Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene

Article abstract of DOI:10.1021/jm901384s

Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tu

Full text of DOI:10.1021/jm901384s

J. Med. Chem. 2010, 53, 1109–1116 1109
DOI: 10.1021/jm901384s
Structure-Activity Studies of Urea, Carbamate, and Sulfonamide Derivatives of Acylfulvene
Trevor C. McMorris,† Ramesh Chimmani,† Kashinatham Alisala,† Michael D. Staake,† Gangadasu Banda,† and
Michael J. Kelner*,‡
†Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0358 and
‡Department of Pathology, UCSD Medical Center, 200 West Arbor Drive, Mail Code 8320, San Diego, California 92103-8320
Received September 17, 2009
Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens.
Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor
activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a
randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic
hormone-refractory prostate cancer who failed prior treatment with two different standard chemothera-
peutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement
with a variety of nucleophiles to produce analogues that retain key functional groups required for
biological activity including the reactive cyclopropylmethyl carbinol and R,β-unsaturated ketone. As
described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key
functional groups and display potent biological activity toward target solid tumor cells in vitro but are
relatively nontoxic toward a nontarget B-cell derived cell line.
Introduction
Illudins S and M (1, 2)1,2 are highly toxic sesquiterpenes
found in the basidiomycete Omphalotus illudens. Illudins and
their derivatives were evaluated for antitumor activity in the
National Cancer Institute Developmental Therapeutics Pro-
gram. Illudin M significantly increased the life span of rats
with Dunning leukemia but had a low therapeutic index in
Figure 1
solid tumor systems.3,4 The acylfulvene derivatives of illudins,
however, display potent in vivo antitumor activity against a
variety of multidrug resistant solid tumors. The lead acylful-
phosphate (NADPH) is the coenzyme involved in this bio-
reductive alkylation (Figure 1).8
The ability of acylfulvenes to undergo bioreductive activa-
vene, clinically known as irofulven, in a randomized phase IIB
clinical trial significantly increased overall survival in patients
tion to a reactive intermediate that is susceptible to nucleo-
with metastatic hormone-refractory prostate cancer who pre-
philic attack by DNA appears to be clinically relevant. Recent
viously failed salvage treatment with docetaxotere.5
studies indicate that acylfulvenes selectively alkylate DNA
to produce N3-deoxyadenosine and N7-deoxyguanosine ad-
The compounds behave as alkylating agents and at room
temperature react spontaneously with thiol nucleophiles, such
ducts, and there is direct correlation between the production
as cysteine or glutathione (GSHa).6 The optimum pH for this
of these adducts and drug cytotoxicity.9 Recently it was
reaction is about 6. Toxicity to myeloid leukemia cells (HL 60)
demonstrated that acylfulvene derivatives can function as
can be modulated by altering glutathione levels in the cells.
both reversible and irreversible inhibitors of cellular glu-
The reaction of illudin S with GSH is illustrated in (Figure 1).7
tathione.10
Three derivatives of illudins have been studied extensively.
Dehydroilludin M (3, Chart 1) is obtained readily by oxida-
tion of illudin M (2),11 whereas acylfulvene (4) is obtained
Michael type addition to the R,β-unsaturated ketone gives a
cyclohexadiene intermediate that is rapidly converted to a
morestablearomaticproduct. Thisnecessitatesopening of the
cyclopropane which results in reaction with nucleophiles
simply by adding dilute sulfuric acid to an aqueous solution of
such as water, DNA, and protein.7 Enzymatic reduction of
illudin S.12 On further treatment of illudin S with formalde-
illudin S leads to a similar reactive intermediate and to a
hyde solution, a hydroxymethyl acylfulvene (5), now renamed
stable aromatic product. Nicotinamide adenosine dinucleotide
irofulven, is obtained.13 The latter, irofulven, has demon-
strated significant antitumor activity in several phase II
clinical trials.
*To whom correspondence should be addressed. Phone: (619) 543-
5976. Fax: (619) 543-3730. E-mail: mkelner@ucsd.edu.
aAbbreviations: Ac2O, acetic anhydride; DABCO, 1,4-diazabicyclo-
(2,2,2,)octane; DMSO, dimethyl sulfoxide; DIPEA, N,N-diisopropy-
lethylamine; DMAP, 4-(dimethylamino)pyridine; EtOAc, ethyl acetate;
GSH, reduced glutathione; MeOH, methanol; NADPH, nicotinamide
adenosine dinucleotide phosphate; PPh3, triphenylphosphine; t-BuOH,
tertiary butanol; TFA, trifluoroacetic acid; THF, tetrahydrofuran.
Dehydroilludin M reacts more slowly with GSH than
illudin M and is 100 times less toxic to HL 60 cells. Likewise,
acylfulvene reacted more slowly than illudin S and was much
less toxic to HL 60 cells. As anticipated, enzymatic reduction
of acylfulvene (NADPH, rat liver cytosol) occurred much
r
2010 American Chemical Society
Published on Web 01/12/2010
pubs.acs.org/jmc

1110 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
McMorris et al.
Chart 1
Table 1. Cytotoxicity IC50 Values (nM) for Urea Derivatives (X ( SD,
N=3)
Table 2. Cytotoxicity IC50 Values (nM) for Carbamate Derivatives
(X ( SD, N=3)
more slowly than with illudin S, yielding the corresponding
aromatic product.8
Irofulven, while similar in properties to acylfulvene, is
uniquebecauseofthe reactivityofthe primary allylichydroxyl
group. Displacement of the hydroxyl takes place with a
variety of nucleophiles giving products retaining the reactive
cyclopropylmethyl carbinol and R,β-unsaturated ketone.
Well over 100 such derivatives have been prepared and tested
for biological activity.14,15 Thus, we have been able to make
structure-activity correlations of these compounds. We have
also included in our study compounds derived from the
reaction of acylfulvene and acrolein which afforded a three
carbonfunctionalizedsidechainasin6. The primaryhydroxyl
in 6, while not as reactive as the corresponding group in
irofulven, nevertheless leads to compounds with potent anti-
tumor activity, both in vitro in xenograft models and in phase
II clinical trials.
Efficacy of various compounds was assessed from the
differential of toxicity in lung carcinoma MV522 cells and in
non target B 8392 human cells. The compounds are listed in
Tables 1-3.
