h. The orange solution
was poured into H2O (8 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic extracts were dried (Na2SO4) and
filtered, and solvents were removed (aspirator). The unstable orange
oil was purified by preparative TLC on silica gel (20 cm × 20 cm
× 250 µm pretreated with NEt3 vapor for 30 min, 100% EtOAc
with 2% NEt3 eluent) to give 4.0 mg (80%) of 56 as an orange oil
that was quickly used in the following reaction to minimize
decomposition; analytical TLC on silica gel 60 F254 pretreated with
NEt3 vapor, 100% EtOAc with 2% NEt3 eluent, Rf ) 0.2: molecular
ion (M + Na) m/z calcd for C36H28Cl3N3NaO6 726.1, found 726.1;
1
buffered silica gel as above gave peaks in the 500 MHz H NMR
(CDCl3, ppm) δ 7.59-7.57 (6H, m) and 7.31-7.19 (9H, m) for
the N-Tr group, 5.31 (1H, s) for the CH-OTBS hydrogen, 4.50 (1H,
d, J ) 13.2 Hz) and 4.38 (1H, dd, J ) 13.2 Hz, 2.2 Hz) for the
CH2OTBS hydrogens, 3.92 (3H, s) for the OCH3 hydrogens, 2.79
(1H, d, J ) 5.4 Hz) and 2.35 (1H, dd, J ) 5.4 Hz, 3.4 Hz) for the
aziridine hydrogens, 1.70 (3H, s) for the C-6 CH3 hydrogens. If
the chromatography was attempted without NEt3 buffer in the
eluent, then increased decomposition was observed, tentatively to
give ca. 10% conversion to 49 according to ESMS data (m/z )
747 amu; 49 + H) and proton chemical shifts of δ 5.06 (s, CH
adjacent to OTBS), 4.83 (AB q, J ) 11.9 Hz) and 4.69 (AB q, J
) 11.9 Hz for methylene adjacent to OTBS), 4.09 (s, OMe), 2.87
(d, J ) 4.9 Hz) and 2.83 (dd, J ) 4.9 Hz, 3.6 Hz) for the aziridine
protons, and 1.84 (s, Me). For preparative purposes, NEt3 (0.16
mL, 1.14 mmol) was added to the crude cycloadduct from above
in CH3CN (7 mL) and the mixture was placed under an atmosphere
of O2 (balloon). The reaction was stirred at rt 10 min and HF-pyr
(0.18 mL of a 3.9 M solution in CH3CN, 0.702 mmol) was then
added. After the solution was stirred at rt for 16 h under O2, the
dark red solution was poured into satd aq NaHCO3 (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were dried (Na2SO4) and filtered, and solvents were removed
(aspirator). The red oil was purified by preparative TLC on silica
gel (20 cm × 20 cm × 1000 µm, 50% EtOAc/hexanes eluent) to
give 3.8 mg (16%) of alcohol 54 as an orange solid, 5.2 mg (18%)
of 45 as an orange oil, and 3.5 mg (14%) of 55 as a red solid (total
of 48% cylclized material), analytical TLC on silica gel 60 F254,
40% EtOAc/hexanes, for 54, Rf ) 0.4. Pure 54 obtained by
crystallization in EtOAc/hexanes as orange needles: mp ) >200
°C dec; molecular ion (M + ) calcd for C33H28N2O4 516.2049, found
m/z ) 516.2051, error ) 0 ppm; IR (neat, cm-1) 3417 OH, 1640
CdO, 1600 CdO; 500 MHz 1H NMR (CDCl3, ppm) δ 7.43-7.42
(6H, m) 7.32-7.29 (6H, m) 7.27-7.24 (3H, m) 4.78 (1H, dd, J )
13.9 Hz, 6.1 Hz) 4.61 (1H, dd, J ) 13.9 Hz, 8.1 Hz) 4.54 (1H, d,
J ) 13.9 Hz) 4.15 (1H, dd, J ) 13.9, 3.9 Hz), 4.03 (3H, s) 3.90
(1H, dd, J ) 8.1 Hz, 6.1 Hz) 2.89 (1H, dd, 4.9 Hz, 3.9 Hz) 2.84
(1H, d, J ) 4.9 Hz) 1.99 (3H, s); 13C NMR (125 MHz, CDCl3,
ppm) δ 180.9, 178.9, 157.5, 144.1, 140.8, 129.3, 129.1, 128.3,
128.1, 127.5, 125.0, 119.5, 74.5, 61.5, 56.7, 50.5, 42.6, 33.9, 8.9.
