Universal NMR Databases for Contiguous Polyols

Article abstract of DOI:10.1021/ja0375481

On the basis of 1,2,3-triols la～d, 1,2,3,4-tetraols 2a～h, and 1,2,3,4,5-pentaols 3a～p, NMR databases with four types of profile-descriptors (¹³C-, ¹H-, and ¹H(OH)-chemical shifts and vicinal spincoupling constants) for con

Full text of DOI:10.1021/ja0375481

Published on Web 11/01/2003
Universal NMR Databases for Contiguous Polyols
Shuhei Higashibayashi, Werngard Czechtizky, Yoshihisa Kobayashi, and
Yoshito Kishi*
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
Received July 25, 2003; E-mail: kishi@chemistry.harvard.edu
Abstract: On the basis of 1,2,3-triols 1a∼d, 1,2,3,4-tetraols 2a∼h, and 1,2,3,4,5-pentaols 3a∼p, NMR
databases with four types of profile-descriptors (13C-, 1H-, and 1H(OH)-chemical shifts and vicinal spin-
coupling constants) for contiguous polyols are reported. To systematically assess the relative values of
these databases, a case study has been conducted on heptaols 4a∼d, through which the γ- and δ-effects
1
have been recognized to refine the 13C and H chemical shift profile predicted via an application of the
concept of self-contained nature. The magnitudes of γ- and δ-effects depend on a specific stereochemical
arrangement of the functional groups present in both the inside and outside of a self-contained box and
are significant only for the stereoisomers belonging to a specific sub-group. With the exception of the
stereochemical arrangement of functional groups belonging to a specific sub-group, the γ- and δ-effects
can, at the first order of approximation, be ignored for the stereochemical analysis of unknown compounds.
For the stereoisomers belonging to a specific sub-group, it is necessary to refine, with incorporation of the
γ- and δ-effects, the profile predicted at the first order of approximation. With use of heptaols 4a∼d, the
values of 3JH,H profiles have been assessed. Two methods, one using profiles consisting of three contiguous
3
3JH,H constants and the other using profiles consisting of two contiguous JH,H constants, have been
3
developed. A stereochemical analysis based on three, or two, contiguous JH,H profiles is operationally
simpler than one based on 13C and 1H chemical shift profiles. Therefore, it is recommended to use a 3JH,H
1
profile as the primary device to predict the stereochemistry of unknown polyols and 13C and H chemical
shift profiles as the secondary devices to confirm the predicted stereochemistry.
Introduction
stereochemical arrangement of the small substituents on the
carbon backbone and are independent from the rest of the
Through the work on palytoxins,1,2 AAL toxin/fumonisin,3,4
and maitotoxin,5,6 we have experimentally demonstrated the
following: (1) the spectroscopic profiles of the stereoclusters
present in these natural products are inherent to the specific
molecules, and (2) steric and stereoelectronic interactions
between structural clusters connected either directly or with a
one-methylene bridged are significant and interactions between
stereoclusters connected with a two- or more-methylene bridge
are negligible. On the basis of these experimental discoveries,
we have advanced the logic of a universal NMR database
approach for assignment of the relative and absolute configu-
ration of (acyclic) compounds. Using the 13C chemical shift
profiles as the primary means, we have demonstrated the
feasibility and reliability of this approach, which has culminated
in the complete stereochemical assignment of the desertomycin/
oasomycin class of antibiotics,7 mycolactone,8 and tetrafibricin.9
(1) (a) Cha, J. K.; Christ, W. J.; Finan, J. M.; Fujioka, H.; Kishi, Y.; Klein. L.
L.; Ko, S. S.; Leder, J.; McWhorter, W. W., Jr.; Pfaff, K.-P.; Yonaga, M.;
Uemura, D.; Hirata, Y. J. Am. Chem Soc. 1982, 104, 7369-7371 and the
preceding papers. (b) Kishi, Y. Curr. Trends Org. Synth. (IUPAC) 1983,
115-130.
(2) For the stereochemical assignment primarily based on spectroscopic
methods, see: Moore, R. E.; Bartolini, G.; Barchi, J.; Bothner-By, A. A.;
Dadok, J.; Ford, J. J. Am. Chem. Soc. 1982, 104, 3776-3779.
(3) For the stereochemical assignment of AAL toxins and fumonisins from
this laboratory, see: (a) Boyle, C. D.; Harmange, J.-C.; Kishi, Y. J. Am.
Chem. Soc. 1994, 116, 4995-4996. (b) Boyle, C. D.; Kishi, Y. Tetrahedron
Lett. 1995, 36, 5695-5698, and references therein.
(4) For the work from other laboratories, see: (c) Oikawa, H.; Matsuda, I.;
Kagawa, T.; Ichihara, A.; Kohmoto, K. Tetrahedron 1994, 50, 13 347-
13 368. (d) Hoye, T. R.; Jime´nez, J. I.; Shier, W. T. J. Am. Chem. Soc.
1994, 116, 9409-9410. (e) ApSimon, J. W.; Blackwell, B. A.; Edwards,
O. E.; Fruchier, A. Tetrahedron Lett. 1994, 35, 7703-7706. (f) Poch, G.
K.; Powell, R. G.; Plattner, R. D.; Weisleder, D. Tetrahedron Lett. 1994,
35, 7707-7710. (g) Blackwell, B. A.; Edwards, O. E.; ApSimon, J. W.;
Fruchier, A. Tetrahedron Lett. 1995, 36, 1973-1976.
(7) (a) Lee, J.; Kobayashi, Y.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2177-
2180. (b) Kobayashi, Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1,
2181-2184. (c) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. HelV. Chim. Acta
2000, 83, 2562-2571. (d) Kobayashi, Y.; Tan. C.-H.; Kishi, Y. Angew.
Chem., Int. Ed. 2000, 39, 4279-4281. (e) Tan. C.-H.; Kobayashi, Y.; Kishi,
Y. Angew. Chem., Int. Ed. 2000, 39, 4282-4284. (f) Kobayashi, Y.;
Hayashi, N.; Tan. C.-H.; Kishi, Y. Org. Lett. 2001, 3, 2245-2248. (g)
Hayashi, N.; Kobayashi, Y.; Kishi, Y. Org. Lett. 2001, 3, 2249-2252. (h)
Kobayashi, Y.; Hayashi, N.; Kishi, Y. Org. Lett. 2001, 3, 2253-2255. (i)
Kobayashi, Y.; Tan. C.-H.; Kishi, Y. J. Am. Chem. Soc. 2001, 123, 2076-
2078. (j) Kobayashi, Y.; Hayashi, N.; Kishi, Y. Org. Lett. 2002, 4, 411-
414.
(5) For the work from this laboratory, see: (a) Zheng, W.; DeMattei, J. A.;
Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am. Chem.
Soc. 1996, 118, 7946-7968. (b) Cook, L. R.; Oinuma, H.; Semones, M.
A.; Kishi, Y. J. Am. Chem. Soc. 1997, 119, 7928-7937.
(6) For the work from the laboratories at Tokyo and Tohoku Universities, see:
(c) Sasaki, M.; Matsumori, N.; Maruyama, T.; Nonomura, T.; Murata, M.;
Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1672-
1675. (d) Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana,
K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1675-1678.
(8) (a) Benowitz, A. B.; Fidanze, S.; Small, P. L.; Kishi, Y. J. Am. Chem. Soc.
2001, 123, 5128-5129. (b) Fidanze, S.; Song, F.; Szlosek-Pinaud, M.;
Small, P. L.; Kishi, Y. J. Am. Chem. Soc. 2001, 123, 10 117-10 118.
(9) Kobayashi, Y.; Czechtizky, W.; Kishi, Y. Org. Lett. 2003, 5, 93-96.
9
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J. AM. CHEM. SOC. 2003, 125, 14379-14393
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A R T I C L E S
Higashibayashi et al.
Scheme 1
Reagents and Reaction Conditions (a) LiAlH4, THF, rt. (b) H2, Lindlar
catalyst, quinoline, hexane, rt. (c) NaH, BnBr, (n-Bu)4NI, DMF, rt. (d) OsO4,
NMO, acetone/H2O, rt. (e) H2, Pd-on-C, MeOH, rt. (f) Ac2O, pyridine, rt.
(g) NaOMe, MeOH, rt.
