Stereochemistry of addition of carbanion reagents to 'diacetone fructose aldehyde'. Configurational assignment of a 1-deoxyheptulose derivative by X- ray crystallography and NMR studies directed to the assignment of isomeric adducts

Article abstract of DOI:10.1016/S0957-4166(99)00035-X

The addition of carbanionic reagents to 'diacetone fructose aldehyde' (6) was investigated with a focus on the stereocontrol. The Grignard reagents, MeMgBr, EtMgBr, i-PrMgBr, and MeMgI, gave a high bias (≥90%) for one diastereomer, assigned as the R-isomer, in ether at -78 to 0°C. The reaction of PhMgBr showed diminished diastereoselectivity under these conditions, with a significant dependence of the isomer ratio on temperature and solvent. PhCH₂MgBr only afforded the adduct of 'allylic rearrangement', namely 13, with poor diastereocontrol (ca. 60:40). MeLi, t-BuLi, PhLi, and LiCH₂CO₂-t-Bu provided adducts of 6 enriched in the R-isomer in the range of 80-89%, whereas 2-lithio-2-ethyl-1,3-dithiane gave a 94:6 ratio of R:S adducts (15a:15b). The R absolute stereochemistry at the carbinol C1 center of 4a was established through X-ray analysis of sulfamate derivative 2a. Carbon-13 NMR chemical shift criteria (the chemical shifts for C1 and C3) were identified to facilitate the stereochemical assignment of C1 adducts of 6.

Full text of DOI:10.1016/S0957-4166(99)00035-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 689–703
Stereochemistry of addition of carbanion reagents to ‘diacetone
fructose aldehyde’. Configurational assignment of a
1-deoxyheptulose derivative by X-ray crystallography and NMR
studies directed to the assignment of isomeric adducts
Michael J. Costanzo, Libuse Jaroskova, Diane A. Gauthier and Bruce E. Maryanoff ∗
Drug Discovery, The R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA
Received 23 November 1998; accepted 20 January 1999
Abstract
The addition of carbanionic reagents to ‘diacetone fructose aldehyde’ (6) was investigated with a focus on the
stereocontrol. The Grignard reagents, MeMgBr, EtMgBr, i-PrMgBr, and MeMgI, gave a high bias (≥90%) for
one diastereomer, assigned as the R-isomer, in ether at −78 to 0°C. The reaction of PhMgBr showed diminished
diastereoselectivity under these conditions, with a significant dependence of the isomer ratio on temperature and
solvent. PhCH2MgBr only afforded the adduct of ‘allylic rearrangement’, namely 13, with poor diastereocontrol
(ca. 60:40). MeLi, t-BuLi, PhLi, and LiCH2CO2-t-Bu provided adducts of 6 enriched in the R-isomer in the range
of 80–89%, whereas 2-lithio-2-ethyl-1,3-dithiane gave a 94:6 ratio of R:S adducts (15a:15b). The R absolute
stereochemistry at the carbinol C1 center of 4a was established through X-ray analysis of sulfamate derivative
2a. Carbon-13 NMR chemical shift criteria (the chemical shifts for C1 and C3) were identified to facilitate the
stereochemical assignment of C1 adducts of 6. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Topiramate (1, Topamax®), an anti-convulsant discovered in our laboratories around 1980, is an im-
portant anti-epileptic drug that is marketed in many countries worldwide.1 Within the broad scope of anti-
convulsant agents, topiramate possesses a unique sugar sulfamate structure and a special combination of
biological mechanisms of action.1,2 As part of an analogue project, we had occasion to synthesize and test
compounds substituted at the C1 position with methyl (2) and ethyl (3) groups.3 Despite the fact that 2 and
3 had greatly attenuated anti-convulsant activity,3b it was interesting to note that the precursor alcohols (4
and 5) were formed from ‘diacetone fructose aldehyde’ (6) with a strong bias for one diastereomer (16:1
∗
Corresponding author. E-mail: bmaryano@prius.jnj.com
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00035-X