In earlier papers we had explored the high susceptibility of
the allylic hydroxyl to SN1 displacement by a variety of
nucleophiles under acidic conditions. There were indications
that biological activity of derivatives could be modified by
altering the polarity of the substituent group; more polar
groups appeared to enhance activity.
irofulven was rapidly replaced by hydroxyurea when the
compounds were dissolved in a 1:1 mixture of 2 M H2SO4
and acetone at room temperature in 1 h. The yield of alkylated
product 7 was 83%.
The efficacy of 7 was similar to that of irofulven, and it was
somewhatless toxic. The acetate8, preparedfrom 7withacetic
anhydride (Ac2O), 4-(dimethylamino)pyridine (DMAP), was
more toxic than that of irofulven. These results were recently
reported.16
We were thus prompted to examine further urea derivatives
listed in Table 1. The study has been extended to carbamate
derivatives (Table 2) and also sulfonamide derivatives
(Table 3).
Chemistry
The syntheses of urea, carbamate, and sulfonamide deri-
vatives of acylfulvene were readily accomplished using
known procedures. Treatment of the amines 9, 1017 with
4-nitrophenylchloroformate in CH2Cl2 in the presence of
1,4-diazabicyclo(2,2,2,)octane (DABCO) gave the activated
It occurred to us that hydroxyurea would be a good
candidate nucleophile. In the event, the hydroxyl group of

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1111
Scheme 3a
Table 3. Cytotoxicity IC50 Values (nM) for Sulfonamide Derivatives
(X ( SD, N = 3)
a Reagents and conditions: (a) R-SO2Cl, DABCO, CH2Cl2, 0 °C.
using trifluoroacetic acid (TFA) with 5% of water to yield
N-hydroxysulfamide derivative 18d.21 The key intermediate
was prepared in single steps outlined in Scheme 5.
Antitumor Activity
For cytotoxicity studies, the compounds were dissolved in
cellculturegradedimethyl sulfoxide(DMSO) (1 mg/mL stock
solution), and the solutions were diluted in sterile 10%
DMSO/phosphate-buffered saline just prior to addition to
cultures of the MV522 lung adenocarcinoma or 8392 B-cells.
Control cells received equal amounts of the DMSO/phos-
phate-buffered saline. Analogues of irofulven selectively tar-
get and kill tumor cells by apoptosis at 24-48 h after drug
exposure.22 Therefore, cell survival was determined at 48 h by
use of trypan blue exclusion studies as previously described in
detail.3,23
A total of 23 novel compounds were assayed for overall
toxicity and selective antitumor activity using conven-
tional cell culture techniques. Overall cytotoxicity was studied
by continuous 48 h exposure to the target human MV522
lung adenocarcinoma and the nontarget 8392 B-cell
lymphoma/leukemia lines. Cell survival was assessed by try-
pan blue exclusion technique. For comparison, the cytotoxi-
city data for irofulven are provided from previous studies.14
All compounds showed considerable greater toxicity in
MV522 cells compared to B 8392 cells in the 48 h cytotoxicity
assay. We had previously noted that one of the parameters
predicting in vivo activity in xenograft models was the ratio of
nontarget B 8392 cytotoxicity (IC50) to the target MV522
cytotoxicity (IC50). All of the analogues displayed favorable
cytotoxicity ratios compared to the parent irofulven (5)
compound
carbamates 11, 12 which on subsequent treatment with appro-
priate amine yielded the urea derivatives 13a-d, 14a-d
(Scheme 1).18
The preparation of carbonate derivatives was achieved in
two steps. Acylfulvene (6) was reacted with 4-nitrophenyl-
chloroformate in the presence of DABCO in CH2Cl2 at 0 °C,
giving the activated carbonate 15 which on treatment with an
appropriate suitable amine afforded the corresponding car-
bamate derivatives 16a-h (Scheme 2).19
Sulfonamide derivatives 17a,b and 18a,b were obtained by
treating amines 9, 10 with the appropriate sulfonyl chloride in
the presence of DABCO in CH2Cl2 at 0 °C (Scheme 3).20
Sulfamide derivatives were prepared by reacting chlorosul-
fonyl isocyanate with tert-butanol (t-BuOH) in presence of
diisopropyl ethylamine in CH2Cl2 at 0 °C (Scheme 4).21
A hydroxysulfamide derivative was prepared by reacting
the key intermediate 21 with 6 under Mitsunobu conditions
to afford compound 22 which was then fully deprotected
Scheme 1a
a Reagents and conditions: (a) 4-nitrophenyl chloroformate, DABCO, CH2Cl2, 0 °C; (b) R-NH2, DIPEA, CH2Cl2, 0 °C.
Scheme 2a
a Reagents and conditions: (a) 4-nitrophenyl chloroformate, Py, DMAP, CH2Cl2, 0 °C; (b) R-NH2, DIPEA, CH2Cl2, 0 °C.

1112 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
McMorris et al.
Scheme 4a
a Reagents and conditions: (a) chlorosulfonyl isocyanate, t-BuOH, CH2Cl2, 0 °C; (b) TFA, anisole, CH2Cl2, room temp.
Scheme 5a
a Reagents and conditions: (a) chlorosulfonyl isocyanate, t-BuOH, CH2Cl2, 0 °C; (b) 6, PPh3, DIAD, THF, 0 °C; (c) TFA-H2O, 5%.
There does not appear to be a correlation between cyto-
toxicity toward the target MV522 cells and chain length, as
evidenced by comparing 13a and 13c versus 14a and 14c
(Table 1) or by comparing 17a and 17b versus 18a and 18c
(Table 3). Presumablya longer side chainwould berequiredto
reveal the effect of a nonpolar chain. In regard to the type of
heteroatom in the chain, there appears to be little difference
between substituting nitrogen (urea derivatives) for oxygen
(carbamate derivatives), as evidenced by comparing 14a, 14b,
and 14d (Table 1) versus 16c, 16e, and 16h (Table 2). The
substitution of a sulfur for carbon to produce sulfonamide
derivatives, however, results in a marked increase in cytotoxi-
city as evidenced by comparing the urea derivative 14c and
carbamate derivative 16a versus the sulfonamide derivative
18d (Table 3). Indeed, the sulfonamide derivative 18d is one of
the most cytotoxic analogues we have synthesized to date. It is
nearly equivalent in cytotoxicity toward MV522 cells com-
pared to the parent compound illudin S.23 Because selective
toxicity against target MV522 cells to nontarget 8392 cells is a
reliable indication of in vivo efficacy, all the urea derivatives
and the majority of both the carbamate and sulfonamide
derivatives are clearly worthy of further development. Indeed,
two compounds (16e and 18c) displayed ratios nearly two logs
higher than irofulven (5) and a log higher than ratios for other
analogues. Preliminary MV522 xenograftstudiesindicate that
several of the described analogues (16e, 18a, 18c) are active
and induce tumor shrinkage at doses that are nontoxic to the
animals (unpublished observations). Given their stability, ease of
synthesis, and potent activity toward the MV522 target cells,
both of these compounds are viable candidates for clinical trials.
