A stereoselective synthetic approach to (2S,3R)-N-(1′,1′- dimethyl-2′,3′-epoxypropyl)-3-hydroxytryptophan, a component of cyclomarin A

Article abstract of DOI:10.1016/j.tetasy.2005.10.040

A stereoselective synthetic approach to (2S,3R)-N-(1′,1′- dimethyl-2′,3′-epoxypropyl)-3-hydroxytryptophan an amino acid contained in cyclomarin A was accomplished. The synthesis is based on a diastereoselective addition of an indole Grignard into a chiral

Full text of DOI:10.1016/j.tetasy.2005.10.040

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 15–21
A stereoselective synthetic approach to
(2S,3R)-N-(10,10-dimethyl-20,30-epoxypropyl)-
3-hydroxytryptophan, a component of cyclomarin A
*
´
Darren B. Hansen, Alan S. Lewis, Steven J. Gavalas and Madeleine M. Joullie
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA
Received 20 June 2005; revised 23 September 2005; accepted 4 October 2005
Available online 9 January 2006
Abstract—A stereoselective synthetic approach to (2S,3R)-N-(10,10-dimethyl-20,30-epoxypropyl)-3-hydroxytryptophan an amino
acid contained in cyclomarin A was accomplished. The synthesis is based on a diastereoselective addition of an indole Grignard
into a chiral serine aldehyde equivalent.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
both in vitro and in vivo, exhibiting a 92% inhibition of
edema in the phorbol ester induced mouse ear edema
assay at the standard testing dose. The combination of
biological activity and complex molecular architecture
has attracted the interest of several synthetic groups,
culminating in the synthesis of cyclomarin C,2 a close
congeners of cyclomarin A and two independent synthe-
ses of (2S,3R)-N-(10,10-dimethyl-20-propenyl)-3-hydroxy-
tryptophan.3,4 We herein report a synthesis of a fully
protected analogue of (2S,3R)-N-(10,10-dimethyl-20,30-
epoxypropyl)-3-hydroxytryptophan 1 based on Lajoieꢀs
serine aldehyde.
Cyclomarin A is a novel cyclic peptide isolated from a
marine actinomycete collected in a sediment sample
from Mission Bay, California1 (Fig. 1). Cyclomarin A
has demonstrated potent biological activity, having a
mean IC50 of 2.6 lM against a panel of human cancer
cells. More impressive was its anti-inflammatory activity
N
O
O
H
N
HO
N
H
O
O
N
O
2. Results and discussion
N
O
O
N
HO
Nucleophilic additions into aldehydes derived from ser-
ine have been a powerful method for the construction of
non-coded amino acids. Garnerꢀs aldehyde has been one
of the most popular variants of this methodology.5 We
examined the possibility of using Garnerꢀs aldehyde,
which we have used extensively in the past, but we were
also intrigued by a similar serine aldehyde developed by
Lajoie.6,7 Lajoieꢀs chiral serine aldehyde seemed to solve
many of the problems associated with the limited stereo-
control during nucleophilic additions to Garnerꢀs alde-
hyde. The high stereoselectivity of the addition also
complements the use of the Sharpless amino hydroxyl-
ation reaction used by Sugiyama et al. in their synthesis
of the b-hydroxytryptophan moiety, because this reac-
tion can be equally complicated because of a mixture
HN
HO
H
N
HN
O
HO
NH2
O
O
MeO
1
Cyclomarin A
N-(1',1'-dimethyl-2-propenyl)-
3-hydroxytryptophan
Figure 1. Cyclomarin A and (2S,3R)-N-(10,10-dimethyl-2,3-epoxyprop-
yl)-3 hydroxytryptophan 1.
*
Corresponding author. Tel.: +1 215 898 3158; fax: +1 215 573
9711; e-mail: mjoullie@sas.upenn.edu
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.040

16
D. B. Hansen et al. / Tetrahedron: Asymmetry 17 (2006) 15–21
of regioisomers resulting in modest yields. Retrosynthet-
ically, we thought that a properly protected b-hydroxy-
tryptophan moiety could be derived from an ortho ester
intermediate that would come from the addition of an
indole derived Grignard with Lajoieꢀs serine aldehyde
(Fig. 2).
OAc
+
N
N
N
H
a
indoline
3
2
Scheme 1. Reagents and conditions: (a) CuCl, TEA.
O
O
N
N
OAc
HO
PO
ZHN
N
N
H
a
O
O
ZHN
CO2P
O
indoline
2
O
c
b
O
H
O
N
N
O
O
+
ZHN
XMg
4
Br
P = Protecting group
Figure 2. Retrosynthetic analysis of 1.
d
N
N
The synthesis of the indole Grignard precursor is based
on the work by Sugiyama who has shown that indoline
can be transformed into a variety of indole Grignard
precursors.8 Construction of the indole Grignard
precursor began from indoline, using a copper-catalyzed
reverse prenylation to provide alkyne 2 (Scheme 2). It
was found that this reaction must be monitored closely
to prevent the formation of a side product of nearly
identical Rf from contaminating alkyne 2. Prolonged
reflux of this reaction allowed for identification of this
intermediate 3 (Scheme 1). This undesired side reaction
made this chemistry unfeasible for the total synthesis
and chromatographic separation of compounds 2 and
3. To better understand this side reaction, we decided
to explore the formation of 3. Our first goal was to
determine if 3 was formed directly from the indoline
and the alkyne acetate or whether the reaction occurred
after the formation of 2. Exposure of 2 to refluxing THF
showed the slow formation of 3. It was found that the
reaction could be driven to completion by using a com-
bination of higher temperature and microwave irradia-
tion. To prevent the formation of 3, the reaction was
left to reflux for 3.5 h to give alkyne 2 in good yield.