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1
and 5:1, respectively; in THF:ether). Analysis of the H and 13C NMR spectroscopic data would not
permit an assignment of stereochemistry to the new stereogenic center, because there was no precedent
established.3a
In 1981, Heathcock et al. reported the preparation of alcohol adducts 5 and 7 via the addition of
EtMgBr (THF:ether, 0°C) and 2-lithio-2-ethyl-1,3-dithiane (THF:hexane, ca. −60°C) to 6, with exclusive
formation of one diastereomer, depicted in their paper with the R configuration at the newly formed
stereogenic center.4 However, this stereochemical assignment must be considered as arbitrary because
no supporting evidence, spectroscopic or otherwise, was provided.5 Around the same time (1980),
Martinez et al. reported the addition of MeMgI to 6 in ether to obtain alcohols 4, although they also
did not assign the two diastereomers.6 Interestingly, they observed that the ratio of diastereomeric
alcohols 4 was temperature dependent, with formation of a single isomer at ca. 23°C and a ca. 60:40
ratio at 35°C (enriched in the first isomer). Recently, Izquierdo et al. found that reaction of 6 with
methyl bromoacetate and zinc (dioxane, 23°C; modified Reformatsky conditions) or with lithio tert-
butyl acetate (THF:ether:hydrocarbons, −78°C) resulted in adducts 8 or 9 with high selectivity for the
diastereomer with the R configuration at the new stereocenter (ca. 10:1 and ca. 5:1, respectively).7 Their
1997 paper provided the first stereochemical assignment for a carbanion addition product from 6, based
on unambiguous stereochemical correlation.8
Concurrent with the work of Izquierdo et al.,7 we established the R configuration for the major isomer
from the reaction of 6 with MeMgBr, i.e., 4a, by X-ray crystallography of the sulfamate derivative, 1a.3a
In this paper, we report the details of our X-ray analysis of 1a. Moreover, we describe results from a series
of experiments involving the addition of carbanionic reagents to 6, which serve to define the scope of the
diastereocontrol, as well as the effects of temperature and solvent. Given the variety of diastereomeric
pairs of carbinols on hand, we obtained extensive proton and carbon-13 NMR data, which has led to a
spectroscopic criterion for the assignment of stereochemistry to such derivatives.
2. Results and discussion
2.1. Addition of carbanion reagents to 6
Subsequent to our initial work,3a we undertook a systematic investigation of the addition of simple
Grignard reagents to aldehyde 6. Our results with MeMgBr, EtMgBr, i-PrMgBr, PhCH2MgBr, and
PhMgBr are shown in Table 1. For MeMgBr, EtMgBr, i-PrMgBr, and PhMgBr, we examined five
temperatures in the range from −78 to 35°C to define the effect of temperature on the stereochemistry.
The reactions were generally conducted in anhydrous ether, except that MeMgBr was also studied in
ether:THF (1:1) for continuity with our earlier experience.3a

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691
Table 1
Reaction of carbanion reagents with 6

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Table 1 (continued)
It is apparent from the data for MeMgBr in ether (entries 1–5) that high diastereoselectivity in favor of
the R-isomer is generally achieved with good yields of adducts 4 (80–95%), along with a small amount
(3–11%) of unreacted aldehyde 6. The best R selectivity is an impressive 98:2 (entry 1), which was
obtained at the lowest temperature of −78°C. We observed just a moderate influence of temperature on
the R:S ratio, which gradually decreased from 98:2 to 91:9 as the temperature increased from −78 to
35°C. At 0°C, the use of 5 mol equiv. of MeMgBr instead of 2 mol equiv., or 1:1 THF:ether instead of
ether, exerted little effect on the R:S ratio (cf. entries 6 and 8 with entry 3).

