Synthesis of a versatile building block for the preparation of 6-N-derivatized α-galactosyl ceramides: Rapid access to biologically active glycolipids

Article abstract of DOI:10.1021/jo102064p

A concise route to the 6-azido-6-deoxy-α-galactosyl-phytosphingosine derivative 9 is reported. Orthogonal protection of the two amino groups allows elaboration of 9 into a range of 6-N-derivatized α-galactosyl ceramides by late-stage introduction of the a

Full text of DOI:10.1021/jo102064p

pubs.acs.org/joc
play a role in alleviating autoimmune diseases5-7 such as multi-
Synthesis of a Versatile Building Block for the
Preparation of 6-N-Derivatized r-Galactosyl
Ceramides: Rapid Access to Biologically Active
Glycolipids
ple sclerosis8 and arthritis.9 When both Th1 and Th2 cytokines
are released together, their effects oppose one another, which
may induce mixed and unpredictable biological effects.10 This is
the case upon R-GalCer/CD1d activation of the immune re-
sponse, which has complicated efforts to develop KRN7000 as a
therapeutic agent. The search for analogues of this glycolipid,
which induce a more biased Th1/Th2 response, is therefore a
current focus of many immunological studies.
Peter J. Jervis,† Liam R. Cox,*,‡ and Gurdyal S. Besra*,†
†School of Biosciences, University of Birmingham, Edgbaston,
Birmingham B15 2TT, United Kingdom, and ‡School of
Chemistry, University of Birmingham, Edgbaston,
Birmingham B15 2TT, United Kingdom
l.r.cox@bham.ac.uk; g.besra@bham.ac.uk
Received October 18, 2010
FIGURE 1. Prototypical KRN7000 (1) and biologically active
analogues 2, 3, 4, and 5.
A number of R-GalCer analogues have been reported that
exhibit more skewed Th1/Th2 cytokine profiles compared
with that elicited by R-GalCer 1 (Figure 1).11 Truncation of
the acyl12 (2) and sphingosine8,13 (OCH (3)) chains and the
incorporation of unsaturation in the acyl chain (R-GalCer
C20:2 (4))14 result in CD1d agonists that generate a more
Th2-biased response. Examples of more Th1-biasing mole-
cules are much rarer;15,16a the C-glycosyl analogue of
KRN7000, R-C-GalCer (5), is one such molecule that has
been shown to induce a useful Th1-biased response.15
There has been recent interest in galactosyl ceramides in
which the hydroxyl group at the 6-position of the sugar head-
group has been modified (Figure 2).16 Crystal structures of the
A concise route to the 6-azido-6-deoxy-R-galactosyl-phy-
tosphingosine derivative 9 is reported. Orthogonal pro-
tection of the two amino groups allows elaboration of 9
into a range of 6-N-derivatized R-galactosyl ceramides by
late-stage introduction of the acyl chain of the ceramide
and the 6-N-group in the sugar headgroup. Biologically
active glycolipids 6 and 8 have been synthesized to
illustrate the applicability of the approach.
(6) Godfrey, D. I.; MacDonald, H. R.; Kronenberg, M.; Smyth, M. J.;
Van Kaer, L. Nat. Rev. Immunol. 2004, 4, 231–237.
(7) Gonzalez-Aseguinolaza, G.; Van Kaer, L.; Bergmann, C. C.; Wilson,
J. M.; Schmieg, J.; Kronenberg, M.; Nakayama, T.; Taniguchi, M.;
Koezuka, Y.; Tsuji, M. J. Exp. Med. 2002, 195, 617–624.
(8) Miyamoto, K.; Miyake, S.; Yamamura, T. Nature 2001, 413, 531–534.
(9) Chiba, A.; Oki, S.; Miyamoto, K.; Hashimoto, H.; Yamamura, T.;
Miyake, S. Arthritis Rheum. 2004, 50, 305–313.
(10) (a) Oki, S.; Chiba, A.; Yamamura, T.; Miyake, S. J. Clin. Invest. 2004,
113, 1631–1640. (b) Yu, K. O. A.; Porcelli, S. A. Immunol. Lett. 2005, 100, 42–55.
(11) (a) Savage, P. B.; Teyton, L.; Bendelac, A. Chem. Soc. Rev. 2006, 35,
771–779. (b) Wu, D.; Fujioa, M.; Wong, C.-H. Bioorg. Med. Chem. 2008, 16,
1073–1083. and references cited therein.
