A combined vinylogous mannich/diels-alder approach for the stereoselective synthesis of highly functionalized hexahydroindoles

Article abstract of DOI:10.1002/ejoc.201100996

A versatile strategy for the formation of hydroindole derivatives is reported. The molecules synthesized are highly functionalized and bear up to six stereogenic centers. We were able to develop a stereoselective route starting from nonchiral commercially

Full text of DOI:10.1002/ejoc.201100996

FULL PAPER
DOI: 10.1002/ejoc.201100996
A Combined Vinylogous Mannich/Diels–Alder Approach for the Stereoselective
Synthesis of Highly Functionalized Hexahydroindoles
Bettina M. Ruff,[a] Sabilla Zhong,[a] Martin Nieger,[b] Marcel Sickert,[c]
Christoph Schneider,[c] and Stefan Bräse*[a]
Keywords: Natural products / Nitrogen heterocycles / Cycloaddition / Stereoselective synthesis
A versatile strategy for the formation of hydroindole deriva-
tives is reported. The molecules synthesized are highly func-
tionalized and bear up to six stereogenic centers. We were
able to develop a stereoselective route starting from nonchi-
former uses
a
1,1Ј-bi-2-napthol (BINOL)-based chiral
Brønsted acid catalyst to build the first stereogenic center.
The [4+2] cycloaddition proceeds highly diastereoselectively
and furnishes one main stereoisomer, which represents the
ral commercially available materials. Key steps in the forma- scaffold of the mycotoxins Rostratin B–D. Other transforma-
tion of the bicyclic products are an organocatalytic vinylo-
gous Mukaiyama–Mannich and a Diels–Alder reaction. The
tions include iodolactonization, a Curtius rearrangement, ad-
ditions, oxidations, and reductions.
The mycotoxins Rostratin A–D (1–4) represent examples
of thiodiketopiperazines (Figure 1), which consist of two
identical octahydroindole amino acid moieties connected as
a diketopiperazine and bridged with a disulfur unit. The
Rostratins have been isolated from Exserohilum rostratum
together with Exserohilone (6) and show in vitro cytotox-
icity against the human colon carcinoma cell line HCT-
116.[5] Exserohilone (6) and Epicorazin A (7) are examples
of thiodiketopiperazines with a hexahydroindole moiety.
Recently, Epicoccin R (8) has been isolated from the endo-
phytic fungus Epicoccum nigrum.[6]
Introduction
The indole moiety can be found in many natural prod-
ucts and pharmaceuticals. Partially or fully hydrogenated
representatives of this class of hetero- and bicyclic com-
pound can be cis or trans annelated. In addition, unsatu-
rated derivatives can contain more stereogenic centers as
they have various substituents. Because of the biological ac-
tivity of many hydroindole substances, a versatile asymmet-
ric strategy for their synthesis is needed. Nevertheless, only
a few examples of the preparation of these structures are
known in the literature. Wipf et al. have synthesized hexahy-
droindolinones starting from tyrosine or its derivatives.[1]
Hexahydroindoles have been prepared by Bäckvall and Yeh
using intramolecular 1,4-additions of amines to cyclic 1,3-
dienes.[2] Hu, Wang et al. have employed a domino cou-
pling/cyclization of 1,6-enynes with aryl halides for the syn-
thesis of functionalized hexahydroindoles.[3] Oppolzer et al.
reported the synthesis of octahydroquinolines and hexahy-
droindoles.[4] Their idea of using an intramolecular Diels–
Alder reaction allows the application of linear precursors,
building up at least two stereogenic centers in one cycload-
dition step.
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-698-48581
Figure 1. Structures of some mycotoxins with a thiodiketopiperaz-
ine core. Different ring-fusion possibilities are highlighted in gray.
E-mail: braese@kit.edu
[b] Laboratory of Inorganic Chemistry, Department of Chemistry,
University of Helsinki,
Many other similar natural products containing a hydro-
indole moiety are known. However, only a few have been
reached by total synthesis to date. The first was Gliotoxin
(5) in 1981, which was also the first reported representative
of this class of mycotoxins.[7] In the last few years, the total
P. O. Box 55, 00014 University of Helsinki, Finland
[c] Institute of Organic Chemistry, University of Leipzig,
Johannisallee 29, 04103 Leipzig, Germany
E-mail: schneider@chemie.uni-leipzig.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100996.
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Stereoselective Synthesis of Functionalized Hexahydroindoles
syntheses of Epicoccin G,[8] (+)-Gliocladine C,[9] and the
dimeric pyrroloindole thiodiketopiperazines (+)-11,11Ј-Di-
deoxyverticillin A, (+)-Chaetocin A, (+)-Chaetocin C, and
(+)-12,12Ј-Dideoxychetracin A have been successful.[10]
We have already reported a unified strategy to access the
hydroindole building blocks needed for the total synthesis
of the Epicoccins A, C, and D, Gliotoxin (5), Aranotins,
Epicoccins (e.g. 8), Exserohilone (6), Epicorazines (e.g. 7),
and Rostratin A (1).[11] This route, accomplishing the annel-
ation of a second ring to a proline ring system by ring clos-
ing metathesis, gives 3a,7a-cis- and 3a,7a-trans-fused aza-
bicyclic systems (for numbering and configuration see Fig-
ure 1). All of the synthesized cis-annelated substrates have
a 2,3a-trans configuration. Using the strategy reported
herein, with an intramolecular Diels–Alder reaction as the
key step, we have developed access to 2,3a-cis configured
azabicyclic structures. This is an important step towards the
total synthesis of other interesting natural products, for ex-
ample, the Rostratins B–D (2–4). Furthermore, it is impor-
tant to develop a versatile strategy for the synthesis of ana-
logues of biologically active secondary metabolites based
on the mycotoxins shown in Figure 1. Modifications can
lead to improved or more selective medicinal effects as well
as better bioavailability and compliance in therapeutic ap-
plications.[12]
Scheme 1. Large-scale application of the vinylogous Mukaiyama–
Mannich reaction: a) 3 mol-% 13, –55 °C, 2-Me-2-butanol/tBuOH/
THF, 1:1:1 (c = 0.65), 0.25 equiv. H2O, 95%, 81–89% ee. See also
ref.[13]
Results and Discussion
We were able to develop a strategy to synthesize hexahy-
droindoles with four stereogenic centers in six steps from
commercially available starting materials. The δ-amino α,β-
unsaturated carboxylic ester 12 was generated in a catalytic,
enantioselective, vinylogous Mukaiyama–Mannich reac-
tion. We have already developed and reported this asym-
metric carbon–carbon bond-forming reaction of a silyldien-
olate and an imine with a BINOL-based phosphoric acid
as a chiral catalyst.[13] For the purpose described here, we
Scheme 2. Synthesis of the Diels–Alder substrate 16 and hexahy-
droindole 18: a) H5IO6, 1 m H2SO4, MeCN/H2O, 1:1, room temp.,
95%; b) NEt3, CH2Cl2, room temp.; molecular sieves 4 Å, Et2O,
crotonaldehyde, room temp.; c) benzylchloroformate, toluene, mo-
lecular sieves 4 Å, 0 °C Ǟ room temp., 65%, 81% ee (two steps);
d) (N,O)-bis(trimethylsilyl)acetamide, o-xylene, 175 °C, 61%, 82%
ee.
The following transformations were carried out accord-
improved the three-component Mannich reaction con- ing to our previously reported procedure for the synthesis
sisting of 2-furfural (9), p-anisidine (10), and silyldienolate of hexahydroindole carboxylic acids.[17] Hydrochloride 14
11 with optimized solvent and temperature conditions for was converted into the free amine using triethylamine as a
large-scale preparations (Scheme 1).
base. This was immediately condensed with crotonaldehyde
Hence, we were able to synthesize the unsaturated ester to give imine 15. The water-sensitive product is only stable
12 in multigram quantities with an excellent yield and good for a few hours. A NMR spectrum measured directly
enantioselectivity starting from commercially available 9 showed clean product, whereas a spectrum recorded after a
and 10, and 11, which is accessible quantitatively from ethyl day showed nothing but decomposed material. Addition of
but-3-enoate in one step.[14] The emerging, yet protected benzylchloroformate with N,N-diethylaniline as a base af-
(the furan ring can be cleaved to a carboxylic acid, see be- forded 16 in 65% yield in two steps. Compound 16 is the
low) amino acid 12 is S configured at the α-carbon atom direct precursor of an intramolecular Diels–Alder reaction.
and retains its stereochemical integrity throughout the syn- Upon heating to 175 °C in a pressure tube with 1 equiv.
thetic process described here. The p-methoxyphenyl protect- (N,O)-bis(trimethylsilyl)acetamide as Lewis acid and o-xyl-
ing group can be cleaved in very good yields with periodic ene as solvent, 16 reacted by [4+2] cycloaddition to give 18
acid to afford hydrochloride 14 (Scheme 2).[15] Deprotection in 61% yield. This yield represents the isolated amount of
with trichloroisocyanuric acid led to similar results. Al- the main stereoisomer with the two rings being cis annel-
though the use of ceric ammonium nitrate also led to de- ated (R-C-3a and S-C-7a) and C-2 and C-4 in S configura-
protection, only decomposed material was observed after tion. A trace amount of a mixture of other diastereoisomers
work up. However, if di-tert-butyldicarbonate was added in was also formed during the reaction, but we were unable to
situ, the Boc-protected amine was isolated.[16]
characterize it and assign the stereochemistry. The structure
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S. Bräse et al.
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of 18 was unequivocally confirmed by the crystallographic the conditions for this reaction are optimized, 23 can be
analysis of 25 (see below). The chiral center at C-2 built in used as a precursor of Rostratin B (2) or D (4).
the vinylogous Mannich reaction in the first step induced
the stereoselective formation of the other three stereogenic
centers in the intramolecular Diels–Alder reaction. The di-
enophile attacks the diene in the exo position[18] in 17
(Scheme 2). This attack is favored here, but theoretical
evaluation of the four possible diastereotopic transition
states has not been performed. Overall, we achieved the
synthesis of enantiomerically enriched hexahydroindole
18 – bearing four stereogenic centers – in only six steps and
36% yield from commercially available materials.
