Syntheses of carbocyclic aminonucleosides and (-)-epi-4′-carbocyclic puromycin: application of palladium(0)/indium iodide-allylations and tethered aminohydroxylations

Article abstract of DOI:10.1016/j.tetlet.2010.04.006

Carbocyclic aminonucleosides and epi-4′-carbocyclic puromycin were prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct. Pd(0)/InI-mediated allylations of a formyl species were used to install the 4′-hydroxymethyl group. A tethered aminohydroxylation strategy was employed to install the cis-2′,3′-aminoalcohol moiety with complete regio- and diastereocontrol.

Full text of DOI:10.1016/j.tetlet.2010.04.006

Tetrahedron Letters 51 (2010) 3053–3056
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Tetrahedron Letters
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Syntheses of carbocyclic aminonucleosides and (ꢀ)-epi-40-carbocyclic
puromycin: application of palladium(0)/indium iodide-allylations
and tethered aminohydroxylations
*
Cara Cesario, Lawrence P. Tardibono Jr., Marvin J. Miller
The University of Notre Dame, Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, Notre Dame, IN 46556, United States
a r t i c l e i n f o
a b s t r a c t
Carbocyclic aminonucleosides and epi-40-carbocyclic puromycin were prepared from an acylnitroso-
derived hetero Diels–Alder cycloadduct. Pd(0)/InI-mediated allylations of a formyl species were used
to install the 40-hydroxymethyl group. A tethered aminohydroxylation strategy was employed to install
the cis-20,30-aminoalcohol moiety with complete regio- and diastereocontrol.
Article history:
Received 1 February 2010
Revised 30 March 2010
Accepted 1 April 2010
Available online 9 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Puromycin is an aminonucleoside natural product that demon-
strates broad spectrum antibiotic and antitumor activities (Fig. 1).1
The 30-aminoacyl moiety structurally resembles the aminoacylade-
nyl region of an aminoacyl tRNA2 and plays a crucial role in termi-
trol.12 Additionally, a N-pentafluorobenzoyloxy carbamate linker
may be constructed from the 40-hydroxymethyl substituent. This
substrate may serve as a precursor for a tethered aminohydroxyla-
tion13 to install the cis-20,30-aminoalcohol moiety. Application of
these key synthetic transformations allows complete functionali-
zation of the cyclopentane core and provides aminonucleosides
( )-1a and (ꢀ)-1b and (ꢀ)-epi-40-carbocyclic puromycin 2 (Fig. 1).
We have previously reported direct hydroxymethylations at the
C-40 position by using Pd(0)/InI allylation chemistry with carbocy-
clic platforms ( )-3a and (+)-3b.12 Functionalized cyclopentene
systems ( )-3a and (+)-3b serve as key intermediates in the syn-
theses of diverse carbocyclic nucleosides14 as well as starting
materials in our route to carbocyclic puromycin derivatives.
Treatment of syn-1,4 scaffold ( )-3a with HCl at 80 °C removed
the Boc group (Scheme 1). The crude amine salt was treated with
5-amino-4,6-dichloropyrimidine in refluxing n-BuOH for 4 d to af-
ford the SNAr product ( )-4a. Cyclization of compound ( )-4a to 6-
chloropurine ( )-5a was achieved with triethylorthoformate in the
presence of catalytic camphor sulfonic acid. The anti-1,4 diastereo-
mer (+)-3b was subjected to identical reaction conditions to pro-
vide chloropurine analog (+)-5b (Scheme 2).