6
5
Scheme 2. Reagents and conditions: (a) CuCl, NEt3, 84%; (b) Lindlar
Cat., H2, 86%; (c) MnO2, 84%; (d) NBS, 70%.
6. At this point in the synthesis, we opted to forego the
formation of the epoxide, and evaluate the Grignard
addition of bromoindole 6 into the serine aldehyde.
Classical Grignard conditions of Mg, I2, and refluxing
diethyl ether overnight consumed most of the magne-
sium. The reaction was cooled to room temperature
and a solution of serine aldehyde 7 then added. After
work-up and chromatography, a moderate yield of the
desired b-hydroxy intermediate 8 was isolated (Scheme
3).
While the yield was lower than previous Grignard
additions to serine aldehyde 7, this reaction did show
that 3-bromoindole could serve as a suitable Grignard
precursor. Intermediate 8 may prove to be a valuable
intermediate at a later point because complete deprotec-
tion would yield N-(10,10-dimethyl-20-propenyl)-b-
hydroxytryptophan, which is one of the amino acids
present in cyclomarin C. Next, we examined the forma-
tion of the terminal epoxide. The number of existing
methods to construct chiral terminal epoxides are lim-
ited. We considered using a direct epoxidation method
such as Shiꢀs chiral ketone catalyzed asymmetric epoxi-
dation, however substrates similar to our mono substi-
tuted olefin gave lower than desired ees. Therefore, we
chose an asymmetric dihydroxylation (AD) to install
Selective reduction of the triple bond provided alkene 4.
Oxidation of the indoline ring was accomplished with
MnO2 to give indole 5. The reaction worked well but
took 3 days for completion. In an effort to reduce the
reaction time, we investigated the use of DDQ as an oxi-
dant, but found it to be inferior to MnO2 giving lower
yields and more impurities. Finally, bromination
occurred smoothly in the presence of NBS to give indole

D. B. Hansen et al. / Tetrahedron: Asymmetry 17 (2006) 15–21
17
Br
I
O
H
O
b
a
O
O
+
ZHN
N
N
N
7
6
9
5
I
I
N
c
HO
N
a, b
N
O
O
ZHN
HO
OH
O
O
10
11
8
Scheme 4. Reagents and conditions: (a) NIS, 87%; (b) (DHQD)2PYR,
K2[OsO2(OH)4], K3Fe(CN)6 80% yield, 91% ee; (c) TsCl, NEt3,
Me3NÆHCl, 74% over two steps.
Scheme 3. Reagents and conditions: (a) Mg turnings, I2; (b) CH2Cl2,
37% yield, 85% de.
the terminal epoxide as it appeared to afford the highest
ees. According to Sugiyama et al., who investigated
the Sharpless asymmetric dihydroxylation of similar
N-(10,10-dimethyl-20,30-epoxypropyl)indoles, the use of
Sharplessꢀs second generation (DHQD)2PYR ligand
gave the highest ees of the desired diol. We, therefore,
examined the Sharplessꢀs AD reaction on a number of
the intermediates 4, 5, and 6 and found that the reaction
proceeded most efficiently on indole 9.
of the desired b-hydroxy intermediate 12 (Scheme 5).
The lower than anticipated yield was disappointing but
with further optimization the yield can probably be
improved. The hydroxyl group of 12 was protected as
a TBS ether to give 13, followed by treatment with aque-
ous acetic acid to give a good yield of diol-ester 14. Basic
hydrolysis of the ester with LiOH provided a crude acid
that was treated with TMSCHN2 to give the desired
methyl ester 15. Our ability to cleave the diol-ester to
give the crude acid, should also allow for direct elabora-
tion with an amino acid for the construction of cyclo-
marin A.
Previously we found that the formation of the indole
Grignard from 3-bromoindole 6 was sluggish and
required prolonged refluxing for its formation. We felt
that such conditions might imperil the terminal epoxide
and decided to use instead a tandem lithium–halogen
exchange followed by transmetalation to magnesium.
Exposure of 6 to n-BuLi at ꢀ78 °C proceeded slowly
and even after 6 h not all of the starting materials had
been consumed. It is well known that 3-lithioindole
derivatives can migrate to the 2-position at higher tem-
peratures and we were therefore not willing to increase
the temperature beyond ꢀ78 °C. In an effort to facilitate
the halogen–lithium exchange, we decided to examine a
3-iodoindole because iodine is more reactive toward
lithium–halogen exchange. Starting with indole 5,
iodination occurred smoothly with NIS to afford 9.
Asymmetric dihydroxylation with Sharplessꢀs second
generation ligand (DHQD)2PYR gave diol 10 in high
yield and 91% ee (Scheme 4). Epoxide formation was
accomplished in a two-step, one-pot procedure. Tosyla-
tion of the primary alcohol of diol 10 with TsCl, trieth-
ylamine, and catalytic trimethylamine hydrochloride9
afforded a quantitative conversion of terminal tosylate,
after which the addition of K2CO3 gave terminal epox-
ide 11 in good yield.
