Indirect N-vinylation of indoles via isomerisation of N-allyl derivatives: Synthesis of (±)-debromoarborescidine B

Article abstract of DOI:10.1016/j.tetlet.2013.06.069

Double bond migration in N-allylindoles has been investigated as a method to access N-vinyl derivatives of this heterocycle. The optimal reaction conditions employed t-BuOK or NaH in DMSO as the solvent at room temperature to afford the products in yields ranging from 51 to 99%. Although in some cases a high degree of stereoselectivity was observed, preferential formation of either the Z- or E-isomer was not predictable. The developed methodology was employed in the synthesis of (±)-debromoarborescidine B.

Full text of DOI:10.1016/j.tetlet.2013.06.069

Tetrahedron Letters 54 (2013) 4536–4539
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indirect N-vinylation of indoles via isomerisation of N-allyl
derivatives: synthesis of ( )-debromoarborescidine B
Gordana Tasic a, Milena Simic a, Stanimir Popovic a, Suren Husinec b, Veselin Maslak c, Vladimir Savic a,
⇑
a University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia
b Institute for Chemistry, Technology and Metallurgy (ICTM), Centre for Chemistry, PO Box 815, Njegoseva 12, 11000 Belgrade, Serbia
c University of Belgrade, Faculty of Chemistry, Studentski trg 16, PO Box 51, 11000 Belgrade, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Double bond migration in N-allylindoles has been investigated as a method to access N-vinyl derivatives
of this heterocycle. The optimal reaction conditions employed t-BuOK or NaH in DMSO as the solvent at
room temperature to afford the products in yields ranging from 51 to 99%. Although in some cases a high
degree of stereoselectivity was observed, preferential formation of either the Z- or E-isomer was not pre-
dictable. The developed methodology was employed in the synthesis of ( )-debromoarborescidine B.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 2 May 2013
Revised 28 May 2013
Accepted 14 June 2013
Available online 22 June 2013
Keywords:
N-Vinylindoles
Isomerisation
Base
Debromoarborescidine B
Indole alkaloids are a large group of natural products with di-
verse chemical structures and a wide spectrum of biological prop-
erties.1 As appealing and challenging synthetic targets, they attract
significant attention from organic chemists.2 The indole skeleton is
also a structural component of many drugs currently in the market,
such as triptans.3
derivatives.9 Additionally, tandem isomerisation–RCM reactions
have been utilised successfully in the synthesis of several heterocy-
clic compounds.10 The double bond migration in N-allyl derivatives
can be accomplished with various reagents, from acids and bases
to supported metals and transition metal complexes.7 Metal com-
plexes, in particular, have been investigated extensively leading to
a good understanding of these processes and the development of
highly stereoselective transformations.11
As a part of our ongoing research on the synthesis of indole
alkaloids possessing an N-vinyl moiety, exemplified by natural
products 1a, 2–4 (Fig. 1),4 we searched for a mild, functional group
tolerable procedure for the N-vinylation of indoles that would al-
low further annelation via ring-closing methathesis (RCM). A num-
ber of methods describing the introduction of complex N-vinyl
moieties have been reported in the literature.5 On the other hand,
insertions of unsubstituted or simple N-vinyl functionality, suit-
able for further RCM elaboration, are rare and often require gas-
eous reactants (acetylene or vinyl bromide), or harsh conditions
(KOH, 100 °C).6 Contrary to a direct N-vinylation, the two step pro-
cedure, involving N-allylation followed by double bond migration,
to form an N-vinyl functionality, is also feasible. The N-allyl to
N-vinyl isomerisation has been investigated extensively.7 Upon
isomerisation, the N-vinyl product can be hydrolysed to afford a
carbonyl compound and this sequence is vital in the industrial pro-
duction of menthol.8 Since the allyl functionality is a useful N-pro-
tecting group, the isomerisation/hydrolysis sequence is also an
integral part of the deprotection strategy of various N-allyl
Our initial attempts to promote migration of a double bond in
allylindole 5 are outlined in Table 1. The use of several transition
metal complexes under mild conditions failed (Scheme 1, Table 1,
H
N
N
N
N
H
N
R
2
1a R = Br
1b R = H
O
H
OH
H
N
N
MeOOC
N
H
MeOOC
4
3
⇑
Corresponding author. Tel.: +381 11 3951 243; fax: +381 11 3972 840.