The stereochemistry of 1,2,3-triols 1a∼d was assigned for
the following reason. The major triol derived from trans-allylic
alcohol B-1 should correspond to either 1a or 1d, whereas the
major triol derived from cis-allylic alcohol B-2 should cor-
respond to either 1c or 1b. On the basis of the empirical rule,12
we predicted that the major diastereomer obtained from trans-
and cis-allylic alcohols B-1 and B-2 corresponds to 1d and 1b,
respectively. This assignment was further supported by NMR
spectroscopy. Ignoring the difference in structure at the two
terminal positions, we recognized the presence of a plane of
symmetry for 1a and 1b but not for 1d and 1c. Indeed, this
Figure 1. NMR Database substrates used for the 1,2,3-triol (1a∼d), 1,2,3,4-
tetraol (2a∼h), and 1,2,3,4,5-pentaol (3a∼p) systems.
Needless to point out, spectroscopic profiles can be described
by other parameters such as vicinal 1H/1H spin-coupling (3JH,H
)
3
constants. In this paper, we will report the JH,H databases, as
1
1
well as the 13C, H, and H(OH) chemical shift databases, for
contiguous polyols, which allows us for the first time to
systematically compare the values of each of the NMR databases
using different descriptors.
1
was well reflected in their H [1a: 3.64 ppm (H5, H7), 3.20
(H6); 1b: 3.59 (H5, H7), 3.29 (H6); 1c: 3.81 (H5), 3.15 (H6),
3.61 (H7); 1d: 3.59 (H5), 3.15 (H6), 3.82 (H7)] and 13C
[1a: 73.5 ppm (C5), 76.7 (C6), 73.3 (C7); 1b: 74.0 (C5), 78.3
(C6), 73.8 (C7); 1c: 71.5 (C5), 76.9 (C6), 72.6 (C7); 1d: 72.7
(C5), 76.9 (C6), 71.1 (C7)] NMR spectra in CD3OD.
The 1,2,3,4-tetraols 2a∼h were synthesized in an optically
active form from D-pentoses (Scheme 2).13 In this synthesis,
the C6,C7,C8-stereochemistry of 2a∼h was predetermined by
D-pentoses used. The left-side chain was introduced via a
Grignard reaction to yield the expected product as a diastere-
omeric mixture at C5. After benzylation, the mixture was
separated by silica gel chromatography (Biotage), to furnish the
stereochemically homogeneous C5 diastereomers. Thus, all the
required 1,2,3,4-triols 2a∼h were obtained in a stereochemically
homogeneous form and fully characterized.
Synthesis and Stereochemical Assignment of NMR Da-
tabase Polyols. We chose, and synthesized, 1a∼d, 2a∼h, and
3a∼p as the substrates to create the NMR database for 1,2,3-
triols, 1,2,3,4-tetraols, and 1,2,3,4,5-pentaols, respectively. To
correlate directly with previously created NMR databases, these
database substrates were designed to share the same structural
moiety at the left- and right-terminals with the database
compounds previously used.
The 1,2,3-triols 1a∼d were synthesized in an optically active
form from the chiral propargyl alcohol A (Scheme 1).10,11 Using
the procedures well precedented in the literature, i.e., LAH and
H2/Lindlar-catalyst, A was selectively reduced to trans- and cis-
allylic alcohols B-1 and B-2, respectively. The spin-coupling
constants observed for the olefinic protons confirmed the
stereochemistry of B-1 and B-2. After benzylation, B-1 and B-2
were subjected to OsO4-dihydroxylation, to furnish a 3:1 mixture
of threo-products and a 9:1 mixture of erythro-products,
respectively, which were effectively separated by silica gel
chromatography. Thus, 1,2,3-triols 1a∼d were obtained in a
stereochemically homogeneous form and fully characterized.
The C5-stereochemistry was assigned as follows: Ignoring
the difference in structure at the termini, we noticed that one of
(12) (a) Christ, W. J.; Cha, J. K.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3947-
50. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247-
55.
(13) Tribenzyl D-xylopyranose, tribenzyl D-arabinopyranose, tribenzyl D-ribopy-
ranose, and tribenzyl D-lyxopyranose were prepared by the method
reported: (a) tribenzyl D-xylopyranose: Tsuda, Y.; Nunozawa, T.; Yoshim-
oto, K. Chem. Pharm. Bull. 1980, 28, 3223-3231. (b) tribenzyl D-
arabinopyranose: Mizutani, K.; Ohtani, K.; Kasai, R.; Tanaka, O.; Matsuura,
H. Chem. Pharm. Bull. 1985, 33, 2266-2272. (c) tribenzyl D-ribopyra-
nose: Tejima, S.; Ness, R. K.; Kaufman, R. L.; Fletcher, H. G. Jr.
Carbohydr. Res. 1968, 7, 485-490. (d) tribenzyl D-lyxopyranose: Dhawan,
S. N.; Chick, T. L.; Goux, W. J. Carbohydr. Res. 1988, 172, 297-307;
Gigg, R,; Warren, C. D. J. Chem. Soc. 1965, 2205-2210.
(10) The optically active propargyl alcohol A was prepared, following the
protocol reported by T. Oriyama: Sano, T.; Imai, K.; Ohashi, K.; Oriyama,
T. Chem. Lett. 1999, 3, 265-266.
(11) The synthesis outlined in Scheme 1 was carried out with the antipode of
A.
9
14380 J. AM. CHEM. SOC. VOL. 125, NO. 47, 2003

Universal NMR Databases for Contiguous Polyols
A R T I C L E S
Scheme 2
Scheme 3
Reagents and Reaction Conditions (a) O3, AcONa, MeOH/CH2Cl2, -78
°C, then DMS, rt. (b) CH3(CH2)2MgBr, THF or Et2O, 0 °C. (c) H2, Pd(OH)2,
EtOH/EtOAc. (d) NaH, BnBr, (n-Bu)4N+I-, DMF, rt. (e) See Scheme 2.
Reagents and Reaction Conditions (a) KHMDS, (Ph)3P+CH2CH3I-, THF,
0 °C to room temperature. (b) (COCl)2, DMSO, CH2Cl2, -78 °C, then
NEt3, -78 °C to room temperature. (c) BnO(CH2)4MgBr, THF or Et2O, 0
°C. (d) NaH, BnBr, (n-Bu)4N+I-, DMF, rt. (e) H2, Pd(OH)2, EtOH/EtOAc.
of the C9-diastereomers formed in the other series and conse-
quently they should exhibit (almost) identical NMR properties.
Using this logic, we could assign the stereochemistry to all the
1,2,3,4,5-pentaols 3a∼p.
the two diastereomers formed in each series contains a symmetry
element, which was clearly detected in its NMR spectra. For
1
example, one of the tetraols derived from xylose gave the H
NMR Databases.
[3.70 ppm (H5, H8), 3.49 (H6, H7)] and 13C [73.0 ppm (C5),
75.3 (C6, C7), 72.7 (C8)] NMR spectra in CD3OD, whereas
a. Carbon Chemical Shift Database. The 13C chemical shifts
were measured in three solvents [CD3OD, (CD3)2SO, D2O] for
each diastereomer of 1a∼d, 2a∼h, and 3a∼p. Following the
previous procedure,7 their 13C chemical shift databases were
then created. For all three polyol series, the 13C chemical shift
databases in CD3OD and (CD3)2SO were found to be very
similar to each other. However, the overall 13C chemical shift
profiles in D2O were found to be similar to those in CD3OD
and (CD3)2SO, but some differences in the magnitude of ∆δ’s
as well as the pattern of profiles were noticed. For illustration,
we show the 13C chemical shift profiles of 1a∼d in CD3OD,
(CD3)2SO, and D2O (Chart 1) and the 13C chemical shift profiles
of 2a∼h and 3a∼p in CD3OD only (Chart 2). Among the three
solvents tested, we slightly prefer CD3OD to (CD3)2SO or D2O,
considering the magnitude of ∆δ’s and the vicinal 1H/1H spin-
coupling (3JH,H) profiles (vide infra). The complete 13C chemical
shift profiles are given in Supporting Information.
1
the other gave the H [3.62 ppm (H5), 3.37 (H6), 3.65 (H7),
3.66 (H8)] and 13C [72.5 (C5), 76.2 (C6), 73.3 (C7), 74.3 (C8)]
NMR spectra. This spectroscopic observation allowed us to
assign 2a and 2f to the former and latter diastereomers,
respectively. Similarly, the stereochemistry was assigned for
the tetraols derived from arabinose, ribose, and lyxose.
The 1,2,3,4,5-pentaols 3a∼p were synthesized in an optically
active form from the synthetic intermediates used in the 1,2,3,4-
tetraol syntheses (Scheme 3). In this synthesis, the right-side
chain was introduced via a Grignard reaction, to yield the
expected product as a diastereomeric mixture at C9. Silica gel
chromatography (Biotage) was effective to obtain all the
1,2,3,4,5-pentaols 3a∼p in a stereochemically homogeneous
form and fully characterized.