Instead of having carboxybenzyl (Cbz) as a protecting
group, other substituents are possible at the indole nitrogen
atom. To show this, we used isobutyryl chloride for the for-
mation of Diels–Alder precursor 19 (Scheme 3). The cyclo-
addition of this substrate furnished indole derivative 20 in
a similar overall yield (35%) to the Cbz-substituted 16. The
stereochemistry of 20 was confirmed by NOESY experi-
ments as well as by analogy to 18.
Scheme 4. Transformations of hexahydroindole 18: a)
NaH2PO4 ϫ2 H2O, H2O2, NaClO2, MeCN/H2O (6:1), 0 °C Ǟ re-
flux, 54%; b) I2, NaHCO3, CH2Cl2, 0 °C Ǟ room temp., 75%; c)
mCPBA, MeOH, CH2Cl2, room temp., 41%, rac; d) H2, 10% Pd/
C, MeOH, room temp., 88%, rac; e) LiHMDS, THF, –78 °C Ǟ
0 °C; PhNO, –78 °C, 55%; f) N,O-dimethylhydroxylamine hydro-
chloride, nBuLi, THF, –78 °C Ǟ room temp.; then 18, THF,
–78 °C, 78%, rac; g) MeMgBr, THF, 0 °C, 82%; h) DPPA, NEt3,
tBuOH, reflux, 70%, rac; i) TFA, H2O, CH2Cl2, room temp., 98%;
j) LiOH, H2O, THF, room temp., 99%; k) TMSCHN2, Et2O,
MeOH, 0 °C Ǟ room temp., 74%, rac.
Scheme 3. Synthesis of hexahydroindole 20: a) (CH3)2CHCOCl,
NEt3, DMAP, CH2Cl2, molecular sieves 4 Å, –78 °C Ǟ 0 °C, 79%
(two steps); b) (N,O)-bis(trimethylsilyl)acetamide, o-xylene, 175 °C,
49%.
Hexahydroindole 18 was subjected to various transfor-
The convenience of Cbz as a protecting group was shown
mations, which are summarized in Scheme 4. The furan ring by its reductive cleavage with hydrogen and 10% palladium/
represents an aldehyde moiety, which can be oxidatively charcoal. The free amine 24 – representing an octahydro-
cleaved with sodium dihydrogen phosphate, sodium chlo- indole derivative – was isolated in very good yields. If the
rite, and hydrogen peroxide. The use of the furan ring as a reduction of the double bond is unwanted, it can be avoided
protecting group for a carboxylic acid improved our pre- by previous functionalization.
viously reported strategy for the (racemic) synthesis of
Addition of nitrosobenzene to the lithium enolate of 18,
hexahydroindoles with two indistinguishable ester moieties generated in situ with lithium bis(trimethylsilyl)amide,
(see ref.[17]). Acid 21 was treated with iodine and sodium yielded hydroxylamine 25.[21] No diastereoselectivity was
hydrogen carbonate in an iodolactonization reaction. The observed here and we obtained the epimers (4S)-25 and
attack occurs from the convex side of bicycle 21 to give the (4R)-25 in a 1:1 ratio. We were able to crystallize racemic[22]
six-membered lactone 22. This step enabled us to introduce (4S)-25 from dichloromethane and n-pentane, and its crys-
an oxygen functionality to the more hindered side of hexa- tal structure is shown in Figure 2.
hydroindole 18. Other attempts, such as Sharpless[19] and
In the course of our work we focused on the modification
Woodward[20] dihydroxylation or epoxidation with mCPBA, of the C-4 ethyl ester moiety. Upon treatment with N,O-
were unsuccessful and led to the isolation of starting mate- dimethylhydroxylamine hydrochloride and n-butyllithium
rials or decomposition. Derivative 22 already contains all we obtained Weinreb amide 26 in good yields. This amide
of the stereochemical information needed for the total syn- was converted to methylketone 27 with methylmagnesium
thesis of the Rostratins B–D (2–5). The iodine atom should bromide in tetrahydrofuran (THF).
be easily replaced by a methoxy group in a nucleophilic
Cleavage of ethyl ester 18 with lithium hydroxide in water
substitution, which would lead to the synthetically challeng- and THF furnished the free carboxylic acid 28 in quantita-
ing scaffold of Rostratin C (3), with the substituents at C-5 tive yields, which was converted into the methyl ester 29
and C-6 lying in the poorly accessible convex side of the with trimethylsilyl diazomethane. Treatment of acid 28 with
bicyclic system. However, a first attempt to replace the diphenylphosphoryl azide (DPPA) and triethylamine with
iodine atom with methanol led to the formation of 23, heating gave carbamate 32.[23] An initially built acyl azide
which nevertheless represents an interesting molecule. After is immediately converted into isocyanate 31 under the elimi-
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Stereoselective Synthesis of Functionalized Hexahydroindoles
pharmaceutical benefit themselves, but also represent pre-
cursors of complex natural products.
Experimental Section
General: NMR spectra were recorded with Bruker AM 400, Bruker
Avance 300 or Bruker DRX 500 spectrometer as solutions. Chemi-
cal shifts are expressed in ppm downfield from tetramethylsilane
and are referenced to residual solvent peaks. All coupling constants
are absolute values expressed in Hz. The descriptions of signals
include: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. The spectra were analyzed according to the first order.
The 13C NMR signal structure was analyzed by DEPT and is de-
scribed as follows: + = primary or tertiary C atom (positive sig-
nal), – = secondary C atom (negative signal) and q = quaternary
C atom (no signal). MS (EI and FAB) were performed with a Fin-
nigan MAT 90 (70 eV). IR spectra were recorded with a FT-IR
Bruker IFS 88. Elemental analysis was performed with an Ele-
mentar Vario Microcube. Optical rotations were determined with
a Perkin–Elmer 241 polarimeter at 20 °C with a glass cuvette and
the D line of sodium. Solvents, reagents, and chemicals were pur-
chased from Aldrich, Fluka, ABCR, and Acros. THF was distilled
with sodium/potassium prior to use. Dichloromethane was distilled
with calcium hydride. Toluene and diethyl ether were distilled with
sodium. All reactions involving moisture-sensitive reactants were
executed under an argon atmosphere using oven-dried glassware.
All other solvents, reagents, and chemicals were used as purchased
unless stated otherwise.
Figure 2. Molecular structure rac-(4S)-25 (displacement param-
eters are drawn at 50% probability; disordered solvent omitted for
clarity).
nation of nitrogen in a Curtius rearrangement (Scheme 5).
Compound 31 is attacked by tert-butanol to give Boc-pro-
tected amine 32, which can be deprotected with trifluoro-
acetic acid (TFA) to furnish the free amine 30.
Ethyl (S,E)-5-(Furan-2-yl)-5-(4-methoxyphenylamino)pent-2-enoate
(12): (gram scale procedure): A solution of p-anisidine (1.39 g,
11.2 mmol, 1.00) and 13 (225 mg, 337 μmol, 0.03 equiv.) in THF/
tert-butanol/2-methylbutan-2-ol (1:1:1, c = 0.65 mol/L, 18 mL) and
H2O (0.25 equiv.) was stirred for 1 min at room temp. 2-Furfural
(1.19 g, 12.4 mmol, 1.10 equiv.) was added and the mixture was
stirred for 30 seconds at room temp. and for 5 min at –55 °C. Com-
pound 11 (3.83 g, 16.8 mmol, 1.50 equiv.) was added over 10 min.
The mixture was stirred for 6 h at –55 °C before silica gel (2 g) was
added, and the mixture stirred for 10 min at room temp. The sol-
vents were evaporated under reduced pressure and the residue was
purified by column chromatography (diethyl ether/n-hexane, 1:5) to
afford 12 (3.36 g, 10.7 mmol, 95%, 81–89% ee[13c]) as a yellow oil.
Rf (cyclohexane/ethyl acetate, 5:1) = 0.32. [α]2D0 = –41.0 (c = 0.58,
CHCl3). HPLC conditions: AS-H chiralpak column; n-heptane/2-
propanol = 90:10; 20 °C; flow rate = 0.7 mL/min; minor enantio-
mer tR = 13.51 min; major enantiomer tR = 16.39 min. For spectro-
scopic data see ref.[13b]
Scheme 5. Curtius rearrangement of acid 28 to give Boc-protected
amine 32: a) DPPA, NEt3, reflux, 78%.
All of these modifications show the versatility of Diels–
Alder product 18 and its potential to serve as a precursor
in the total synthesis of natural products [e.g. Rostratins B–
D (2–4)]. Rostratins are C2 symmetrical thiodiketopiperaz-
ines with two octahydroindole moieties as monomers, which
are similar to many molecules described in Scheme 4. The
applicability of our earlier method to condense two amino
acids to give diketopiperazines[24] for complex hydroindole
systems has already been proven in previous studies in our
group.[11]
(S,E)-5-Ethoxy-1-(furan-2-yl)-5-oxopent-3-en-1-aminium Chloride
(14): To a solution of 12 (523 mg, 1.49 mmol) in MeCN/H2O (1:1,
38 mL) were added periodic acid (339 mg, 1.49 mmol) and 1 m
aqueous sulfuric acid (2.28 mL). The mixture was stirred for 2 h at
Conclusions
We were able to combine vinylogous Mukaiyama–Man-
nich and Diels–Alder reactions to build hexahydroindoles
18 and 20 in only six steps in 36 and 35% yield, respectively. room temp. and then washed with dichloromethane (3ϫ100 mL).
