A general chemoenzymatic synthesis of enenatiopures cis β-amino alcohols from microbially derived cis-glycols

Article abstract of DOI:10.1055/s-1998-6082

Enantiomerically pure cis-glycols, derived through the microbial metabolism of hydrocarbons, represent a valuable chiral pool for the synthesis of cis β-amino alcohols. One generally applicable route to these important chiral intermediates is described. Reaction of the metabolically formed diol with α-acetoxyisobutyryl chloride affords regio- and stereoselectively a single trans-1,2-chlorohydrin acetate isomer. Displacement of chloride by azide, aminolysis of the ester and reduction of the azide provides the requisite amino alcohols. This 4-step route is highly efficient and affords the cis β-amino alcohol enantiomers in 41-57% overall yields. Using the highly enantiopure amino alcohols diastereomeric oxazaborolidines were prepared with both (-)-(S)- and (+)-(R)-[2-(1-methoxyethyl)phenyl]boronic acids. As described herein, these derivatives are potentially useful for absolute configurational assignments to cis amino alcohols.

Full text of DOI:10.1055/s-1998-6082

SYNTHESIS
Papers
1352
A General Chemoenzymatic Synthesis of Enantiopure cis â-Amino Alcohols from
Microbially Derived cis-Glycols
Mahesh K. Lakshman,*a,† Surendrakumar Chaturvedi,a,‡ Barbara Zajc,*b David T. Gibson,c Sol M. Resnick*c,§
a Chemsyn Science Laboratories, 13605 West 96th Terrace, Lenexa KS 66215, USA
b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
c The Department of Microbiology and The Center for Biocatalysis and Bioprocessing, The University of Iowa, Iowa City, IA 52242, USA
Received 5 December 1997; revised 23 January 1998
Abstract: Enantiomerically pure cis-glycols, derived through the
microbial metabolism of hydrocarbons, represent a valuable chiral
pool for the synthesis of cis β-amino alcohols. One generally
applicable route to these important chiral intermediates is de-
scribed. Reaction of the metabolically formed diol with α-acetoxy-
isobutyryl chloride affords regio- and stereoselectively a single
trans-1,2-chlorohydrin acetate isomer. Displacement of chloride
by azide, aminolysis of the ester and reduction of the azide pro-
vides the requisite amino alcohols. This 4-step route is highly effi-
cient and affords the cis β-amino alcohol enantiomers in 41–57%
overall yields. Using the highly enantiopure amino alcohols dias-
tereomeric oxazaborolidines were prepared with both (–)-(S)- and
(+)-(R)-[2-(1-methoxyethyl)phenyl]boronic acids. As described
herein, these derivatives are potentially useful for absolute config-
urational assignments to cis amino alcohols.
enantiopure β-amino alcohols from microbially derived
cis 1,2-diols. Additionally, we have made a preliminary
evaluation of the utility of (–)-(S)- and (+)-(R)-[2-(1-
methoxyethyl)phenyl]boronic acids for stereochemical
analysis via the formation of diastereomerically pure ox-
azaborolidines with the amino alcohols.
In the present study the synthesis of enantiopure cis β-
amino alcohols from the corresponding aryl fused 5-, 6-
and 7-membered ring glycols is described. Using previ-
ously reported general procedures15, 16 (+)-1, naphthalene
and anthracene dihydrodiols as well as (–)-4 were pre-
pared with bacterial strains expressing naphthalene diox-
ygenase. A bacterial strain expressing toluene dioxygena-
se was used for preparing (–)-1. Indanediol (–)-1 of high
enantiopurity was prepared from indan-2-ol as
described14 except that Pseudomonas putida strain F39/D
was used as the biocatalyst.17 The indanediols (–)-
(1S,2R)-1 and (+)-(1R,2S)-1 were of 92 and 68% ee re-
spectively, and the (–)-(5R,6S)-6,7,8,9-tetrahydro-5H-
benzocycloheptene-5,6-diol (4) was >98% ee. The (+)-
(1R,2S)-dihydrodiol of naphthalene (>98% ee) as well as
the (+)-(1R,2S)-dihydrodiol of anthracene (>98% ee)
were catalytically reduced with 5% Pd-C in MeOH to the
requisite tetrahydrodiol precursors 2 and 3, respectively.