chromatography was carried out with silica gel (Davisil 230-
425 mesh, Fisher Scientific). Analytical TLC was carried out on
Whatman 4420 222 silica gel plates. Reactions were routinely
monitored by TLC. Purity of the compounds was determined by
ThermoFinnigan LCQDECA and NMR spectroscopy. All the
compounds were g95% pure based on NMR and analytical
HPLC data using chromatography conditions as previously
described.24 Yields were calculated by taking into account
recovered starting materials.
(R)-30-(Aminomethyl)-60-hydroxy-20,40,60-trimethylspiro[cyclo-
propane-1,50-inden]-70(60H)-one (9). A synthesis and yield of this
key intermediate were previously published.17 1H NMR (CDCl3 þ
CD3OD) δ 0.72 (m, 1H), 1.08 (m, 1H), 1.32 (s, 3H), 1.34 (m, 1H),
1.48 (m, 1H), 2.03 (s, 3H), 2.12 (s, 3H), 4.07, 4.13 (each d, J=
12 Hz, 2H), 7.05 (s, 1H); 13C NMR (CDCl3 þ CD3OD) δ 9.52,
12.62, 14.43, 16.0, 26.84, 36.2, 38.04, 76.55, 94.40, 126.9, 134.21,
137.28, 145.77, 161.18, 198.68; MS ESI m/z 368 (M þ Na)þ.
(R)-30-(3-Aminopropyl)-60-hydroxy-20,40,60-trimethylspiro[cyclo-
propane-1,50-inden]-70(60H)-one (10). A synthesis and yield of
this key intermediate were previously published.17 1H NMR
(CD3OD) δ 0.77 (m, 1H), 1.06 (m, 1H), 1.33 (s, 3H), 1.42 (m,
2H), 1.84 (m, 2H), 2.07 (s, 3H), 2.11 (s, 3H), 2.79 (m, 2H), 2.97 (t,
J = 7.8 Hz, 2H), 7.07 (s, 1H); 13C NMR (CD3OD) δ 9.5, 13.1,
14.5, 16.7, 25.4, 27.5, 29.4, 38.6, 40.4, 77.4, 127.8, 135.5, 136.7,
139.7, 141.1, 159.7, 198.6.
(R)-4-Nitrophenyl (60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-
dihydrospiro[cyclopropane-1,50-indene]-30-yl)methylcarbamate (11).
To a solution of compound 9 (244 mg, 0.68 mmol) in 5.0 mL of
CH2Cl2 was added DABCO (152.7 mg, 1.36 mmol). The result-
ing solution was cooled to 0 °C. Then p-nitrophenylchlorofor-
mate (161.6 mg, 0.8 mmol) was added. The reaction mixture was
stirred at 0 °C for 3 h. Then the reaction mixture was partially
concentrated and then subjected to column chromatography
(50% ethyl acetate (EtOAc)-hexanes) to give 200.7 mg of 11
(72%) as a yellow liquid. 1H NMR (CDCl3) δ 0.74 (m, 1H), 1.10
(m, 1H), 1.27 (m, 1H), 1.37 (s, 3H), 1.54 (m, 1H), 2.04,
(s, 3H), 2.17 (s, 3H), 3.89 (s, 1H), 4.47 (m, 2H), 5.11 (brs, 1H),
7.11 (s, 1H), 7.31 (d, J=9.2 Hz, 2H), 8.24 (d, J =9.2 Hz, 2H).
Experimental Section
1
General. Melting points are uncorrected. H and 13C NMR
spectra were measured at 400 and 100 MHz, respectively. All

Article
(R)-4-Nitrophenyl 3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1113
5.51 (brs, 1H), 7.11 (s, 1H), 7.39 (s, 1H); 13C NMR (CDCl3)
δ 9.5, 13.1, 14.4, 16.0, 27.5, 36.1, 37.8, 64.3, 76.2, 126.9,
128.9, 134.8, 138.5, 143.2, 159.4, 159.8, 197.8; MS (ESI) m/z
341 (M þ Na)þ.
dihydrospiro[cyclopropane-1,50-indene]-30-yl)propylcarbamate (12).
To a solution of compound 10 (81.4 mg, 0.21 mmol) in 5.0 mL of
CH2Cl2 was added DABCO (42.2 mg, 0.42 mmol). The resulting
solution was cooled to 0 °C. Then p-nitrophenylchloroformate
(50.7 mg, 0.25 mmol) was added. The resulting reaction mixture
was stirred at 0 °C for 5 h. Then the reaction mixture was
partially concentrated and then subjected to column chroma-
tography (50% EtOAc-hexanes) to give 62.5 mg of 12 (68%) as
a yellow liquid. 1H NMR (CDCl3) δ 0.67 (m, 1H), 1.06 (m, 1H),
1.32 (m, 1H), 1.35 (s, 3H), 1.46 (m, 1H), 1.93 (m, 2H), 2.05 (s,
6H), 2.75-2.82 (m, 2H), 4.23, (m, 2H), 7.12 (s, 1H), 7.33 (d,
J =9.2 Hz, 2H), 8.22 (d, J= 9.2 Hz, 2H).
(R)-1-(2-Chloroethyl)-3-(3-(60-hydroxy-20,40,60-trimethyl-70-oxo-
60,70-dihydrospiro[cyclopropane-1,50-indene]-30-yl)propyl)urea (14a).