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693
Results for the reaction of EtMgBr and 6 in ether (entries 10–14) were very similar to those obtained
with MeMgBr (entries 1–5). From −78 to 35°C, the yield of adducts 5 ranged from 75 to 90% and the
R:S ratio gradually changed from 98:2 to 89:11. One difference in this case was the formation of reduced
product 10, the yield of which ranged from 7–11% with high yields occurring at higher temperatures.
The formation of 10 was more accentuated in the reaction of i-PrMgBr and 6 in ether, with yields ranging
from 31–47% (entries 15–19). This reductive side reaction with Grignard reagents is more prevalent for
sterically hindered carbonyl substrates and bulkier organomagnesium reagents, such as those bearing
secondary alkyl groups.9 Thus, in the reaction of i-PrMgBr with 6 the yield of adducts 11 was only ca.
45–50%.10 At −78°C, the R:S ratio of 98:2 for i-PrMgBr addition (entry 15) was identical to those for
MeMgBr and EtMgBr addition. However, the R:S ratios at higher temperatures receded somewhat: e.g.,
at −20°C, 93:7 for i-PrMgBr (entry 16) vs. 97:3 for MeMgBr (entry 2); at 35°C, 86:14 for i-PrMgBr
(entry 19) vs. 91:9 for MeMgBr (entry 5).
The reaction of PhCH2MgCl with 6 proved to be problematic in that the major product turned out to
be an isomeric mixture of o-tolyl adducts 13, rather than benzyl adducts 12 (entries 20 and 21). At 35°C,
we obtained a 69% yield of 13 with an R:S ratio of 63:37. Although it is well known that allylic Grignard
reagents add to carbonyl compounds with structural 1,3-rearrangement of the allylic group,9b this is a
much less documented event with benzylic Grignard reagents.11 There was too little benzyl adduct 12
formed to permit isolation of this material.
The addition of PhMgBr to 6 in ether proceeded smoothly, with yields of adducts 14 ranging from
80–97% and unreacted 6 ranging from 1–8% (entries 22–26). The R:S ratio decreased incrementally
from 89:11 at −78°C to 76:24 at 35°C. For PhMgBr, the solvent had a strong impact on the R:S ratio,
with THF and toluene at −78°C giving 64:36 (entry 27) and 46:54 (entry 28), respectively, relative to
89:11 for ether (entry 22).
Addition of MeLi to 6 in ether at −78°C afforded an R:S ratio of 89:11 (entry 29), which falls
significantly short of the 98:2 ratio attained with MeMgBr (entry 2). By the same token, the R:S ratio
of 80:20 for PhLi addition to 6 in ether at −78°C (entry 30) was lower than the 89:11 ratio attained with
PhMgBr (entry 22). Bulky t-BuLi gave only a 30% yield of adduct, with a ratio of 87:13 (entry 31).
Two other lithium reagents, LiCH2CO2-t-Bu and 2-lithio-2-ethyl-1,3-dithiane, were also studied because
of the above-mentioned reports of Izquierdo et al.7 and Heathcock et al.,4 respectively. The addition of
LiCH2CO2-t-Bu to 6 in ether:hexanes (2:1) at −78°C furnished adducts 9 in 87% yield with an R:S ratio
of 80:20 (entry 32). The related Reformatsky reaction of 6 with BrCH2CO2Me and zinc was conducted
under sonication conditions in 1,4-dioxane, starting at 23°C but with the temperature being elevated over
time, to afford 8 in 80% yield with an improved R:S ratio of 90:10 (entry 33). Reaction of 2-lithio-2-
ethyl-1,3-dithiane with 6 in THF:hexanes (1:1) at −70°C, followed by warming to 23°C, gave a 63%
yield of adducts 15 (EDT=2-ethyl-1,3-dithian-2-yl) with an excellent R:S ratio of 94:6 (entry 34). One
might be tempted to attribute this 94:6 stereoselectivity to the bulkiness of the nucleophile; however,
the 87:13 ratio of 16a:16b obtained with t-BuLi would suggest otherwise. Perhaps this very favorable
result for the dithiane addition is connected with stabilization of the nucleophile or a reagent aggregation
phenomenon.
Our results when adding the lithio dithiane to 6 are fairly consistent with the results of Heathcock
et al.,4 although they did not report the formation of the minor diastereomer, 15b, or its hydrolysis
product, 7b. Similarly, our results when adding LiCH2CO2-t-Bu and BrZnCH2CO2Me to 6 are consistent
with those reported by Izquierdo et al.7 However, our experience when adding MeMgBr to 6 is not in
agreement with the results described by Martinez et al.6 At 20°C, we obtained an R:S ratio of 91:9, rather
than a single isomer (4a); also, we obtained an R:S ratio of ca. 90:10 at 35°C, rather than a 60:40 mixture
of 4a and 4b. Since our Grignard reagent was different (MeMgBr vs. MeMgI), we decided to react 6