(12) Goff, R. D.; Gao, Y.; Mattner, J.; Zhou, D.; Yin, N.; Cantu, C.;
Teyton, L., III; Bendelac, A; Savage, P. B. J. Am. Chem. Soc. 2004, 126,
13602–13603.
The synthetic glycolipid R-galactosyl ceramide (R-GalCer),1
also known as KRN7000 (1) (Figure 1), has been shown to
bind to the protein CD1d. Recognition of the resulting
glycolipid-protein complex by T cell receptors (TCRs)
located on the surface of invariant natural killer T (iNKT)
cells leads to activation of the immune response through the
release of a diverse range of cytokines, including both Th1
(IFNγ) and Th2 (IL-4) cytokines.2-4 The release of Th1
cytokines may contribute to antitumor and antimicrobial
functions, while the release of Th2 cytokines is believed to
(13) Oki, S.; Tomi, C.; Yamamura, T; Miyake, S. Int. Immunol. 2005, 17,
1619–1629.
(14) (a) Yu, K. O. A.; Im, J. S.; Molano, A.; Dutronc, Y.; Illarionov, P. A.;
Forestier, C.; Fujiwara, N.; Arias, I.; Miyake, S.; Yamamura, T.; Chang, Y. T.;
Besra, G. S.; Porcelli, S. A. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 3383–3388.
(b) Im, J. S.; Arora, P.; Bricard, G.; Molano, A.; Venkataswamy, M. M.; Baine, I.;
Jerud, E. S.; Goldberg, M. F.; Baena, A.; Yu, K. O. A.; Ndonye, R. M.; Howell,
A. R.; Yuan, W. M.; Cresswell, P.; Chang, Y. T.; Illarionov, P. A.; Besra, G. S.;
Porcelli, S. A. Immunity 2009, 30, 888–898.
(15) (a) Schmieg, J.; Yang, G.; Franck, R. W.; Tsuji, M. J. Exp. Med.
2003, 198, 1631–1641. (b) Yang, G.; Schmeig, J.; Tsuji, M.; Franck, R. W.
Angew. Chem., Int. Ed. 2004, 43, 3818–3822.
(16) (a) Trappeniers, M.; Van Beneden, K.; Decruy, T.; Hillaert, U.; Linclau,
B.; Elewaut, D.; Van Calenbergh, S. J. Am. Chem. Soc. 2008, 130, 16468–16469.
(b) Liu, Y.; Goff, R. D.; Zhou, D.; Mattner, J.; Sullivan, B. A.; Khurana, A.;
Cantu, C., III;Ravkov, E. V.;Ibegbu,C. C.;Altman, J. D.;Teyton, L.;Bendelac,
A.; Savage, P. B. J. Immunol. Methods 2006, 312, 34–39. (c) Xia, C.; Zhang, W.;
Zhang, Y.; Woodward, R. L.; Wang, J.; Wang, P. G. Tetrahedron 2009, 65, 6390–
6395. (d) Zhou, X. T.; Forestier, C.; Goff, R. D.; Li, C.; Teyton, L.; Bendelac, A.;
Savage, P. B. Org. Lett. 2002, 4, 1267–1270.
(1) Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.; Kaneko, Y.; Motoki, K.;
Ueno, H.; Nakagawa, R.; Sato, H.; Kondo, E.; Koseki, H.; Taniguchi, M.
Science 1997, 278, 1626–1629.
(2) Crowe, N.; Uldrich, A. P.; Kyparissoudis, K.; Hammond, K. J. L.;
Hayakawa, Y.; Sidobre, S.; Keating, R.; Kronenberg, M.; Smyth, M. J.;
Godfrey, D. I. J. Immunol. 2003, 171, 4020–4027.
(3) Burdin, N.; Brossay, L.; Kronenberg, M. Eur. J. Immunol. 1999, 29,
2014–2025.
(4) Carnaud, C.; Lee, D.; Donnars, O.; Park, S. H.; Beavis, A.; Koezuka,
Y.; Bendelac, A. J. Immunol. 1999, 163, 4647–4650.
(5) Taniguchi, M.; Harada, M.; Kojo, S.; Nakayama, T.; Wakao, H.