Key words: cis-diols, cis amino alcohols, chemoenzymatic syn-
thesis, diastereomeric oxazaborolidines, absolute configurational
assignments
Vicinal amino alcohols are an increasingly important
class of compounds. Members of this group have found
pharmacological applications such as modulators of the
potassium channel in cells,1 as core moieties of antiviral
agents2 and as intermediates in the synthesis of ligands for
sigma and kappa opiate receptors.3 The amino alcohol
moiety is also found in biologically important natural
products such as taxol.4 In organic synthesis, optically
pure cis β-amino alcohols are finding extensive use as
chiral auxiliaries.5–7 Among the cis and trans β-amino
alcohol isomers, the 1,2-cis stereochemistry is particular-
ly difficult to achieve. For these reasons substantial effort
has been directed towards their preparation. The Sharpless
aminohydroxylation8 and its asymmetric variant9 have
provided a facile, general entry to this class of com-
pounds. Additionally, synthesis of individual racemic or
enantiopure amino alcohols has also been achieved. Par-
ticularly noteworthy in this respect is the use of the Ritter
reaction.10, 11 In these cases the requisite optically pure ep-
oxide or diol precursors have been derived through chem-
ical transformations. Since syntheses utilizing optically
pure diols obtained from microbial sources are rapidly
gaining importance,12 we became interested in developing
a synthetic route to enantiopure amino alcohols from these
intermediates. We have recently reported a facile, regio-
and stereoselective synthesis of racemic cis amino alco-
hols from aryl substituted cis-glycols.13 Herein we de-
scribe details on the application of such a route to the syn-
thesis of optically pure cis β-amino alcohols. To our
knowledge, there is only a single example in the recent
literature of cis β-amino alcohol synthesis from a micro-
bially derived diol precursor.14 Therefore, this report con-
stitutes the first general chemoenzymatic synthesis of
Each diol 1–4 when allowed to react with α-acetoxy-
isobutyryl chloride (2-acetoxy-2-methylpropanoyl chlo-
ride) in acetonitrile at 0°C (~15 min) and then at room
temperature (~45 min), provides a single trans chlorohy-
drin acetate isomer (Scheme).13 Due to possible instabili-
ty, this intermediate was immediately converted to the cis
azido acetate 5–8 by displacement of chloride with azide
anion in DMF. Consistent with our previous observa-
tions,13 this transformation was complete within 4 hours
at ~55 ºC in the naphthalene and anthracene cases. On the
other hand, a slow SN2 displacement of chloride was ob-
served in the indane case and complete conversion to the
azido acetate 5 required about 24 hours. An even slower
reaction was observed in the benzocycloheptene case
wherein complete conversion to the azido acetate 8 re-
quired about 40 hours. The azidohydrins 9–12 were sub-
sequently obtained by aminolysis of the ester with ammo-
niacal methanol and were utilized for the next step with-
out additional purification. Finally, catalytic reduction of
the azide moiety with 5% Pd-C in THF/MeOH
1:1 furnished the amino alcohols 13–16 in 41–57% over-
all yield.
Certain points need specific mention. The (1S,2R)-amino
alcohol 1 has continued to attract significant interest due

SYNTHESIS
September 1998
1353
Table 1. Structures and Optical Rotation Data for the Precursor Diols
and the Amino Alcohols
Diol
[α]D
Amine
[α]D
g/100 mL
mg/mL
+3425
+24.7
(c = 0.37,
CHCl3)
(c = 5.1,
MeOH)
–51.026
–37.3
(c = 0.40,
CHCl3)
(c = 16,
MeOH)
+21127
–64.2
(c = 0.096,
MeOH)
(c = 8.7,
MeOH)
+24628
+18.4
(c = 0.056,
MeOH)
(c = 4.5,
MeOH)
–20.816
(c = 0.40,
MeOH)
+172.3
(c = 4.5,
MeOH)
Diastereomeric boronate derivatives of diols with (–)-(S)-
and (+)-(R)-[2-(1-methoxyethyl)phenyl]boronic acid
[(–)-(S)- and (+)-(R)-MPBA] have proven useful for the
stereochemical analysis of bacterially-produced chiral cis
diols.15, 21 Additionally, a single example in the literature
suggests potential utility for MPBA in the analysis of
acyclic 1,2-amino alcohols as well.22 Therefore, in the
Scheme
to its use as the non-peptidic core of indinavir, an HIV present study we have examined the use of these chiral
protease inhibitor that has recently been approved by the boronic acids for the stereochemical analysis of cis 1,2-
1
US Food and Drug Administration.2,18 Although enzy- amino alcohols 13–16. H NMR analysis of the (–)-(S)-