Using the same logic as the one used in the 1,2,3,4-tetraol
series, we assigned the C9-stereochemistry for the diastereomers
formed in the Grignard reaction for each series. In the D-1, D-2,
D-5, and D-6 series, one of the two C9-diastereomers contains
a (pseudo)symmetry element which was clearly detected by
NMR spectroscopy. In the remaining four series, neither of the
C9-diastereomers have a (pseudo)symmetry element. Ignoring
the difference in structure at the termini, we noticed that one of
the C9-diastereomers formed in these series is identical to one
b. Proton Chemical Shift Database. The 1H chemical shifts
were measured in three solvents [CD3OD, (CD3)2SO, D2O] for
each diastereomer of 1a∼d, 2a∼h, and 3a∼p. Following the
procedure used for the 13C chemical shifts, the 1H chemical shift
profiles were created. The overall trends found in 1H chemical
shift profiles are amazingly parallel to those found in the 13C
1
chemical shift profiles, including the following: (1) the H
chemical shift profiles in CD3OD and (CD3)2SO are very similar
9
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A R T I C L E S
Higashibayashi et al.
Chart 1. Difference in 13C Chemical Shifts (100 MHz) between
the Average and the Values of 1a∼d in CD3OD (Panel A),
((CD3)2SO (Panel B), and D2O (Panel C)a
Chart 3. Difference in 1H Chemical Shifts (500 MHz) between the
Average and the Values of 1a∼d in CD3OD (Panel A), (CD3)2SO
(Panel B), and D2O (Panel C)a
a The x and y axes represent carbon number and ∆δ ) δ1a∼d - δave in
ppm, respectively.
a The x and y axes represent proton number and ∆δ ) δ1a∼d - δave in
ppm, respectively.
Chart 2. Difference in 13C Chemical Shifts (100 MHz) between
the Average and the Values of Triols 1a∼d (Panel A), Tetraols
2a∼h (Panel B), and Pentaols 3a∼p (Panel C) in CD3ODa
c. Hydroxy-Proton Chemical Shift Database. During data-
collection for the H chemical shift databases, we noticed the
1
following: (1) all the hydroxy-protons give a sharp resonance
in (CD3)2SO; (2) a chemical shift observed for each hydroxy-
proton differs from others; (3) the chemical shift for a given
hydroxy-proton is not concentration-dependent at [C] ) 1.6 ×
102, 1.6 × 10, and 1.6 mM. Following the same procedure as
before, the hydroxy-proton chemical shift profiles, referred to
1
as a H(OH) chemical shift NMR database, were created for
1,2,3-triols 1a∼d, 1,2,3,4-tetraols 2a∼h, and 1,2,3,4,5-pentaols
3a∼p (Chart 5). Although their potentials are not fully exploited
1
yet, we believe that the H(OH) chemical shift NMR database
should become an additional means, possibly complementary
1
to the 13C and H chemical shift NMR databases, for stereo-
chemical analysis of unknown compounds.
1
d. Vicinal H/1H Spin-Coupling Database. Thus far, we
have focused on the NMR databases whose profiles are
described by 13C and 1H chemical shifts. Obviously, some other
parameters could be used for profiling NMR characteristics, and
we have been curious to explore the potential that the vicinal
1H/1H spin-coupling (3JH,H) constants offer for the universal
database approach. In this context, the contiguous polyol NMR
database compounds such as 1a∼d, 2a∼h, and 3a∼p should
provide us with an ideal testing ground.
The apparent 3JH,H constants were extracted from 1D 1H NMR
spectra and presented in the form of a bar graph. It should be
noted that an experimentally observed 3JH,H constant is directly
3
used in the JH,H profiles, whereas a deviation of an experi-
mentally observed chemical shift from the averaged chemical
shift for a given nucleus is used for 13C and H chemical shift
1
a The x and y axes represent carbon number and ∆δ ) δeach sub - δave
profiles. Three solvents CD3OD, (CD3)2SO, and D2O were tested
in ppm, respectively.
for all the substrates; well-defined 3JH,H constants were observed
3
in CD3OD and D2O, but accurate JH,H constants in (CD3)2SO
1
each other and (2) the H chemical shift profiles in D2O are
were difficult to determine due to serious signal-broadenings.
Later, pyridine-d5 was also found to be an excellent solvent for
this purpose.
Interestingly, both overall profiles and 3JH,H constants in CD3-
OD, pyridine-d5, and D2O were found to be almost identical.
For illustration, Charts 6 and 7 show the 3JH,H profiles of 1a∼d
in CD3OD, D2O, and pyridine-d5, and the 3JH,H profiles of 2a∼h
similar to those in CD3OD and (CD3)2SO, but some differences
in the magnitude of ∆δ’s as well as the pattern of profiles are
1
noticeable. Charts 3 and 4 show the H chemical shift profiles
1
of 1a∼d in CD3OD, (CD3)2SO, and D2O and the H chemical
shift profiles of 2a∼h and 3a∼p in CD3OD only. The complete
1H chemical shift profiles are given in Supporting Information.
9
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Universal NMR Databases for Contiguous Polyols
A R T I C L E S
Chart 5. Difference in Hydroxy-1H Chemical Shifts (500 MHz)
Chart 4. Difference in 1H Chemical Shifts (500 MHz) between the
Average and the Values of Triols 1a∼d (Panel A), Tetraols 2a∼h
(Panel B), and Pentaols 3a∼p (Panel C) in CD3ODa
between the Average and the Values of Triols 1a∼d (Panel A),
Tetraols 2a∼h (Panel B), and Pentaols 3a∼p (Panel C) in
((CD3)2SOa
a The x and y axes represent proton number and ∆δ ) δeach sub - δave in
ppm, respectively.
a The x and y axes represent proton number and ∆δ ) δeach sub - δave in
ppm, respectively.
and 3a∼p in CD3OD, respectively. The complete 3JH,H profiles
are included in Supporting Information.
Analysis of NMR Databases. To develop the NMR database
approach for the stereochemical assignment of unknown com-
pounds, we have used the 13C chemical shift profile as the
primary vehicle to demonstrate its feasibility, reliability, and
applicability.7 In the present work, we have created the 13C,
1H, and H(OH) chemical shift databases, as well as the JH,H
databases, for contiguous polyols, which allows us to systemati-
cally compare for the first time the values of each of the NMR
databases using different descriptors.
question are as follows: (1) inherent to the specific stereo-
chemical arrangements of (small) substituents on its carbon
backbone and (2) independent from the rest of the molecule.5,7
Thus, we expect that the substrates bearing the same structural
motif should exhibit an (almost) identical profile. This trend is
indeed recognized in three ways. First, ignoring the difference
in structure at the termini, one notices that 1a,b in the triol series,
2a∼d in the tetraol series, and 3a∼d in the pentaol series contain
a symmetry element and therefore expects that they should
exhibit an NMR profile with a symmetrical nature. Indeed, a
beautifully symmetrical pattern is recognized in all the 13C, 1H,
1
3
As seen from Charts 1∼7, each diastereomer of 1a∼d, 2a∼h,
and 3a∼p exhibits a distinct and differing profile in all the 13C,
3
3
1H, 1H(OH), and JH,H NMR databases for the 1,2,3-triol-,
1H(OH), and JH,H NMR profiles. Second, ignoring the differ-
1,2,3,4-tetraol-, and 1,2,3,4,5-pentaol-systems. Therefore, any
one of these NMR databases can be used for stereochemical
analysis of unknown compounds bearing these structural motifs.
The NMR database approach has been founded on the
hypothesis, and experimental observations supporting this
hypothesis, that the structural properties of a compound in
ence in structure at the termini, one notices that the pair of 1c/
1d in the triol series, the pairs of 2e/2f and 2g/2h in the tetraol
series, and the pairs of 3e/3f, 3g/3h, 3i/3j, 3k/3l, 3m/3n, and
3o/3p in the pentaol series contain the stereoclusters with a same
relative stereochemistry in an opposite direction and therefore
expects that these pairs should have the mirror images of
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A R T I C L E S
Higashibayashi et al.
Chart 6. Vicincal 1H/1H Spin-Coupling Constants of 1a∼d in
Chart 7. Vicincal 1H/1H Spin-Coupling Constants of Triols 1a∼d
(Panel A), Tetraols 2a∼h (Panel B), and Pentaols 3a∼p (Panel C)
in CD3ODa
CD3OD (Panel A), C5D5N (Panel B), and D2O (Panel C)a
3
a The x and y axes represent proton number and the JH,H constant in
Hz, respectively.