3. Conclusion
A stereoselective synthesis of a fully protected inter-
mediate toward the synthesis of (2S,3R)-N-(10,10-
dimethyl-20,30-epoxypropyl)-3-hydroxytryptophan 1 has
been accomplished. Our ability to add highly functional-
ized Grignard reagents in a stereoselective fashion to
Lajoieꢀs chiral serine aldehyde is a significant extension
of this synthetically useful method for the synthesis of
b-hydroxy amino acids.
4. Experimental
Reactions requiring air-sensitive manipulations were
conducted under an argon atmosphere. Methylene chlo-
ride was distilled from calcium hydride, while tetra-
hydrofuran and diethyl ether were distilled from
sodium/benzophenone. Analytical TLC was performed
on 0.25 mm E. silica gel 60 F254 plates. Silica gel (60,
particle size 0.040–0.063 mm) was used for flash column
chromatography. NMR spectra were recorded on a
500 MHz spectrometer and calibrated by using residual
undeuterated solvent or TMS as the internal reference.
Exposure of indole 11 to n-BuLi, followed by MgBr2
and the addition of serine aldehyde 7, gave a low yield

18
D. B. Hansen et al. / Tetrahedron: Asymmetry 17 (2006) 15–21
O
I
N
MgBr
O
H
O
HO
a
b
O
O
+
N
N
ZHN
O
ZHN
O
O
O
O
7
12
11
O
O
O
N
N
N
e
c
d
TBSO
ZHN
TBSO
ZHN
TBSO
ZHN
O
O
O
OH
OH
OMe
O
O
O
13
14
15
Scheme 5. Reagents and conditions: (a) (1) n-BuLi, (2) MgBr2; (b) CH2Cl2, 24% yield, 88% de; (c) TBSOTf, proton spongeÒ, 64%; (d) HOAc,
dioxane, water, 75%; (e) (1) LiOH, (2) TMSCHN2 38% yield two steps.
Chemical shifts (d) were measured in parts per million,
while coupling constants (J values) are given in Hertz
(Hz). Infrared spectra (IR) were recorded on an FT-IR
spectrometer. High-resolution mass spectra (HRMS)
were recorded using electrospray ionization (ESI).
Optical rotations were recorded on a polarimeter at
the sodium D line. Melting points were determined in
an open capillary tube and were uncorrected.
(2.0 mL, 14.3 mmol) were combined in a sealed tube.
The reaction was heated to 160 °C for 30 min in a
CEM mono-mode microwave reactor. The residue was
purified by flash silica gel chromatography, eluting with
2% EtOAc–Hex to give a yellow oil (1.10 g, 42%): TLC
(5% EtOAc–hexanes) Rf = 0.32; 1H NMR (CDCl3,
500 MHz) d 6.89 (d, J = 7.3, 1H), 6.72 (d, J = 7.4,
1H), 6.49 (t, J = 7.4, 1H), 6.26 (d, J = 9.6, 1H), 5.35
(d, J = 9.6, 1H), 3.53 (t, J = 8.4, 2H), 2.99 (t, J = 8.4,
2H), 1.33 (s, 6H); 13C NMR (CDCl3, 125 MHz) d
148.30, 131.93, 126.4, 123.9, 122.9, 122.2, 117.0, 116.9,
55.4, 45.9, 28.1, 16.2; IR (thin film) 3049 m, 3025 m,
2963 s, 2928 s, 2862 m, 1632 s, 1607 m, 1485 s, 1437
m, 1382 m, 1281 s, 1234 s, 1138 m, 763 m, 744 s, 723
s; HRMS (CI): m/z calcd for C13H15N 185.1205, found
185.1204.
4.1. 1-(2-Methylbut-3-yn-2-yl)indoline 2
Indoline (30 mL, 0.27 mol), 2-methyl-3-butyn-2-ol (54
mL, 0.40 mol), CuCl (1.33 g, 13.4 mmol), and triethyl-
amine (38 mL, 0.27 mol) were dissolved in THF
(500 mL). The flask was fitted with a reflux condenser
and allowed to reflux for 3.5 h until judged complete
by TLC. The solvent was reduced in vacuo and the res-
idue purified by flash silica gel chromatography, eluting
with 1–10% EtOAc–Hex to give an orange oil (41.8 g,
4.3. 1-(2-Methylbut-3-en-2-yl)indoline 4
1
84%): TLC (5% EtOAc–hexanes) Rf = 0.40; H NMR
Indoline 2 (1.00 g, 5.40 mmol), Lindlarꢀs catalyst (20.0
mg), and quinoline (2.4 mg, 0.019 mmol) were dissolved
in MeOH (15 mL) in a Parr hydrogenation flask. The
reaction mixture was allowed to shake under a H2 atmo-
sphere (45 psi) at room temperature for 30 min and
judged to be complete by TLC. The reaction mixture
was diluted with EtOAc and filtered through Celite.