For 55, analytical TLC on silica gel 60 F254, 40% EtOAc/hexanes,
Rf ) 0.2. Pure 55 was obtained by crystallization in EtOAc/hexanes
as fine red needles: mp ) 165-168 °C dec; molecular ion (M +
Na) calcd for C34H29N3NaO5 582.2005, found m/z ) 582.2007, error
) 0 ppm; IR (neat, cm-1) 3415 OH, 1650 CdO, 1574 CdO; 500
MHz 1H NMR (CDCl3, ppm) δ 7.58-7.57 (6H, m) 7.33-7.30 (6H,
m) 7.27-7.23 (3H, m) 4.65 (1H, dd, J ) 11.7 Hz, 2.4 Hz), 4.27
(1H, dd, J ) 11.7 Hz, 2.4 Hz) 4.12 (1H, d, J ) 12.2 Hz) 4.05 (3H,
s) 4.03 (1H, s) 3.84 (1H, dd, J ) 11.7 Hz, 11.7 Hz) 3.66 (1H, dd,
J ) 12.2 Hz, 4.4 Hz) 2.96 (1H, d, J ) 5.4 Hz) 2.64 (1H, broad dd,
J obsc) 1.89 (3H, s); 13C NMR (125 MHz, CDCl3, ppm) δ 182.3,
179.3, 158.3, 152.8, 143.5, 129.6, 128.1, 127.5, 126.0, 121.4, 116.7,
82.8, 75.9, 64.3, 61.8, 52.7, 45.6, 41.1, 8.6.
1
partial 500 MHz H NMR (CDCl3, ppm) δ 7.44-7.43 (6H, m)
and 7.31-7.23 (9H, m) for the N-Tr group, 5.47 (2H, s) for the
CH2-O hydrogens, 4.58 (1H, d, J ) 13.9 Hz) and 4.15 (1H, dd, J
) 13.9 Hz, 3.9 Hz) for the N-CH2-NTr hydrogens, 4.05 (3H, s)
for the OCH3 hydrogens, 3.14 (1H, d, J ) 6.1 Hz) and 2.90 (1H,
dd, J ) 6.1 Hz, 3.9 Hz) for the aziridine hydrogens, 1.98 (3H, s)
for the C-6 CH3 hydrogens. To a solution of crude 56 from above
(1.0 mg, 0.0014 mmol) in CH2Cl2 (0.4 mL) at 0 °C was added
triethylsilane (7 µL of a 0.629 M solution in CH2Cl2, 0.043 mmol)
followed by methanesulfonic acid (8 µL of a 0.514 M solution in
CH2Cl2, 0.043 mmol). After the orange solution was stirred at 0 °C
for 25 min, NEt3 (4 µL, 0.030 mmol) was added and the solution
stirred an addition 25 min at 0 °C. A 0.2 mL portion of a 5% K2-
CO3 aqueous solution in MeOH (1:1, v/v) was added, and the
reaction was allowed to warm to rt and stir an addition 1 h.
Formation of known amino alcohol 5929 was indicated by the
molecular ion (M + Na) for C15H17N3NaO6 358.1, together with a
weak mass peak corresponding to aziridinomitosene A8 (4),
molecular ion (M + Na) for C15H15N3NaO5 340.1. Characteristic
signals to support the formation of 4 could not be found in the
NMR spectrum.
(1S,2,S)-9-Carbamoyloxymethyl-2,3-dihydro-7-methoxy-6-
methyl-1,2-(N-tritylaziridino)-1H-pyrrolo[1,2-a]indole (57). To
the tetracyclic alcohol 54 (2.8 mg, 0.0050 mmol) in CH2Cl2 (0.5
mL) at -78 °C was added trichloroacetyl isocyante (13 µL of a
0.42 M solution in CH2Cl2, 0.054 mmol), and the reaction was
stirred at -78 °C for 1 h. The reaction was allowed to warm to rt
over 20 min and then stirred for an additional 1 h. Next, 0.5 mL of
a 5% K2CO3 aqueous solution in MeOH (1:1, v:v) was added and
the reaction was stirred vigorously at rt. After being stirred
vigorously at rt for 3 h, the biphasic solution was poured into H2O
(5 mL) and extracted with CH2Cl2 (3 × 7 mL). The combined
organic extracts were dried (Na2SO4), filtered, and solvents were
removed (aspirator). The orange solid was purified by preparative
TLC on silica gel (20 cm × 20 cm × 250 µm pretreated with NEt3
vapor for 30 min, 100% EtOAc with 2% NEt3 eluent) to give 2.0
mg (67%) of 57 as an orange solid, analytical TLC on silica gel 60
F254 pretreated with NEt3 vapor, 100% EtOAc with 2% NEt3
eluent, Rf ) 0.6: molecular ion (M + Na) calculated for C34H29N3-
NaO5 m/z ) 582.2, found 582.2; IR (neat, cm-1) 3465 NH, 3346
NH, 1725 CdO, 1659 CdO, 1642 CdO; 500 MHz 1H NMR
(CDCl3, ppm) δ 7.46-7.45 (6H, m) 7.32-7.24 (9H, m) 5.36 (1H,
AB, J ) 13.4 Hz) 5.31 (1H, AB, J ) 13.4 Hz) 4.57 (1H, d, J )
13.7 Hz) 4.19 (2H, bs) 4.14 (1H, dd, J ) 13.7 Hz, 3.9 Hz) 4.03
Preparation of (1S,2,S)-9-Hydroxymethyl-2,3-dihydro-7-
methoxy-6-methyl-1,2-(N-tritylaziridino)-1H-pyrrolo[1,2-a]in-
dole (54) from 45. To a solution of tetracycle 45 (8.0 mg, 0.013
mmol) in CH3CN (0.6 mL) at rt was added NEt3 (11 µL, 0.076
mmol) dropwise. HF‚pyr (10 µL of a 3.9 M solution in CH3CN,
J. Org. Chem, Vol. 72, No. 22, 2007 8517

Bobeck et al.