(almost) identical NMR profiles. Indeed, it is the case for all
the 13C, 1H, 1H(OH), and 3JH,H NMR profiles observed for these
pairs. Third, one notices that the stereoclusters in the higher
polyol series contain the stereoclusters in the lower series and
therefore expects that the NMR profile found in the lower polyol
series should be inherited in the stereoclusters in the higher
polyol series. Due to the additional functional group(s) present
within a stereocluster in the higher polyol series, the NMR
profile of the lower polyol series may be distortedly inherited
to the higher polyol series.7 Nevertheless, this trend is recogniz-
able; for example, the C5∼C8 stereocluster of 3h and 3p, as
well as the C9∼C6 stereocluster of 3g and 3o, corresponds to
the C5∼C8 stereocluster of 2h and the characteristics in the
NMR profiles of 2h are indeed noticeable in the relevant
portions of the NMR profile of 3h and 3p, as well as 3g and
3o.
3
a The x and y axes represent proton number and the JH,H constant in
Hz, respectively. The 3JH,H’s indicated by an asterisk were not determined.
These characteristics recognized in the 13C, 1H, 1H(OH), and
3JH,H NMR profiles argue for the usefulness of these NMR
databases for predicting the stereochemistry of unknown
compounds bearing a relevant structural motif. As will be
3
discussed in the following section, among them, the JH,H
database provides us with the operationally simplest device for
analysis of the stereochemistry of unknown contiguous polyols.
Application of NMR Databases for Stereochemical As-
signment of Unknown Contiguous Polyols.
a. Carbon Chemical Shift NMR Database. The 13C
chemical shift NMR databases created for the 1,2,3-triol, 1,2,3,4-
tetraol, and 1,2,3,4,5-pentaol systems can be used for the
stereochemical assignments of unknown compounds bearing
these structural motifs. For their applications, several guidelines
are in order.
Figure 2. Self-contained boxes are highlighted by a broken line. The
As stated in the previous work, steric and/or stereoelectronic
interactions between the structural motifs connected either
directly or with a one-bridging carbon are significant, whereas
interactions between the structural motifs connected with two-
or more-bridging carbons are negligible at least to the first order
of approximation.7-9 Thus, for the partial structure E (Figure
carbons indicated by a dot are usable for analysis.
2), the chemical shift of the carbon marked by a dot is expected
to be independent of the stereochemistry of the substituents C,
D, c, and d, but dependent on the stereochemistry of the
substituents A, B, a, and b.
9
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Universal NMR Databases for Contiguous Polyols
A R T I C L E S
Chart 8. 13C Chemical Shift Profile Observed for 4a∼d in CD3OD
(100 MHz)a
Figure 3. Stereochemistry of heptaols 4a∼d.
Taking this characteristic into account, referred to as “self-
contained nature”,7 we need to exclude certain nuclei from
comparison of the NMR databases with the structural motifs
present in unknown compounds. This situation is schematically
exemplified with a pentaol system (Figure 2). Depending on
the substitution pattern, the carbons marked with a dot are
expected to be independent of the stereochemistry of the
substituents present in the outside of a self-contained box and
therefore can be used for comparison with NMR databases, cf.,
E-1, E-2, E-3, and E-4. In an extreme case such as E-4,
only one carbon is available for an NMR comparison, and a
conclusive stereochemical assignment might not always seem
possible. However, it has been demonstrated that even for such
a case, a combined use of multiple descriptors such as 13C and
1H chemical shifts is effective in deducing the stereochemistry
of unknown compounds.5,7,8
a The x and y axes represent carbon number and 13C chemical shift in
ppm, respectively.
We have recognized one important consequence derived from
the self-contained nature of NMR databases. Because of this
nature, small universal databases can be applied separately to
relevant structural moieties contained in a larger stereocluster
for its stereochemical analysis, and therefore, it is not required
to create an NMR database to cover the entire structure of the
larger stereocluster. Indeed, with only three, small NMR
databases, we were able to predict correctly the relative
configuration of the C21∼C38 portion of oasomycin A.7
Adopting the same approach, we should be able to apply the
contiguous polyol 13C chemical shift NMR databases for
stereochemical analyses of unknown higher order polyols. The
NMR databases using other descriptors such as 1H and 1H(OH)
chemical shifts can similarly be used.
Figure 4. Protocol for predicting the 13C chemical shift profile for 4a∼d.
Structural correlation of 4a∼d with 1a∼d (first correlation), 2a∼h (second
correlation), and 3a∼p (third correlation) allows prediction of the C3/C4/
C5, C4/C5/C6, and C5/C6/C7 chemical shifts of 4a∼d, repectively.
compared with their observed 13C chemical shifts (Panel B,
Chart 9).14,15 As seen from the comparison shown in Panel B,
the 13C chemical shift profiles predicted for 4c and 4d were
found to agree well with their observed 13C profiles.16 However,
the 13C chemical shifts predicted for 4a and 4b were noticeably
different from the observed profiles, thereby suggesting that the
chemical shift of the self-contained carbon, cf., the carbon
marked by a dot in E (Figure 2), is affected even by a functional
group(s) present in the outside of a self-contained box. Clearly,
it is desirable to formulate an increment(s) to count in these
To assess fully the potentials of NMR databases using
different descriptors, we chose four heptaols 4a∼d for a case
study (Figure 3). The four heptaols 4a∼d were synthesized from
the synthetic intermediates used for the pentaol NMR databases.
The stereochemistry of 4a∼d was established in a similar
manner as before, and its details are given in the Supporting
Information.
The observed 13C chemical shifts of 4a∼d are shown in Chart
8. Each diastereomer exhibits a differing pattern from the others,
thereby suggesting that the 13C chemical shift profile can be
utilized as a fingerprint to deduce their stereochemistry.
(14) The C3∼C5 and C11∼C13 stereoclusters present in 4a∼d can be
represented by the C3∼C5 and C7∼C9 moieties in the triol series, the
C3∼C5 and C8∼10 in the tetraol series, or the C3∼C5 and C9∼C11
moieties in the pentaol series. In this prediction, the profiles observed for
1a∼d were used to estimate the C3∼5 and C11∼13 chemical shifts of
4a∼d. Similarly, the profiles of 2a∼h were used to estimate the C6 and
C10 chemical shifts of 4a∼d. The profiles observed for 3a∼p were used
to estimate the remaining 13C chemical shifts of 4a∼d. For the detailed
procedure, see the Supporting Information.
With the procedure outlined in Figure 2, we predicted the
13C chemical shifts for the C3∼C13 carbons of 4a∼d. With
focus on the self-contained box indicated in the first correlation,
the C3/C4/C5 chemical shifts of 4a∼d were predicted, based
on the 1a∼d database (Figure 4). Similarly, on comparison with
the 2a∼h and 3a∼p databases, the C4/C5/C6 and C5/C6/C7
chemical shifts of 4a∼d were predicted, respectively, cf., the
second and third correlations in Figure 4. Continuing this
operation for the remaining carbons, we predicted the 13C
chemical shifts for 4a∼d (Panel A, Chart 9), which were then
(15) Charts 9∼13 show the profiles covering the C5∼C11 portions only. The
complete profiles are included in Supporting Information.
(16) In the NMR database approach, a match/mismatch judgment is made, on
the basis of an overall fitness of the predicted profile, rather than a single
data point, over the obserVed profile. Nevertheless, from a large number
of examples studied in this laboratory, we consider the 0.5 and 0.03 ppm
differences in 13C and 1H chemical shifts, respectively, to be significant
even for a comparison of a single data point.
9
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A R T I C L E S
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Chart 9. Panel A: 13C Chemical Shift Profiles Predicted for 4a∼d
and Panel B: Difference between the Observed and Predicted 13C
Chemical Shift Profiles (100 MHz, CD3OD)a
Figure 5. Estimation of the effect on 13C chemical shift from the hydroxyl
group(s) present in the outside of the self-contained box indicated by a
broken line. Panel A: A comparison of the C3/C4/C5 chemical shifts of
1a∼d with those of 2a∼h and 3a∼p allows estimation of the degree of
effect from the C8 hydroxyl group over the C3/C4/C5 13C chemical shifts.
Panel B: A comparison of the C7/C8/C9 chemical shifts of 1a∼d with the
C8/C9/C10 of 2a∼h and the C9/C10/C11 of the 3a∼p allows estimation
of the degree of effect from the C5 (2a∼h) or C6 (3a∼p) over the C7/C8/
C9 13C chemical shifts.
a The x axis represents carbon number and the y axis represents 13C
chemical shift (Panel A) and ∆δ ) δpredicted - δobserved (Panel B) in ppm.
effects on the NMR databases. Thus, we have conducted the
following comparisons.