The solvent was removed in vacuo, and the residue
was purified by flash silica gel chromatography, eluting
with 2% EtOAc–hexanes to yield a yellow-orange
oil (866 mg, 86%): TLC (5% EtOAc–hexanes) Rf =
(CDCl3, 500 MHz) d 7.20 (d, J = 8.0, 1H), 7.09–7.05
(m, 2H), 6.71 (t, J = 7.3, 1H), 3.39 (t, J = 8.1, 2H),
2.91 (t, J = 8.1, 2H), 2.38 (s, 1H), 1.61 (s, 6H); 13C
NMR (CDCl3, 125 MHz) d 149.9, 131.6, 126.6, 124.3,
118.3, 111.6, 87.4, 70.7, 51.00, 49.4, 28.1, 27.1; IR (thin
film) 3285 m, 2985 m, 2932 w, 2834 w, 1598 s, 1480 s,
1454 m, 1382 w, 1355 w, 1330 w, 1303 w, 1258 s, 1225
s, 1199 s, 1166 m, 1062 w, 1029 w, 748 s; HRMS (CI):
m/z calcd for C13H15N 185.1205, found 185.1204.
1
4.2. 4,4-Dimethyl-2,4-dihydro-1H-pyrrolo[3,2,1]quinoline
3
0.28; H NMR (CDCl3, 500 MHz) d 7.05 (d, J = 7.0,
1H), 6.94 (dt, J = 0.6, J = 8.0, 1H), 6.78 (d, J = 7.9,
1H), 6.62 (dt, J = 0.6, J = 7.4, 1H), 6.16–6.10 (m, 1H),
5.22 (dd, J = 0.9, J = 17.6, 1H), 5.13 (dd, J = 0.8,
J = 10.7, 1H), 3.43 (t, J = 8.3, 2H), 2.91 (t, J = 8.3,
Indoline (1.6 mL, 14.3 mmol), 2-methyl-3-butyn-2-ol
(1.9 mL, 0.40 mmol), CuCl (5.0 mg), and triethylamine

D. B. Hansen et al. / Tetrahedron: Asymmetry 17 (2006) 15–21
19
2H), 1.34 (s, 6H); 13C NMR (CDCl3, 125 MHz) d 150.7,
147.0, 131.4, 126.4, 126.14, 117.2, 112.1, 111.1, 57.3,
49.0, 28.1, 24.1; IR (thin film) 2975 s, 2842 m, 1605 s,
1485 s, 1460 s, 1412 w, 1382 m, 1352 m, 1328 m, 1304
w, 1255 s, 1195 s, 1171 m, 1026 m, 990 m, 917 m, 742
s; HRMS (CI): m/z calcd for C13H17N1 187.1361, found
187.1357.
added at 0 °C and the reaction mixture was allowed to
stir for 10 min. The reaction was quenched with 5%
aqueous NH4Cl and diluted with Et2O (50 mL). The
organic layer was separated and washed with 5% aque-
ous NH4Cl, and brine. The solution was dried over
MgSO4 and the solvent reduced in vacuo. The residue
was redissolved in EtOAc (10 mL), and EtOH (10 mL)
and NaBH4 then added to reduce any remaining alde-
hyde. The reaction was stirred for 30 min, then quenched
with 5% aqueous NH4Cl and diluted with Et2O (50 mL).
The organic layer was washed with 5% aqueous NH4Cl,
brine, dried over MgSO4, and reduced in vacuo. An 85%
de was calculated from integrating the a proton of the
crude product. The residue was purified by flash silica
4.4. 1-(2-Methylbut-3-en-2-yl)-1H-indole 5
Indoline 4 (30.75 g, 0.16 mol) and MnO2 (71.38 g,
0.82 mmol) were combined in toluene (500 mL). The
flask was fitted with a reflux condenser and the mixture
was allowed to reflux for 3 days. The reaction was
diluted with EtOAc and filtered through Celite. The
solvent was reduced in vacuo, and the residue purified
by flash silica gel chromatography, eluting with 2.5%
EtOAc–hexanes to yield an orange oil (25.5 g, 84%):
TLC (1% EtOAc–hexanes) Rf = 0.21; 1H (CDCl3,
500 MHz) d 7.63–7.61 (m, 1H), 7.54–7.21 (m, 1H),
7.31 (d, J = 3.3, 1H), 7.13–7.06 (m, 2H), 6.49–6.48
(m, 1H), 6.17 (dd, J = 10.7, J = 6.7, 1H), 5.23–5.15
(m, 2H), 1.79 (s, 6H); 13C NMR (CDCl3, 125 MHz) d
144.2, 135.3, 130.1, 125.0, 120.9, 120.6, 119.1, 113.7,
113.4, 100.6, 59.0, 27.9; IR (thin film) 2976 w, 1504 w,
1445 s, 1314 m, 1229 m, 1203 m, 915 m, 739 s; HRMS
(CI): m/z calcd for C13H15N 185.1204, found 185.1198.