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with MeMgI in ether at 35°C. The R:S ratio turned out to be 89:11 (91% yield), virtually the same as for
MeMgBr addition.
2.2. Stereochemistry of addition
Addition of carbanion reagents, such as Grignard reagents, to sugar aldehydes has been noted to
occur with high diastereoselectivity in various cases.12 However, current models of asymmetric induction
that are useful for predicting the direction, and even degree, of stereochemical bias for the addition of
nucleophiles to α-chiral aldehydes may not be suitable for carbohydrate systems.12d,13 A cyclic chelate
model was originated by Wolfram and Hanessian to explain the high diastereoselectivity of addition of
carbanion reagents to furanose aldehyde 17.12a For the addition of MeMgI in THF:ether, they suggested
formation of a five-membered ring bidentate chelate, involving the aldehyde and furanose ring oxygen
atoms (viz. 18), which would then be attacked preferentially from the less hindered α face of the carbonyl
group to furnish mainly 19.
3
For aldehyde 6, in a skew S0 conformation, oxygen atoms O1, O2, O4, and O6 are available for
bidentate chelation to Mg2+, to provide cyclic complexes 20, 21, or 22. Approach of the Grignard reagent
is disfavored from the β face of the aldehyde in these three structures due to the steric hindrance imposed
by H3 and the proximal methyl group of the 2,3-ketal. Hence, attack from the α face would be strongly

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695
Figure 1. Stereoview of a ball and stick model of the X-ray crystal structure of 2a
preferred. A seven-membered ring chelate 20 is considered, despite its being structurally challenged,
since an intramolecular hydrogen bond between the C1 hydroxyl and O4 in diacetone fructose (10)
has been noted.3a,14a If chelates 20 and 21 were predominant, then attack from the α face would favor
formation of 23, which is the minor S-diastereomer. On the other hand, chelate 22, a five-membered ring
complex involving O1 and O2, is the only bidentate chelate that would favor formation of 24, which is the
major R-diastereomer. In support of chelate 22, we observed a significant decrease in diastereoselectivity
(98:2 to 89:11) with MeLi compared to MeMgBr (cf. entries 29 and 1 in Table 1). A similar decrease in
diastereoselectivity (95:5 to 72:27) was found12b in the reactions of phenylsulfonylmethides with 17 after
changing the counterion from Mg2+ to Li+, and Kim et al.12b attributed the decrease to the stronger β-
chelating ability of Mg2+ relative to Li+. Major diastereomer 24 could also be produced by a Felkin–Anh
transition state17 instead of cyclic chelate 22. A likely structure for the Felkin–Anh pathway would have
O6 antiperiplanar to the aldehyde oxygen, as depicted in 25. In the other possible Felkin–Anh structure,
with O2 antiperiplanar to the aldehyde oxygen, attack from the aldehyde β face would result in the
formation of the minor diastereomer, 23.
2.3. X-Ray crystal structure of 2a
A single crystal of 2a was subjected to an X-ray diffraction study, which established the R stereo-
chemistry at the carbinol carbon (C1). It is apparent that the pyran ring of 2a adopts a skew conformation
(3S0) in the solid state (Fig. 1). This conformation is the one adopted by such tricyclic sugars, as with
topiramate (1) and related compounds, in the solid state and in solution, presumably because of the
‘cis–anti–cis’ arrangement for the 5–6–5 tricyclic ring system.1a,3a,14–16
2.4. NMR studies of the adducts
There are no spectroscopic criteria available to assign R:S configuration to the products of carbanion
addition to 6. Although the recent paper by Izquierdo et al.7 discloses 1H NMR data for the isomers of 8
and 9, the information provided is not sufficient to offer a method for making stereochemical assignments.
1
Thus, we have collected H and 13C NMR data for several pairs of R- and S-isomers (Tables 2–7) to
identify trends in the spectral parameters that would be useful for making such predictions.
1
It is worth noting initially that the values for the H NMR coupling constants J3,4, J4,5, J5,6e, and
J5,6a (Tables 4 and 5) indicate a skew conformation (3S0), as the corresponding coupling constants
for topiramate (1) are 2.6, 8.0, 1.9, and 0.8 Hz. Inspection of the proton chemical shifts and coupling

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Table 2
1H NMR chemical shifts (ppm) for major isomers
Table 3
1H NMR chemical shifts (ppm) for minor isomers
constants for the major (a) and minor (b) isomeric series (Tables 2–5) does not reveal any parameter
suitable for assigning stereochemistry at C1.
Many of the carbon chemical shifts (Tables 6 and 7) are also uninformative with respect to assigning
stereochemistry; however, the chemical shifts for C1 and C3 appear to be nicely diagnostic. For eight
isomeric pairs, the δC1 values for the major isomer (R series on the basis of the assignment for 4a via
2a) are significantly upfield, by ca. 2–4 ppm, relative to the δC1 values for the minor isomer (S series).
Furthermore, the δC3 values for the major isomer (R series) are significantly upfield, by ca. 2.5 ppm,
relative to the δC3 values for the minor isomer (S series). This latter parameter is quite impressive in that
the difference between the δC3 values for the isomeric pairs is so constant, basically 2.5ꢀ0.1, over eight