We developed a method to key homoallylic alcohols ( )-5a and
(+)-5b and turned our attention in installing the cis-20,30-amino-
alcohol by using a tethered aminohydroxylation reaction.15,16
N-Sulfonyloxy carbamates17 and N-pentafluorobenzoyloxy carba-
mates13b have emerged as reoxidants in tethered aminohydroxyla-
tion reactions and avoided the use of chlorinating agents and basic
reaction conditions. Although this powerful methodology has
already been used in total synthesis,18 few examples of tethered
hydroxyaminations with functionalized homoallylic alcohols have
been reported.13b,16c–e,17
nating protein biosynthesis. Specifically, the
a-amino group is
transferred to a carboxyl-activated peptidyl-tRNA to form a new
peptide bond.3 However, subsequent aminoacyl-group transfer
reactions are precluded due to the presence of an unreactive
30-amide in the ribosomal acceptor site rather than an activated
30-ester linkage. As a result, the nascent polypeptide chain is
prematurely released from the ribosome.4
Although puromycin effectively inhibits transpeptidation, the
ribonucleoside is rapidly metabolized in vivo to inactive and toxic
components.5 In order to circumvent enzymatic degradation and
toxicity issues, carbocyclic puromycin and related analogs have
been prepared and studied extensively.6 The carbocyclic aminonu-
cleosides have the same mode of action as puromycin and retain
antimicrobial activity.7 Also, carbocyclic nucleosides lack an enzy-
matically labile glycosidic bond and provide a more metabolically
robust scaffold.8 Structure–activity relationships (SARs) revealed
that the 40-hydroxymethyl group was not required for activity9
and the 10,20,30,40-diastereomer lacked biological function. The
cis-20,30-aminoalcohol stereochemistry was essential for activity.
Additionally, replacement of the functionalized cyclopentane core
with a cyclohexyl ring resulted in decreased inhibition of protein
synthesis.10
Our research group’s continued interest in the syntheses of
diverse carbocyclic nucleosides11 led us to investigate carbocyclic
puromycin derivatives. By employing Pd(0)/InI-mediated allyla-
tions of
a
formyl species, 40-hydroxymethyl groups may be
installed in the carbocyclic scaffold with regio- and diastereocon-
In order to prepare the appropriate tethered aminohydroxyla-
tion precursor, we employed a two-step sequence19 to N-hydrox-
ycarbamate ( )-7a. When chloropurine ( )-5a was treated with
* Corresponding author. Tel.: +1 574 631 7571; fax: +1 574 631 6652.
E-mail address: mmiller1@nd.edu (M.J. Miller).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.006

3054
C. Cesario et al. / Tetrahedron Letters 51 (2010) 3053–3056
Cl
N
N
N
N
N
N
TFA
N
N
N
1. CDI, CH3CN, 2 h
N
anisole
( )-5a
O
N
N
5'
N
X
1 h, rt
60%
2. (PMB)ONH2• HCl
NaHCO3, H2O 24 h,
66%
O
Cl
O
4'
3'
1'
2'
N
H
PMB
HO
O
N
HO
( )-6a
H3CO
3'
2'
NH OH
Cl
N
Cl
H2N
OH
O
NH2
N
N
N
N
N
lyxo-carbocyclic
aminonucleoside
PFP
puromycin
carbocyclic
X = O,
X = CH ,
O
O
N
N
puromycin
2
PFP
O
N
HO
(
)-1a
CH3CN, pyr
O
O
N
H
2 h, 0 °C, 67%
H
( )-7a
O
( )-8a
N
N
N
N
Cl
N
N
N
N
N
N
4 mol %
K2OsO4• 2H2O
N
1. NHMe2, H2O
MeOH, 60 °C, 2 h
4'
HO
N
N
N
( )-1a
4'
CH3CN:H2O
(1.5:1)
1.5 h, 58%
2. LiOH, H2O
HO
O
H3CO
O
NH OH
NH2
MeOH, 80 °C, 18 h
84% (2 steps)
H2N
OH
N
H
OH
O
( )-9a
carbocyclic
PMB = p-methoxybenzyl
PFP = pentafluorobenzoyl
epi-4'-carbocyclic
puromycin (−)-2
aminonucleoside
(−)-1b
Figure 1. Puromycin and related carbocyclic analogs.
Scheme 3. Tethered aminohydroxylation to ( )-9a and elaboration to lyxo-carbo-
cyclic aminonucleoside ( )-1a.
1. 12M HCl, EtOH
80 °C 3 h, quant.