Annu. Rev. Immnunol. 2003, 21, 483–513.
320 J. Org. Chem. 2011, 76, 320–323
Published on Web 12/14/2010
DOI: 10.1021/jo102064p
r
2010 American Chemical Society

Jervis et al.
JOCNote
FIGURE 2. Biologically active 6-derivatized R-galactosyl cera-
mides 6-8 and our target precursor 9.
FIGURE 3. Retrosynthetic analysis of targets 9 and 10.
CD1d-KRN7000 complex17 and a TCR-KRN7000-CD1d
complex18 show that the 6-hydroxyl group is not involved
directly in hydrogen bonding with either the CD1d protein or
the TCR. Moreover, it has been shown that the TCR-
glycolipid-CD1d interaction can tolerate derivatization at
C6.16d,19 Savage has reported that GalCer 6 (PBS-57) offers
improved solubility over KRN7000, effectively stains both
mouse and human NKT cells, and stimulates cytokine
release at low concentrations.16b Wang has synthesized the
biotinylated R-GalCer analogue 7 to facilitate detection of
this antigen in flow cytometry assays.16c In this study, the
problematic low solubility of these R-GalCer analogues was
remedied by incorporating a truncated acyl chain. Of parti-
cular interest, Van Calenbergh recently found that substitut-
ing the 6-hydroxyl group of 1 for a range of aryl ureas, such
as 8, induced a more Th1-biased cytokine response than is
observed with R-GalCer.16a
Previously reported routes to 6-derivatized R-GalCer
analogues are somewhat lengthy, involve extensive protect-
ing group manipulation, and often suffer from poor overall
yields. In addition, they do not allow the late-stage variation
of the acyl chain; a change of acyl chain therefore requires a
complete repeat of the synthetic sequence. Here we present
a concise synthesis of the orthogonally protected diamino
R-GalCer analogue 9 (Figure 2), which is primed for further
elaboration to 6-N-derivatized galactosyl ceramides. The
described route allows both the acyl chain of the ceramide
unit and the 6-substituent of the sugar headgroup to be varied
at a late stage of the synthesis, thus providing access to a
potentially large and varied library of this class of com-
pound.
derivative 10) could be accessed in a single step from fully
protected azide 11, which in turn could be accessed from
alcohol 12, using a Mitsunobu reaction to install the azide.
At this point we would require a selective monodeprotection
of the primary 6-OH for which there was precedent from
ꢀ
Fernandez, who showed that 1,2,3,4-tetra-O-trimethylsilyl-
galactose could be obtained by treating 1,2,3,4,6-penta-O-
trimethylsilyl-galactose 13 with acetic acid.20 We therefore
reasoned that alcohol 12 could be accessed from 14 in a
similar manner. Glycoside 14 was further disconnected to
glycosyl donor 15 and sphingosine acceptor 16.
Trimethylsilyl groups were chosen as the protecting
groups for the sugar unit owing to (1) their ease of attach-
ment to the galactose starting material,20,23 (2) the ability to
monodeprotect the primary silyl ether selectively,20 (3) the
ease with which the remaining silyl groups can be removed
when required, and (4) the “arming” effect that silyl groups
impart on the sugar donor in glycosylation reactions.21 tert-
Butyldimethylsilyl (TBDMS) groups were chosen as the
protecting groups for the sphingosine acceptor. While con-
ferring an increased level of stability during the synthesis, as
1
well as providing an extra handle for H and 13C NMR
spectroscopic analysis, we envisaged these bulkier silyl groups
could also be removed along with the trimethylsilyl groups of
the sugar head unit in a single step.
Per-TMS-protected galactose 13 was synthesized in quan-
titative yield by treating D-galactose with chlorotrimethylsi-
lane and hexamethyldisilazane in the presence of pyridine.22
Acceptor 16 was accessed in three steps from commercially
available phytosphingosine 17 (Scheme 1): Boc protection
afforded carbamate 18, which underwent 3-fold silylation of
the triol functionality to provide silyl ether 19. Selective
monodeprotection of the primary silyl ether in 19 with HF-
pyridine23 concluded the synthesis of glycosyl acceptor 16.
The retrosynthesis of our target 9 is shown in Figure 3.