gel chromatography, eluting with 50% EtOAc–Hex to
20
give a yellow oil (225 mg, 37% yield): ½aꢁD ¼ ꢀ27:0 (c
0.9, CHCl3); TLC (50% EtOAc–Hex), Rf = 0.28; 1H
NMR (CDCl3, 500 MHz) d 7.69 (d, J = 6.5, 1H), 7.43
(d, J = 10.8, 1H), 7.35–7.27 (m, 6H), 7.08–7.00 (m,
2H), 6.06 (dd, J = 10.7, 17.4, 1H), 5.69 (s, 1H), 5.64 (d,
J = 10.2, 1H), 5.16–4.95 (m, 4H), 4.25 (d, J = 10.2,
1H), 4.00 (br s, 6H), 1.62 (br s, 6H), 0.85 (s, 3H); 13C
NMR (CDCl3, 125 MHz) d 156.5, 144.2, 136.7, 135.6,
128.3, 128.1, 127.9, 127.9, 122.7, 120.7, 119.3, 118.9,
113.7, 113.3, 113.1, 109.1, 72.8, 66.4, 65.8, 58.9, 57.1,
30.7, 28.0, 27.8, 14.4; IR (thin film) 3517 w, 3447 w,
2936 w, 2880 w, 1724 s, 1513 m, 1456 m, 1397 w, 1336
w, 1314 m, 1218 m, 1193 m, 1049 s, 1021 s, 991 m, 912
w, 738 s; HRMS (EI): m/z calcd for C29H34O6N2Na
529.2315, found 529.2297.
4.5. 3-Bromo-1-(2-methylbut-3-en-2-yl)-1H-indole 6
Indole 5 (290 mg, 1.57 mmol) was dissolved in DMF
(10 mL), and the solution cooled to 0 °C. NBS
(278 mg, 1.57 mmol) was added and the reaction shielded
from light and allowed to stir for 3 h at 0 °C. The reac-
tion was judged to be complete by TLC and quenched
with satd NaHCO3 (10 mL), diluted with water
(20 mL), and the aqueous layer extracted twice with
Et2O. The organic layers were combined, washed with
brine, dried over MgSO4, and reduced in vacuo. The res-
idue was purified by flash silica gel chromatography,
eluting with 2.5% EtOAc–Hex to give a yellow oil
(289 mg, 70% yield): TLC (1% EtOAc–Hex), Rf =
0.21; 1H NMR (CDCl3, 500 MHz) d 7.57–7.55 (m,
1H), 7.52–7.50 (m, 1H), 7.31 (s, 1H), 7.18–7.15 (m,
2H), 6.16–6.11 (m, 1H), 5.25–5.16 (m, 2H), 1.75 (s,
6H); 13C NMR (CDCl3, 125 MHz) d 143.6, 134.8,
128.6, 124.2, 121.8, 119.9, 119.3, 113.9, 89.4, 59.7, 27.9;
IR (thin film) 3049 w, 2981 m, 2931 w, 1454 s, 1366 m,
1310 s, 1229 s, 1179 s, 924 m, 737 s; HRMS (EI): m/z
calcd for C13H14BrN 263.0310, found 263.0312.
4.7. 3-Iodo-1-(2-methylbut-3-en-2-yl)-1H-indole 6
Indole 5 (7.37 g, 39.8 mmol) was dissolved in DMF
(265 mL) and the reaction cooled to 0 °C. N-Iodosuccin-
imide (9.85 g, 43.8 mmol) was added in one portion and
the reaction allowed to stir for 20 min. The reaction was
judged complete by TLC, quenched with NaHCO3, stir-
red for 10 min, diluted with H2O, and extracted with
Et2O. The organic layers were combined, washed with
H2O and brine, dried over MgSO4, and the solvent
removed in vacuo. The residue was purified by flash
silica gel chromatography eluting with 2.5% EtOAc–
hexanes + 0.1% TEA to give an orange oil (10.75 g,
1
87%): TLC (5% EtOAc–hexanes) Rf = 0.49; H NMR
(CDCl3, 500 MHz) d 7.49–7.47 (m, 1H), 7.44–7.42 (m,
1H), 7.36 (s, 1H), 7.16–7.15 (m, 2H), 6.14–6.08 (m,
1H), 5.24–5.15 (m, 2H), 1.74 (s, 6H); 13C NMR (CDCl3,
125 MHz) d 143.6, 135.4, 131.7, 129.3, 121.8, 121.3,
120.1, 113.9, 113.9, 59.8, 55.2, 27.9; IR (thin film) 2979
m, 1504 w, 1450 s, 1412 w, 1366 w, 1305 s, 1229 s,
1184 s, 1018 w, 923 m, 740 s; HRMS (CI): m/z calcd
for C13H14NI 311.0171, found 311.0176.