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697
Table 4
1H NMR coupling constants (Hz) for major isomers
Table 5
1H NMR coupling constants (Hz) for minor isomers
adducts. Although only 4a is firmly established as having the R configuration at C1 by X-ray analysis
of 2a, we suggest that the trend observed in 13C NMR chemical shifts for C1 and C3 may offer a useful
diagnostic for the assignment of R:S configuration for the carbanion adducts of 6.
The X-ray crystal structure of 2a (Fig. 1) displays a staggered conformation about the C1–C2 bond
in which the methyl group is directed between O2 and O6, while H1 is directed between O6 and C3.
This is a reasonable candidate for the most stable of the three staggered conformations for C1–C2 in
solution because the larger groups would impinge on the endo (more proximal) methyl group on the 4,5-
ketal in the two other conformers and the bulkier methyl group is favorably disposed between two ether
oxygen atoms. For the corresponding S-isomer, 2b, while maintaining this favorable arrangement, the

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Table 6
13C NMR chemical shifts (ppm) for major isomers
Table 7
13C NMR chemical shifts (ppm) for minor isomers
methyl group and O1 would be interchanged, resulting in a somewhat less favorable steric positioning
of the methyl group vis-à-vis O2 and C3. In the case of the related alcohols, the hydroxyl group on C1
is probably involved in intramolecular hydrogen bonding with O4, as in diacetone fructose (10),3a,14a
whereas this interaction does not occur in the corresponding sulfamates.3a Thus, in the R-isomer the
methyl group would be oriented between O2 and C3 and in the S-isomer the methyl group would be
oriented between O2 and O6, which is a less sterically demanding situation. This arrangement for the R-
isomer would place C3 in a particularly crowded environment. Given such a steric picture, it is reasonable
to think that the 13C NMR chemical shift differences at C2 and C3 — significant shielding for the R-
isomer relative to the S-isomer — is a consequence of standard 13C NMR steric shielding effects.18

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699
3. Conclusion
The addition of various carbanionic reagents to ‘diacetone fructose aldehyde’ (6) can afford a high
level of stereocontrol at C1 (≥80%). The reagents MeMgBr, EtMgBr, i-PrMgBr, MeMgI, and 2-lithio-
2-ethyl-1,3-dithiane resulted in a high bias (≥90%) for one diastereomer, assigned as the R-isomer. The
reaction of PhMgBr showed lower diastereoselectivity and a significant dependence of the isomer ratio
on temperature and solvent. Contrary to an earlier report,6 methyl Grignard reagents were found not to
show a pronounced temperature dependence for the isomer ratio. The R absolute stereochemistry at the
carbinol C1 center of 4a was established through X-ray analysis of sulfamate derivative 2a. Carbon-13
NMR chemical shift data, specifically the trends in chemical shifts for C1 and C3, were identified as a
tool for assigning stereochemistry to the C1 adducts of 6.
4. Experimental
4.1. General methods
The X-ray crystallography work on 2a was conducted by Crystalytics Co., Lincoln, NE. TLC
separations were conducted on Whatman MK6F silica gel 60A plates (250 µm) with visualization by
iodine staining and by charring with EtOH:H2SO4 (95:5). Column chromatography was performed
on silica gel 60 (40–63 mm; EM Science). Optical rotations were measured on a Perkin–Elmer 241
polarimeter at the sodium D line (λ=589 nm). NMR spectra were acquired as described below (s, singlet;
d, doublet; t, triplet; m, multiplet; br, broad). GLC was performed on a Hewlett Packard 5890 Series II
capillary gas chromatograph equipped with a Chrompack CPSil 5CB capillary column (25 m×0.25 mm
I.D.×0.12 µm film thickness) and flame-ionization detector with helium as the carrier gas with a flow
rate of 30 cm/s at 185°C. The injection port and detector temperatures were 280 and 300°C, respectively.
GLC analysis conditions used: 120–140°C at 2°C/min for 4 and 16; 120°C for 5; 120–180°C at 7°C/min
for 8, 9, and 14; 120–180°C at 5°C/min for 7; 120–200°C at 10°C/min for 15; 140°C for 11; 150–180°C
at 2°C/min for 13. HPLC analysis was performed on a Hewlett–Packard Series 1100 high-performance
liquid chromatograph, eluting isocratically with water:acetonitrile:trifluoroacetic acid (350:150:1) at 0.75
mL/min on a Supelcosil ABZ+plus column (5 cm×2.1 mm; 3 µm particle size) at 40°C and recording
signals simultaneously at 220 nm and 254 nm with a diode array detector. GC–MS samples were analyzed
on a Hewlett–Packard 5890 gas chromatograph equipped with a HP-1 capillary column (12 m×0.2 mm
I.D.×0.33 µm film thickness) interfaced to a Hewlett–Packard 5970 mass-selective detector, with helium
as the carrier gas. The injector and transfer line of the instrument were held at 280°C and the column
temperature was increased from 80–280°C at 10°C/min. The ionization method used was electron impact
(70 eV) and the mass spectrometer was scanned from 40–800 amu at 425 amu/s. Compounds 4–16 were
generally identified by a diagnostic (M−15)+ peak, which corresponds to loss of a methyl group; no parent
ions were ever observed. Chemical ionization mass spectra were obtained on a Hewlett–Packard 5989A
instrument using ammonia (source pressure=1 torr). Samples were introduced by a Hewlett–Packard
1050 LC system coupled to a Hewlett–Packard 59980B particle beam interface. The mass spectrometer
was scanned from 110–1000 amu at a rate of 712 amu/s. Accurate mass determinations were performed
on an Autospec E high resolution magnetic sector mass spectrometer tuned to a resolution of 6 K. The
ions were produced in a fast-atom bombardment source at an accelerating voltage of 8 kV. Linear voltage
scans at 33 amu/s were collected to include the sample ion and two polyethylene glycol ions, which were
used as internal reference standards.