The aqueous phase was brought to pH 10.5 by addition of 5 m
aqueous KOH solution and extracted into ethyl acetate
(3ϫ100 mL). The combined organic phases were dried with so-
dium sulfate, acidified to pH 1 with HCl (1 m in ethyl acetate), and
evaporated under reduced pressure to give 14 (347 mg, 95%) as a
Both transformations were accomplished with excellent
stereoselectivities. One of four stereogenic centers found in
the bicyclic product is introduced using a chiral BINOL-
based phosphoric acid as a catalyst in the Mannich reac-
tion. This stereogenic information induces the configura-
tion of three other stereogenic centers during the highly dia-
stereoselective Diels–Alder reaction.
1
brown oil. [α]2D0 = +14.3 (c = 0.41, CHCl3). H NMR (400 MHz,
CDCl3): δ = 1.24 (t, 3J = 7.1 Hz, 3 H, CH3), 2.99–3.07 (m, 2 H,
3
CH2CH=CH), 4.14 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.54–4.63 (m,
1 H, CHNH3), 5.93 (d, 3J = 15.5 Hz, 1 H, CH2CH=CH), 6.31–
6.35 (m, 1 H, Hfur), 6.52–6.57 (m, 1 H, Hfur), 6.68–6.79 (m, 1 H,
Furthermore, various highly functionalized hydroindoles
can be synthesized using many different types of reactions.
The derivatives described herein have not only a potential CH2CH=CH), 7.39–7.42 (m, 1 H, OfurCH=CHCH), 8.82 (br. s, 3
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H, NH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1 (+, CH3),
91 (100). HRMS: calcd. for C23H26NO5 [M]+ 396.1811; found
34.2 (–, CH2CH=CH), 48.1 (+, CHNH3), 60.6 (–, CH2CH3), 110.4 396.1807. HPLC conditions: OD chiralcel column; n-heptane/2-
(+, Cfur), 110.8 (+, Cfur), 128.8 (+, CH2CH=CH), 140.8 propanol = 95:5; 10 °C; flow rate = 0.7 mL/min; minor enantiomer
(+, OfurCH=CHCH), 143.6 (+, CH2CH=CH), 148.0 (q, Cfur), tR = 13.16 min; major enantiomer tR = 14.59 min.
165.9 (q, C=O) ppm. IR (film): ν = 3417 (s), 2922 (s), 1714 (s),
˜
1-Benzyl 4-Ethyl (2S,3aR,4S,7aS)-2-(Furan-2-yl)-3,3a,4,5-tetra-
hydro-1H-indole-1,4(2H,7aH)-dicarboxylate (18): To a solution of
16 (383 mg, 969 μmol, 1.) was added (N,O)-bis(trimethylsilyl)acet-
amide (240 μL, 197 mg, 969 μmol). The mixture was heated in a
vial at 175 °C for 7 d. It was evaporated under reduced pressure
and the residue was purified by column chromatography (cyclohex-
ane/ethyl acetate, 10:1) to afford 18 (234 mg, 61%, 82% ee) as a
1659 (m), 1505 (m), 1472 (m), 1184 (m), 1036 (m), 760 (m), 598
(w) cm–1. MS (FAB, matrix: 3-NBA): m/z (%) = 210 (25) [M]+, 193
(100), 154 (22), 136 (28), 119 (26), 109 (30). HRMS: calcd. for
C11H16NO3 [M – Cl]+ 210.1125; found 210.1127. C11H16ClNO3
(245.71): calcd. C 53.77, H 6.56, N 5.70; found C 53.05, H 6.58, N
6.19.
Ethyl (S,E)-5-[(Z)-{(E)-But-2-enylidene}amino]-5-(furan-2-yl)pent-2- yellow oil. Rf (cyclohexane/ethyl acetate, 5:1) = 0.24. [α]2D0 = +85.4
1
3
enoate (15): To a solution of 14 (820 mg, 3.34 mmol) in dichloro-
methane (15 mL) was added Et3N (463 μL, 3.34 mmol). The mix-
ture was stirred for 2 h at room temp., filtered, and evaporated
under reduced pressure (T = 20 °C). The residue was dissolved in
diethyl ether (15 mL), filtered, and evaporated under reduced pres-
sure (T = 20 °C). The resulting free amine was dissolved in diethyl
ether over molecular sieves (4 Å) and treated drop wise with cro-
tonaldehyde (304 μL, 3.67 mmol, 1.10 equiv.) at 0 °C. The mixture
was brought to room temp., stirred for 15 h, filtered, and evapo-
rated under reduced pressure (T = 20 °C) to give 15 as a brown
oil. The hydrolysis-sensitive product was used immediately without
purification in the next step. 1H NMR (400 MHz, CDCl3): δ =
1.26 (t, 3J = 7.1 Hz, 3 H, CH2CH3), 1.87 (d, 3J = 5.2 Hz, 3 H,
(c = 0.52, CHCl3). H NMR (400 MHz, CDCl3):[25] δ = 1.25 (t, J
= 7.1 Hz, 3 H, CH2CH3), 2.09–2.19, 2.22–2.42 [2ϫm, 4 H,
CH2CH(COOEt)CHCH2], 2.59–2.68 (m, 1 H, CHCOOEt), 2.75–
2.87 (m, 1 H, CHCHCOOEt), 4.09–4.21 (m, 2 H, CH2CH3), 4.51–
3
4.59 (m, 1 H, CH=CHCHN), 4.96 (t, J = 7.6 Hz, 1 H, CHCfur),
5.05–5.17 (m, 2 H, OCH2Ph), 5.72–5.81 (m, 1 H, CH=CHCHN),
5.87–6.03 (m, 1 H, CH=CHCHN), 6.03–6.20 (m, 1 H, Ofur
-
CH=CHCH), 6.26–6.31 (m, 1 H, OfurCH=CHCH), 7.27–7.40 (m,
6 H, 5ϫHPh, OfurCH=CHCH) ppm. 13C NMR (100 MHz,
CDCl3):[25] δ = 14.2 (+, CH3), 23.6 (–, CHCH2CH), 33.4 (–,
CHCH2CH), 36.9 (+, CHCHCOOEt), 39.6 (+, CHCHCOOEt),
54.5 (+, CHN), 55.0 (CHN), 60.7 (–, CH2CH3), 66.8 (–, CH2OPh),
106.0 (+, OfurCH=CHCH), 110.3 (+, OfurCH=CHCH), 125.2,
CH3CH=CH), 2.75–2.95 (m, 2 H, CH2CH=CH), 4.16 (q, 3J = 126.8, 127.7, 127.8, 128.3 (+, 7ϫ= CH), 130.3 (q, CPh), 136.6 (q,
3
7.1 Hz, 2 H, CH2CH3), 4.37 (t, J = 7.0 Hz, 1 H, CH2CHN), 5.87
Cfur), 141.2 (+, OfurCH=CHCH), 155.1 (q, NC=O), 174.3 (q, CO-
OEt) ppm. IR: ν = 3033 (w), 2979 (m), 1703 (vs), 1499 (s), 1447
3
(d, J = 15.6 Hz, 1 H, CH2CH=CH), 6.15–6.31 (m, 4 H, 2ϫHfur
,
˜
CH3CH=CH), 6.85 (dt, 3J = 7.1, 15.6 Hz, 1 H, CH2CH=CH), (s), 1299 (s), 1108 (s), 1027 (m), 736 (m) cm–1. MS (EI): m/z (%) =
7.34–7.36 (m, 1 H, OfurCH=CHCH), 7.86 (d, 3J = 8.0 Hz, 1 H,
N=CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2 (+,
CH2CH3), 18.5 (+, CH3CH=CH), 37.1 (–, CH2CH=CH), 60.3 (–,
CH2CH3), 66.1 (+, CH2CHN), 106.6 (+, Cfur), 110.3 (+, Cfur),
116.6, 123.9, 130.9, 142.2, 144.6 (+, 5ϫ= CH), 154.0 (q, Cfur),
164.6 (+, N=CH), 166.4 (q, C=O) ppm. GC–MS: m/z = 261 [M]+,
246, 216, 207, 188, 148, 130, 119.
395 (8) [M]+, 304 (64), 260 (44), 186 (10), 91 (100). HRMS: calcd.
for C23H25NO5 [M]+ 395.1733; found 395.1736. C23H25NO5
(395.17): calcd. C 69.86, H 6.37, N 3.54; found C 69.38, H 6.47,
N 3.29. HPLC conditions: AS-H chiralpak column; n-heptane/2-
propanol = 98:2; 10 °C; flow rate = 0.7 mL/min; major enantiomer
tR = 29.38 min; minor enantiomer tR = 33.69 min.