Assuming no effect from a functional group present in the
outside of the self-contained box indicated, we would expect
an identical or at least a close chemical shift for the C3, C4,
and C5 carbons of 1a in the triol series, 2a,e in the tetraol series,
and possibly 3a,e,g,i in the pentaol-series,17 because the 1,2,3-
triol system present in these substrates bears the same stereo-
chemistry. The same stereochemical environment is shared by
the substrates belonging to the sub-groups of 1b/2h,b/3h,p,b,n,
1c/2g,d/3d,m,k,j, and 1d/2c,f/3l,o,c,f, respectively. Thus, through
the comparison of the C3, C4, and C5 chemical shifts observed
for 1a∼d with those observed for the corresponding sub-group
members of 2a∼h and 3a∼p, it is possible to estimate the effects
on the chemical shift from the functional group(s) present in
the outside of self-contained boxes (Panel A, Figure 5 and Table
1).
This exercise sheds light on several characteristics of a self-
contained box. First, the C3 chemical shift observed for all the
substrates is clustered within the 0.1-ppm range, suggesting that
the stereochemical information is not transmitted from the C8
hydroxyl group to the C3 carbon in a significant degree, and
therefore, it is not necessary to take this effect into account for
refinement of the predicted profiles. Second, the C5 chemical
shifts observed spread over the range of +1.2 ∼ -1.0 ppm,
demonstrating that the self-contained carbons are affected even
by the hydroxyl group(s) present in the outside of a self-
contained box. Interestingly, the chemical shifts observed for
the substrates belonging to the 1b/2h,b/3h,p,b,n, 1c/2g,d/
3d,m,k,j, and 1d/2c,f/3l,o,c,f, sub-groups are clustered within
the 0.5-ppm range,16 whereas only those for the substrates
belonging to the 1a/2a,e/3a,e,g,i sub-group spread over a wide
range. In other words, the magnitudes of this effect depend on
a specific stereochemical arrangement of the hydroxyl groups
present in not only the outside but also the inside of a self-
contained box. Therefore, on application of the concept of self-
contained box to stereochemical analysis, a small increment due
to this effect, referred to as a γ-effect,18 needs to be added to
refine the profile predicted for some stereoisomers at the first-
order approximation. Third, the C4 chemical shifts spread over
the range of +0.3 ∼ -0.7 ppm. Once again, the degree of
deviation depends on a specific stereochemical arrangement of
(18) The γ- and δ-effects are referred to the effects by a substituent on the
carbon connected to the nuclei in question with two- and three-bridging
carbons, respectively. The ∆δ’s at C4 and C5 obtained from the triol/tetraol-
comparison represent the γ- and δ-effects from the C8-OH, respectively
(Table 1). On the other hand, the ∆δ’s at C4 and C5 obtained from the
triol/pentaol-comparison include the δ- and γ-effects from the C8-OH as
well as the ꢀ- and δ-effects from the C9-OH. Likewise, the ∆δ’s at H5
include the δ-effect from the C8-OH in the triol/tetraol-comparison and
the δ- and ꢀ-effects from the C8- and C9-OH’s in the triol/pentaol-
comparison (Table 2).
(17) Strictly speaking, the effect from the C9-OH is included in the triol/pentaol-
comparison. To estimate the γ- and δ-effects further, we have also
conducted the comparison of the C4/C5/C6-chemical shifts observed in
the tetraol series over the pentaol and found the overall trend of this
comparison to be similar to the one discussed in the text.
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Universal NMR Databases for Contiguous Polyols
A R T I C L E S
Table 1. Comparison between 13C Chemical Shifts at C3, C4, and
C5 of Triols 1a∼d and Those of Tetraols 2a∼h and Pentaols
3a∼pa
Figure 6. Procedure used for refining the 13C chemical shift profile
predicted for 4a by addition of the estimated γ- and δ-effects of the hydroxyl
groups present in the outside of the self-contained box.
found to exhibit almost identical behavior in the two series of
comparison. These observations support the previous statement,
i.e., the magnitudes of γ- and δ-effects depend on a specific
stereochemical arrangement of the hydroxyl groups present in
both the inside and outside of self-contained boxes.
a δ and ∆δ ) δ(tetraol or pentaol) - δ(triol) are in ppm. A box highlights
the same relative stereochemistry shared with all the members in each sub-
group.
Back to the predicted and experimental 13C chemical shifts
of 4a∼d, it is interesting to note that the identified, specific
stereochemical arrangement is incorporated in the stereochemical
array of 4a and 4b, but is not in the stereochemical array of 4c
and 4d. With use of the γ- and δ-effects listed in Table 1, the
predicted 13C profiles were refined for 4a∼d in the stepwise
manner as exemplified for 4a in Figure 6. The γ- and δ-effects
of the C8-OH group on the C5 and C4 carbons of 4a were
approximated with those found in the comparison of 1a with
2a. Similarly, the γ- and δ-effects of the C9-OH group on the
C6 and C5 carbons were approximated with those found in the
comparison of 2a with 3e, and so on. The refined, predicted
13C profiles thus obtained, including those of 4a and 4b, match
well with their observed 13C chemical profiles (Chart 10).
Overall, an analysis only with a self-contained box predicts
an NMR profile satisfactorily similar to the observed profile
for some stereoisomers, but significantly different from the
observed profile for others. The discrepancy between the
predicted and observed profile is primarily due to γ- and
δ-effects. Importantly, the magnitudes of γ- and δ-effects
depend on a stereochemical arrangement of the functional groups
present in both the inside and outside of a self-contained box.
the hydroxyl groups present in both the outside and inside of a
self-contained box. As expected, the magnitude of this effect,
referred to as a δ-effect,18 is less significant than that of the
γ-effect. Nevertheless, to refine the profile predicted at the first
order of approximation, we suggest including an increment due
to δ-effects as well.
With focus on the C7, C8, and C9 carbons, a similar
comparison of the triol series over the tetraol series, as well as
the pentaol series, was made (Panel B, Figure 5).19 An overall
trend found in the C7/C8/C9-comparison was found to be
virtually identical to the trend found in the C3/C4/C5-carbon
comparison. Once again, the C7 chemical shifts of 1a∼d,
corresponding to the C5 chemical shifts in the first comparison,
in three out of four sub-groups were found to be clustered within
the range of 0.4 ppm, whereas those in the forth sub-group were
found to spread over the range of +1.2 ∼ -1.0 ppm. The
behaviors of the C8 and C9 chemical shifts were well compared
with those to the C4 and C3 chemical shifts in the previous
comparison, respectively. Interestingly, the substrates sharing
the same stereochemical arrangement of hydroxyl groups were
(19) For the details, see the Supporting Information.
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A R T I C L E S
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Chart 10. Panel A: Refined, Predicted 13C Chemical Shift Profiles
of 4a∼d and Panel B: Difference between the Observed and
Refined, Predicted 13C Chemical Shift Profiles (100 MHz, CD3OD)a
Chart 11. 1H Chemical Shift Profiles Observed for 4a∼d in CD3OD
(500 MHz)a
1
a The x and y axes represent proton numbers and H chemical shift in
ppm.
Chart 12. Panel A: 1H Chemical Shift Profiles Predicted for 4a∼d
and Panel B: Difference between the Observed and Predicted 1H
Chemical Shift Profiles (500 MHz, CD3OD)a
a The x axis represents carbon number and the y axis represents 13C
chemical shift (Panel A) and ∆δ ) δpredicted - δobserved (Panel B) in ppm.
Except the stereochemical arrangement of functional groups
belonging to a specific sub-group, the γ- and δ-effects can, at
least at the first order of approximation, be ignored for the
stereochemical analysis of unknown compounds. However, for
the stereoisomers belonging to the specific sub-group, it is
necessary to refine the profile predicted at the first order of
approximation, with incorporation of the γ- and δ-effects. With
these procedures, it is possible to properly predict an NMR
profile for unknown polyols. However, as discussed later, an
analytical procedure using a 3JH,H profile is operationally simpler
a The x axis represents proton number and the y axis represents 1H
chemical shift (Panel A) and ∆δ ) δpredicted - δobserved (Panel B) in ppm.
3
than this procedure. Therefore, we suggest a JH,H profile as
the primary device for predicting the stereochemistry of
unknown polyols and a 13C chemical shift profile as the
secondary device to confirm the predicted stereochemistry.