To a solution of compound 12 (17.4 mg, 0.039 mmol) and 2-chlo-
roethylamine (10.6 mg, 0.156 mmol) in CH2Cl2 (2.5 mL) was
added N,N-diisopropylethylamine (20.16 mg, 0.156 mmol) at
room temperature. The solution was stirred for about 2 h and
then partially concentrated in high vacuum and subjected to
column chromatography (2% MeOH-EtOAc) to give 11.7 mg
of 14a (78%) as a yellow solid. 1H NMR (CDCl3) δ 0.66 (m, 1H),
1.03 (m, 1H), 1.31 (m, 1H), 1.34 (s, 3H), 1.45 (m, 1H), 1.67 (m, 2H),
2.02 (s, 6H), 2.66 (m, 2H), 3.21 (m, 2H), 3.53 (q, J=4.4 Hz, 2H),
3.61 (t, J=5.8 Hz, 2H), 3.9 (brs, 1H), 4.58 (brs, 1H), 4.84 (brs, 1H),
7.11 (s, 1H); 13C NMR (CDCl3) δ 9.1, 13.0, 13.9, 16.0, 25.1, 27.1,
30.9, 37.4, 40.4, 42.1, 45.1, 75.9, 94.4, 135.9, 136.2, 139.1, 139.6,
157.6, 157.7, 197.1; MS (ESI) m/z 401 (M þ Na)þ.
(R)-1-(2-Chloroethyl)-3-((60-hydroxy-20,40,60-trimethyl-70-oxo-
60,70-dihydrospiro[cyclopropane-1,50-indene]-30-yl)methyl)urea (13a).
To a solution of compound 11 (21.4 mg, 0.052 mmol) and
2-chloroethylamine (24.4 mg, 0.210 mmol) in CH2Cl2 (2.0 mL)
was added N,N-diisopropylethylamine (14.4 mg. 0.112 mmol) at
room temperature. The solution was stirred for about 2 h and
then partially concentrated in high vacuum and subjected
to column chromatography (2% methanol (MeOH) in EtOAc)
to give 11.7 mg of 13a (78%) as a yellow solid. 1H NMR (CDCl3)
δ 0.66 (m, 1H), 1.05 (m, 1H), 1.32 (m, 1H), 1.35 (s, 3H), 1.45
(m, 1H), 2.01 (s, 3H), 2.09 (s, 3H), 3.52 (m, 2H), 3.60 (t, J =
4.8 Hz, 2H), 3.86 (brs, 1H), 4.32 (each dd, J = 10.8 Hz, 2H),
4.58 (brs, 1H), 5.09 (brs, 1H), 7.04 (s, 1H); 13C NMR (CDCl3)
δ 9.6, 13.0, 14.4, 16.0, 27.5, 36.9, 37.7, 42.1, 45.1, 76.2, 129.8,
134.9, 138.4, 142.7, 157.4, 160.0, 197.9; MS (ESI) m/z 373
(M þ Na)þ.
(R)-1-(3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydros-
piro[cyclopropane-1,50-indene]-30-yl)propyl)-3-(2-hydroxyethyl)urea
(14b). To a solution of compound 12 (24.6 mg, 0.056 mmol) and
ethanolamine (13.68 mg, 0.224 mmol) in CH2Cl2 (2.0 mL) was
added N,N-diisopropylethylamine (14.47 mg, 0.112 mmol) at
0 °C. The solution was stirred for about 40 min at 0 °C and then
partially concentrated in high vacuum and subjected to column
chromatography (5% MeOH-EtOAc) to give 14.9 mg of 14b
(73%) as a yellow solid. 1H NMR (CDCl3) δ 0.66 (m, 1H), 1.03
(m, 1H), 1.29 (m, 1H), 1.34 (s, 3H), 1.45 (m, 1H), 1.67 (m, 2H),
2.02 (s, 6H), 2.67 (m, 2H), 3.21 (m, 2H), 3.31 (t, J=5.2 Hz, 2H),
3.68 (t, J=4.8 Hz, 2H), 7.11 (s, 1H); 13C NMR (CDCl3) δ 9.1,
13.0, 14.0, 16.0, 25.2, 27.5, 30.8, 37.5, 40.5, 43.3, 63.3, 76.0, 94.4,
136.0, 136.3, 139.6, 157.9, 159.3, 170.4, 197.2; MS (ESI) m/z 361
(M þ H)þ.
(R)-1-((60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)methyl)-3-(2-hydroxyethyl)urea
(13b). To a solution of compound 11 (20.0 mg, 0.048 mmol) and
ethanolamine (14.6 mg, 0.24 mmol) in CH2Cl2 (2.5 mL) was
added N,N-diisopropylethylamine (12.4 mg, 0.096 mmol) at 0 °C.
The solution temperature was raised to room temperature. After
15 min the solution was partially concentrated in high vacuum
and then subjected to column chromatography (5% MeOH-
EtOAc) to give 11.3 mg of 13b (83%) as an orange-red gum. 1H
NMR (CDCl3) δ 0.66 (m, 1H), 1.05 (m, 1H), 1.31 (m, 1H), 1.32
(s, 3H), 1.45 (m, 1H), 2.01 (s, 3H), 2.08 (s, 3H), 3.32 (q, J =
4.8 Hz, 2H), 3.67 (t, J = 5.20 Hz, 2H), 3.96 (brs, 1H), 4.30 (m,
2H), 4.84 (brs, 1H), 5.22 (m, 1H), 7.02 (s, 1H); 13C NMR
(CDCl3) δ 9.5, 13.0, 14.4, 15.9, 27.5, 29.6, 36.8, 37.7, 43.1,
63.1, 76.2, 129.8, 134.9, 138.3, 142.6, 158.9, 160.0, 197.9; MS
(ESI) m/z 333 (M þ H)þ.
(R)-1-Hydroxy-3-(3-(60-hydroxy-20,40,60-trimethyl-70-oxo-60,70-
dihydrospiro[cyclopropane-1,50-indene]-30-yl)propyl)urea (14c).
To a solution of compound 12 (36.1 mg, 0.082 mmol) and
hydroxylamine hydrochloride (22.8 mg, 0.328 mmol) in CH2Cl2
(3.0 mL) was added N,N-diisopropylethylamine (21.2 mg, 0.164
mmol) at 0 °C. The solution was stirred for about 3 h and then
partially concentrated in high vacuum and subjected to column
chromatography (1% MeOH-EtOAc) to give 20.9 mg of 14c
(76%) as a yellow solid. 1H NMR (CDCl3) δ 0.67 (m, 1H), 1.04
(m, 1H), 1.30 (m, 1H), 1.34 (s, 3H), 1.44 (m, 1H), 1.73 (m, 2H),
2.03 (s, 6H), 2.69 (m, 2H), 3.22 (m, 2H), 7.12 (s, 1H); MS (ESI)
m/z 401 (M þ Na)þ.