4.6. Benzyl-(1S,2R)-2-hydroxy-1-(400-methyl-200,600,700-tri-
oxabicyclo[2.2.2]octan-100-yl)-2-[1-(20-methylbut-30-en-20-
yl)-1H-indol-3-yl]ethylcarbamate 8
4.8. (R)-3-(3-Iodo-1H-indol-1-yl)-3-methylbutane-1,2-diol
10
Bromoindole 6 (1.00 g, 3.79 mmol) was dissolved in
anhydrous THF (10 mL), magnesium turnings (100 mg,
4.17 mmol) then added to the solution, and the reaction
refluxed under argon overnight. The next day, the mag-
nesium turnings had been consumed and the reaction
was cooled to room temperature, diluted with Et2O
(5 mL), and then cooled to 0 °C. Serine aldehyde 7
(385 mg, 1.20 mmol) dissolved in CH2Cl2 (10 mL) was
K2[OsO2(OH)4] (107 mg, 0.29 mmol), (DHQD)2-PYR
(320 mg, 0.36 mmol), K3Fe(CN)6 (28.67 g, 87.1 mmol),
and K2CO3 (12.0 g, 87.1 mmol) were dissolved in
300 mL of 1:1 tert-butanol–H2O. 3-Iodoindole 9 (9.03
g, 29.0 mmol) was added and the reaction stirred at
room temperature for 24 h and judged to be complete

20
D. B. Hansen et al. / Tetrahedron: Asymmetry 17 (2006) 15–21
by TLC. Na2S2O3Æ5H2O (43.4 g, 175 mmol) was added
and the reaction allowed to stir for 10 min. The resulting
mixture was diluted with CH2Cl2 and H2O and
extracted. The combined organic layers were washed
with brine, dried over MgSO4, and the solvent reduced
in vacuo. The residue was purified by flash silica gel
chromatography eluting with 40–80% EtOAc–hex-
anes + 0.1% TEA to yield a viscous, yellow oil (8.06 g,
5% NH4Cl, diluted with Et2O, washed with 5% NH4Cl
and brine, then dried over MgSO4 and the solvent
reduced in vacuo. An 88% de was calculated from inte-
grating the a-proton of the crude product. The residue
was purified by flash silica gel chromatography (5%
CH3CN–CH2Cl2 + 0.1% TEA) to give a pale yellow
20
foam (2.07 g, 21%): ½aꢁD ¼ ꢀ28:0 (c 1.0, CHCl3), TLC
(1:1 EtOAc–hexanes) Rf = 0.12; 1H NMR (CDCl3,
500 MHz) d 7.72 (d, J = 7.8, 1H), 7.63 (d, J = 8.3,
1H), 7.29 (m, 5H), 7.26 (d, J = 3.1, 1H), 7.11 (m, 2H),
5.68 (s, 1H), 5.65 (d, J = 10.2, 1H), 5.12 (d, J = 12.4,
1H), 5.00 (d, J = 12.4, 1H), 4.25 (d, J = 10.3, 1H),
4.01 (m, 6H), 3.19 (d, J = 1.97, 1H), 3.14 (dd, J = 2.9,
J = 3.6, 1H), 2.84 (t, J = 4.3, 1H), 2.73 (m, 1H), 1.53
(s, 3H), 1.49 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3,
125 MHz) d 156.5, 136.681, 135.8, 128.4, 128.2, 128.0,
127.9, 122.7, 121.3, 119.5, 119.3, 113.6, 112.9, 109.0,
72.8, 66.6, 65.6, 57.88, 57.61, 56.9, 45.6, 30.7, 23.8,
23.6, 14.4; IR (thin film) 3521 w, 2936 w, 2881 w, 1721
s, 1512 m, 1456 m, 1398 w, 1336 w, 1219 m, 1049 s,
734 s; HRMS (ES): m/z calcd for C29H34N2O7Na
545.2264, found 545.2243.
80%, 91% ee by 19F spectrum of the Mosherꢀs ester):
20
½aꢁD ¼ ꢀ3:3 (c 1.0, CHCl3); TLC (40% EtOAc–hexanes)
1
Rf = 0.30; H NMR (CDCl3, 500 MHz) d 7.54–7.50 (m,
1H), 7.44–7.41 (m, 1H), 7.29 (s, 1H), 7.17–7.13 (m, 2H),
4.26 (t, J = 4.0, 1H), 3.29–3.25 (m, 2H), 2.75–2.70 (m,
1H), 2.27–2.23 (m, 1H), 1.68–1.62 (m, 6H); 13C NMR
(CDCl3, 125 MHz) d 134.9, 1312.0, 130.4, 122.2, 121.8,
120.4, 113.4, 75.5, 62.4, 61.9, 55.9, 24.4, 24.1; IR (thin
film) 3382 br s, 2985 m, 2942 m, 1603 w, 1448 s, 1303
s, 1222 s, 1191 s, 1088 s, 1030 s, 908 m, 738 s, HRMS
(ES): m/z calcd for C13H16INO2Na 368.0123, found
368.0135.
4.9. (R)-3-Iodo-1-[2-(oxiran-2-yl)propan-2-yl]-1H-indole
11
4.11. Benzyl-(1S,2R)-2-(tert-butyldimethylsilyloxy)-1-
(400-methyl-200,600,700-trioxabicyclo-[2.2.2]octan-100-yl)-2-
[1-(20-((R)-oxiran-20-yl)propan-20-yl)-1H-indol-3-yl]eth-
ylcarbamate 13
Diol 10 (7.46 g, 22.2 mmol), TEA (6.1 mL, 43 mmol),
and Me3NÆHCl (206 mg, 2.2 mmol) were dissolved in
CH2Cl2 (43 mL) and cooled to 0 °C. TsCl (4.12 g,
21.6 mmol) was then added. The reaction was stirred
at 0 °C for 20 min and judged to be complete by TLC.