With careful choice of protecting groups, it was envisaged
that 9 (or the potentially more useful Boc-deprotected
ꢀ
(20) Fernandez, C.; Nieto, O.; Rivas, E.; Montenegro, G.; Fontenla,
ꢀ
(17) Koch, M.; Stronge, V. S.; Shepherd, D.; Gadola, S. D.; Mathew, B.;
Ritter, G.; Fersht, A. R.; Besra, G. S.; Schmidt, R. R.; Jones, E. Y.;
Cerundolo, V. Nat. Immunol. 2005, 6, 819–826.
(18) Borg, N. A.; Wun, K. S.; Kjer-Nielson, L.; Wilce, M. C.; Pellicci,
D. G.; Koh, R.; Besra, G. S.; Bharadwaj, M.; Godfrey, D. I.; McCluskey, J.;
Rossjohn, J. Nature 2007, 448, 44–49.
(19) Prigozy, T. I.; Naidenko, O.; Qazba, P.; Elewaut, D.; Brossay, L.;
Khurana, A.; Natori, T.; Koezuka, Y.; Kulkarni, A.; Kronenberg, M.
Science 2001, 291, 664–667.
J. A.; Fernandez-Mayoralas, A. Carbohydr. Res. 2000, 327, 353–365.
(21) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B.
J. Am. Chem. Soc. 1988, 110, 5583–5584. (b) Hashimoto, S.; Sakamoto, H.;
Honda, T.; Abe, H.; Nakamura, S.; Ikegami, S. Tetrahedron Lett. 1997, 38,
8969–8972. (c) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115–4118.
(22) Toubiana, R.; Das, B. C.; Defaye, J.; Mompon, B.; Toubiana, M. J.
Carbohydr. Res. 1975, 44, 308–312.
(23) Mormeneo, D.; Casas, J.; Llebaria, A.; Delgado, A. Org. Biomol.
Chem. 2007, 5, 3769–3777.
J. Org. Chem. Vol. 76, No. 1, 2011 321

Jervis et al.
JOCNote
SCHEME 1. Synthesis of Glycosyl Acceptor 16
SCHEME 2. Synthesis of r-Galactosides 9 and 10
The key step in the synthesis of 9 employed Gervay-
Hague’s elegant glycosylation methodology in which the
glycosyl iodide donor 15 was generated in situ by treating
per-TMS-protected galactose 13 with iodotrimethylsilane.24
Glycosyl iodide 15 reacted with acceptor 16 in the presence of
€
Bu4NI and Hunig’s base, to provide glycoside 20 exclusively
as the R-anomer in 75% yield, thus providing a short and
scalable route to galactosyl ceramide precursors (Scheme 2).
With this method of glycosylation, the protecting groups are
usually removed immediately via an acidic workup.24 How-
ever, it was desirable in our case to leave the silyl protecting
groups in the product intact and effect a selective mono-
deprotection of the primary trimethylsilyl group instead. To
ꢀ
this end, following Fernandez’s method for 6-trimethylsilyl
ether deprotection,20 treatment of 20 with acetic acid in
acetone/methanol gave monodeprotected 21 in a satisfactory
78% yield, and provided the valuable handle for modifying
the 6-position. Alcohol 21 was converted in 87% yield to
azide 22 by a Mitsunobu reaction employing diphenylpho-
sphoryl azide (DPPA), diisopropyl azodicarboxylate
(DIAD), and triphenylphosphine.25 Treating azide 22 with
tetrabutylammonium fluoride (TBAF) successfully removed
the five silyl protecting groups; however, the residual tetra-
butylammonium byproduct could not be separated from the
polar product by flash column chromatography. While the
use of silica-supported TBAF ameliorated this problem, a
better deprotection method involved stirring 22 with 10%
trifluoroacetic acid (TFA) in dichloromethane overnight.
Interestingly, while this method produced pentaol 9 exclu-
sively, treatment of azide 22 with neat TFA for 10 min
resulted in clean conversion to Boc-deprotected amine 10
(Scheme 2).