(R)-1-Hydroxy-3-((60-hydroxy-20,40,60-trimethyl-70-oxo-60,70-
dihydrospiro[cyclopropane-1,50-indene]-30-yl)methyl)urea (13c).
To a solution of compound 11 (35.5 mg, 0.086 mmol) and
hydroxylamine hydrochloride (17.9 mg, 0.258 mmol) in CH2Cl2
(2.0 mL) was added N,N-diisopropylethylamine (22.2 mg, 0.172
mmol) at 0 °C. After 1 h the solution was partially concentrated
in high vacuum and then subjected to column chromatography
(1% MeOH-EtOAc) to give 19.6 mg of 13c (73%) as an orange-
(R)-N-(3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl)-1,40-bipiperidine-10-car-
boxamide (14d). To a solution of compound 12 (20.5 mg, 0.046
mmol) in DMF (0.5 mL) was added 4-piperidinopiperidine
(15.4 mg, 0.092 mmol) at 0 °C. After 30 min, the solution was
concentrated in high vacuum. The residue was purified by column
chromatography (10% methanol-EtOAc) to yield 14.8 mg of
14d (67%) as an orange-red gum. 1H NMR (CDCl3 þ CD3OD)
δ 0.65 (m, 1H), 1.04 (m, 1H), 1.28 (m, 1H), 1.33 (s, 3H), 1.45
(m, 5H), 1.60 (m, 4H), 1.68 (m, 2H), 1.83 (m, 2H), 2.02, (s, 6H),
2.45 (m, 1H), 2.64 (m, 2H), 2.71 (m, 4H), 3.27 (m, 2H), 3.92 (brs,
2H), 4.50 (t, J = 4.5 Hz, 1H), 7.10 (s, 1H); MS (ESI) m/z 468
(M þ H)þ.
1
yellow solid. H NMR (CDCl3) δ 0.71 (m, 1H), 1.08 (m, 1H),
1.30 (m, 1H), 1.35 (s, 3H), 1.48 (m, 1H), 2.00 (s, 3H), 2.11 (s, 3H),
4.39 (m, 2H), 5.86 (brs, 1H), 7.09 (s, 1H); 13C NMR (CDCl3) δ
9.5, 13.1, 14.4, 16.0, 27.5, 36.1, 37.8, 76.2, 126.9, 128.7, 134.9,
138.4, 143.2, 159.8, 161.4, 197.9; MS (ESI) m/z 327 (M þ Na)þ.
(R)-1-((60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)methyl)-3-methoxyurea (13d).
To a solution of compound 11 (15.0 mg, 0.036 mmol) and
methoxylamine hydrochloride (12 mg, 0.144 mmol) in CH2-
Cl2 (2.0 mL) was added N,N-diisopropylethylamine (9.3 mg,
0.072 mmol) at 0 °C. The reaction mixture was warmed to room
temperature and stirred for about 2 h. Then the solution was
partially concentrated in high vacuum and then subjected to
column chromatography (1% MeOH-EtOAc) to give 11.39 mg
of 13d (72%) as a yellow solid. 1H NMR (CDCl3) δ 0.69 (m, 1H),
1.09 (m, 1H), 1.33 (m, 1H), 1.37 (s, 3H), 1.51 (m, 1H), 2.02
(s, 3H), 2.14 (s, 3H), 3.64 (s, 3H), 3.92 (brs, 1H), 4.26 (m, 2H),
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 4-Nitrophenylcarbonate
(15). To a solution of compound 6 (453 mg, 1.65 mmol) in 5.0 mL
of CH2Cl2 was added DABCO (370.3 mg, 3.3 mmol). The resul-
ting solution was cooled to 0 °C. Then p-nitrophenylchloroformate
(370 mg, 1.65 mmol) was added, and the mixture was stirred at the
same temperature for about 5 h. The reaction mixture was concen-
trated partially and then subjected to column chromatography (50%
EtOAc-hexanes) to give 478 mg of 15 (66%) as a yellow liquid. 1H
NMR (CDCl3) δ 0.68 (m, 1H), 1.07 (m, 1H), 1.25 (m, 1H), 1.36
(s, 3H), 1.46 (m, 1H), 1.93 (m, 2H), 2.04 (s, 3H), 2.06 (s, 3H), 2.8

1114 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
McMorris et al.
(m, 2H), 3.92 (s, 1H), 4.32, (m, 2H), 7.13 (s, 1H), 7.36 (d, J=9.2 Hz,
2H), 8.22 (d, J= 9.2 Hz, 2H).
(m, 1H), 1.35 (s, 3H), 1.45 (m, 1H), 1.80 (m, 2H), 2.04 (s, 6H), 2.73
(m,2H),3.36(d,J=4.8 Hz, 2H), 3.73 (t, J=5.2 Hz, 2H), 4.11 (t, J=
6.0 Hz, 2H), 5.05 (brs, 1H), 7.12 (s, 1H); 13C NMR (CDCl3) δ 8.9,
12.7, 13.8, 15.8, 24.0, 27.4, 29.5, 37.3, 43.2, 61.9, 64.2, 75.9, 125.4,
135.7, 136.3, 138.9, 139. 8, 157.1, 157. 6, 197.1; MS (ESI) m/z 360
(M - H)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propylhydroxycarbamate (16a).
To a solution of compound 15 (53.4 mg, 0.121 mmol) and
hydroxylamine hydrochloride (12.6 mg, 0.181 mmol) in CH2Cl2
(3.0 mL) was added N,N-diisopropylethylamine (62.5 mg, 0.484
mmol) at 0 °C. The solution temperature was raised to room
temperature. After 4.0 h the solution was partially concentrated
and then subjected to column chromatography (40% EtOAc-
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl Morpholine-4-carboxylate
(16f). To a solution of compound 15 (46.4 mg, 0.105 mmol) in
DMF (1.0 mL) was added morpholine (22.8 mg, 0.262 mmol) at
0 °C. Then the mixture was warmed to room temperature. After
1 h the solution was concentrated in high vacuum. The residue
was purified by column chromatography (50% EtOAc-hexanes)
to yield 36.4 mg of 16f (84%) as a yellow syrup. 1H NMR
(CDCl3) δ 0.66 (m, 1H), 1.05 (m, 1H), 1.30 (m, 1H), 1.34 (s, 3H),
1.44 (m, 1H), 1.83 (m, 2H), 2.03 (s, 6H), 2.73-2.67 (m, 2H), 3.45
(s, 4H), 3.64 (s, 4H), 4.13 (m, 2H), 7.11 (s, 1H); 13C NMR
(CDCl3) δ 9.0, 12.9, 13.8, 15.8, 24.1, 27.4, 29.6, 37.4, 43.8, 64.9,
66.5, 75.9, 125.5, 135.4, 136.2, 139.0, 139.7, 155.2, 157.3, 197.0;
MS (ESI) m/z 410 (M þ Na)þ.