NHBoc
HO
HO
2. 5-amino-4,6-
dichloropyrimidine
DIPEA, n-BuOH
110 °C, 4 d, 76%
The tethered aminohydroxylation was the key step en route to
carbocyclic aminonucleoside core structures. We expected
complete regiocontrol and anticipated diastereofacial selectivity
to favor the same side where the tether originated. Dihydroxyla-
tion of syn-1,4-disubstituted cyclopentenes has been studied23
( )-3a
Cl
Cl
N
H2N
N
N
CSA
N
N
CH(OEt)3
N
N
and the
p-facial selection of these reactions was governed by ster-
3 h, 73%
H
HO
ics and the Cieplak effect.24
( )-4a
( )-5a
A
t-BuOH/H2O (3:1) solution of homoallyl N-penta-
fluorobenzoyloxy carbamate ( )-8a was treated with catalytic
K2OsO4, and hydroxyamination product ( )-9a was obtained. How-
ever, two competing side reactions contributed to the low conver-
sion to ( )-9a. Hydrolysis of N-pentafluorobenzoyloxy carbamate
( )-8a provided N-hydroxycarbamate ( )-7a. Additionally, the
presence of a homoallyl carbamate25 suggested that hydrolysis of
the imidotrioxoosmium (VII) species26 was also competitive. When
the tethered aminohydroxylation reaction was conducted in
n-BuOH/H2O (3:1), the homoallyl carbamate was the dominant
product and hydroxyamination product ( )-9a was also observed.
Although LC–MS and 1H NMR of the crude product mixtures
indicated the formation of an exclusive diastereomer, unwanted
by-products precluded the use of these solvent conditions.
Early work on the catalytic asymmetric aminohydroxylation
reaction reported the use of CH3CN/H2O as an effective solvent sys-
tem.27 When a CH3CN/H2O (1.5:1) solution of homoallyl N-penta-
fluorobenzoyloxy carbamate ( )-8a was treated with catalytic
K2OsO4, tethered aminohydroxylation product ( )-9a was the ma-
jor component of the reaction mixture (Scheme 3). Cyclic carba-
mate ( )-9a was isolated in 58% yield as the exclusive regio- and
diastereoisomer. The relative stereochemistry was determined by
NOE correlations in the ROESY spectrum.28
Scheme 1. Preparation of chloropurine ( )-5a.
CDI followed by an aqueous solution of O-p-methoxybenzylhydr-
oxylamine,20 N-benzyloxycarbamate derivative ( )-6a was isolated
in 66% yield. Removal of the p-methoxybenzyl group with neat TFA
provided N-hydroxycarbamate ( )-7a (Scheme 3).
Initial attempts to synthesize N-pentafluorobenzoyloxy carba-
mate ( )-8a were thwarted by undesired by-products. When N-
hydroxycarbamate ( )-7a was treated with pentafluorobenzoyl
chloride in the presence of Et3N, the bis-benzoylated product
dominated the reaction mixture (ca. 42% by LC–MS). Although
bis-benzoylation has not been reported in the syntheses of
N-pentafluorobenzoyloxy carbamates,13b we suspected that
deprotonation of the NH with Et3N readily occurred after
mono-benzoylation21 and the stabilized anion reacted with an-
other equivalent of the acid chloride. In order to minimize the
unwanted bis-benzoylation reaction, we exchanged Et3N for a
weaker base. When a CH3CN solution of N-hydroxycarbamate
( )-7a was treated with pentafluorobenzoyl chloride in the pres-
ence of pyridine, mono-benzoylated derivative ( )-8a was iso-
lated as the major product in 67% yield.22
Treatment of compound ( )-9a with dimethylamine afforded
the SNAr product and the cyclic carbamate was cleaved with LiOH
in refluxing MeOH to provide unprecedented lyxo-carbocyclic
aminonucleoside ( )-1a.
1. 12M HCl, EtOH
80 °C 3 h, quant.
NHBoc
HO
HO
2. 5-amino-4,6-
dichloropyrimidine
DIPEA, n-BuOH
110 °C, 4 d, 74%
We had successfully developed methodology to prepare the
N-pentafluorobenzoyloxy carbamate linker and identified optimal
conditions for the tethered aminohydroxylation reaction by start-
ing with syn-1,4-disubstituted cyclopentene diastereomer ( )-5a.
We applied this optimized route to synthesize carbocyclic amino-
nucleoside precursor (ꢀ)-9b (Scheme 4).