E-mail address: vladimir.savic@pharmacy.bg.ac.rs (V. Savic).
Figure 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.069

G. Tasic et al. / Tetrahedron Letters 54 (2013) 4536–4539
4537
Table 1
entries a and b), resulting in recovery of the starting material.
Similar results were obtained using a Grignard reagent (Scheme 1,
Table 1, entry c). The use of t-BuOK in these processes at room tem-
perature and in DMSO as the solvent resulted in the formation of
the expected product 6 but, as shown, it was dependent on the
amount of the base used. Catalytic or equimolar amounts of t-
BuOK were not efficient (Scheme 1, Table 1, entries f and g).
Increasing the amount of base to 2.2 equiv afforded the product
in 33% yield, but with only 50% conversion (Scheme 1, Table 1, en-
try h). A further increase in quantity of the base resulted in the for-
mation of N-vinyl derivative 6 in excellent yield (Scheme 1, Table 1,
entry i). Analysis of the 1H NMR spectral data showed the product
to be the E-isomer contaminated with only a trace amount of the Z-
isomer. DMF as the solvent proved to be as efficient as DMSO
(Scheme 1, Table 1, entry j). Attempts were also made to use weak-
er bases, such as Cs2CO3 or DBU (Scheme 1, Table 1, entries d and e)
at room temperature, but these reactions resulted in recovery of
the starting material.
Reaction conditions for the double bond migration
Entry
Conditions
Z/Ea
Yieldb (%)
a
b
c
d
e
f
g
h
i
Ru(CO)(PPh3)3H2 (10 mol %), THF, rt
Rh(PPh3)3Cl (5 mol %), toluene, rt
allylMgBr (4 equiv), Et2O, rt
Cs2CO3 (4.5 equiv), DMSO, rt
DBU (4.5 equiv), DMSO, rt
t-BuOK (0.2 equiv), DMSO, rt
t-BuOK (1 equiv), DMSO, rt
t-BuOK (2.2 equiv), DMSO, rt
t-BuOK (4.5 equiv), DMSO, rt
t-BuOK (4.5 equiv), DMF, rt
—
—
—
—
—
—
—
—
—
—
—
—
—
—
c
—
33 (50)d
85 (99)d
88 (99)d
Ee
Ee
j
a
b
c
Established by analysis of the 1H NMR spectra of the crude reaction mixtures.
Isolated yield after column chromatography.
Not determined.
d
e
Conversion is given in parentheses.
The 1H NMR spectrum showed the presence of a trace amount of the Z isomer.
Using the t-BuOK/DMSO conditions (Table 2, conditions A),12
we explored briefly the scope of this transformation and the results
are outlined in Table 2. In addition to indole derivatives, benzimid-
azole 9 and benzotriazole 11 were shown to be suitable substrates
(Table 2, entries c and d). Although the reactions produced N-vinyl
derivatives 10 and 12, slightly lower yields were observed. Since
benzimidazole and benzotriazole are expected to be better leaving
conditions
N
N
5
6
Scheme 1.