1
hexanes) to give 34.0 mg of 16a (81%) as an orange gum. H
NMR (CDCl3) δ 0.7 (m, 1H), 1.07 (m, 1H), 1.34 (m, 1H), 1.37 (s,
3H), 1.46 (m, 1H), 1.93 (m, 2H), 2.05 (s, 6H), 2.75-2.80 (m, 2H),
3.96 (brs, 1H), 4.23 (m, 2H), 6.92 (brs, 1H), 7.15 (s, 1H); 13C
NMR (CDCl3) δ 9.3, 13.1, 14.1, 16.1, 24.0, 27.6, 29.5, 37.5, 65.5,
76.6, 125.4, 135.0, 136.2, 138.8, 139.8, 157.5, 158.9, 196.9; MS
(ESI) m/z 356 (M þ Na)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 2-Fluoroethylcarbamate
(16b). To a solution of compound 15 (50.1 mg, 0.114 mmol)
and 2-fluoroethylamine hydrochloride (22.6 mg, 0.228 mmol) in
DMF (1.0 mL) was added triethylamine (28.78 mg, 0.285 mmol)
at 0 °C. After 30 min the solution was concentrated in high
vacuum. The residue was purified by column chromatography
(40% EtOAc-hexanes) to yield 39.8 mg of 16b (96%) as a
yellow syrup. 1H NMR (CDCl3) δ 0.65 (m, 1H), 1.04 (m, 1H),
1.31 (m, 1H), 1.34 (s, 3H), 1.44 (m, 1H), 1.84-1.77 (m, 2H), 2.03
(s, 6H), 2.73-2.67 (m, 2H), 3.44, 3.51 (m, 2H), 3.96 (brs, 1H),
4.09 (m, 2H), 4.42, 4.53 (m, 2H), 5.05 (brs, 1H), 7.11 (s, 1H); 13C
NMR (CDCl3) δ 9.0, 12.9, 13.9, 15.9, 24.0, 27.5, 29.6, 37.4, 41.3,
64.4, 75.9, 82.0, 82.3, 125.8, 136.0, 136.3, 139.0, 139.8, 157.5,
197.3; MS (ESI) m/z 364 (M þ H)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl Piperidine-1-carboxylate
(16g). To a solution of compound 15 (34.8 mg, 0.079 mmol) in
DMF (1.0 mL) was added piperidine (13.9 mg, 0.164 mmol) at
0 °C. After 30 min the solution was concentrated in high vac-
uum. The residue was purified by column chromatography
(20% acetone-hexanes) to yield 28.9 mg of 16g (94%) as an
1
orange-red gum. H NMR (CDCl3) δ 0.66 (m, 1H), 1.04 (m,
1H), 1.28 (m, 1H), 1.34 (s, 3H), 1.45 (m, 1H), 1.51 (m, 4H), 1.58
(m, 4H), 1.81 (m, 2H), 2.03 (s, 6H), 2.70 (m, 2H), 3.40 (m, 4H),
4.09-4.13 (m, 2H), 7.12 (s, 1H); 13C NMR (CDCl3) δ 9.0, 12.8,
13.8, 15.8, 24.3, 25.6, 27.5, 29.7, 37.4, 44.7, 64.5, 75.9, 125.4,
135.7, 136.3, 139.1, 139.7, 155.5, 157.4, 197.0; MS (ESI) m/z 386
(M þ H)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 2-Chloroethylcarbamate
(16c). To a solution of compound 15 (95.6 mg, 0.217 mmol)
and 2-chloroethylamine (37.5 mg, 0.325 mmol) in DMF (0.5 mL)
was added N,N-diisopropylethylamine (33.6 mg, 0.260 mmol) at
0 °C. The solution temperature was raised to room temperature.
After 30 min the solution was partially concentrated in high
vacuum and then subjected to column chromatography (40%
EtOAc-hexanes) to give 86.5 mg of 16c (71%) as an orange-red
gum. 1H NMR (CDCl3) δ 0.67 (m, 1H), 1.05 (m, 1H), 1.30 (m,
1H), 1.36 (s, 3H), 1.47 (m, 1H), 1.82 (m, 2H), 2.04 (s, 6H), 2.72
(m, 2H), 3.53 (t, J=5.2 Hz, 2H) 3.62 (d, J=5.2 Hz, 2H), 4.11 (m,
2H), 5.09 (brs, 1H), 7.12 (s, 1H); MS (ESI) m/z 402 (M þ Na)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 2-Bromoethylcarbamate
(16d). To a solution of compound 15 (100.3 mg, 0.228 mmol)
and 2-bromoethylamine (70.5 mg, 0.344 mmol) in DMF (1.0 mL)
was added N,N-diisopropylethylamine (36.97 mg, 0.286 mmol)
at 0 °C. The solution temperature was raised to room tempera-
ture. After 30 min the solution was partially concentrated in
high vacuum and then subjected to column chromatography
(40% EtOAc-hexanes) to give 84.6 mg of 16d (87%) as an
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 1,40-Bipiperidine-10-carboxy-
late (16h). To a solution of compound 15 (48.6 mg, 0.11 mmol) in
DMF (1.0 mL) was added 4-piperidinopiperidine (37 mg, 0.22
mmol) at 0 °C. After 30 min the solution was concentrated in
high vacuum. The residue was purified by column chromato-
graphy (10% methanol-EtOAc) to yield 45.8 mg of 16h (88%)
as an orange-red gum. 1H NMR (CDCl3) δ 0.66 (m, 1H), 1.03
(m, 1H), 1.29 (m, 1H), 1.31 (s, 3H), 1.45 (m, 4H), 1.58 (m, 4H),
1.81 (m, 2H), 2.02 (s, 6H), 2.41 (m, 1H), 2.48 (m, 4 H), 2.66-2.76
(m, 6H), 4.10 (m, 2H), 7.11 (s, 1H); 13C NMR (CDCl3) δ 9.0,
12.8, 13.8, 15.8, 24.2, 24.5, 26.1, 27.5, 29.7, 31.5, 37.4, 43.5, 50.1,
62.4, 64.6, 75.9, 125.4, 135.6, 136.2, 139.1, 139.7, 155.1, 157.4,
197.0. MS (ESI) m/z 386 (M þ H)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 1H-Imidazole-1-carboxy-
late (16i). To a solution of compound 6 (70.0 mg, 0.255 mmol)
in anhydrous CH2Cl2 (2.0 mL) was added carbodiimidazole
(49.4 mg, 0.304 mmol). The reaction mixture was stirred at room
temperature for 3 h and then purified by column chromatogra-
phy (50% EtOAc-hexanes) to yield 57.8 mg of 16i (60%) as an
orange-yellow syrup. 1H NMR (CDCl3) δ 0.66 (m, 1H), 1.26 (m,
1H), 1.29 (m, 1H), 1.34 (s, 3H), 1.97 (m, 2H), 2.04 (s, 6H), 2.79
(m, 2H), 4.44 (t, J=6.0 Hz, 2H), 7.07 (s, 1H), 7.10 (s, 1H), 7.39
(s, 1H), 8.11 (s, 1H); 13C NMR (CDCl3) δ 9.1, 12.9, 13.9, 15.9,
23.9, 27.4, 29.1, 37.4, 67.6, 75.9, 116.9, 125.8, 130.7, 134.1, 136.0,
136.9, 138.9, 140.1, 157.5, 197.0; MS (ESI) m/z 369 (M þ H)þ.