(+)-3b
Cl
Cl
N
H2N
N
N
CSA
N
N
CH(OEt)3
N
N
3 h, 83%
H
HO
Chloropurine analog (+)-5b was treated with CDI for 2 h. Then, a
solution of O-p-methoxybenzylhydroxylamine was introduced to
(+)-4b
(+)-5b
Scheme 2. Preparation of chloropurine ( )-5b.
provide
N-(p-methoxy)benzyloxycarbamate
analog
(+)-6b.

C. Cesario et al. / Tetrahedron Letters 51 (2010) 3053–3056
3055
Cl
employed to prepare a highly functionalized carbocyclic core with
complete diastereo- and regiocontrol.
N
N
TFA
anisole
N
1. CDI, CH3CN, 2 h
(+)-5b
O
1 h, rt
55%
N
2. (PMB)ONH2• HCl
NaHCO3, H2O 24 h,
55%
O
O
Acknowledgments
N
H
PMB
(+)-6b
Cl
Cl
N
We would like to thank Dr. Jed Fisher (University of Notre
Dame) for helpful discussions, Dr. Bill Boggess (University of Notre
Dame) and Nonka Sevova (University of Notre Dame) for mass
spectroscopic analyses, and Dr. Jaroslav Zajicek (University of
Notre Dame) for NMR assistance. We acknowledge The University
of Notre Dame and NIH (GM068012) for support of this work.
O
N
N
N
N
N
PFP
Cl
O
O
N
N
PFP
O
N
HO
CH3CN, pyr
2 h, 0 °C,
53%
O
O
N
H
H
(+)-7b
(+)-8b
O
Cl
N
N
4 mol %
K2OsO4• 2H2O
Supplementary data
N
N
CH3CN:H2O
(1.5:1)
1.5 h, 83%
O
PMB = p-methoxybenzyl
PFP = pentafluorobenzoyl
N
OH
Supplementary data (general methods, experimental details
and characterization for compounds ( )-1a, (ꢀ)-1b, (ꢀ)-2, ( )-4a,
(+)-4b, ( )-5a, (+)-5b, ( )-6a, (+)-6b, ( )-7a, (+)-7b, ( )-8a, (+)-8b,
( )-9a, (ꢀ)-9b, and (ꢀ)-10. Complete proton and carbon assign-
ments of ( )-9a and (ꢀ)-9b) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.04.006.
O
H
(−)-9b
Scheme 4. Tethered aminohydroxylation to (ꢀ)-9b.
N-Hydroxycarbamate (+)-7b was revealed when (+)-6b was
treated with neat TFA to remove the p-methoxybenzyl group.
The tethered aminohydroxylation precursor (+)-8b was obtained
by treatment of substrate (+)-7b with a CH3CN solution of penta-
fluorobenzoyl chloride in the presence of pyridine. On the first
attempt to effect aminohydroxylation, homoallyl N-penta-
fluorobenzoyloxy carbamate (+)-8b was treated with catalytic
K2OsO4 in CH3CN/H2O (1.5:1) to afford hydroxyamination product
(ꢀ)-9b in 83% isolated yield. In this case, the 10-nucleobase is ori-
entated on the opposite side of the tether. The reduced steric bulk
may contribute to the increased yield of (ꢀ)-9b compared to the
reaction of diastereomer ( )-8a.
References and notes
1. Porter, J. N.; Hewitt, R. I.; Hesseltine, C. W.; Krupka, J.; Lowery, J. A.; Wallace, W.
S.; Bohonos, N.; Williams, J. H. Antibiot. Chemother. 1952, 2, 409–410.
2. Yarmolinsky, M. B.; de la Haba, G. L. Proc. Natl. Acad. Sci. U.S.A. 1959, 45, 1721–
1729.
3. Allen, D. W.; Zamecnik, P. C. Biochim. Biophys. Acta 1962, 55, 865–874.
4. (a) Nathans, D. Proc. Natl. Acad. Sci. U.S.A. 1964, 51, 585–592; (b) Smith, J. D.;
Traut, R. R.; Blackburn, G. M.; Monro, R. E. J. Mol. Biol. 1965, 13, 617–628.
5. Nathans, D.. In Antibiotics; Gottlieb, D., Shaw, P. D., Eds.; Springer: New York,
1967; Vol. 1, pp 259–277.