Ethyl rac-(E)-5-[N-{(E)-Buta-1,3-dienyl}isobutyramido]-5-(furan-2-
yl)pent-2-enoate (19): To a solution of isobutyryl chloride (69.5 μg,
68.4 μL, 653 μmol, 1.20 equiv.) in dichloromethane (5.0 mL) with
molecular sieves (4 Å) were added Et3N (15.1 μL, 109 μmol,
Ethyl (S)-5-[(Benzyloxycarbonyl){(E)-buta-1,3-dienyl}amino]-5-(fur-
an-2-yl)pent-2-enoate (16): N,N-diethylaniline (219 μL, 1.76 mmol,
1.50 equiv.) was added to a solution of benzylchloroformate
(256 μL, 21.41 mmol, 1.20 equiv.) in toluene (10 mL) with molecu-
lar sieves (4 Å) at 0 °C. After 30 min, a solution of 15 (307 mg,
1.18 mmol) in toluene (10 mL) was added and the mixture was
stirred for 2 d at room temp. It was filtered, washed with dichloro-
methane, and evaporated under reduced pressure. Column
chromatography (cyclohexane/ethyl acetate, 10:1) afforded 16
(303 mg, 65% over 2 steps, 81% ee) as a yellow oil. [α]2D0 = –20.8
2.00 equiv.)
and
4-N,N-dimethylaminopyridine
(3.32 mg,
27.0 μmol, 0.05 equiv.) at –78 °C. A solution of 15 (142 mg,
544 μmol) in dichloromethane (5.0 mL) was added dropwise. The
mixture was slowly brought to 0 °C with stirring overnight. It was
filtered, washed with dichloromethane, and silica was added. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (cyclohexane/ethyl acetate,
5:1) to afford 19 (143 mg, 79% over 2 steps) as a yellow oil. Rf
1
(c = 0.23, CHCl3). Rf (cyclohexane/ethyl acetate, 10:1) = 0.25. H
NMR (400 MHz, CDCl3): δ = 1.27 (t, 3J = 7.1 Hz, 3 H, CH2CH3), (cyclohexane/ethyl acetate, 10:1) = 0.19. 1H NMR (400 MHz,
2.94–3.10 (m, 2 H, CH2CHN), 4.17 (q, 3J = 7.1 Hz, 2 H, CH2CH3), CDCl3): δ = 1.11 [d, 3J = 6.7 Hz, 6 H, CH(CH3)2], 1.25 (t, 3J =
3
3
4.92 (d, Jcis = 10.4 Hz, 1 H, CH2=CH), 5.01 (d, Jtrans = 16.9 Hz, 7.1 Hz, 3 H, CH2CH3), 2.86–2.93 [m, 3 H, CH2CH=CH, CH-
3
1 H, CH2=CH), 4.98–5.05 (m, 2 H, OCH2Ph), 5.49–5.60 (m, 1 H,
(CH3)2], 4.15 (q, 3J = 7.1 Hz, 2 H, CH2CH3), 5.06 (d, Jcis
=
CH2CHN), 5.77–5.93 (m, 2 H, =CH), 6.16–6.27 (m, 2 H, =CH), 10.2 Hz, 1 H, CH2=CH), 5.12 (d, 3Jtrans = 17.0 Hz, 1 H, CH2=CH),
3
6.31–6.35 (m, 1 H, =CH), 6.77 (d, J = 14.4 Hz, 1 H, NCH=CH),
5.75–5.91, 6.18–6.35, 6.79–6.87 (3ϫm, 8 H, CH2CHN, 7 ϫ=CH),
7.33–7.36 (m, 1 H, OfurCH=CHCH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.2 (+, CH2CH3), 19.2, 19.3 [+, CH(CH3)2], 31.7 [+,
3
6.89 (dt, J = 7.0, 15.3 Hz, 1 H, CH2CH=CH), 7.30–7.40 (m, 6 H,
5ϫHPh, OfurCH=CHCH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 14.2 (+, CH2CH3), 32.6 (–, CH2CH=CH), 52.6 (+, CH2CHN), CH(CH3)2], 32.4 (–, CH2CH=CH), 50.3 (+, CH2CHN), 60.3 (–,
60.3 (–, CH2CH3), 68.3 (–, OCH2Ph), 107.7 (+, Cfur), 110.4 (+,
Cfur), 114.4 (–, CH2=CH), 115.9, 124.3, 128.0, 128.3, 128.5, 129.1,
135.2 (+, 9ϫ=CH), 135.7 (q, CPh), 142.0, 143.3 (+, 2ϫ=CH),
151.8 (q, NC=O), 153.9 (q, Cfur), 166.0 (q, C=OOEt) ppm. IR
CH2CH3), 107.8, 110.3 (2ϫ =CH), 117.4 (–, CH2=CH), 124.1,
128.1, 133.9, 142.0, 143.6 (+, 6ϫ=CH), 152.3 (q, Cfur), 166.0 (q,
C=OOEt), 177.0 (q, NC=O) ppm. IR (film): ν = 2976 (w), 2932
˜
(w), 1719 (w), 1637 (w), 1469 (vw), 1389 (vw), 1315 (vw), 1269
(ATR): ν = 2938 (vw), 1698 (w), 1400 (vw), 1336 (vw), 1155 (vw), (vw), 1012 (vw), 740 (vw) cm–1. MS (EI): m/z (%) = 331 (20)
˜
1008 (vw), 731 (vw), 696 (vw) cm–1. MS (FAB, matrix: 3-NBA):
[M]+, 193 (73), 192 (11), 162 (58), 119 (49), 43 (100). HRMS: calcd.
m/z (%) = 396 (8) [M + H]+, 283 (8), 203 (9), 193 (28), 154 (18), for C19H25NO4 [M]+ 331.1784; found 331.1785.
6562
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6558–6566

Stereoselective Synthesis of Functionalized Hexahydroindoles
rac-Ethyl 2-(Furan-2-yl)-1-isobutyryl-2,3,3a,4,5,7a-hexahydro-1H-
indole-4-carboxylate (20): To a solution of 19 (56.3 mg, 170 μmol)
in o-xylene (5.0 mL) was added (N,O)-bis(trimethylsilyl)acetamide
(41.5 μL, 170 μmol). The mixture was heated in a vial at 175 °C for
7 d. It was evaporated under reduced pressure, and the residue was
purified by column chromatography (cyclohexane/ethyl acetate,
extracted into dichloromethane (3ϫ15 mL), dried with sodium sulf-
ate, and evaporated under reduced pressure. The residue was puri-
fied by column chromatography (cyclohexane/ethyl acetate, 3:1) to
afford 22 (50.0 mg, 75%) as a yellow oil. Rf (cyclohexane/ethyl acet-
ate, 3:1) = 0.30. [α]2D0 = –3.6 (c = 0.59, CHCl3). 1H NMR (400 MHz,
3
CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H, CH3), 1.59–1.64, 2.29–2.37,
3:1) to afford 20 (27.6 mg, 49%) as a yellow oil. Rf (cyclohexane/
2.44–2.54, 2.56–2.73 [4ϫm, 5 H, CH2CH(COOEt)CHCH2], 3.14–
1
ethyl acetate, 3:1) = 0.29. H NMR (400 MHz, CDCl3): δ = 0.85– 3.24 (m, 1 H, CHCHCOOEt), 4.21 (q, 3J = 7.1 Hz, 2 H, CH2CH3),
0.93, 1.07–1.17 [2ϫm, 6 H, CH(CH3)2], 1.24–1.30 (m, 3 H, 4.35–4.45 (m, 1 H, ICH), 4.63–4.73 (m, 1 H, CHC=Olac), 4.89–4.95
CH2CH3), 2.10–2.88 [m, 7 H, CH2CH(COOEt)CHCH2, CH- (m, 1 H, CHCHN), 4.95–5.03 (m, 1 H, ICHCHOlac) 5.13–5.25 (m,
(CH3)2], 4.09–4.24 (m, 2 H, CH2CH3), 4.58–4.79, 4.95–5.02, 5.08–
5.17 (3ϫm, 2 H, CH=CHCHNCH), 5.65–5.81, 6.04–6.16, 6.23–
6.36 (3ϫm, 4 H, 2ϫCHCfur, CH=CHCHN), 7.27–7.38 (m, 1 H,
2 H, OCH2Ph), 7.31–7.41 (m, 5 H, Har) ppm. 13C NMR (100 MHz,
CDCl3): 14.0 (+, CH2CH3), 18.8 (+, ICH), 25.1 [–,
CH2CH(COOEt)CHCH2], 29.7 (+, CHCHCOOEt), 40.6 (+,
δ
=
O
furCH=CHCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2 (+, CHCHCOOEt), 50.2 (+, ICHCOCHN), 56.1 (+, CHC=Olac), 61.6
CH2CH3), 19.2 [+, CH(CH3)2], 24.2 (–, CH=CHCH2), 31.9 [+, (–, CH2CH3), 67.9 (–, OCH2Ph), 80.9 (+, ICHCHOlac), 128.1,
CHCHCOOEt or CHCHCOOEt or CH(CH3)2], 35.8 (–, 128.5, 128.7 (+, 5ϫCPh), 135.6 (q, CPh), 153.6 (q, CHC=Olac),
CH2CHCHCOOEt), 36.5, 40.0 [+, CHCHCOOEt or
167.6 (NC=O), 172.7 (CHC=OOEt) ppm. IR (film): ν = 2979 (m),
˜
CHCHCOOEt or CH(CH3)2], 53.3 (+, CHN), 54.8 (CHN), 60.7 (–, 1763 (s), 1717 (vs), 1413 (s), 1351 (s), 1313 (s), 1292 (s), 1260 (s),
CH2CH3), 106.1 (+, OfurCH=CHCH), 110.5 (+, OfurCH=CHCH), 1214 (s), 1113 (s), 1026 (s), 994 (s), 911 (m), 734 (s), 699 (m) cm–1.
125.2 (+, CH=CHCH2), 126.6 (+, CH=CHCH2), 141.8 (+, MS (EI): m/z (%) = 499 (1), [M]+, 372 (1), 328 (10), 284 (11), 120
O
furCH=CHCH), 155.9 (q, Cfur), 174.4 (q, C=OOEt), 174.3 (q, (5), 118 (8), 91 (100). HRMS: calcd. for C20H22INO6 [M]+
NC=O) ppm. IR: ν = 2976 (m), 2935 (m), 1729 (s), 1642 (s), 1472 499.0492; found 499.0495.