(R)-N-((60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)methyl)methanesulfonamide (17a).
To a solution of compound 9 (145.6 mg, 0.405 mmol) in 2.0 mL
of DMF/CH2Cl2 (1:3) was added DABCO (91 mg, 0.811 mmol).
The resulting solution was cooled to 0 °C. Then methanesulfo-
nyl chloride (69.5 mg, 0.607 mmol) was added. The reaction
mixture was stirred for 2 h at 0 °C, then partially concentrated
and purified by silica gel column chromatography to afford
compound 17a as a deep-red gum in 48% yield (62.8 mg).
1
orange-red gum. H NMR (CDCl3) δ 0.67 (m, 1H), 1.06 (m,
1H), 1.31 (m, 1H), 1.36 (s, 3H), 1.45 (m, 1H), 1.84 (m, 2H),
2.04 (s, 6H), 2.73 (m, 2H), 3.48 (t, J=5.20 Hz, 2H) 3.59 (d, J=
5.2 Hz, 2H), 4.11 (m, 2H), 5.29 (brs, 1H), 7.13 (s, 1H); 13C NMR
(CDCl3) δ 9.3, 13.1, 14.1, 16.1, 24.3, 27.7, 29.8, 32.8, 37.7, 42.9,
64.7, 76.2, 125.8, 136.5, 140.1, 157.7, 197.3; MS (ESI) m/z 447
(M þ Na)þ.
(R)-3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl 2-Hydroxyethylcarbamate
(16e). To a solution of compound 15 (139.6 mg, 0.317 mmol)
in DMF (1.0 mL) was added ethanolamine (23 mg, 0.380 mmol)
at 0 °C. The solution temperature was raised to room tempera-
ture. After 15 min the solution was partially concentrated in
high vacuum and then subjected to column chromatography
(40%EtOAc-hexanes) to give 109.5 mg of 16e (95%) asanorange-
1
red gum. H NMR (CDCl3) δ 0.68 (m, 1H), 1.06 (m, 1H), 1.30

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1115
1H NMR (CDCl3) δ 0.71 (m, 1H), 1.09 (m, 1H), 1.34 (s, 3H),
1.37 (m, 1H), 1.49 (m, 1H), 2.12 (s, 3H), 2.14 (s, 3H), 2.92 (s, 3H),
3.85 (brs, 1H), 4.27 (m, 2H), 4.34 (m, 1H), 7.01 (s, 1H); 13C
NMR (CDCl3) δ 9.6, 13.1, 14.5, 16.4, 27.4, 34.5, 37.9, 39.3, 40.1,
76.25, 127.2, 134.3, 138.0, 143.3, 160.5, 197.9; MS (ESI) m/z 350
(M þ Na)þ.
(CDCl3þ CD3OD) δ 9.0, 12.9, 13.9, 15.4, 16.0, 24.9, 27.4, 30.1,
37.4, 43.1, 75.9, 135.6, 136.4, 138.9, 139.9, 157.9, 197.2; MS
(ESI) m/z 353 (M þ H)þ.
(R)-N-(3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydros-
piro[cyclopropane-1,50-indene]-30-yl)propyl)hydroxysulfamide (18d).
To a solution of tert-butanol (225 mg, 3.0 mmol) in anhydrous
CH2Cl2 (5.0 mL) was added chlorosulfonyl isocyanate (430 mg,
3.0 mmol) at 0 °C. After 20 min the resulting solution was then
added to a solution of O-(tert-butyldimethylsilyl)hydroxyl-
amine 20 (345.4 mg, 2.34 mmol) in DIPEA (910 mg, 7.035 mmol)
in anhydrous CH2Cl2 (8.0 mL). The temperature was raised to
room temperature, and the mixture was stirred for 3 h and then
purified by column chromatography (50% EtOAc-hexanes) to
yield 104.4 mg of 21 (47%) as a white solid. To the solution of 21
(47.2 mg, 0.184 μmol) and 6 (50.4 mg, 0.184 mmol) in anhydrous
tetrahydrofuran (THF) (3.0 mL) was added triphenylphosphine
(48.6 mg, 0.184 mmol) and diisopropyl azodicarboxylate (DIAD)
(37.2 mg, 0.184 mmol). The reaction mixture was stirred for 30 min
at 0 °C and then concentrated in high vacuum and purified by
column chromatography to give 37.71 mg of compound 22 (78%)
as a yellow solid. To the above compound 22 (43 mg, 0.074 mmol)
was added a few drops of anisole followed by 2.0 mL of TFA-H20,
5%. Reaction mixture was stirred for 2 h at 0 °C and then
concentrated in high vacuum. The residue was purified by silica
gel column chromatography to afford 18.4 mg of compound 18d
(68%) as a yellow gum. 1H NMR (CDCl3) δ 0.65 (m, 1H), 0.99 (m,
1H), 1.29 (m, 1H), 1.31 (s, 3H), 1.42 (m, 1H), 1.70 (m, 2H), 2.06 (s,
6H), 2.68 (m, 2H), 3.01 (t, J=6.4 Hz, 2H), 7.09 (s, 1H); 13C NMR
(CDCl3 þ CD3OD) δ 9.1, 12.8, 13.8, 13.9, 16.0, 24.8, 27.4, 30.3,
37.4, 43.2, 76.2, 136.0, 136.4, 140.1, 140.2, 158.4, 197.4; MS (ESI)
m/z 391 (M þ Na)þ.