It is worth adding that the γ- and δ-effects are also noticed
on some stereoclusters related to the polyketide class of natural
products. Once again, the magnitudes of γ- and δ-effects have
been found to depend on a specific stereochemical arrangement
of the functional groups present in both the inside and outside
of a self-contained box. A significant magnitude of these effects
has been observed only for the stereoisomers belonging to a
specific sub-group and, interestingly, this specific sub-group
shares the same stereochemical array with the sub-group in the
contiguous polyol series.20
pentaol systems can be used for stereochemical analysis of
unknown compounds bearing these structural motifs. It is worth
noting that the 13C and 1H chemical shift databases often provide
complementary information each other5,7,8 and therefore, when-
ever possible, we suggest a combined use of both databases for
stereochemical analysis of unknown compounds.
To illustrate this point, 4a∼d are again used for a case study.
1
The observed H chemical shifts of 4a∼d are shown in Chart
11. Each diastereomer exhibits a differing profile from the
others, thereby indicating that the 1H chemical shift profile can
be used as a tool to deduce its stereochemistry.
1
With the procedure depicted in Figure 4, the H chemical
shift profile was predicted for 4a∼d without consideration of
the effects from the outside of a self-contained box (Panel A,
Chart 12), and the differences between the predicted and
observed profiles are shown (Panel B, Chart 12). For all of
4a∼d, significant differences are noticed between the predicted
and observed profiles, thereby raising a question on the
b. Proton Chemical Shift NMR Database. Similarly as the
13C chemical shift databases, the 1H chemical shift NMR
databases created for the 1,2,3-triol, 1,2,3,4-tetraol, and 1,2,3,4,5-
(20) Zeng, H.; Kishi, Y. unpublished work.
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Universal NMR Databases for Contiguous Polyols
A R T I C L E S
Table 2. Comparison between 1H Chemical Shifts at H5 of Triols
1a∼d and Those of Tetraols 2a∼h and Pentaols 3a∼pa
Chart 13. Panel A: Refined, Predicted 1H Chemical Shift Profiles
of 4a∼d and Panel B: Difference between the Observed and
Refined, Predicted 1H Chemical Shift Profilesa
a The x axis represents proton number and the y axis represents 1H
chemical shift (Panel A) and ∆δ ) δpredicted - δobserved (Panel B) in ppm.
chemical shift profiles satisfactorily for stereochemical analysis
of unknown polyols. However, an analysis with the δ-effects
1
included yields a good match between the H chemical shift
profiles and the observed profiles, thereby demonstrating the
value of 1H chemical shift profiles for stereochemical analysis
of unknown polyols. However, as mentioned before, an analyti-
cal procedure using a 3JH,H profile is operationally simpler than
3
this procedure. Therefore, we suggest a JH,H profile as the
a δ and ∆δ ) δ(tetraol or pentaol) - δ(triol) are in ppm. A box highlights
the same relative stereochemistry shared with all the members in each sub-
group.
primary device for predicting the stereochemistry of unknown
higher polyols and a 1H chemical shift profile as the secondary
device to confirm the predicted stereochemistry.
1
c. Vicinal H/1H Spin-Coupling NMR Database. With a
1
predictability of H chemical shift profiles. It is interesting to
1,2-disubstituted system, it is known as a general trend that a
note that all these discrepancies are observed in a negative
3
1
syn-diol gives a smaller JH,H constant than the corresponding
direction, i.e., all the predicted H chemical shifts are in more
anti-diol. The 3JH,H’s observed for pentaols 3a∼p are organized
upfields than the observed values.
3
3
under two sub-groups, (1) J6,7 and J7,8 constants, referred to
We were curious in estimating the effects from the hydroxyl
groups present in the outside of a self-contained box. It should
be noted that, because of one extra nucleus present between
the two functional groups concerned, the self-contained box
already includes the γ-effect in the 1H chemical shift profiles.18
With application of the procedure outlined in Figure 6, the H5
chemical shifts of 1a∼d were compared with those of 2a∼h
and 3a∼p, yielding an approximate δ-effect (Table 2).17 As seen
in the 13C chemical shifts, the magnitudes of δ-effects depend
on a specific stereochemical arrangement of the hydroxyl groups
present in both the outside and inside of a self-contained box.
Interestingly, parallel with the 13C series, the members in the
1b sub-group exhibit the most significant deviation.
With use of the estimated δ-effects listed in Table 2, the 1H
chemical shift profiles predicted for 4a∼d were refined, thereby
yielding the profiles matching well with the observed profiles
(Chart 13).
3
3
as the internal JH,H’s (Panel A, Chart 14), and (2) J5,6 and
3J8,9 constants, referred to as the terminal 3JH,H’s (Panel A, Chart
15). As seen from these Charts, the general trend, i.e., a syn-
diol gives a smaller 3JH,H constant than the corresponding anti-
3
diol, is recognized for both the internal and terminal JH,H
3
constants. However, the JH,H constants observed for these
3
substrates spread in a wide range and, critically, the JH,H
constants observed for some of syn-diols in both of internal and
terminal series are very close to those for anti-diols. Because
of this fact, it is not a straightforward task to translate a single
3JH,H constant to a syn- or anti-stereochemistry present in an
3
unknown compound.21 Remarkably, 17 out of the 24 JH,H
(21) To overcome this difficulty, Murata and co-workers have suggested a
combined use of 3JH,H, 3JH,C, and 2JH,C constants and NOE and this approach
has been applied to predict the stereochemistry of several unknown natural
products: Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866-876. For reviews of this
approach, see: Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293-
314; Riccio, R.; Bifulco, G.; Cimino, P.; Bassarello, C.; Gomez-Paloma,
L. Pure. Appl. Chem. 2003, 75, 295-308.
Overall, an analysis at the first order of approximation, i.e.,
1
with focus only on a self-contained box, does not give the H
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A R T I C L E S
Higashibayashi et al.
3
3
Chart 14. Panel A: Internal JH,H’s of Pentaols 3a∼p; Panel B:
Table 3. JH,H’s Observed on Heptaols 4a∼d in Hz (500 MHz,
3
CD3OD)
Sub-grouped, Internal JH,H’sa
5/6
6/7
7/8
8/9
9/10
10/11
4a
4b
4c
4d
3.5
3.5
6.5
6.0
5.0
4.0
6.0
6.0
2.0
5.0
6.0
6.0
7.0
1.5
6.0
0.0
6.0
7.5
6.0
7.0
6.0
6.0
6.5
6.0
One of the key logics used for developing the NMR database
approach was to analyze a profile, rather than a single data-
point, to deduce the stereochemistry of an unknown compound.
The following simple exercise immediately indicates that this
logic is powerful also for analyzing the characteristics of 3JH,H
constants. Depending on the relative stereochemistry of the
adjacent glycols, the internal syn, abbreviated as S, and anti,
abbreviated as A, diols are divided into the SXS, AXS, SXA,
3
and AXA sub-groups, respectively, and their JH,H constants
3
were analyzed. As seen from Panel B in Chart 14, the JH,H
a The y axis indicates the stereochemistry of the adjacent glycols,
representing A ) anti, S ) syn, and X ) stereochemistry at 6/7 or 7/8.
constants observed for SSS, ASS, SSA, ASA, SAS, AAS, SAA,
and AAA sub-groups now cluster in a much narrower range.
Similarly, we tested the terminal syn- and anti-diols. For the
first attempt, we used only the adjacent internal glycol to divide
the terminal syn- and anti-diols into the XS and XA sub-groups.
3
The x axis gives the JH,H’s observed for the 6,7- and 7,8-glycol systems,
with b and O representing the syn- and anti-6,7-glycols, respectively,
whereas with 9 and 0 representing the syn- and anti-7,8-glycols.
3
Chart 15. Panel A: Terminal JH,H’s of Pentaols 3a∼p; Panel B:
3
3
As seen from Panel B in Chart 15, the JH,H constants in the
Sub-grouped, Terminal JH,H’s, Including the Stereochemistry of
3
SA, AA, and AS sub-groups cluster in a narrower range, but
those in the SS sub-group still spread in a wide range.
Interestingly, including the relative stereochemistry of the glycol
system one further away, i.e., dividing them into the XSA, XSS,
the Adjacent Glycol Only; Panel C: Sub-grouped, Terminal JH,H’s,
Including the Stereochemistry of the Adjacent and Next Glycolsa
3
XAA, and XAS sub-groups, the JH,H constants in all the sub-
groups now cluster in a much narrower range (Panel C, Chart
15). This result is not surprising; namely, with an additional
parameter included, a higher resolution should be obtained on
the NMR profiles.22
The sub-grouping exercise convincingly indicates the poten-
tials that the 3JH,H-based NMR profiles offer for stereochemical
3
analysis of unknown compounds. We first examined the JH,H
profiles composed of the two adjacent spin-coupling constants.