˜
(m), 1311 (m), 1181 (s), 1091 (m), 1028 (m), 738 (m) cm–1. MS (EI):
4-Benzyl 6-Ethyl rac-(3S,4aR,5R,6S,8aS)-2-Oxo-4a,5,6,8a-tetra-
m/z (%) = 331 (14) [M]+, 179 (63), 164 (43), 146 (16), 110 (28), 55
(100). HRMS: calcd. for C19H25NO4 [M]+ 331.1784; found
331.1786. C19H25NO4 (331.41): calcd. C 68.86, H 7.60, N 4.23;
found C 68.61, H 7.64, N 4.19.
hydro-2H-3,5-methanobenzo[b][1,4]oxazine-4,6(3H)-dicarboxylate
(23): To a solution of 22 (25.9 mg, 52.0 μmol) in methanol (2 mL)
and dichloromethane (0.6 mL) was added mCPBA (70 wt.-%,
32.0 mg, 130 μmol, 2.50 equiv.). The mixture was stirred for 90 min
(2S,3aR,4S,7aS)-1-(Benzyloxycarbonyl)-4-(ethoxycarbonyl)- at room temp. Ethyl acetate (20 mL) was added and the organic
2,3,3a,4,5,7a-hexahydro-1H-indole-2-carboxylic Acid (21): To
a
phase was washed with 5% sodium hydrogen carbonate solution
solution of 18 (88.0 mg, 223 μmol) in MeCN/H2O (6:1, 10.5 mL)
(2ϫ20 mL), dried with sodium sulfate, and evaporated under re-
at 0 °C were added NaH2PO4 ϫ2 H2O (208 mg, 1.34 mmol, duced pressure. The residue was purified by column chromatog-
6.00 equiv.), NaClO2 (201 mg, 2.23 mmol, 10.0 equiv.), and hydro-
gen peroxide (35 wt.-% in H2O, 90.0 μL, 834 μmol, 3.75 equiv.).
The mixture was heated to reflux for 8 h, cooled to room temp.,
diluted with H2O (5 mL), acidified (pH 2) with diluted aqueous
hydrogen chloride solution, and extracted into dichloromethane
(3ϫ15 mL). The combined organic phases were dried with sodium
sulfate and evaporated under reduced pressure. The residue was
purified by column chromatography (dichloromethane/methanol,
raphy (cyclohexane/ethyl acetate, 3:1) to obtain 23 (8.00 mg,
22.0 μmol, 41%) as a yellow oil. Rf = 0.21 (cyclohexane/ethyl acet-
1
3
ate, 3:1). H NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3
2
3
3
H, CH2CH3), 1.47 (ddd, J = 13.7, J = 7.4, J = 7.4 Hz, 1 H, 9-
HA), 2.59–2.72 (m, 1 H, 9-HB), 2.76–2.96 (m, 1 H, 8a-H), 3.25–
3.36 (m, 1 H, 6-H), 4.18 (q, 3J = 7.1 Hz, 2 H, CH2CH3), 4.55–4.74
(m, 2 H, 3-H, 4a-H), 4.78–5.06 (m, 1 H, 5-H), 5.09–5.24 (m, 2 H,
OCH2Ph), 5.99–6.10 (m, 2 H, 7-H, 8-H), 7.22–7.45 (m, 5 H,
98:2 + 0.5% acetic acid) to afford 21 (45.0 mg, 54%) as a colorless 5ϫHPh) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (+, CH2CH3),
oil. Rf (CH2Cl2/MeOH, 98:2 + 0.5% AcOH) = 0.24. [α]2D0 = +61.4
32.7 (–, C-9), 33.6 (+, C-8a), 43.6 (+, C-6), 51.8, 56.3 (+, C-3, C-
(c = 0.50, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 4a), 61.6 (–, CH2CH3), 67.9 (–, OCH2Ph), 69.4 (+, C-5), 125.7,
7.1 Hz, H, CH3), 1.94–2.48, 2.66–2.86 [2ϫm, H, 127.2 (+, C-7, C-8), 128.1, 128.4, 128.6 (+, 5ϫCPh), 134.7, 135.7
CH2CH(COOEt)CHCH2], 4.15 (q, 3J = 7.1 Hz, 2 H, CH2CH3), (q, CPh, NC=O), 169.2, 171.3 (q, COOEt, C-2) ppm. IR (ATR): ν
1
3
3
6
˜
3
3
4.40 (t, J = 7.7 Hz, 1 H, CHCOOH), 4.53 (d, J = 4.7 Hz, 1 H, = 3306 (m), 2956 (m), 1759 (w), 1712 (m), 1636 (m), 1533 (w), 1462
CH=CHCHN), 5.10–5.21 (m, 2 H, OCH2Ph), 5.63–6.04 (m, 2 H,
CH=CH), 7.28–7.39 (m, 5 H, Har), 7.92 (br. s, 1 H, COOH) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.1 (+, CH3), 23.0 (–,
CHCH2CH), 31.1 (–, CHCH2CH), 36.8 (+, CHCHCOOEt) 39.0
(w), 1400 (m), 1359 (w), 1322 (w), 1301 (w), 1264 (m), 1215 (w),
1145 (w), 1096 (vw), 1026 (w), 951 (m), 849 (w), 751 (m), 697 (w),
525 (m) cm–1. MS (FAB, 3-NBA): m/z (%) = 372 (4) [M + H]+, 328
(7), 236 (3), 149 (30), 91 (100). HRMS: calcd. for C20H22NO6
(+, CHCHCOOEt), 54.8 (+, =CHCHN), 58.5 (+, NCHCOOH), [M]+ 372.1447; found 372.1446.
60.9 (–, OCH2Ph), 67.8 (–, CH2CH3), 125.5, 125.7, 128.0, 128.2,
Ethyl rac-2-(Furan-2-yl)octahydro-1H-indole-4-carboxylate (24): To
128.5 (+, 7ϫ=CH), 136.0 (q, CPh), 156.2 (q, NC=O), 174.0 (q,
a solution of 18 (60.2 mg, 152 μmol) in methanol (2.0 mL) was
added palladium/charcoal (10%, 0.81 mg, 7.6 μmol, 0.05 equiv.),
and the mixture was stirred for 3 h at room temp. under a hydrogen
atmosphere. It was filtered through Celite®, evaporated under re-
duced pressure, and the residue was purified by column chromatog-
raphy (CH2Cl2/MeOH, 98:2 + 0.5% Et3N) to afford 24 (34.8 mg,
88%) as a yellow oil. Rf (CH2Cl2/MeOH, 98:2 + 0.5% NEt3) =
CHC=OOEt), 175.3 (q, CHCOOH) ppm. IR (ATR): ν = 2936 (w),
˜
1701 (m), 1414 (m), 1157 (m), 1112 (m), 1025 (m), 734 (m), 696
(m) cm–1. MS (EI): m/z (%) = 373 (2) [M]+, 328 (7), 284 (21), 238
(44), 194 (7), 120 (12), 91 (100). HRMS: calcd. for C20H23NO6
[M]+ 373.1525; found 373.1522.
4-Benzyl 6-Ethyl (3S,4aR,5R,6S,8R,8aR)-8-Iodo-2-oxohexahydro-
2H-3,5-methanobenzo[b][1,4]oxazin-4,6(3H)-dicarboxylate (22): To
a solution of 21 (49.7 mg, 133 μmol) in dichloromethane (2 mL)
and saturated aqueous sodium hydrogen carbonate solution (2 mL)
was added iodine (67.6 mg, 266 μmol, 2.00 equiv.) at 0 °C. The mix-
ture was stirred for 4 h at room temp., diluted with H2O (5 mL),
1
3
0.19. H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.35–1.94, 2.24–2.32, 2.52–2.56 [3ϫm, 10 H,
CH2CH(COOEt)CHCH2CH2CH2],
3.30–3.35
(m,
1
H,
CH2CH2CHN), 4.13 (q, 3J = 7.1 Hz, 2 H, CH2CH3), 4.27–4.32 (m,
1 H, CHCfur), 6.19 (d, 3J = 3.1 Hz, 1 H, OfurCH=CHCH), 6.30
Eur. J. Org. Chem. 2011, 6558–6566
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6563

S. Bräse et al.
FULL PAPER
3
3
(dd, J = 3.1, J = 1.9 Hz, 1 H, OfurCH=CHCH), 7.34–7.37 (m, 1 70.7, 70.9 (q, C-4), 105.5, 106.3 (+, C-3Ј), 110.0, 110.1 (+, C-4Ј),
H, OfurCH=CHCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2
(+, CH3), 19.8, 27.5, 28.3, 36.3 (4ϫ–, CH2), 39.8, 44.8, 54.0, 57.6,
122.8, 122.9 (+, C-6), 123.4, 125.9, 127.4, 127.5, 127.6, 127.8, 128.0,
128.2, 128.6, (+, 10ϫCPh), 126.5, 126.5 (+, C-7), 136.2, 136.5 (q,
(4ϫ+, CH), 60.2 (–, CH2CH3), 105.0 (+, OfurCH=CHCH), 110.1 CH2CPh), 140.9, 141.1 (+, C-5Ј), 148.1, 154.4, 154.6, 154.7, 155.6
(+, OfurCH=CHCH), 141.7 (+, OfurCH=CHCH), 157.8 (q, Cfur), (q, NCPh, C-2Ј, NCOOBn), 170.9, 171.0 (q, COOEt) ppm. IR
176.2 (q, COOEt) ppm. IR: ν = 2934 (s), 1728 (s), 1452 (m), 1376 (ATR): ν = 3367 (vw), 2922 (vw), 1698 (w), 1595 (vw), 1487 (vw),
˜
˜
(m), 1238 (m), 1110 (m), 802 (w), 735 (m) cm–1. MS (EI): m/z (%) 1451 (w), 1407 (w), 1353 (w), 1289 (w), 1239 (w), 1148 (w), 1109
= 263 (39) [M]+, 218 (13), 190 (72), 109 (19), 99 (100). HRMS:
calcd. for C15H21NO3 [M]+ 263.1521; found 263.1523.
(w), 1010 (w), 931 (vw), 884 (vw), 765 (w), 734 (w), 696 (m) cm–1.
MS (EI): m/z (%) = 502 (7) [M]+, 486 (4), 413 (4), 393 (26), 320
(26), 276 (15), 266 (11), 234 (6), 212 (13), 184 (12), 118 (13), 109
(18), 91 (100). HRMS: calcd. for C29H30N2O6 [M]+ 502.2104;
found 502.2107. C29H30N2O6 (502.57): calcd. C 69.31, H 6.02, N
5.57; found C 68.72, H 5.89, N 5.34.