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4.2. Procedures for reaction of aldehyde 6 with organometallic reagents
To a solution of aldehyde 6 (260 mg, 1 mmol) in 10 mL of dry solvent under argon was added the
organometallic reagent (2 mmol) at the given temperature (Table 1). The reaction mixture was stirred at
the same temperature for 2 h, at which time the reaction was quenched with 10 mL of 10% ammonium
chloride. The organic layer was separated and the aqueous phase was extracted twice with 5 mL of
ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried (Na2SO4), and
concentrated to give the crude product, which was analyzed by GLC, GLC–MS, and 1H NMR.
The reactions of 6 with methyl bromoacetate, lithio tert-butylacetate, and 2-lithio-2-ethyl-1,3-dithiane
were conducted exactly as described in literature.4,7
4.3. 1-Deoxy-3,4:5,6-bis-O-(1-methylethylidene)-β-D-gluco-3-heptulopyranose sulfamate (2b)
Alcohol 4b (2.2 mg, 0.008 mmol) was reacted with sodium hydride (0.4 mg, 0.016 mmol) and
sulfamoyl chloride (1.9 mg, 0.016 mmol) in DMF (0.5 mL) as described for compound 2a.3a The
crude product was triturated three times with+hexanes and dried in vacuo to afford crude+2b (2.8 mg,
100%). CI/MS m/z 354 (MH)+, 371 (M+NH4 ); HR/MS calcd for C13H23NO8S (M+NH4 ) 371.1483,
found 371.1488.
4.4. General methods for the isolation of stereoisomerically enriched alcohols
To obtain both isomers pure, the crude product mixtures with the poorest stereoselectivity were
subjected to column chromatography on silica gel with CH2Cl2:hexane:acetone (25:5:1) for 4 and 5;
hexane:ethyl acetate (4:1) for 7, 13, and 14; hexane:ethyl acetate (5:1) for 8 and 9; and toluene:acetone
(15:1) for 11. In most cases, we obtained each isomer stereochemically pure as colorless sticky syrups
or white crystals; however, in the case of the minor isomers of ester 8 and ketone 7 we obtained only
enriched mixtures in a ratio of 75:25 in favor of minor isomer. The diastereomers of compound 16 were
not separated [1H NMR (16a) δ 1.06 (s, 9H, t-Bu), 1.35, 1.44, 1.50, 1.55 (4s, 3H, Me), 1.81 (d, 1H, OH),
3.40 (d, 1H, H1, J1,OH=11.35 Hz), 3.75 (d, 1H, H6e), 3.90 (dd, 1H, H6a, J6a,6e=12.91 Hz), 4.21 (dd, 1H,
H5, J4,5=7.83 Hz, J5,6a=1.96 Hz), 4.51 (d, 1H, H3), 4.62 (dd, 1H, H4, J3,4=2.74 Hz). 13C NMR (16a) δ
24.32, 27.38, 28.19, 36.28, 61.51, 70.74, 71.07, 72.27, 78.44, 106.59, 109.16, 109.32]. HR/MS calcd for
C13H22O6 (MH)+ 317.1937, found 317.1942.
4.5. Stereoisomerically enriched alcohols
4a: Yield of pure isomer after chromatography was 77%; [α]D25 −23.7 (c 0.7, CHCl3). CI/MS m/z 275
(MH)+, 292 (M+NH4+); HR/MS calcd for C13H22O6 (MH)+ 275.1495, found 275.1487.
4b: Yield of pure isomer after chromatography was 6%; [α]D25 −8.8 (c 0.3, CHCl3). HR/MS calcd for
C13H22O6 (MH)+ 275.1495, found 275.1492.
5a: Yield of pure isomer after chromatography was 47%; [α]D25 −13.9 (c 0.8, CHCl3). CI/MS m/z 289
(MH)+, 306 (M+NH4)+; HR/MS calcd for C14H24O6 (MH)+ 289.1651, found 289.1651.
5b: Yield of pure isomer after chromatography was 4%; [α]D25 −18.5 (c 1.0, CHCl3). CI/MS m/z 289
(MH)+, 306 (M+NH4)+; HR/MS calcd for C14H24O6 (MH)+ 289.1651, found 289.1655.
7a: Yield of pure isomer after chromatography was 31%; [α]D25 +55.0 (c 1.0, CHCl3). CI/MS 316 m/z
(MH)+, 334 (M+NH4)+; HR/MS calcd for C15H24O7 (M−H)+ 315.1444, found 315.1438.