These profiles are described by placing the first and second
3JH,H’s on the X- and Y-axes, respectively. Panels A and B in
Chart 16 show the profiles thus obtained for the internal and
terminal 3JH,H pairs present in 3a∼p. Depending on their relative
3
stereochemistry, the internal JH,H pairs are distributed in four
areas, cf., S/A, S/S, A/A, and A/S. For the case of terminal
3JH,H pairs, the S/A, A/A, and A/S pairs are distributed in
relatively narrow areas, whereas the S/S pairs are spread over
a wider area. However, including the glycol system of one
further away for analysis, i.e., dividing the S/S-group into the
3
S/S/S- and S/S/A-sub-groups, the JH,H pairs now cluster in
narrow areas.
The 3JH,H profiles thus obtained for the internal and terminal
3
pairs of JH,H constants are useful for analyzing the relative
a The x axis gives the 3JH,H’s observed for the 5,6- and 8,9-glycol systems,
with b and O representing the syn- and anti-5,6-glycols, respectively,
whereas with 9 and 0 representing the syn- and anti-8,9-glycols. The y
axis indicates the stereochemistry of the adjacent glycols, representing
A ) anti, S ) syn, and X ) stereochemistry at 5/6 or 8/9.
(22) On comparison with the 3JH,H distributions shown in Charts 10B and 11C,
it is possible to analyze the relative stereochemistry of unknown contiguous
polyols. In this approach, the stereochemical analysis is conducted, one at
a time, based on one vicinal spin-coupling constant as a function of the
relative stereochemistry of the adjacent glycols. However, in the terms of
applicability and ease-of-use, we assess the analytical procedures discussed
in the text to be far superior to this procedure. The details of procedure are
given for 4a∼d in the Supporting Information.
constants observed for 4a∼d were in the border-line (6 ( 1
Hz) region (Table 3).
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Universal NMR Databases for Contiguous Polyols
A R T I C L E S
Chart 16. 2D-Representation of the Internal (Panel A) and
Terminal (Panel B) JH,H’s Observed for Triols 3a∼pa
Chart 17. Prediction of the Relative Stereochemistry of 4a, by
3
3
Plotting the Observed, Two Contiguous JH,H’s on the Internal
(Panel A) and Terminal (Panel B) 2D-panelsa
3
a The x and y axes represent JH,H’s, with abbreviations of A ) anti,
S ) syn. The filled circle gives the two contiguous 3JH,H’s observed on 4a,
with indications of the position and stereochemistry; for example, 5/6/7
3
(S/S) represents J5,6/3J6,7 (the relative configuration at 5/6 and 6/7 ) syn
and syn).
The 3JH,H profiles composed of three contiguous spin-coupling
constants could be given in a 3D presentation by placing the
first, second, and third 3JH,H constants on the X-, Y-, and Z-axes,
respectively. However, for convenience of the presentation, we
chose to depict the profiles composed of three contiguous 3JH,H
constants in a 1D format.
3
a The x and y axes represent the two contiguous JH,H’s indicated by
arrows on 3a∼p, with abbreviations of S ) syn and A ) anti.
stereochemistry of unknown compounds. For example, on
comparison with these profiles, the observed J5,6 ) 3.5
(terminal), J6,7 ) 5.0 (internal), J7,8 ) 2.0 (internal), J8,9
3
Using all the relevant spin-coupling constants observed on
3a∼p, the profiles composed of three contiguous 3JH,H constants
in CD3OD were created (Chart 18). There are several comments
3
3
3
)
7.0 (internal), 3J9,10 ) 6.0 (internal), and 3J10,11 ) 6.0 (terminal)
correctly predict the relative stereochemistry of 4a at C5/C6/
C7, C6/C7/C8, C7/C8/C9, C8/C9/C10, C9/C10/C11, C10/C11/
C12 to be S/S, S/S, S/A, A/A, A/A, respectively, cf., the filled
circles marked in Panels A and B in Chart 17. Similarly, the
relative stereochemistry of 4b∼d can be correctly predicted as
included in Supporting Information.
3
worthy to make. First, practically identical JH,H profiles were
observed in pyridine-d6, DMSO-d6, and D2O. Second, a virtually
3
identical JH,H profile is recognized for all the members
belonging to each of the AAA, SAS, AAS, SAA, and ASA
sub-groups, regardless of whether they are at the internal or
3
terminal position. Third, two different JH,H profiles are
The 3JH,H profiles discussed above are composed of the two
adjacent vicinal spin-coupling constants. Naturally, we were
interested in the stereochemical analysis with the three contigu-
ous vicinal spin-coupling constants; with an addition of the third
vicinal spin-coupling constant, we would expect a higher
resolution on the NMR profile and the resultant NMR profile
to become a more powerful device for stereochemical analysis.
recognized for the SSS, SSA, and ASS sub-group members,
depending on the glycol system at one remote position, cf., the
profiles of the SSS(S) vs SSS(A) sub-groups as well as (A)-
SSA vs (S)SSA and ASS(A) vs ASS(S). Forth, the AAA and
SSS(S) sub-groups seem to exhibit a similar overall profile.
3
However, it should be noted that JH,H constants for the AAA
sub-group members are around 6 Hz, whereas those for the SSS-
9
J. AM. CHEM. SOC. VOL. 125, NO. 47, 2003 14391

A R T I C L E S
Higashibayashi et al.
3
3
Chart 18. JH,H Profiles Composed of Three Contiguous
Chart 19. Comparison of the JH,H Profilesa
Spin-Coupling Constantsa
a The y axis represents 3JH,H’s, with abbreviations of A ) anti and S )
syn.
(S) sub-group members are around 4 Hz. The 2 Hz difference
in 3JH,H constants is significant in this analysis. Fifth, similarly,
the overall profile of the (S)SSA and ASS(S) sub-group
members may seem to be similar to that of the ASA sub-group
3
members, but the differences in JH,H constants between them
are significantly large. Sixth, tetraols 2a∼h contain the three
contiguous 3JH,H systems and are expected to exhibit the profiles
corresponding to those defined in the pentaol series. Indeed,
2a∼h give the expected profiles, cf., Panel B, Chart 7.
3
a The JH,H profile of 4a (Panel A) is imaginarily disected into the four
3
3
small JH,H profiles and each of them is compared with the JH,H profiles
composed of three contiguous spin-coupling constants. The x and y axes
represent proton numbers and 3JH,H’s (Hz), with indication of their relative
stereochemistry, i.e., A ) anti and S ) syn.
Overall, the profile recognized for each sub-group member
is distinct and different from others. Naturally, these NMR
profiles can be refined further by incorporating additional spin-
coupling constants for analysis. However, as it will be seen from
the case of 4a∼d, the NMR profiles composed of only the three
contiguous spin-coupling constants are, at least to the first order
of analysis, sufficient for stereochemical analysis of unknown
contiguous polyols.
delightfully found the resultant profiles to perfectly match the
3JH,H profiles listed in Chart 18.
A structural array of contiguous polyols is contained in a
number of natural products, including the butyrolactols,24 the
zooxanthellatoxins,25 the palytoxins,1,26 the prymnesins,27 the
aflastatins,28 the blasticidins,29 and others. Using the NMR
database discussed in this paper, we have studied their relative
For the analysis using the profiles composed of three
3
contiguous JH,H constants, an unknown compound is imagi-
(23) For the reported 1H chemical shift and 3JH,H’s of hexa- and hepta-alditol in
D2O, see: (a) Hawkes. S. E.; Lewis, D. J. Chem. Soc., Perkin Trans. 2
1984, 2073-2078. (b) Gillies, D. G.; Lewis, D. J. Chem. Soc., Perkin Trans.
2 1985, 1155-1159. (c) Lewis, D. J. Chem. Soc., Perkin Trans. 2 1986,
467-470. (d) Angyal, S. J.; Sanders, J. K.; Grainger, C. T.; Le Fur, R.;
Williams. P. G. Carbohydr. Res. 1986, 150, 7-21. (e) Lewis, D.; Angyal,
S. J. J. Chem. Soc., Perkin Trans. 2 1989, 1763-1765. (f) Franks, F.;
Dabok, J.; Ying, S.; Kay, R. L.; Grigeera, J. R. J. Chem. Soc., Perkin Trans.
1 1991, 87, 579-585.
(24) Kotake, C.; Yamasaki, T.; Moriyama, T.; Shinoda, M.; Komiyama, N.;
Furumai, T.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 1442-1450.