1-Benzyl 4-Ethyl (2S,3aS,7aS)-2-(Furan-2-yl)-4-[hydroxy(phenyl)-
amino]-3,3a,4,5-tetrahydro-1H-indole-1,4(2H,7aH)-dicarboxylate as
C-4 epimers (25): To a solution of 18 (273 mg, 691 μmol) in THF
(20 mL) was added LiHMDS (1.00 m in THF, 1.04 mL, 1.04 mmol,
1.50 equiv.) at –78 °C, and the mixture was stirred for 15 min at this
temperature and for 30 min at 0 °C. A solution of nitrosobenzene
(118 mg, 1.11 mmol, 1.60 equiv.) in THF (15 mL) was added over
30 min at –78 °C. The solution was stirred at –78 °C for 3 h. Water
(10 mL) was added and, after warming to room temp., the mixture
was extracted into ethyl acetate (3ϫ150 mL), washed with 0.5 m
sodium hydroxide solution (2ϫ80 mL) and brine (80 mL), dried
with sodium sulfate, and evaporated under reduced pressure. The
residue was purified by column chromatography (cyclohexane/ethyl
acetate, 5:1) to afford (4S)-25, which was recrystallized from cyclo-
hexane to give a colorless solid (82.5 mg, 164 μmol). The isomer
(4R)-25 was obtained as a yellow oil (82.7 mg, 165 μmol). Further-
more, a fraction of a 1:1 mixture of both isomers (24.5 mg,
49 μmol) was afforded. The epimers were obtained in a total yield
Benzyl 2rac-(2S,3aR,4S,7aS)--(Furan-2-yl)-4-[methoxy(methyl)carb-
amoyl]-2,3,3a,4,5,7a-hexahydro-1H-indole-1-carboxylate (26): To a
suspension of N,O-dimethylhydroxylamine hydrochloride (209 mg,
2.14 mmol, 4.50 equiv.) in THF (5 mL) was added a 2.5 m n-butyl-
lithium solution (1.71 mL, 4.28 mmol, 9.00 equiv.) at –78 °C. The
solution was stirred for 20 min at room temp. before cooling to
–78 °C. A solution of 18 (188 mg, 476 μmol) in THF (5 mL) was
added and the resulting mixture was stirred for another 2 h at
–78 °C. Saturated aqueous ammonium chloride solution (10 mL)
and water (5 mL) were added, and the mixture was extracted into
ethyl acetate (3ϫ30 mL), dried with sodium sulfate, and evapo-
rated under reduced pressure. The residue was purified by column
chromatography (cyclohexane/ethyl acetate, 3:2) to afford 26
(153 mg, 372 μmol, 78%) as a colorless oil. Rf = 0.23 (cyclohexane/
ethyl acetate, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.98–2.04 (m,
of 55%. (4S)-25: Rf = 0.31 (cyclohexane/ethyl acetate, 3:1). [α]2D0
+58.7 (c = 1.24, CHCl3). M.p. 146–147 °C. Ratio of inversion iso-
mers = 0.57:0.43. H NMR (400 MHz, CDCl3): δ = 1.01–1.15 (m,
=
2
2 H, 3-HA, 5-HA), 2.19–2.23 (m, 1 H, 5-HB), 2.39 (ddd, J = 13.6,
3J = 8.4, J = 8.4 Hz, 1 H, 3-HB), 2.78–2.84 (m, 1 H, 3a-H), 2.82–
3
1
2.90 (m, 1 H, 4-H), 3.13 (s, 3 H, NCH3), 3.38 (s, 3 H, OCH3), 4.50–
4.55 (m, 1 H, 7a-H), 5.05 (dd, 3J = 8.4, 3J = 3.4 Hz, 1 H, 2-H),
5.13 (s, 2 H, OCH2Ph), 5.81–5.86 (m, 1 H, 6-H), 6.06–6.11 (m, 1
H, 3Ј-H), 6.09–6.25 (m, 1 H, 7-H), 6.26 (dd, J = 3.1, J = 1.8 Hz,
1 H, 4Ј-H), 7.23–7.35 (m, 6 H, 5ϫHPh, 5Ј-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 25.9 (–, C-5), 32.2 (+, NCH3), 34.8 (–, C-
3), 37.2, 37.4 (+, C-3a, C-4), 55.2 (+, C-2), 55.5 (+, C-7a), 61.4 (+,
OCH3), 66.9 (–, OCH2Ph), 105.9 (+, C-3Ј), 110.3 (+, C-4Ј), 126.3,
126.6 (+, C-6, C-7), 127.7, 127.8, 128.4 (+, 5ϫCPh), 136.6 (q, CPh),
141.2 (+, C-5Ј), 155.2, 156.1 (q, C-2Ј, NCOOBn), 175.6 [q, C(=O)-
3 H, CH2CH3), 1.84–2.01 (m, 1 H, 3-HA), 2.11–2.40 (m, 3 H, 3-
HB, 5-H2), 3.25–3.43 (m, 1 H, 3a-H), 4.02–4.16 (m, 2 H, CH2CH3),
4.80–5.10 (m, 4 H, 2-H, 7a-H, OCH2Ph), 5.56–5.64 (m, 1 H, 6-H),
5.74–5.93 (m, 2 H, 7-H, 3Ј-H), 6.14–6.20 (m, 1 H, 4Ј-H), 6.32–6.76
(br. s, 1 H, OH), 6.97–7.32 (m, 11 H, 10ϫHPh, 5Ј-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.9 (+, CH2CH3), 26.9, 27.1 (–, C-
5), 32.1, 33.6 (–, C-3), 39.4, 40.0 (+, C-3a), 54.1, 54.2, 56.5, 57.0
(+, C-2, C-7a), 60.5, 60.7 (–, CH2CH3), 66.8 (–, OCH2Ph), 70.7,
70.9 (q, C-4), 105.6, 106.5 (+, C-3Ј), 110.0 (+, C-4Ј), 122.4 (+, C-
6), 123.7, 123.9, 125.4, 125.6, 127.5, 127.6, 127.7, 128.0, 128.3 (+,
10ϫCPh), 127.2, 127.3 (+, C-7), 136.1, 136.5 (q, CH2CPh), 140.9,
3
3
N(OCH )CH ] ppm. IR (film): ν = 3114 (vw), 3033 (w), 3936 (w),
˜
3
3
2246 (vw), 1701 (s), 1669 (s), 1498 (w), 1444 (m), 1408 (w), 1354
(s), 1320 (m), 1299 (m), 1174 (m), 1110 (m), 1077 (w), 1007 (m),
911 (w), 855 (w), 807 (vw), 770 (w), 734 (m), 698 (m), 599 (w), 469
(vw), 436 (vw) cm–1. MS (EI): m/z (%) = 410 (10) [M]+, 379 (4),
322 (13), 319 (17), 275 (28), 91 (58), 84 (100). HRMS: calcd. for
C23H26N2O5 [M]+ 410.1842; found 410.1845.
141.1 (+, C-5Ј), 148.3, 148.7, 154.2, 154.8, 155.0, 155.4 (q, NCPh
C-2Ј, NCOOBn), 171.0, 171.1 (q, COOEt) ppm. IR (ATR): ν =
,
˜
3304 (w), 2982 (vw), 1732 (w), 1662 (m), 1465 (w), 1422 (m), 1356
(m), 1234 (m), 1190 (w), 1168 (w), 1142 (w), 1078 (w), 1065 (w),
1034 (w), 1011 (w), 967 (w), 940 (w), 890 (w), 879 (w), 838 (w), 818
(w), 795 (w), 746 (m), 733 (m), 701 (m), 677 (m), 601 (w), 563 (w),
539 (w), 505 (w) cm–1. MS (EI): m/z (%) = 502 (2) [M]+, 486 (3),
413 (4), 393 (45), 349 (7), 302 (4), 276 (6), 258 (10), 234 (7), 212
(14), 184 (13), 118 (8), 109 (26), 91 (100). HRMS: calcd. for
Benzyl rac-(2S,3aR,4S,7aS)-4-Acetyl-2-(furan-2-yl)-2,3,3a,4,5,7a-
hexahydro-1H-indole-1-carboxylate (27): To
(35.8 mg, 87 μmol) in THF (2.5 mL) at 0 °C was added methylmag-
a solution of 26
C29H30N2O6 [M]+ 502.2104; found 502.2107. C29H30N2O6 (502.57): nesium bromide (3 m in THF, 145 μL, 436 μmol, 5.00 equiv.), and
calcd. C 69.31, H 6.02, N 5.57; found C 68.72, H 5.89, N 5.34.
(4R)-25: Rf = 0.24 (cyclohexane/ethyl acetate, 3:1). Ratio of inver-
sion isomers = 0.65:0.35. [α]2D0 = +94.1 (c = 0.83, CHCl3). 1H NMR
solution was stirred at this temperature for 30 min. Saturated am-
monium chloride solution (1 mL) was added and the mixture was
diluted with water (2 mL), extracted into ethyl acetate (3ϫ10 mL),
(400 MHz, CDCl3): δ = 1.11–1.29 (m, 3 H, CH2CH3), 1.95–2.08 dried with sodium sulfate, and evaporated under reduced pressure.