Table 2
Base-promoted N-allyl to N-vinyl isomerisations
Entry
Starting material
Product
Conditionsa
Yieldb Z/E
Conditionsa
Yieldb (%) Z/Ec
N
N
a
A
85 (E only)
B
73 (4.7:1)
5
6
b
A
99 (1:5)
—
—
N
N
8
7
N
N
N
N
c
A
A
68 (5:1)
51 (1:8)
B
B
64 (9:1)
10
9
N
N
N
N
N
N
d
70 (1:16)
12
11
O
O
H
H
N
N
I
I
N
N
N
N
e
A
95 (2:1)
—
—
14
13
NHCOOEt
NHCOOEt
f
A
A
56 (4:1)
B
60 (Z only)
16
15
O
O
H
H
N
N
I
I
N
g
N
79
—
—
17
18
(continued on next page)

4538
G. Tasic et al. / Tetrahedron Letters 54 (2013) 4536–4539
Table 2 (continued)
Entry
Starting material
NHCOOEt
Product
Conditionsa
A
Yieldb Z/E
Conditionsa
B
Yieldb (%) Z/Ec
NHCOOEt
N
N
N
h
97
98
80
20
19
OH
OH
N
i
A
—
—
22
21
a
Conditions A: allyl compound (0.1 mmol), t-BuOK (0.45 mmol), DMSO (3 mL), rt, TLC monitoring (reaction times: 1–3 h); conditions B: allyl compound (0.1 mmol), NaH
(0.45 mmol), DMSO (3 mL), rt, TLC monitoring (reaction times: 3–24 h).
b
Isolated yield after column chromatography.
c
Established by analysis of the 1H NMR spectra of the crude reaction mixture.
SN2 processes on the allyl moiety, but also is itself prone to nucle-
ophilic additions. Although t-BuOK is often used as a base in syn-
CN
t-BuOK
CN
thetic transformations, it possesses nucleophilic properties as
well. Bearing in mind that hydride is a weak nucleophile due to
its low polarisability, we hoped to suppress the side processes by
using NaH. Gratifyingly, replacing t-BuOK with NaH resulted in
the formation of the expected product 24 in a good yield as 3.6:1
mixture of Z- and E-isomers. This outcome prompted a brief explo-
ration of NaH in the isomerisation process and the results are sum-
marised in Table 2 (conditions B). In all of the cases investigated
(Table 2, entries a, c, d, f and h) the products were isolated in good
yields with variable Z/E selectivity. Compared to the t-BuOK meth-
od, the process employing NaH as the base seemed to be slightly
less efficient requiring generally longer reaction times (1–3 h for
t-BuOK reactions vs 3–24 h for NaH reactions, as monitored by
TLC).
N
x
N
DMSO
24
23
NaH
DMSO
70%
3.6:1 Z/E
Scheme 2.
O
O
H
N
H
I
N
I
Grubbs II
(5 mol%)
N
N
The vinyl indoles prepared by the described methods were
shown to participate efficiently in RCM transformations
(Scheme 3).
1,2-DCE
92%
25
14
The methodology described above has been applied in the syn-
thesis of ( )-debromoarborescidine B (1b), a derivative of naturally
occurring arborescidine B (1a).13 Compound 1b possesses antipro-
liferative properties and it is significantly more potent than 1a.13a
The synthesis was initiated with allylation of dihydrocarboline
27 under typical basic conditions to afford compound 28 (Scheme 4).
Sequential, one-pot treatment of 28 with ethyl chloroformate to
quaternise the imine functionality followed by indium-promoted
allylation furnished diallylated compound 29. Subsequent RCM,
carried out with Grubbs’ second generation catalyst, afforded prod-
uct 30 in almost quantitative yield. The allyl to vinyl isomerisation
was then carried out using the above discussed procedures.
Although both methods afforded the expected product 31, the pro-
cess employing NaH as the base was shown to be more efficient. Fi-
nally, reduction of the carbamate functionality employing LiAlH4
afforded the target compound, ( )-debromoarborescidine B (1b).
In conclusion, a mild method for N-allyl indole to N-vinyl indole
double bond migration employing t-BuOK or NaH has been de-
scribed. The reactions were carried out at room temperature
affording the products in good yields, usually as Z/E mixtures,
while the conditions tolerated a range of functional groups. The
methodology was applied for the synthesis of ( )-debromoarbore-
scidine B.