6. (a) Daluge, S.; Vince, R. J. Org. Chem. 1978, 43, 2311–2320; (b) Vince, R.; Daluge,
S.; Brownell, J. J. Med. Chem. 1986, 29, 2400–2403.
7. Vince, R.; Daluge, S.; Palm, M. Biochem. Biophys. Res. Commun. 1972, 46, 866–
870.
8. (a) Casu, F.; Chiacchio, M. A.; Romeo, R.; Gumina, G. Curr. Org. Chem. 2007, 11,
999–1016; (b) Jeong, L. S.; Lee, J. A. Antiviral Chem. Chemother. 2004, 15, 235–
250; (c) Rodriguez, J. B.; Comin, M. J. Mini-Rev. Med. Chem. 2003, 3, 95–114; (d)
Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1–40.
9. (a) Vince, R.; Daluge, S. J. Med. Chem. 1974, 17, 578–583; (b) Pestka, S.; Vince, R.;
Daluge, S.; Harris, R. Antimicrob. Agents Chemother. 1973, 4, 37–43; (c) Daluge,
S.; Vince, R. J. Med. Chem. 1972, 15, 171–177.
Carbocyclic aminonucleoside (ꢀ)-1b was synthesized by
installation of the dimethylamino moiety followed by cleavage
of the cyclic carbamate with LiOH (Scheme 5). The carbocyclic
derivative (ꢀ)-1b was coupled to N-benzyloxycarbonyl-p-
methoxyphenyl-
L
-alanine to provide 30-derivative (ꢀ)-10. Hydro-
genation in the presence of Pd/C removed the CBz-protecting
group and revealed targeted carbonucleoside, epi-40-carbocyclic
puromycin (ꢀ)-2.
10. Vince, R.; Daluge, S. J. Med. Chem. 1977, 20, 930–934.
11. (a) Cesario, C.; Miller, M. J. J. Org. Chem. 2009, 74, 5730–5733; (b) Jiang, M. X.;
Jin, B.; Gage, J. L.; Priour, A.; Savela, G.; Miller, M. J. J. Org. Chem. 2006, 71, 4164–
4169; (c) Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. J. Org. Chem.
2004, 69, 4538–4540.
12. Cesario, C. Miller, M. J. Tetrahedron Lett., in press. doi:10.1016/
j.tetlet.2010.04.007.
13. (a) Morales-Serna, J. A.; Diaz, Y.; Matheu, M. I.; Castillon, S. Synthesis 2009, 5,
710–712; (b) Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.; Rossignol,
E. Org. Lett. 2007, 9, 1725–1728.
In summary, we have synthesized biologically relevant carbocy-
clic aminonucleosides ( )-1a and (ꢀ)-1b and epi-40-carbocyclic
puromycin (ꢀ)-2 from an acylnitroso-derived hetero Diels–Alder
cycloadduct. Our route highlighted two key synthetic transforma-
tions. Pd(0)/In-mediated allylations were used to install the requi-
site hydroxymethyl group. A tethered aminohydroxylation was
14. For the synthesis of 3a, see: (a) McGuigan, C.; Hassan-Abdallah, A.; Srinivasan,
S.; Wang, Y.; Siddiqui, A.; Daluge, S. M.; Gudmundsson, K. S.; Zhou, H.; McLean,
E. W.; Peckham, J. P.; Burnette, T. C.; Marr, H.; Hazen, R.; Condreay, L. D.;
Johnson, L.; Balzarini, J. J. Med. Chem. 2006, 49, 7215–7226; (b) Vince, R.; Hua,
M. J. Med. Chem. 1990, 33, 17–21; (c) Daluge, S. M.; Martin, M. T.; Sickles, B. R.;
Livingston, D. A. Nucleosides Nucleotides Nucleic Acids 2000, 19, 297–327; For
the synthesis of 3b, see: (d) Grumann, A.; Marley, H.; Taylor, R. J. K. Tetrahedron
Lett. 1995, 36, 7767–7768.