(R)-N-((60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)methyl)sulfamide (17b). To a solu-
tion of compound 9 (135.4 mg, 0.377 mmol) and sulfamyl chloride
(87 mg, 0.754 mmol) in anhydrous CH2Cl2/DMF (3.0/0.5 mL)
was added N,N-diisopropylethylamine (146.2 mg, 1.13 mmol) at
-20 °C. The reaction mixture was warmed to room temperature,
stirred for 6 h, concentrated in high vacuum, and then subjected to
column chromatography to give 29.8 mg of compound 17b (24%)
as a yellow solid. 1H NMR (CDCl3 þ CD3OD) δ 0.69 (m, 1H),
1.06 (m, 1H), 1.31 (s, 3H), 1.33 (m, 1H), 1.45 (m, 1H), 2.09 (s, 3H),
2.10 (s, 3H), 4.21 (m, 2H), 4.58 (br, 1H), 7.04 (s, 1H); 13C
NMR (CDCl3 þ CD3OD) δ 9.5, 12.8, 14.4, 16.1, 27.3, 37.7,
39.4, 76.2, 127.6, 134.5, 138.1, 143.2, 160.7, 198.1; MS (ESI) m/z
325 (M þ H)þ.
(R)-N-(3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl)methanesulfonamide (18a).
To a solution of compound 10 (19.4 mg, 0.05 mmol) in 2.0 mL of
CH2Cl2 was added DABCO (8.4 mg, 0.075 mmol). The resulting
solution was cooled to 0 °C. Then methanesulfonyl chloride (8.6 mg,
0.075 mmol) was added. The reaction mixture was stirred for
15 min at 0 °C, partially concentrated, and purified by silica gel
column chromatography to afford the expected compound 18a
1
as an orange-yellow liquid in 69% yield (12.2 mg). H NMR
(CDCl3) δ 0.68 (m, 1H), 1.06 (m, 1H), 1.31 (m, 1H), 1.35 (s, 3H),
1.46 (m, 1H), 1.77 (m, 2H), 2.04 (s, 6H), 2.71 (m, 2H), 2.95 (s,
3H), 3.17 (q, J = 6.8 Hz, 2H), 4.38 (brs, 1H), 7.12 (s, 1H); 13C
NMR (CDCl3) δ 9.3, 13.2, 14.1, 16.3, 24.9, 27.6, 31.1, 37.6, 40.4,
43.1, 75.9, 134.7, 135.9, 138.8, 139.7, 139.7, 157.7; MS (ESI) m/z
350 (M - H)þ.
Supporting Information Available: NMR spectral data of
analogues 9-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
(R)-N-(3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl)-4-methylbenzenesulfon-
amide (18b). To a solution of compound 10 (45.3 mg, 0.117
mmol) and DABCO (19.6 mg, 0.175 mmol) in CH2Cl2 (2.5 mL)
was added p-toluenesulfonyl chloride (33.4 mg, 0.175 mmol) at
0 °C. After 1.0 h the reaction mixture was partially concentrated
and then subjected to column chromatography (50% EtOAc-
hexanes) to give 15.4 mg of 18b (90%) as an orange-red liquid.
1H NMR (CDCl3) δ 0.64 (m, 1H), 1.05 (m, 1H), 1.27 (m, 1H),
1.33 (s, 3H), 1.35 (s, 3H), 1.44 (m, 1H), 1.66 (m, 2H), 1.95 (s, 3H),
1.97 (s, 3H), 2.42 (s, 3H), 2.64 (m, 2H), 2.96 (m, 2H), 4.59 (brs,
1H), 7.08 (s, 1H), 7.31 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H);
13C NMR (CDCl3) δ 9.1, 12.9, 13.9, 16.0, 21.5, 24.9, 27.5, 30.3,
37.4, 43.0, 75.9, 125.5, 127.0, 129.7, 135.1, 136.1, 136.7, 138.9,
139.8, 143.5, 157.8, 197.1.
(R)-N-(3-(60-Hydroxy-20,40,60-trimethyl-70-oxo-60,70-dihydrospiro-
[cyclopropane-1,50-indene]-30-yl)propyl)sulfamide (18c). To a so-
lution of tert-butanol (30 mg, 0.41 mmol) in anhydrous CH2Cl2
(4.0 mL) was added chlorosulfonyl isocyanate (58 mg, 0.41
mmol) at 0 °C. After 10 min the resulting solution was then
added to a solution of 10 (123.1 mg, 0.31) in N,N-diisopropy-
lethylamine (DIPEA) (120 mg, 0.93 mmol) in anhydrous methy-
lene chloride. The temperature was raised to room temperature,
and the mixture was stirred for 3 h and then purified by column
chromatography (50% EtOAc-hexanes) to yield 104.4 mg of 19
(72%) as a yellow solid. To the solution of 19 (42.4 mg, 93.8
μmol) in anhydrous CH2Cl2 (2.0 mL) was added a few drops of
anisole followed by 1.0 mL of TFA. The reaction mixture was
stirred for 45 min, then concentrated in high vacuum, then
washed several times with hexanes and finally with 5% EtOAc/
hexanes, and then dried under high vacuum to give 26.1 mg of
compound 18c (79%) as a yellow gum. 1H NMR (CDCl3) δ 0.66
(m, 1H), 1.02 (m, 1H), 1.28 (m, 1H), 1.32 (s, 3H), 1.41 (m, 1H),
1.72 (m, 2H), 2.04, (s, 6H), 2.69 (m, 2H), 3.10
(t, J = 7.2 Hz, 2H), 5.09 (brs, 1H), 7.09 (s, 1H); 13C NMR
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