SCHEME 3. Synthesis of r-Galactosyl Ceramides 6 and 8
To illustrate the versatility of amine 10 we completed the
synthesis of two biologically active 6-derivatized R-galactosyl
ceramides 6 (PBS-57) and 8, which differ in both the acyl
chain of the ceramide base and the nitrogen-containing
functionality at the 6-position of the sugar headgroup
(Scheme 3). Treating a biphasic mixture of amine 10 in
THF/8 M aqueous NaOAc with nervonoyl chloride afforded
6-azido GalCer 23 in 81% yield. Subsequent Staudinger24d,26
reaction followed by treatment with acetyl chloride afforded
PBS-57 (6).16b Alternatively, acylation of 10 with hexacosa-
noyl chloride, to provide amide 24, followed by Staudinger
reduction24d,26 and then treatment with phenylisocyanate,
afforded Th1-biasing R-GalCer derivative 8.16a
An even more convergent route to our target molecules
would employ 6-azido galactose 25 in the key glycosylation
step (Scheme 4). Azide 25 was synthesized by deprotecting
the primary silyl ether in per-TMS-protected galactose 13 to
afford alcohol 26, followed by Mitsunobu reaction with
DPPA, DIAD, and PPh3. Following the same procedure as
with per-TMS-protected galactose 13, 6-azido galactose 25
was treated with TMSI and the resulting glycosyl iodide 27
(24) (a) Du, W.; Kulkarni, S. S.; Gervay-Hague, J. Chem. Commun. 2007,
2336–2338. (b) Du, W.; Gervay-Hague, J. Org. Lett. 2005, 7, 2063–2065. (c)
Schombs, M.; Park, F. E.; Du, W.; Kulkarni, S. S.; Gervay-Hague, J. J. Org.
Chem. 2010, 75, 4891–4898. (d) Jervis, P. J.; Veerapen, N.; Bricard, G.; Cox,
L. R.; Porcelli, S. A.; Besra, G. S. Bioorg. Med. Chem. Lett. 2010, 20, 3475–
3478.
(25) Johansson, P.-O.; Chen, Y.; Belfrage, A. K.; Blackman, M. J.;
€
Kvarnstrom, I.; Jansson, K.; Vrang, L.; Hamelink, E.; Hallberg, A.;
Rosenquist, A.; Samuelsson, B. J. Med. Chem. 2004, 47, 3353–3366.
˚
€
added to a solution of acceptor 16, Bu4NI, and Hunig’s
base in dichloromethane. Unfortunately, this reaction was
(26) Worthington, R. J.; Bell, N. M.; Wong, R.; Micklefield, J. Org.
Biomol. Chem. 2008, 6, 92–103.
322 J. Org. Chem. Vol. 76, No. 1, 2011

Jervis et al.
JOCNote
SCHEME 4. Attempted More Convergent Synthesis of R-Ga-
lactoside 22
column chromatography (EtOAc in hexane) to afford alcohol
21 (from 20) or 26 (from 13) as a colorless oil.
General Procedure for the Mitsunobu Reaction (Azides 22 and
25). PPh3 (1.86 mmol), DIAD (1.86 mmol), and DPPA (1.86
mmol) were added sequentially to a cooled solution of alcohol
21 or 26 (0.90 mmol) in THF (20 mL). The mixture was allowed
to warm to rt and then stirred overnight. Concentration under
reduced pressure followed by purification of the residue by flash
column chromatography (EtOAc in hexane) afforded azide 22
(from 21) or 25 (from 26) as a colorless oil.
Pentaol 9. TFA (0.50 mL, 6.6 mmol) was added dropwise over
5 min to a solution of azide 22 (200 mg, 0.19 mmol) in CH2Cl2
(5 mL) at rt. After 30 min, the reaction mixture was concentrated
under reduced pressure to afford pentaol 9 as a colorless oil
(115 mg, quant.): [R]20 þ12.4 (c 0.5, CDCl3:CD3OD, 2:1);
D
ν
max(film) (cm-1) 3282s br (O-H), 2114s (N3), 1696 m (CdO);
1H NMR (300 MHz, CDCl3:CD3OD, 2:1) 0.85 (t, J=6.0 Hz,
3H), 1.18-1.39 (stack, 22H), 1.40-1.71 (stack, 4H), 1.44 (s, 9H),
3.26 (A of ABX, JA-B=12.6 Hz, JA-X=4.9 Hz, 1H), 3.51-3.64
unsuccessful, only providing various TMS-deprotection pro-
ducts of 6-azido galactose 25. The failure of this sugar donor
to undergo glycosylation can be understood by the electron-
withdrawing nature of the azide group imparting a strongly
deactivating effect.27 Acceptors such as alcohol 16 already
display attenuated nucleophilicity owing to the presence of a
hydrogen bond between the alcohol oxygen atom and the
carbamate hydrogen atom,28 and while the reaction of 16
proceeds readily with “armed” per-TMS donor 15, the
corresponding less-armed per-benzylated glycosyl iodide is
unreactive to this class of acceptor.24a,b These observations
serve to highlight how sensitive is the reactivity of these glycosyl
iodide donors to small changes in the sugar substitution pattern.