(3H, s) 2.98 (1H, d, J ) 4.8 Hz) 2.88 (1H, dd, J ) 4.8 Hz, 3.9 Hz)
1.97 (3H, s); 13C NMR (125 MHz, CDCl3, ppm) δ 179.6, 179.0,
157.5, 156.7, 142.4, 129.4, 128.2, 128.1, 127.8, 127.5, 123.8, 113.7,
106.5, 74.6, 61.5, 59.1, 50.4, 42.3, 34.8, 8.8.
mmol). After the orange solution was stirred at 0 °C for 30 min,
diisopropylethylamine (2 µL, 0.010 mmol) was added and the
solution stirred at 0 °C for an additional 30 min. Solvents were
removed (aspirator), and the orange solid was purified by prepara-
tive TLC on silica gel (20 cm × 20 cm × 250 µm, 10:1 CH2Cl2/
MeOH eluent) to give 1.0 mg (83%) of amino alcohol 59 identical
Detritylation of 57: Detection of 58 and Isolation of 59. To
a solution of 57 (2.7 mg, 0.0048 mmol) and triphenylsilane (78 µL
of a 0.0614 M solution in CH2Cl2, 0.0048 mmol) in CH2Cl2 (0.45
mL) cooled to -78 °C was added triflic acid (0.5 µL, 0.0048 mmol).
The reaction was allowed to stir at -78 °C for 5 min and then
slowly warmed to -40 °C over 30 min and stirred an additional
15 h at -40 °C. To the orange solution was added pH 10.3 buffer
(0.2 mL) cooled to 0 °C. The biphasic solution was warmed to rt
and extracted with CH2Cl2 (5 × 1 mL). The combined organic
extracts were dried (Na2SO4) and filtered, and solvents were
removed (aspirator). The orange solid was purified by preparative
TLC on silica gel (20 cm × 20 cm × 250 µm, 10:1 CH2Cl2/MeOH
eluent) to give 2.0 mg (72%) of 58 as a 3:1 mixture of diastereomers
as an orange solid, analytical TLC on silica gel 60 F254, 10:1 CH2-
Cl2/MeOH, Rf ) 0.63 for the less polar major diastereomer and Rf
) 0.60 for the more polar minor diastereomer: molecular ion (M
+ Na) calcd for C34H31N3NaO6 m/z ) 600.2, found 600.2; partial
1
by H NMR and mass spectrometry comparisons with literature
data.29,30
Alternatively, a solution of tetracycle 57 (2.0 mg, 0.0036 mmol)
and triphenylsilane (109 µL of a 0.0653 M solution in CH2Cl2,
0.0071 mmol) in CH2Cl2 (0.40 mL) cooled to -78 °C was treated
with triflic acid (0.6 µL, 0.0071 mmol). The reaction was allowed
to stir at -78 °C for 5 min and then was slowly warmed to -40 °C
over 30 min and stirred an additional 15 h at -40 °C. To the orange
solution was added DIEA (2 µL, 0.011 mmol), and the mixture
was stirred at -40 °C for an additional 30 min. Solvents were then
removed (aspirator), and the orange solid was purified by prepara-
tive TLC on silica gel as above to give 1.0 mg (83%) of amino
alcohol 59.29
1
Acknowledgment. We thank Prof. L. Jimenez for kindly
providing an NMR spectrum of synthetic aziridinomitosene A.
This work was supported by the National Institutes of Health
(CA17918).
500 MHz H NMR (CDCl3, ppm) δ 7.60 (6H, m) and 7.32-7.22
(9H, m) for the N-Tr group, 5.02 (1H, AB, J ) 12.2 Hz) and 5.01
(1H, AB, J ) 12.2 Hz) for the CH2OC(O)NH2 hydrogens, 4.60
(2H, br s) for the C(O)NH2 hydrogens, 4.52 (1H, dd, J ) 12.4 Hz,
7.7 Hz) for one of the N-CH2-CHNTr hydrogen, 4.00 (3H, s) for
the OCH3 hydrogens, 3.25 (1H, d, J ) 5.1 Hz) for the CH-OH
hydrogen, 1.94 (3H, s) for the C-6 CH3 hydrogens.
Supporting Information Available: NMR spectra of new
compounds; X-ray data tables; procedures for oxidation of 32 to
31. This material is available free of charge via the Internet at
http://pubs.acs.org.
To a solution of amino alcohol 58 (2.0 mg, 0.0035 mmol)
prepared above in CH2Cl2 (0.3 mL) at 0 °C were added triethylsilane
(11 µL of a 0.628 M solution in CH2Cl2, 0.0069 mmol) and
trifluoroacetic acid (12 µL of a 0.573 M solution in CH2Cl2, 0.0069
JO7013559
8518 J. Org. Chem., Vol. 72, No. 22, 2007