matic resolution has been utilized for the synthesis of MPBA derivatives of racemic cis amino alcohols 13–15,
13,18, 19 the only method for the conversion of microbially prepared in CHCl3,15 showed the presence of well re-
derived 1 to 13, via the Ritter reaction, has been reported solved diastereomeric methyl signals (∆δ = 61 to 106
by Boyd et al.14 Although the Ritter reaction works ppb). Analysis of the (–)-(S)-MPBA derivatives prepared
reasonably well on the 5- and 6-membered ring sys- with the highly enantiomerically enriched amino alcohols
tems,10, 11, 14, 19 the cis selectivity drops when applied to 7- 13–15 having a benzylic R configuration showed that the
membered rings.11 Specifically, the cis stereoselectivity is methyl signals were consistently shifted upfield from the
~85% in the benzocycloheptene case. In this respect our corresponding signal of the diastereomer formed with (+)-
method appears to be superior to the Ritter reaction since (R)-MPBA (Table 2). Based upon our observations we
it provides exclusively the cis stereochemistry for 5-, 6- can make the following prediction for racemic 1-amino-2-
and 7-membered ring systems. In order to unequivocally hydroxyacenaphthylene12 and 4-amino-3-hydroxy-1,2,3,4-
prove the cis stereochemistry in the benzocycloheptene tetrahydrophenanthrene12 (see Table 2). Upon derivatiza-
case,
(±)-trans-5-azido-6,7,8,9-tetrahydro-5H-benzo- tion of each compound with (–)-(S)-MPBA, the upfield
cyclohepten-6-ol was synthesized via a nucleophilic ring methyl resonance should correspond to the amino alcohol
opening of 5,6-epoxy-6,7,8,9-tetrahydro-5H-benzocyclo- isomer which has an R absolute configuration at the
1
heptene.20 Inspection of the H NMR spectrum of this amine-bearing carbon. Another trend, namely a correla-
compound indicated H-5 to be a sharp doublet with J5,6
=
tion between conformational rigidity and the ∆δ values,
7.8 Hz, on the other hand the corresponding proton in 12 seems apparent from Table 2. The diastereomeric ox-
appears as a broadened singlet. Additionally, the NMR azaborolidines of the relatively rigid 5-membered ring
spectrum of the cis azidohydrin 12 prepared from diol 4 systems show the greatest chemical shift difference for the
revealed no detectable trans azidohydrin in the product. methyl resonances, whereas a smaller difference is ob-
Since the 1H NMR spectra of the benzocycloheptene de- served in the more flexible 6-membered naphthalene and
rivatives are complex, unambiguous proton assignments anthracene systems. In 4-amino-3-hydroxy-1,2,3,4-tet-
to diol 4 and the azido acetate 8 derived from it were made rahydrophenanthrene, steric hindrance in the bay region
through HMQC, COSY and DEPT experiments (see the restricts the amino group to an axial orientation. The dias-
experimental section). Table 1 provides a listing of the op- tereomeric oxazaborolidines of this rigid 6-membered
tical rotation data for the starting diols and the corre- ring system again show a larger chemical shift difference
sponding amines derived from them.
for the methyl signals compared to the naphthalene and

SYNTHESIS
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1354
Table 2. Chemical Shift and ∆δ Values for the Methyl Resonances of
the Diastereomeric Oxazaborolidines
diols are more significant compared to the methyl reso-
nances.15, 22 In the present study we have found the methyl
resonances of the oxazaborolidine derivatives to be more
useful. Amino alcohol 16 proved to be extremely insolu-
ble and efforts to derivatize this compound in CHCl3,
THF, and 20% DMF in THF at ambient and elevated tem-
peratures were unsuccessful.
Derivative
of
Chemical Shift of the Oxazaboro-
lidine Methyl Signal
δ (ppm)
∆δ (ppb)b
Chirally Pure Amino Alcohols
In conclusion, we have developed a general and efficient
4-step chemoenzymatic synthesis of cis β-amino alcohols
from chiral cis diols. The reaction conditions are extreme-
ly mild and can therefore be applied to sensitive diols
which could undergo degradation under harsher condi-
tions. The ability of bacterial aromatic hydrocarbon diox-
ygenases to produce enantiomerically pure cis 1,2-diols
from a wide variety of aromatic substrates (substituted
benzenes, polycyclic aromatic compounds and heteroaro-
matics),21, 23, 24 when coupled with the described method-
ology, provides convenient access to a wide range of new
homochiral cis 1,2-amino alcohols.