In summary, a short and convenient route to 6-N-deriva-
tized galactosyl ceramides has been developed, which allows
late-stage variation of both the N-acyl chain of the sphingo-
sine unit and the substituent introduced at the 6-position of
the sugar. Azides 23 and 24 are also primed for further
functionalization via Click Chemistry. Future work will focus
on using such derivatization strategies in the synthesis and
biological evaluation of novel 6-N-derivatized glycolipids.
(stack, 3H), 3.65-3.98 (stack, 7H), 4.89 (d, J=3.3 Hz, 1H); 13
C
NMR (100 MHz, CDCl3:CD3OD, 2:1) 14.3 (CH3), 23.2 (CH2),
26.4 (CH2), 28.6 (CH3), [29.9, 30.2, 32.4, 32.8 (CH2, resonance
overlap)], 51.7 (CH), 51.8 (CH2), 68.3 (CH2), 69.3 (CH), 70.4
(CH), 70.6 (2 ꢀ CH, resonance overlap), 72.5 (CH), 75.3 (CH),
80.1 (C), 156.8 (C); MS (TOF ESþ) m/z 627.3 ([M þ Na]þ,
100%); HRMS (TOF ESþ) calcd for C29H56N4O9Na [M þ
Na]þ 627.3945, found 627.3956.
Amine 10 from Azide 22. TFA (1.0 mL, 13.2 mmol) was added
dropwise over 5 min to azide 22 (400 mg, 0.38 mmol) at rt. After
30 min, the reaction mixture was concentrated under reduced
pressure. The resulting colorless oil was used in the next step
without further purification (192 mg, quant.).
From Azide 9. TFA (0.50 mL, 6.6 mmol) was added dropwise
over 5 min to azide 9 (114 mg, 0.19 mmol) at rt. After 30 min, the
reaction mixture was concentrated under reduced pressure. The
resulting colorless oil was used in the next step without further
purification (96 mg, quant.).
Acknowledgment. G.S.B. acknowledges support in the
form of a Personal Research Chair from Mr. James Bardrick,
Royal Society Wolfson Research Merit Award, and as a
former Lister Institute-Jenner Research Fellow; and P.J.J.
acknowledges The Wellcome Trust (084923/B/08/Z) for
funding. The NMR spectrometers used in this research were
funded in part through Birmingham Science City: Innovative
Uses for Advanced Materials in the Modern World (West
Midlands Centre for Advanced Materials Project 2), with
support from Advantage West Midlands and part-funded by
the European Regional Development Fund.
Experimental Section
General Procedure for Selective 6-Desilylation (Alcohols 21
and 26). AcOH (3.00 mmol) was added to a solution of galacto-
side 20 or 13 (1.57 mmol) in acetone (3.5 mL) and MeOH (4.7
mL) at 0 °C. The reaction mixture was allowed to warm to rt.
After 8 h, the reaction was quenched by the addition of NaHCO3
(5.95 mmol) and then filtered. After concentration of the filtrate
under reduced pressure, the resulting oil was purified by flash
(27) (a) Li, Z.; Gildersleeve, J. C. Tetrahedron Lett. 2007, 48, 559–562.
(b) Li, Z.; Gildersleeve, J. C. J. Am. Chem. Soc. 2006, 128, 11612–11619.
(28) (a) Polt, R.; Szabo, L.; Treiberg, J.; Li, Y.; Hruby, V. J. J. Am. Chem.
Soc. 1992, 114, 10249–10258. (b) Schmidt, R. R.; Zimmermann, P. Angew.
Chem., Int. Ed. Engl. 1986, 25, 725–726.
Supporting Information Available: Experimental procedures,
characterization, and 1HNMRand13C NMR spectra for products
6, 8-10, 13, 16, 18, and 20-25. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 1, 2011 323