The reaction was diluted with MeOH (43 mL), K2CO3
(5.97 g, 43.2 mmol) then added, and the mixture allowed
to warm to room temperature and stirred for 24 h. The
solvent was reduced in vacuo and the residue dissolved
in Et2O and H2O. The organic layer was separated,
washed with brine, and then dried over MgSO4. The
solvent was reduced in vacuo. The residue was purified
by flash silica gel chromatography (15% EtOAc–
Compound 12 (551 mg, 1.1 mmol) and Proton SpongeÒ
(678 mg, 3.2 mmol) were dissolved in CH2Cl2 (10.0 mL),
tert-butyldimethylsilyltriflate (0.49 mL, 2.1 mmol) then
added and the reaction stirred for 20 min at room tem-
perature and judged to be complete by TLC. The reac-
tion was diluted with H2O and Et2O and the layers
separated. The organic layer was washed twice with
5% NH4Cl, saturated NaHCO3, brine, dried with
MgSO4, and the solvent was reduced in vacuo. Both dia-
stereomers were visible by TLC and separated by flash
silica gel chromatography (30% EtOAc–hexanes + 0.1%
hexanes + 0.1% TEA) to yield a viscous, orange oil
20
(5.96 g, 84% two steps): ½aꢁD ¼ ꢀ3:6 (c 1.0, CHCl3);
TLC (10% EtOAc–hexanes) Rf = 0.28; 1H NMR
(CDCl3, 500 MHz) d 7.70 (d, J = 8.4, 1H), 7.45–7.43
(m, 1H), 7.38 (s, 1H), 7.24–7.17 (m, 2H), 3.26 (dd,
J = 2.9, J = 4.0, 1H), 2.89 (t, J = 4.14, 1H), 2.76 (dd,
J = 2.8, J = 4.6, 1H), 1.68 (s, 3H), 1.60 (s, 3H); 13C
NMR (CDCl3, 500 MHz) d 135.6, 131.7, 129.4, 122.4,
121.5, 120.4, 113.2, 58.7, 57.7, 56.1, 45.4, 24.4, 23.1;
IR (thin film) 2983 m, 1450 s, 1305 s, 1226 m, 1190 s,
1018 w, 879 w, 741 s; HRMS (CI): m/z calcd for
C13H14INO 327.0120, found 327.0111.
TEA) to yield a pale yellow foam (362.8 mg, 54%):
20
½aꢁD ¼ ꢀ7:6 (c 1.0, CHCl3); TLC (30% EtOAc–hexane)
1
Rf = 0.26; H NMR (CDCl3, 500 MHz, rotameric pairs
are indicated where possible) d 7.71–7.58 (m, 2H), 7.35–
7.27 (m, 3H), 7.20–7.16 (m, 1H), 7.13–7.06 (m, 1H),
7.06–7.02 (m, 1H), 6.95 (t, J = 7.7, 0.5H), 6.45 (d,
J = 7.5, 0.5H), [5.64–5.60 (major rot., m), 5.38 (minor
rot., d, J = 10.7) 2H], [5.02–4.94 (major rot., m), 4.73
(minor rot., d, J = 12.7), 4.58 (minor rot., d, J = 12.7)
2H], 3.98–3.91 (m, 7H), [3.18–3.17 (major rot., m),
3.14–3.13 (minor rot., m) 1H], [2.83 (major rot., t,
J = 4.4), 2.79 (minor rot., t, J = 4.3) 1H], [2.71–2.70
(major rot., m), 2.68–2.67 (minor rot., m) 1H], 1.58–
1.51 (m, 6H), 0.90–0.82 (m, 12H), 0.04 (d, J = 9.0,
3H), ꢀ0.15 (m, 3H); 13C NMR (CDCl3, 125 MHz, rota-
meric pairs are indicated where possible) d [156.4 min.,
156.3 maj.], 136.9, [136.1 min., 135.8 maj.], 128.4,
128.1, [127.9, 127.8], 127.3, 127.0, 126.7, 124.0, 123.2,
[121.1 min., 121.0 maj.], 119.4, 119.1, 119.0, 118.9,
[117.0 maj., 116.8 min.], [113.0 min., 112.7 maj.],
108.4, 107.9, [72.6, 72.5], [66.4 maj., 66.3 min.], [65.8
min., 65.8 maj.], [59.6 min., 59.4 maj.], 58.0, [57.6
min., 57.5 maj.], 45.6, 45.3, [30.6, 30.5], [25.8, 25.7],
24.3, 24.0, 23.9, 23.8, 23.4, 18.2, 14.4; IR (thin film)
4.10. Benzyl-(1S,2R)-2-hydroxy-1-(400-methyl-200,600,700-
trioxabicyclo[2.2.2]octan-100-yl)-2-[1-(20-((R)-oxiran-20-
yl)propan-20-yl)-1H-indol-3-yl]ethylcarbamate 12
3-Iodoindole 11 (12.14 g, 37.1 mmol) was dissolved in
Et2O (350 mL) and cooled to ꢀ78 °C. n-BuLi (10.0 M
in hexane, 4.4 mL, 44 mmol) was added dropwise, and
allowed to stir for 1 h. Freshly prepared MgBr2
(6.83 g, 37.1 mmol) in Et2O (40 mL) was added and
allowed to stir for 1 h at ꢀ78 °C and then warmed to
0 °C. Serine aldehyde 7 (5.96 g, 18.56 mmol) in 100 mL
of CH2Cl2 was added and the reaction allowed to stir
for 30 min at 0 °C. The reaction was quenched with

D. B. Hansen et al. / Tetrahedron: Asymmetry 17 (2006) 15–21
21
3452 w, 2929 m, 2879 m, 1733 s, 1508 s, 1456 m, 1398 w,
1284 m, 1197 m, 1104 m, 1052 s, 1001 m, 838 m, 738 s;
HRMS (ES): m/z calcd for C35H48N2O7SiNa 659.3128,
found 659.3137.