Grubbs II
(5 mol%)
NHCOOEt
NHCOOEt
N
N
1,2-DCE
88%
16
26
Scheme 3.
groups than indole, they may participate in side processes such as
the SN2 reactions involving the allyl moiety and the nucleophilic
base. Generally, simple N-allyl heterocycles (Table 2, entries a, b
and d) produced a mixture of geometric stereoisomers with the
E-isomer being the major product. The exception was benzimid-
azole 9, which gave completely opposite results (Table 2, entry
c). As we intended to use this methodology for the synthesis of
some indole-based natural products, the efficiency of the process
was tested on more complex substrates (Table 2, entries e–i).
Bis-allylated compounds 13 and 15 (Table 2, entries e and f) were
isomerised highly chemoselectively and, contrary to most of the
above examples, with preference for the Z-stereoisomer. The pres-
ence of amide, carbamate, aryl iodide or an additional alkene func-
tionality did not interfere with the reaction pathway. Cyclic N-allyl
derivatives were also suitable substrates for this transformation
(Table 2, entries g–i). The isomerised products, 18, 20 and 22, were
isolated in good yields, and, again, the conditions tolerated the
presence of various functional groups.
Acknowledgments
Attempts to isomerise indole derivative 23 using the above con-
ditions surprisingly failed (Scheme 2). Upon mixing 23 and the
base in DMSO the reaction mixture instantaneously turned black,
while TLC showed the presence of only a baseline material. As
the electron acceptor functionality, the nitrile is likely to facilitate
Financial support from the Serbian Ministry of Education, Sci-
ence and Technological Development (grant no. 172009) is greatly
appreciated. We thank the Faculties of Pharmacy and Chemistry,
Belgrade University for their assistance. We would also like to
thank Dr A. E. A. Porter for fruitful discussions.

G. Tasic et al. / Tetrahedron Letters 54 (2013) 4536–4539
4539
Br
N
N
NaH
DMF
40%
N
H
N
a. ClCOOEt,
b.
THF
Br
27
28
In
81%
O
N
N
OEt
N
N
29
(+)-debromoarborescidine B
1b
Grubbs II
CH2Cl2
98%
LiAlH4
THF
80%
t-BuOK
O
DMSO
45%
N
O
OEt
N
N
OEt
N
NaH
30
31
DMSO
75%
Scheme 4.
8. Jakel, C. Paciello, R. In Asymmetric Catalysis on Industrial Scale; Blaser, H.-U.,
Federsel, H.-J., Eds.; Wiley-VCH: Weinheim, 2010; pp 187–204.
Supplementary data
9. For recent selected examples, see: (a) Im, G.-Y. J.; Bronner, S. M.; Goetz, A. E.;
Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132,
17933–17944; (b) Ohmura, N.; Nakamura, A.; Hamasaki, A.; Tokunaga, M. Eur.
J. Org. Chem. 2008, 5042–5045; (c) Zacuto, M. J.; Xu, F. J. Org. Chem. 2007, 72,
6298–6300.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.
069.
10. (a) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.; Nishida, A. Chem. Rec.
2007, 7, 238–253; (b) Arisawa, M.; Terada, Y.; Theeraladanon, C.; Takahashi, K.;
Nakagawa, M.; Nishida, A. J. Organomet. Chem. 2005, 690, 5398–5406; (c)
Michalak, M.; Wicha, J. Synlett 2005, 2277–2280; (d) van Otterlo, W. A. L.;
Morgans, G. L.; Khanye, S. D.; Aderibigbe, B. A. A.; Michael, J. P. D. Billing, G
Tetrahedron Lett. 2004, 45, 9171–9175; (e) Arisawa, M.; Terada, Y.; Nakagawa,
M.; Nishida, A. Angew. Chem., Int. Ed. 2002, 41, 4732–4734.
11. (a) Nova, A.; Ujaque, G.; Albeniz, A. C.; Espinet, P. Chem. Eur. J. 2008, 14, 3323–
3329; (b) Otsuka, S.; Tani, K. Synthesis 1991, 665–680; (c) Inoue, S.; Takaya, H.;
Tani, K.; Otsuka, S.; Sato, T.; Noyori, R. J. Am. Chem. Soc. 1990, 112, 4897–4905;
(d) Tani, K. Pure Appl. Chem. 1985, 1845–1854; (e) Akutagawa, S.; Tani, K. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp
146–161.