(m, 1 H, 3-HA), 2.18–2.48, 2.54–2.67, (2ϫm, 3 H, 3-HB, 5-H2), The residue was purified by column chromatography (cyclohexane/
3.27–3.44 (m, 1 H, 3a-H), 4.10–4.18 (m, 2 H, CH2CH3), 4.61–4.71,
4.84–4.96 (2ϫm, 1 H, 7a-H), 4.90–5.18 (m, 3 H, 2-H, OCH2Ph),
ethyl acetate, 3:1), which gave 27 (26.1 mg, 73 μmol, 82%) as a
colorless oil. Rf = 0.19 (cyclohexane/ethyl acetate, 3:1). 1H NMR
5.57–5.71 (m, 1 H, 6-H), 5.73–5.99 (m, 1 H, 7-H), 6.04–6.31 (m, 2 (400 MHz, CDCl3): δ = 2.06–2.16, 2.28–2.35 (2ϫm, 2 H, 3-H2),
H, 3Ј-H, 4Ј-H), 7.06–7.42 (m, 11 H, 10ϫHPh, 5Ј-H) ppm. 13C 2.11 (s, 3 H, CH3), 2.16–2.28 (m, 2 H, 5-H2), 2.62–2.69 (m, 1 H,
NMR (100 MHz, CDCl3): δ = 13.7, 13.8 (+, CH2CH3), 28.2, 28.7
(–, C-5), 32.2, 33.7 (–, C-3), 39.1, 39.4 (+, C-3a), 53.8, 54.0 (+, C-
4-H), 2.71–2.78 (m, 1 H, 3a-H), 4.48–4.50 (m, 1 H, 7a-H), 4.97 (t,
3J = 7.2 Hz, 1 H, 2-H), 5.11 (s, 2 H, OCH2Ph), 5.73–5.80 (m, 1 H,
2), 56.7, 57.1 (+, C-7a), 60.9, 61.0 (–, CH2CH3), 66.6 (–, OCH2Ph), 6-H), 5.91–6.05 (m, 1 H, 7-H), 6.07–6.16 (m, 1 H, 3Ј-H), 6.29 (dd,
6564
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6558–6566

Stereoselective Synthesis of Functionalized Hexahydroindoles
3
3J = 3.0, J = 1.8 Hz, 1 H, 4Ј-H), 7.26–7.35 (m, 6 H, 5ϫHPh, 5Ј-
(w), 885 (w), 807 (w), 769 (w), 732 (m), 696 (m), 598 (w), 574 (vw),
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.9 (–, C-5), 28.8 (+, 458 (w) cm–1. MS (EI): m/z (%) = 381 (6) [M]+, 350 (5), 336 (6),
CH3), 34.5 (–, C-3), 36.5 (+, C-3a), 47.2 (+, C-4), 54.4 (+, C-2),
55.1 (+, C-7a), 66.9 (–, OCH2Ph), 106.1 (+, C-3Ј), 110.4 (+, C-4Ј),
125.1 (+, C-6), 127.1 (+, C-7), 127.8, 127.8, 128.4 (+, 5ϫCPh),
136.6 (q, CPh), 141.1 (+, C-5Ј), 155.2, 155.5 (q, NC=O, C-2Ј), 210.0
304 (5), 290 (100), 264 (9), 246 (59), 149 (30), 91 (69). HRMS:
calcd. for C22H23NO5 [M]+ 381.1576; found 381.1572.
Benzyl (2S,3aR,4S,7aS)-4-Amino-2-(furan-2-yl)-2,3,3a,4,5,7a-hexa-
hydro-1H-indole-1-carboxylate (30): To a solution of 32 (113 mg,
257 μmol) in dichloromethane (1.2 mL) were added water (40 μL)
and TFA (410 μL, 610 mg, 5.30 mmol, 21.0 equiv.), and the mixture
was stirred for 45 min at room temp. The solvent was removed
under reduced pressure, and the residue was dissolved in ethyl acet-
ate (20 mL). The resulting solution was brought to pH 8 by ad-
dition of Et3N, washed with saturated sodium hydrogen carbonate
solution (15 mL), dried with sodium sulfate, and evaporated under
reduced pressure. Compound 30 (85.2 mg, 252 μmol, 98%) was ob-
tained as a slightly brown oil. Rf = 0.25 (CH2Cl2/MeOH, 10:1).
[α]2D0 = +82.0 (c = 1.19, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.92–2.40 (m, 5 H, 3-H2, 3a-H, 5-H2), 3.05–3.35 (m, 1 H, 4-H),
4.51–4.69 (m, 1 H, 7a-H), 4.94 (t, 3J = 7.6 Hz, 1 H, 2-H), 4.99–
5.20 (m, 2 H, OCH2Ph), 5.57–5.73 (m, 1 H, 6-H), 5.76–6.20 (m, 2
H, 7-H, 3Ј-H), 6.25–6.30 (m, 1 H, 4Ј-H), 7.08–7.38 (m, 6 H,
5ϫHPh, 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.9 (–, C-
5), 33.8 (–, C-3), 43.3 (+, C-3a), 46.3 (+, C-4), 54.6 (+, C-2), 55.0
(+, C-7a), 66.9 (–, OCH2Ph), 105.6 (+, C-3Ј), 110.3 (+, C-4Ј), 124.1
(+, C-6), 126.5 (+, C-7), 127.7, 127.8, 128.3 (+, 5ϫCPh), 136.5 (q,
CPh), 141.1 (+, C-5Ј), 155.1, 155.7 (q, NC=O, C-2Ј) ppm. IR (film):
(q, COMe) ppm. IR (film): ν = 3032 (w), 2946 (w), 1703 (vs), 1499
˜
(w), 1446 (m), 1354 (s), 1297 (s), 1242 (m), 1173 (m), 1153 (m),
1107 (s), 1009 (m), 932 (w), 864 (w), 808 (w), 770 (m), 738 (m), 698
(w), 599 (w), 462 (vw) cm–1. MS (EI): m/z (%) = 365 (6) [M]+, 274
(100), 230 (14), 172 (14), 91 (66). HRMS: calcd. for C22H23NO4
[M]+ 365.1627; found 365.1629.
(2S,3aR,4S,7aS)-1-[(Benzyloxy)carbonyl]-2-(furan-2-yl)-2,3,3a,4,
5,7a-hexahydro-1H-indole-4-carboxylic Acid (28): To a solution of
18 (155 mg, 392 μmol) in THF (6.5 mL) was added a solution of
lithium hydroxide (93.9 mg, 3.92 mmol, 10.0 equiv.) in water
(6.5 mL), and the mixture was stirred for 19 h at room temp. THF
was evaporated under reduced pressure and the remaining aqueous
solution was brought to pH 1 by addition of 1 m HCl. The mixture
was extracted into ethyl acetate (3ϫ30 mL), dried with sodium sul-
fate, and evaporated under reduced pressure to give 28 (144 mg,
392 μmol, 99%) as a slightly brown oil. Rf = 0.33 (CH2Cl2/MeOH,
20:1 + 0.5% acetic acid). [α]2D0 = +70.1 (c = 0.80, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 2.12–2.20 (m, 1 H, 3-HA), 2.28–2.44 (m, 3
H, 3-HB, 5-H2), 2.68–2.74 (m, 1 H, 4-H), 2.79–2.86 (m, 1 H, 3a-
3
H), 4.56–4.62 (m, 1 H, 7a-H), 4.97 (t, J = 7.6 Hz, 1 H, 2-H), 5.10
ν = 3366 (w), 3032 (w), 2906 (m), 1699 (s), 1587 (w), 1499 (w),
˜
(s, 2 H, OCH2Ph), 5.73–5.79 (m, 1 H, 6-H), 5.85–6.00 (m, 1 H, 7-
1451 (m), 1410 (s), 1354 (s), 1299 (m), 1213 (w), 1177 (m), 1153
(m), 1112 (s), 1010 (m), 992 (m), 930 (w), 874 (w), 808 (w), 770
(m), 735 (m), 698 (m), 600 (w), 478 (vw) cm–1. MS (FAB, 3-NBA):
m/z (%) = 339 (42) [M + H]+, 278 (4), 247 (3), 231 (5), 203 (5), 186
(10), 91 (100). HRMS: calcd. for C20H23N2O3 [M + H]+ 339.1709;
found 339.1707.
3
H), 6.05–6.20 (m, 1 H, 3Ј-H), 6.28 (dd, 3J = 2.7, J = 1.9 Hz, 1 H,
4Ј-H), 7.10–7.41 (m,
6 H, 5ϫHPh,
5Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.3 (–, C-5), 34.4 (–, C-3), 36.5 (+, C-3a),
39.4 (+, C-4), 54.5 (+, C-2), 54.9 (+, C-7a), 67.0 (–, OCH2Ph),
106.1 (+, C-3Ј), 110.3 (+, C-4Ј), 124.9 (+, C-6), 126.8 (+, C-7),
127.8, 127.9, 128.3 (+, 5ϫCPh), 136.5 (q, CPh), 141.3 (+, C-5Ј),
155.2 (q, C-2Ј, NC=O), 179.9 (q, CO H) ppm. IR (film): ν = 3032
˜
2
Benzyl (2S,3aR,4S,7aS)-4-[(tert-Butoxycarbonyl)amino]-2-(furan-2-
(w), 2950 (w), 1697 (s), 1499 (w), 1406 (m), 1354 (m), 1297 (m),
1175 (m), 1153 (m), 1108 (m), 1076 (m), 1009 (m), 930 (w), 885
(w), 807 (w), 732 (s), 695 (m), 598 (m), 461 (w) cm–1. MS (FAB, 3-
NBA): m/z (%) = 391 (42) [M + H + Na]+, 368 (46) [M + H]+, 324
(6), 323 (6), 276 (27), 232 (12), 210 (38), 91 (100). HRMS: calcd.
for C21H22NO5 [M]+ 368.1498; found 368.1495.