was removed in vacuo, and the residue purified by flash
silica gel chromatography (25% AcOEt–hexanes) to
give a pale, yellow oil (17.1 mg, 88% for two steps):
20
½aꢁD ¼ ꢀ8:2 (c 2.1, CHCl3); TLC (30% AcOEt–Hex)
Rf = 0.51; 1H NMR (CDCl3, 500 MHz) d 7.68–7.64
(m, 2H), 7.33–7.30 (m, 4H), 7.29 (s, 1H), 7.26–7.19 (m,
2H), 7.18–7.10 (m, 1H), 5.65–5.63 (m, 2H), 4.98 (d,
J = 2.0, 2H), 4.58 (dd, J = 2.0, J = 9.4, 1H), [rotamer
pair: 3.79 (s, 2H), 3.75 (s, 1H)], 3.22 (t, J = 3.5, 1H),
2.87 (t, J = 4.0, 1H), 2.71 (t, J = 2.7, 1H), [rotamer pair:
1.62 (s, 3H), 1.59 (s, 3H)], 0.93–0.86 (m, 9H), [rotamer
pair: 0.00 (s), ꢀ0.01 (s), 3H], [rotamer pair: ꢀ0.1 (s),
ꢀ0.2 (s), 3H]; 13C NMR (CDCl3, 125 MHz) d 171.6,
156.7, 136.8, 136.2, 128.9, 128.7, 128.6, 128.6, 124.3,
121.9, 119.9, 119.5, 114.8, 113.6, 69.9, 67.3, 60.7, 58.4,
52.8, 45.9, 26.1, 24.7, 23.9, 18.5, ꢀ4.2, ꢀ5.1; IR (thin
film) 2929 m, 2856 w, 1728 s, 1507 m, 1456 m, 1317 w,
1253 m, 1201 m, 1063 m, 836 m, 778 m, 740 m; HRMS
(ES): m/z calcd for C31H42N2O6SiNa 589.2709, found
589.2713.
4.12. (2S,3R)-300-Hydroxy-200-(hydroxymethyl)-200-meth-
ylpropyl-2-(benzyloxycarbonylamino)-3-(tert-butyldi-
methylsilyloxy)-3-[10-(20-((R)-oxiran-20-yl)propan-20-yl)-
1H-indol-3-yl]propanoate 14
Compound 13 (35.2 mg, 0.057 mmol) was dissolved in
dioxane (0.25 mL) and glacial acetic acid (0.5 mL)
added, followed by water (0.5 mL). The reaction was
allowed to stir for 10 min until judged to be complete
by TLC. Solvent was then removed in vacuo. The resi-
due was purified by flash silica gel chromatography
(3% MeOH–CH2Cl2) to give a pale yellow foam
20
(26.1 mg, 72%): ½aꢁD ¼ ꢀ5:5 (c 1.0, CHCl3); TLC (5%
MeOH–CH2Cl2) Rf = 0.35; 1H NMR (CDCl3,
500 MHz) d 7.70 (d, J = 8.4, 1H), 7.64 (d, J = 7.8,
1H), 7.36–7.30 (m, 4H), 7.27 (s, 1H), 7.26–7.16
(m, 2H), 7.16–7.12 (m, 1H), 5.64 (d, J = 8.5, 1H), 5.58
(d, J = 3.0, 1H), 5.06–4.99 (m, 2H), 4.59 (dd, J = 3.1,
J = 8.5, 1H), 4.20 (s, 2H), 3.52–3.41 (m, 4H), 3.25 (t,
J = 2.9, 1H), 2.88 (t, J = 4.3, 1H), 2.73 (dd, J = 2.7,
J = 4.4, 1H), 2.69 (br s, 1H), 2.64 (br s, 1H), 1.65
(s, 3H), 1.59 (s, 3H), 0.87 (s, 9H), 0.79 (s, 3H), 0.01
(s, 3H), ꢀ0.15 (s, 3H); 13C NMR (CDCl3, 125 MHz) d
171.7, 156.5, 136.1, 135.8, 128.5, 128.3, 128.3, 127.1,
124.0, 121.6, 119.6, 119.0, 114.1, 113.2, 69.4, 67.7,
67.6, 67.5, 67.1, 60.1, 57.9, 45.4, 40.5, 25.7, 24.4, 23.3,
18.1, 16.8, ꢀ0.7, ꢀ5.5; IR (thin film) 3443 m, 2953 m,
2856 m, 1722 s, 1506 m, 1457 m, 1255 s, 1199 s, 1058
s, 837 s, 740 s; HRMS (ES): m/z calcd for C35H50O8N2-
SiNa 677.3234, found 677.3240.
Acknowledgments
We thank the NSF (CHEM-0130958) and the Univer-
sity of Pennsylvania for support. We also acknowledge
additional financial support in the form of undergradu-
ate fellowships from Wyeth and Lilly to A.S.L.
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