References and notes
1. (a) Ndagijimana, A.; Wang, X.; Pan, G.; Zhang, F.; Feng, H.; Olaleye, O.
Fitoterapia 2013, 86, 35–47; (b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat.
Prod. Rep. 2013, 30, 694–752; (c) Kochanowska-Karamyan, A. J.; Hamann, M. T.
Chem. Rev. 2010, 110, 4489–4497; (d) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep.
2006, 23, 532–547.
2. For selected recent examples, see: (a) Bennasar, M.-L.; Sole, D.; Zulaica, E.;
Alonso, S. Tetrahedron 2013, 69, 2534–2541; (b) Manzo, E.; Pagano, D.; Carbone,
M.; Ciavatta, M. L.; Gavagnin, M. Arkivoc 2012, 220–228; (c) Crooke, S.;
Whitlock, C. Molecules 2012, 17, 14841–14845; (d) Seetham Naidu, P.; Bhuyan
Pulak, J. Tetrahedron Lett. 2012, 53, 426–428; (e) Bhat, V.; MacKay, J. A.; Rawal,
V. H. Tetrahedron 2011, 67, 10097–10104; (f) Zeldin, R. M.; Toste, F. D. Chem. Sci.
2011, 2, 1706–1709; (g) Frebault, F. C.; Simpkins, N. S. Tetrahedron 2010, 66,
6585–6596.
12. General procedure for the t-BuOK promoted N-allyl to N-vinyl double bond
migration: A mixture of 1-allylindole (0.1 mmol), and t-BuOK (0.45 mmol,
4.5 equiv) in DMSO (3 mL) was stirred at rt. The reaction was monitored by TLC
and when complete (1–3 h), Et2O (30 mL) was added and the mixture was
washed with H2O (3 Â 5 mL). The organic layer was then dried (Na2SO4) and
the solid was separated by filtration. The filtrate was evaporated under
reduced pressure and the oily residue was purified by column chromatography
(SiO2, petroleum ether/Et2O) to afford the product.Spectral data for 2-iodo-N-
[1-(1-propenyl-1H-indol-2-yl)but-3-enyl]benzamide (14): Isolated after
column chromatography (SiO2, 7:3 v/v petroleum ether–Et2O) as a colourless
solid (mp 127–129 °C) in 95% yield as a 2:1 mixture of Z and E isomers. IR:
3. Li, J. J.; Johnson, D. S.; Sliskovic, D. R.; Roth, B. D. Contemporary Drug Synthesis;
Springer: New jersey, 2004. pp 161–187.
4. (a) England, D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792–2802; (b) Schultz, A.
G.; Malachowski, W. P.; Pan, Y. J. Org. Chem. 1997, 62, 1223–1229; (c) Belle, D.
D.; Tolvanen, A.; Lounasmaa, M. Tetrahedron 1996, 52, 11361–11378; (d)
Banim, M.; Pais, A. J. Nat. Prod. 1993, 56, 99–104; (e) Verpoorte, R. J. Nat. Prod.
1986, 49, 1–25.
5. For selected recent examples, see: (a) Verma, A. K.; Joshi, M.; Singh, V. P. Org.
Lett. 2011, 13, 1630–1633; (b) Kabir, M. S.; Lorenz, M.; Namjoshi, O. A.; Cook, J.
M. Org. Lett. 2010, 12, 464–467; (c) Ivachtchenko, A. V.; Frolov, E. B.; Mitkin, O.
D.; Kysil, V. M.; Khvat, A. V.; Tkachenko, S. E. Arch. Pharm. 2009, 342, 740–747;
(d) Liao, Q.; Wang, Y.; Zhang, L.; Xi, C. J. Org. Chem. 2009, 74, 6371–6373; (e)
Mao, J.; Hua, Q.; Guo, J.; Shi, D.; Ji, S. Synlett 2008, 2011–2016.