15. Compound ( )-5a was first reacted with trichloroacetyl isocyanate followed by
basic work-up to afford a homoallyl carbamate. In an early attempt to affect
hydroxyamination, the carbamate was treated with catalytic K2OsO4 in the
presence of t-BuOCl and NaOH. The substrate was not compatible with the
harsh oxidizing conditions and a complex product mixture resulted within
10 min; compound ( )-9a was not observed by this method.
16. For tethered aminohydroxylations with allyl carbamates as substrates, see: (a)
Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am. Chem. Soc. 2002,
124, 12934–12935; (b) Donohoe, T. J.; Johnson, P. D.; Pye, R. J. Org. Biomol.
Chem. 2003, 1, 2025–2028; For tethered amino-hydroxylations with homoallyl
carbamates as substrates, see: (c) Kenworthy, M. N.; McAllister, G. D.; Taylor, R.
J. K. Tetrahedron Lett. 2004, 45, 6661–6664; (d) Curtis, K. L.; Fawcett, J.; Handa,
S. Tetrahedron Lett. 2005, 46, 5297–5300; (e) Curtis, K. L.; Evinson, E. L.; Handa,
S.; Singh, K. Org. Biomol. Chem. 2007, 5, 3544–3553.
N
1. NHMe2, H2O
MeOH, 60 °C, 2 h
N
N
Z-Tyr(Me)-OH
DCC, NHS
N
(−)-9b
N
2. LiOH, H2O
MeOH, 80 °C, 18 h
74% (2 steps)
DMF, rt, 24 h
73%
HO
H2N
(−)-1b
OH
N
N
N
N
Pd/C, H2
N
(−)-2
HO
O
AcOH, rt, 1 h
88%
H3CO
NH OH
NHCBz
(−)-10
17. Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.; Griffin, D.; Campbell, A. D. J. Am.
Chem. Soc. 2006, 128, 2514–2515.
18. In the synthesis of dysiherbaine, see: de la Pradilla, R. F.; Lwoff, N.; Viso, A.
Tetrahedron Lett. 2007, 48, 8141–8144.
Scheme 5. Elaboration to carbocyclic aminonucleoside (ꢀ)-1b and epi-40-carbocy-
clic puromycin (ꢀ)-2.

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C. Cesario et al. / Tetrahedron Letters 51 (2010) 3053–3056
19. Attempts to directly prepare N-hydroxycarbamate ( )-7a from ( )-5a occurred
with limited success. When homoallylic alcohol ( )-5a was stirred with CDI for
2 h and then treated with a solution of hydroxylamine hydrochloride and
triethylamine, starting material ( )-5a was recovered and low conversion to N-
hydroxycarbamate ( )-7a was observed.
20. For preparation of O-p-methoxybenzylhydroxylamine hydrochloride, see: Zhu,
G.; Yang, F.; Balachandran, R.; Hook, P.; Vallee, R. B.; Curran, D. P.; Day, B. W. J.
Med. Chem. 2006, 49, 2063–2076.
23. Katagiri, N.; Ito, Y.; Kitano, K.; Toyota, A.; Kaneko, C. Chem. Pharm. Bull. 1994,
42, 2653–2655.
24. Diastereofacial addition will be directed anti to the electron rich bonds that
stabilize the developing antibonding orbitals in the transition state, see: (a)
Cieplak, A. S. Chem. Rev. 1999, 99, 1265–1336; (b) Cieplak, A. S. J. Am. Chem. Soc.
1981, 103, 4540–4552.
25. Carbamates
have
been
observed
as
by-products
in
tethered
aminohydroxylations, see: Ref. 13b, footnote 7.
21. The pKa <7 for the NH of O-acylhydroxamic acids, see: Bauer, L.; Exner, O.
Angew. Chem., Int. Ed. Engl. 1974, 13, 376–385.
22. LC–MS of the crude reaction mixture indicated that ( )-8a was the major
component of the reaction mixture (74%). Unreacted ( )-7a (16%), N-mono-
benzolylated product (3%), and bis-benzolylated product (7%) were also
present.
26. An imidotrioxoosmium (VII) species is proposed in the tethered
aminohydroxylation reaction mechanism, see: Ref. 16b.
27. Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451–
454.
28. Refer to Supplementary data for complete carbon and proton assignments for
( )-9a and (ꢀ)-9b.