M. J. Costanzo et al. / Tetrahedron: Asymmetry 10 (1999) 689–703
701
25
8a: Yield of pure isomer after chromatography was 48%; [α]D −4.0 (c 1.0, CHCl3). HR/MS calcd
for C15H24O8 (M−H)+ 331.1393, found 331.1399.
25
9a: Yield of pure isomer after chromatography was 40%; [α]D −4.0 (c 0.7, CHCl3). CI/MS m/z 375
(MH)+; HR/MS calcd for C18H30O8 (MH)+ 375.2019, found 375.2005.
9b: Yield of pure isomer after chromatography was 13%; [α]D25 −14.5 (c 1.0, CHCl3). CI/MS m/z 375
(MH)+; HR/MS calcd for C18H30O8 (MH)+ 375.2019, found 375.2014.
25
11a: Yield of pure isomer after chromatography was 23%; [α]D −23.6 (c 1.0, CHCl3). CI/MS m/z
303 (MH)+, 320 (M+NH4)+; HR/MS calcd for C15H26O6 (MH)+ 301.1651, found 301.1639.
11b: Yield of pure isomer after chromatography was 3%; CI/MS m/z 303 (MH)+, 320 (M+NH4)+;
HR/MS calcd for C15H26O6 (M−H)+ 301.1651, found 301.1642.
25
13a: Yield of pure isomer after chromatography was 17%; [α]D −45.8 (c 1.0, CHCl3). CI/MS m/z
350 (MH)+, 368 (M+NH4)+; HR/MS calcd for C19H26O6 (M−Me)+ 335.1495, found 335.1495.
25
13b: Yield of pure isomer after chromatography was 13%; [α]D +20.4 (c 1.0, CHCl3). CI/MS m/z
350 (MH)+, 368 (M+NH4)+; HR/MS calcd for C19H26O6 (MH)+ 349.1651, found 349.1652.
25
14a: Yield of pure isomer after chromatography was 40%; [α]D −25.3 (c 0.8, CHCl3). CI/MS m/z
337 (MH)+, 354 (M+NH4)+; HR/MS calcd for C18H24O6 (M−Me)+ 321.1338, found 321.1335.
14b: Yield of pure isomer after chromatography was 16%; [α]D25 +3.1 (c 1.0, CHCl3). CI/MS m/z 337
(MH)+, 354 (M+NH4)+; HR/MS calcd for C18H24O6 (M−Me)+ 321.1338, found 321.1341.
1
4.6. H and 13C NMR studies
All 1H and 13C 1D and 2D NMR spectra were recorded on a Bruker DMX-400 spectrometer at 298°K
using a 5 mm multinuclear inverse Z-gradient probe. Samples were dissolved in CDCl3 at concentrations
ranging from 6–40 mg to 0.8 mL. Chemical shifts were measured relative to the solvent peak at 7.28
1
ppm for H and 77.4 ppm for 13C. Carbon multiplicities were assigned by distortionless enhancement
1
by polarization-transfer experiments (DEPT). One-dimensional H NMR spectra were collected with
32 K complex points and sweep widths ranging from 2400–6400 Hz, as needed. One-dimensional 13C
NMR (100.61 MHz) and DEPT spectra were collected with 64 K complex points and a sweep width
of 22 kHz. Mild apodization functions were applied during data processing. Compounds 15a and 15b
were additionally recorded in methanol-d4 and at 600.13 MHz for resolution enhancement of pertinent
peaks. These NMR spectra were recorded on a Bruker DMX-600 spectrometer equipped with an inverse
5 mm triple resonance probe (1H:13C:15N) and triple axis gradients at 298 K. Two-dimensional gradient
enhanced 1H:1H COSY and 1H:13C HETCOR experiments were conducted for some compounds to assist
in making peak assignments. Two-dimensional COSY spectra were acquired in the magnitude mode
with 1024 complex points collected in t2 and 128 t1 increments of 128 transients each. Two-dimensional
HETCOR spectra were acquired in the magnitude mode with 2048 complex points collected in t2 and 256
t1 increments of 128 transients each. Two-dimensional data sets were processed using Bruker software.
Matrix files were 1024×512 points in size for the COSY experiments and 2048×512 points in size for the
HETCOR experiments. The t2 and t1 time domain transforms were weighted with a sine-shaped function
shifted by 0° for both cases.
4.7. X-Ray crystallography of 2a19
Single crystals of 2a3a (C13H23NO8S, mw 353.4, colorless rectangular parallelpipeds from etha-
nol:water; mp 152–153°C) are orthorhombic (space group P212121 with a=7.9726(5) Å, b=14.395(1)
Å, c=14.912(1) Å, α=β=γ=90.0°, V=1711.4(2) Å3, and dcalcd=1.372 g cm−3 for Z=4. The intensity