6. (a) Trofimov, B. A.; Vasiltsov, A. M.; Ushakov, I. A.; Ivanov, A. V.; Schmidt, E. Y.;
Mikhaleva, A. I.; Protsuk, N. I.; Kobychev, V. B. Mendeleev Commun. 2007, 17,
296–298; (b) Abele, E.; Dzenitis, O.; Rubina, K.; Lukevics, E. Chem. Heterocyc.
Compd. 2002, 38, 682–685; (c) Lebedev, A. Y.; Izmer, V. V.; Kazyulkin, D. N.;
Beletskaya, I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623–626.
7. For a recent review, see: (a) Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak,
H. Coord. Chem. Rev. 2008, 252, 1819–1841; For recent selected examples, see:
(b) Bujak, P.; Krompiec, S.; Malarz, J.; Krompiec, M.; Filapek, M.; Danikiewicz,
W.; Kania, M.; Gebarowska, K.; Grudzka, I. Tetrahedron 2010, 66, 5972–5981;
(c) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J.
Am. Chem. Soc. 2010, 132, 7998–8009; (d) Morgans, G. L.; Ngidi, E. L.; Madeley,
L. G.; Khanye, S. D.; Michael, J. P.; de Koning, C. B.; van Otterlo, W. A. L.
Tetrahedron 2009, 65, 10650–10659; (e) Tsang, D. S.; Yang, S.; Alphonse, F.-A.;
Yudin, A. K. Chem. Eur. J. 2008, 14, 886–894.
3272, 1661, 1521, 1458, 739 and 716 cmÀ1 1H NMR (500 MHz, CDCl3) d 1.57
.
(d, 3H, CH3, Z isomer, J = 5.0 Hz), 1.97 (d, 3H, CH3, E isomer, J = 6.5 Hz), 2.81–
2.87 (m, 2H,@CHCH2CH), 5.12–5.26 (m, 2H, CH2@ CHCH2CH), 5.48 (q, 1uH,
CH2CHNH, Z isomer, J = 7.0 Hz), 5.60 (q, 1H, CH2CHNH, E isomer, J = 7.0 Hz),
5.89–5.96 (m, 2H,@CHCH2CHNH), 6.03–6.06 (m, 1H, CH3CH@CHN, Z and E
isomers), 6.55 (d, 1H, ArH), 6.74 (d, 1H, CH3CH@CHN, Z isomer, J = 8.0 Hz), 6.86
(d, 1H, CH3CH@CHN, E isomer, J = 14.0 Hz), 7.08–7.21 (m, 4H ArH), 7.33–7.34
(m, 2H, ArH), 7.50–7.59 (m, 1H, ArH), 7.85 (d, 1H, ArH, J @ 8.0 Hz). 13C NMR
(125 MHz, CDCl3)
d 13.1 (CH3, Z isomer), 15.7 (CH3, E isomer), 38.8
(@CHCH2CH), 38.9 (@CHCH2CH), 45.8, 46.2, 92.4, 100.5, 100.9, 110.9, 111.0,
118.7 (CH2@CHCH2CH), 120.1, 120.4, 120.5, 120.5, 122.2, 122.4, 123.6
(CH3CH@CHN Z isomer), 124.3 (CH3CH@CHN E isomer), 127.4, 127.7, 128.1,
128.2, 129.0,131.2, 133.6, 133.7, 136.7, 136.8, 138.8, 139.4, 140.1, 141.7, 167.9.
m/z: 456 (M+), 415, 281, 253, 231, 207, 168. HRMS (ESI): calcd for C22H21IN2O
(M+H)+: 457.07713 found: 457.07780.
13. (a) Santos, L. S.; Theoduloz, C.; Pilli, R. A.; Rodriguez, J. Eur. J. Med. Chem. 2009,
44, 3810–3815; (b) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.;
Davis, A. Org Lett. 2005, 7, 1047–1050; (c) Santos, L. S.; Pilli, R. A.; Rawal, V. H. J.
Org. Chem. 2004, 69, 1283–1289; (d) Korver, J.; Wanner, M. J.; Koomen, G.-J.
Tetrahedron 1998, 54, 6135–6146.