(25) (a) Nakamura, H.; Asari, T.; Ohizumi, Y.; Kobayashi, J.; Yamasu, T.; Murai,
A. Toxicon 1993, 31, 371-376. (b) Nakamura, H.; Asari, T.; Murai, A. J.
Am. Chem. Soc. 1995, 117, 550-551. (c) Nakamura, H.; Maruyama, K.;
Fujimaki, K.; Murai, A. Tetrahedron Lett. 2000, 41, 1927-1930 and
references therein. For a related marine natural product zooxanthellamide
A, see: (d) Onodera, K.; Nakamura, H.; Oba, Y.; Ojika, M. Tetrahedron
2003, 59, 1067-1071.
(26) For the complete NMR assignment, see: Kan, Y.; Uemura, D.; Hirata, Y.;
Ishiguro, M.; Iwashita, T. Tetrahedron Lett. 2001, 42, 3197-3202.
(27) (a) Igarashi, T.; Satake, M.; Yasumoto, T. J. Am. Chem. Soc. 1996, 118,
479-480. (b) Igarashi, T.; Satake, M.; Yasumoto, T. J. Am. Chem. Soc.
1999, 121, 8499-8511. (c) Sasaki, M.; Shida, T.; Tachibana, K. Tetrahe-
dron Lett. 2001, 42, 5725-5728 and references therein.
(28) (a) Sakuda, S.; Ono, M.; Furihata, K.; Nakayama, J.; Suzuki, A.; Isogai,
A. J. Am. Chem. Soc. 1996, 118, 7855-7856. (b) Ikeda, H.; Matsumori,
N.; Ono, M.; Suzuki, A.; Isogai, A.; Nagasawa, H.; Sakuda, S. J. Org.
Chem. 2000, 65, 438-444, and references therein.
narily dissected into small stereoclusters composed of three
contiguous 3JH,H systems and the resultant 3JH,H profile of each
3
small stereocluster is compared with the JH,H profiles shown
in Chart 18. With 4a as an example, this analytical procedure
is outlined in Chart 19. The 3JH,H constants observed for 4a are
imaginarily dissected into the profiles composed of three
contiguous constants, i.e., 3J5,6/3J6,7/3J7,8 (first profile), 3J6,7/3J7,8/
3
3
3J8,9 (second profile), J7,8/3J8,9/3J9,10 (third profile), and J8,9
/
3J9,10/3J10,11 (fourth profile) and each of the profiles is compared
with the profiles shown in Chart 18. This comparison allows
us to immediately predict the relative stereochemistry at C5/
C6/C7/C8, C6/C7/C8/C9, C7/C8/C9/C10, and C8/C9/C10/C11
to be SSS(A), (S)SSA, SAA, and AAA, respectively and,
therefore, the relative stereochemistry of 4a at C5/C6/C7/C8/
C9/C10/C11 is SSSAAA. With the application of the same
analytical procedure, the relative stereochemistry of 4b∼d is
correctly predicted. The details of this analysis are given in the
Supporting Information.
(29) (a) Sakuda, S.; Ono, M.; Ikeda, H.; Inagaki, Y.; Nakayama, J.; Suzuki, A.;
Isogai, A. Tetrahedron. Lett. 1997, 38, 7399-7402. (b) Sakuda, S.; Ikeda,
H.; Nakamura, T.; Kawachi, R.; Kondo, T.; Ono, M.; Sakurada, M.; Inagaki,
H.; Ito, R.; Nagasawa, H. J. Antibiot. 2000, 53, 1378-1384 and references
therein.
Vicinal spin coupling constants were reported for the polyols
derived from hexoses and heptoses in the literature.23 With the
3
reported constants, we have created their JH,H profiles and
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14392 J. AM. CHEM. SOC. VOL. 125, NO. 47, 2003

Universal NMR Databases for Contiguous Polyols
A R T I C L E S
stereochemistry, which have given several interesting results.
Among them, we should comment specifically on the relative
stereochemistry proposed for the C27∼C31 portion of the
aflastatins. Upon comparison of the reported spin-coupling
is to analyze a profile, rather than a single data-point, to deduce
the stereochemistry of an unknown compound. This logic was
3
demonstrated to be very powerful for the analysis of JH,H
profiles as well. Two methods, one using profiles consisting of
3
3
constants with the adjacent or three contiguous JH,H profiles,
three contiguous JH,H constants and the other using profiles
it immediately becomes evident that the reported relative
stereochemistry at C27∼C31 must be revised from syn/syn/syn/
syn28 to anti/syn/syn/syn.30 Similarly, the relative stereochemistry
at C25∼C29 of the blasticidins can be suggested as anti/syn/
syn/syn.30
consisting of two adjacent 3JH,H constants, have been developed.
Overall, among the methods discussed, an approach based
3
on three, or two, contiguous JH,H profiles is operationally
1
simpler than one based on 13C and H chemical shift profiles.
Therefore, it has been suggested that a 3JH,H profile be used as
the primary device for predicting the stereochemistry of
unknown polyols and 13C and 1H chemical shift profiles be used
as the secondary devices to confirm the predicted stereochem-
istry.
Conclusion
Using 1,2,3-triols 1a∼d, 1,2,3,4-tetraols 2a∼h, and 1,2,3,4,5-
3
pentaols 3a∼p, we created the JH,H databases, as well as the
1
1
13C, H, and H(OH) chemical shift databases, for contiguous
polyols. The fact that each diastereomer of 1a∼d, 2a∼h, and
3a∼p exhibits a distinct and differing profile in all the 13C, 1H,
Experimental Section
The 1H and 13C NMR spectra were recorded on a Varian Inova 500
spectrometer and a Mercury 400 spectrometer, respectively. The central
residual solvent-signal [1H NMR spectrum: 3.30 ppm (CD3OD) and
2.49 ppm (DMSO-d6); 13C NMR spectrum: 49.0 ppm (CD3OD) and
39.5 ppm (DMSO-d6)] was used as the internal reference. For 1H NMR
spectra in C5D5N, the most upfield residual solvent-signal (7.19 ppm)
3
1H(OH) and JH,H NMR databases argues for their usefulness
for stereochemical analysis of unknown compounds bearing
these structural motifs.
To systematically assess their relative values, a case study
was conducted on heptaols 4a∼d, through which the γ- and
δ-effects were recognized, to refine the 13C chemical shift profile
predicted via an application of the concept of self-contained
nature. Interestingly, the magnitudes of γ- and δ-effects were
found to depend on a specific stereochemical arrangement of
the functional groups present in both the inside and outside of
a self-contained box. However, these effects were found
significant only for the stereoisomers belonging to a specific
sub-group. With the exception of the stereochemical arrange-
ment of functional groups belonging to the specific sub-group,
the γ- and δ-effects can, at least at the first order of approxima-
tion, be ignored for the stereochemical analysis of unknown
compounds. However, for stereoisomers belonging to the
specific sub-group, it is necessary to refine, with incorporation
of the γ- and δ-effects, the profile predicted at the first order
of approximation. With these procedures, it is possible to
properly predict an NMR profile for unknown polyols. A parallel
trend was found also for the case of 1H chemical shift profiles.
With use of heptaols 4a∼d, the values of 3JH,H profiles were
tested. One of the key logics used in the NMR database approach
1
was used as the internal reference. For H and 13C NMR spectra in
D2O, the residual solvent-signal of C6D6 in a WILMAD coaxial insert
(WGS-5BL, 50 mm L × 2 mm stem o.d.) was used as the external
reference (1H NMR spectrum: 7.15 ppm; 13C NMR spectrum: 128.0
ppm). The apparent vicinal 1H/1H spin-coupling constants were obtained
1
from 1D H NMR spectra.
The synthesis of 1a∼d, 2a∼h, 3a∼p, and 4a∼d, the raw NMR data,
the NMR profiles, the predicted profiles, and the stereochemical
predictions of 4a∼d are included in the Supporting Information.
Acknowledgment. Financial support from the National
Institutes of Health (NS 12108) is gratefully acknowledged. S.H.
and W.C. greatly thank a postdoctoral fellowship from the Naito
Foundation and the Swiss National Science Foundation, respec-
tively.
Supporting Information Available: The synthesis of 1a∼d,
2a∼h, 3a∼p, and 4a∼d, the raw NMR data, the NMR profiles,
the predicted profiles, and the stereochemical predictions of
4a∼d are included in Supporting Information (50 pages, print/
PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(30) Higashibayashi, S.; Kobayashi, Y.; Zeng, H.; Kishi, Y. unpublished work.
JA0375481
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