702
M. J. Costanzo et al. / Tetrahedron: Asymmetry 10 (1999) 689–703
data [a total of 2241 independent reflections having 2θ(MoKα)<54.98°] were collected from a single
crystal on a computer-controlled Siemens/Bruker P4 Autodiffractometer by using full ω scans at 293
K and graphite-monochromated MoKα radiation (λ=0.71073 Å). The Siemens/Bruker SHELXTL-
PC software package was used to solve the structure by using the direct methods technique. All
stages of weighted full-matrix least-squares refinement were performed with F2o data and SHELXTL-
PC Version 5 to converge at R1 (unweighted, based on F)=0.053 for 1593 independent reflections
having 2θ(MoKα)<54.98° and I>2σ(I), and wR2 (weighted, based on F2)=0.127 for 2080 independent
reflections having 2θ(MoKα)<54.98° and I>0. The structural model incorporated anisotropic thermal
parameters for all nonhydrogen atoms and isotropic thermal parameters for all hydrogen atoms. The
sulfamate hydrogen atoms (H1N and H2N) were located from a difference Fourier map and refined
as independent isotropic atoms. The remaining hydrogen atoms were included in the structure factor
calculations as idealized atoms on their respective carbon atoms. The five methyl groups and their
hydrogens were refined as rigid rotors with sp3-hybridized geometry and a C–H bond length of 0.96
Å. The isotropic thermal parameters for H1N and H2N refined to final Uiso values of 0.08(2) and 0.09(3)
Å2. The remaining hydrogen atoms were included in the structure factor calculations fixed at 1.2 times
(tertiary) and 1.5 times (methyl) the equivalent isotropic thermal parameter of the carbon to which they
were bonded. The final refined value of 0.34(16) for the ‘Flack’ absolute structure parameter did not
permit an assignment of the absolute configuration by use of the diffraction data alone.
Acknowledgements
We thank Samuel O. Nortey for some technical assistance.
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