yl)-2,3,3a,4,5,7a-hexahydro-1H-indole-1-carboxylate (32): To
a
solution of 28 (210 mg, 572 μmol) in tert-butanol (8 mL) were
added DPPA (250 μL, 320 mg, 1.10 mmol, 2.00 equiv.) and Et3N
(96.0 μL, 70.0 mg, 690 μmol, 1.20 equiv.). The mixture was heated
to reflux for 4 h and stirred overnight at room temp. Water (10 mL)
was added, and the aqueous phase was extracted into ethyl acetate
1-Benzyl
rac-(2S,3aR,4S,7aS)-4-Methyl-2-(furan-2-yl)-3,3a,4,5- (3ϫ60 mL). The combined organic phases were dried with sodium
tetrahydro-1H-indole-1,4(2H,7aH)-dicarboxylate (29): To a solution
of 28 (45.6 mg, 124 μmol) in diethyl ether (2.2 mL) and methanol
(0.22 mL) was added a 2 m trimethylsilyldiazomethane solution in
diethyl ether (0.22 mL, 424 mmol, 3.50 equiv.) at 0 °C. The mixture
was stirred for 1 h at 0 °C and 1 h at room temp. The solvent was
evaporated under reduced pressure at 20 °C, and the residue was
purified by column chromatography (cyclohexane/ethyl acetate,
5:1) to obtain 29 (35.1 mg, 92.0 μmol, 74%) as a colorless oil. Rf
= 0.26 (cyclohexane/ethyl acetate, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 2.09–2.17, 2.22–2.42 (2ϫm, 4 H, 3-H2, 5-H2), 2.62–
sulfate, evaporated under reduced pressure, and purified by column
chromatography (cyclohexane/ethyl acetate, 5:1) to give 32 (175 mg,
400 μmol, 78%) as a slightly yellow oil. Rf = 0.37 (cyclohexane/
ethyl acetate, 3:1). [α]2D0 = +49.3 (c = 0.96, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 1.96–2.08, 2.29–
2.36, 2.41–2.46 (3ϫm, 4 H, 3-H2, 5-H2), 2.56–2.79 (m, 1 H, 3a-H),
3.90–4.09 (m, 1 H, 4-H), 4.43–4.63 (m, 1 H, 7a-H), 4.75–4.84 (m,
1 H, NHBoc), 4.85–4.95 (m, 1 H, 2-H), 5.07 (s, 2 H, OCH2Ph),
5.65–5.72 (m, 1 H, 6-H), 5.82–5.98 (m, 1 H, 7-H), 5.99–6.23 (m, 1
H, 3Ј-H), 6.24–6.30 (m, 1 H, 4Ј-H), 7.05–7.20, 7.20–7.45 (2ϫm, 6
2.74 (m, 1 H, 4-H), 2.78–2.85 (m, 1 H, 3a-H), 3.69 (s, 3 H, CH3), H, 5ϫHPh, 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.7
3
4.52–4.70 (m, 1 H, 7a-H), 4.96 (t, J = 7.6 Hz, 1 H, 2-H), 5.10 (s,
(–, C-5), 28.4 [+, C(CH3)3], 34.0 (–, C-3), 39.9 (+, C-3a), 45.7 (+,
2 H, OCH2Ph), 5.72–5.81 (m, 1 H, 6-H), 5.83–6.03 (m, 1 H, 7-H), C-4), 54.6 (+, C-2, C-7a), 66.9 (–, OCH2Ph), 79.5 [q, C(CH3)3],
6.05–6.23 (m, 1 H, 3Ј-H), 6.24–6.36 (m, 1 H, 4Ј-H), 7.20–7.44 (m, 105.9 (+, C-3Ј), 110.2 (+, C-4Ј), 123.6, 127.2 (+, C-6, C-7), 127.7,
6 H, 5ϫHPh, 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.6 127.8, 128.3 (+, 5ϫCPh), 136.5 (q, CPh), 141.2 (+, C-5Ј), 155.2 (q,
(–, C-5), 34.8 (–, C-3), 36.9 (+, C-3a), 39.6 (+, C-4), 52.0 (+, CH3), 2ϫNC=O, C-2Ј) ppm. IR (film): ν = 3331 (vw), 3114 (vw), 3032
˜
54.5 (+, C-2), 55.0 (+, C-7a), 66.9 (–, OCH2Ph), 106.0 (+, C-3Ј), (vw), 2975 (w), 2930 (w), 1695 (w), 1499 (w), 1454 (w), 1408 (w),
110.3 (+, C-4Ј), 125.0 (+, C-6), 126.9 (+, C-7), 127.8, 128.4 (+,
5ϫCPh), 136.6 (q, CPh), 141.2 (+, C-5Ј), 155.1 (q, C-2Ј, NC=O),
1353 (w), 1302 (w), 1245 (w), 1169 (w), 1110 (w), 1052 (w), 1009
(vw), 932 (vw), 876 (vw), 805 (vw), 770 (vw), 732 (w), 697 (vw),
174.8 (q, CO Me) ppm. IR (film): ν = 3032 (vw), 2950 (w), 1731 599 (vw), 462 (vw) cm–1. MS (EI): m/z (%) = 438 (16) [M]+, 381
˜
2
(m), 1697 (s), 1498 (vw), 1438 (w), 1404 (m), 1352 (m), 1297 (m),
(21) [M – C4H8]+, 347 (15) [M – C7H7]+, 337 (7) [M – C4H9,
1172 (m), 1153 (m), 1103 (m), 1077 (m), 1010 (m), 993 (m), 931 CO2]+, 291 (10), 247 (75) [C13H15N2O3]+, 186 (24), 91 (100)
Eur. J. Org. Chem. 2011, 6558–6566
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6565

S. Bräse et al.
FULL PAPER
[C7H7]+. HRMS: calcd. for C25H30N2O5 [M]+ 438.2155; found
438.2157.
[8] K. C. Nicolaou, S. Totokotsopoulos, D. Giguère, Y.-P. Sun, D.
Sarlah, J. Am. Chem. Soc. 2011, 133, 8150–8153.
[9] J. E. DeLorbe, S. Y. Jabri, S. M. Mennen, L. E. Overman, F.-
L. Zhang, J. Am. Chem. Soc. 2011, 133, 6549–6552.
[10] a) (+)-11,11Ј-Dideoxyverticillin A: J. Kim, J. A. Asenhurst, M.
Movassaghi, Science 2009, 324, 238–241; b) (+)-Chaetoxin A:
E. Iwasa, Y. Hamashima, S. Fujishiro, E. Higuchi, A. Ito, M.
Yoshida, M. Sodeoka, J. Am. Chem. Soc. 2010, 132, 4078–
4079; c) (+)-Chaetocin A and C and (+)-12,12Ј-Dideoxychetra-
cin A: J. Kim, M. Movassaghi, J. Am. Chem. Soc. 2010, 132,
14376–14378.
Crystal Structure Determination of rac-(4S)-25: The single-crystal
X-ray diffraction study of rac-(4S)-28 was carried out with a
Bruker–Nonius Kappa-CCD diffractometer at 123(2) K using Mo-
Kα radiation (λ = 0.71073 Å). Direct methods (SHELXS-97) were
used for structure solution, and refinement was carried out using
SHELXL-97[26] (full-matrix least-squares on F2). Non-hydrogen
atoms were refined anisotropically, hydrogen atoms were localized
by difference electron-density determination and refined using a
riding model [H(O) free]. The solvent pentane is disordered about
[11] a) U. Gross, M. Nieger, S. Bräse, Org. Lett. 2009, 11, 4740–
4742; b) U. Gross, M. Nieger, S. Bräse, Chem. Eur. J. 2010, 16,
11624–11631.
a
center of symmetry. rac-(4S)-25: colorless crystals,
[12] A. Harvey, Drug Discov. Today 2000, 5, 294–300.
[13] a) M. Sickert, C. Schneider, Angew. Chem. Int. Ed. 2008, 47,
3631–3634; b) M. Sickert, F. Abels, M. Lang, J. Sieler, C. Birke-
meyer, C. Schneider, Chem. Eur. J. 2010, 16, 2806–2818. c) Af-
ter optimization, the vinylogous Mukaiyama–Mannich reac-
tion proceeded in 89% ee. For first studies, we used 81% ee
enriched material and determined the optical purity for com-
pounds 16 and 18 to prove the persistency of the ee values.
[14] S. E. Denmark, G. L. Beutner, J. Am. Chem. Soc. 2003, 125,
7800–7801.
[15] J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
P. L. Alsters, F. L. van Delft, F. P. J. T. Rutjes, Tetrahedron Lett.
2006, 47, 8109–8113.
[16] Details of the structure, synthesis, and spectroscopy of the Boc-
protected product can be found in the Supporting Information.
[17] Conditions of this transformation have been previously opti-
mized, see: A. Friedrich, M. Jainta, C. F. Nising, S. Bräse, Syn-
lett 2008, 589–591.
C29H30N2O6·0.5C5H12, 538.62, crystal size:
M
=
¯
0.15ϫ0.10ϫ0.05 mm, triclinic, space group P1 (No. 2), a =
10.528(1) Å, b = 11.781(2) Å, c = 13.104(2) Å, α = 116.05(2)°, β
= 95.20(2)°, γ = 104.29(2)°, V = 1377.5(3) Å3, Z = 2, ρ(calc) =
1.299 Mgm–3, F(000) = 574, μ = 0.090 mm–1, 16581 reflections
(2θmax = 50°), 4815 unique [Rint = 0.063], 357 parameters, 14 re-
straints, R1 [IϾ2σ(I)] = 0.058, wR2 (all data) = 0.141, S = 1.01,
largest diff. peak and hole: 0.844 and –0.349 eÅ–3.
CCDC-823873 [for rac-(4S)-25] contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental data for 11, rac-12, and ethyl rac-(E)-5-(tert-
butoxycarbonylamino)-5-(furan-2-yl)pent-2-enoate and spectro-
scopic data for all new compounds.
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Acknowledgments
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We thank the Deutsche Forschungsgemeinschaft (DFG) (BR 1750/
17-1 and SCHN 441/7–1) and the Fonds der Chemischen Industrie
(fellowship to B. M. R.) for financial support. We gratefully
acknowledge the valuable experimental assistance of Simone
Grässle.
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found in the Supporting Information) throughout the whole
synthetic sequence before accomplishing the most important
steps with enantiomerically enriched material.
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Received: July 8, 2011
Published Online: September 14, 2011
6566
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Eur. J. Org. Chem. 2011, 6558–6566