1.309a and 1.415
1.357a and 1.431
–106
–74
1.382a and 1.443
–61
Racemic Amino Alcohols
1.518 and 1.523
1.241 and 1.434
5
The diols and MPBAs were prepared as described in the litera-
ture.14–17, 22 1H NMR spectra were obtained at 300 MHz in CDCl3
unless stated otherwise. Commercially available α-acetoxyisobutyryl
chloride (1-chlorocarbonyl-1-methylethyl acetate) was purchased and
used without further purification. CH3CN was refluxed over CaH2
and distilled, THF was refluxed over LiAlH4 and distilled. General
experimental procedures are presented, with exceptions being listed
under the specific compound heading.
193
1.285 and 1.415
130
trans-2-Acetoxy-1-chloro Compounds; General Procedure:
To a well stirred solution (or suspension) of the diol (0.41 mmol) in
anhyd CH3CN (2.2 mL) at 0°C was added α-acetoxyisobutyryl chlo-
ride (1.24 mmol). After allowing the reaction to proceed for 15 min at
this temperature, the mixture was warmed to r.t. and the reaction al-
lowed to proceed for an additional 45 min. The mixture was diluted
with EtOAc and washed twice with sat. aqueous NaHCO3. The organ-
ic layer was dried (Na2SO4) and evaporated to dryness. This product
was used in the next step without additional purification.
a
Spectra obtained at 360 MHz in CDCl3. These higher field reso-
nances correspond to the methyl signal (d, J ~ 6.4 Hz) from the (–)-
(S)-MPBA derivatized with the amino alcohol having a benzylic R
absolute configuration.
A negative ∆δ value indicates that the methyl of the (–)-(S)-MPBA
derivatized amino alcohol was upfield from the corresponding
signal of the diastereomer formed with (+)-(R)-MPBA.
b
anthracene derivatives. The acyclic phenyl glycinol deriv-
atives show the smallest chemical shift difference (∆δ = 5
ppb). The 1H NMR analysis of the diastereomers also es-
tablished that amino alcohols 14 and 15 were >98% ee.
cis-2-Acetoxy-1-azido Compounds; General Procedure:
To a solution of the crude trans-2-acetoxy-1-chloro compound
(0.41 mmol) in anhyd DMF (2.2 mL) was added LiN3 (4.1 mmol),
and the mixture was heated at 55°C. Upon completion of the reaction,
the mixture was diluted with EtOAc and washed with H2O. The aque-
ous layer was back-extracted with EtOAc, the organic layers were
combined, dried (Na2SO4) and evaporated. The crude product was
loaded onto a silica gel column and eluted with benzene.
The upfield directional shift for the methyl signals of the
(S)-MPBA oxazaborolidines of amino alcohols 13 and 14
contrasts to the downfield shift of the corresponding sig-
nals in the boronate derivatives of the cis diol precursors
1 and 2, as well as the boronate derivatives of the naphthal-
ene and anthracene dihydrodiols.15 It should be noted that
the formation of the oxazaborolidines (in CHCl3 or THF)
did not proceed as efficiently as the boronate esters.29
While stoichiometric conversion was not observed in the
cis-1-Azido-2-hydroxy Compounds; General Procedure:
Into a well stirred solution of the cis-2-acetoxy-1-azido derivative
(0.28 mmol) in MeOH (5 mL) at 0°C was bubbled NH3 gas for
~15 min. The ice-bath was removed and the mixture was stirred at r.t.
overnight under an ammonia atmosphere. The mixture was evaporat-
ed to dryness, redissolved in CH2Cl2 and washed with H2O. The aque-
ous layer was back-extracted with CH2Cl2, the organic layers were
combined, dried (Na2SO4) and evaporated. The product was of suffi-
ciently high purity and was used in the next step without additional
purification.
1
derivatization of the amino alcohols, H NMR analysis
showed that the resolved signals of the diastereomers re-
flected the enantiopurity of the amino alcohol that is, no
enantiomeric discrimination occurred in the derivatiza-
tion. Despite this apparent limitation, the oxazaboro-
lidines appear very promising for the stereochemical anal-
ysis of cis amino alcohols. From a diagnostic standpoint,
the methoxy resonances of the boronate derivatives of cis
cis-1-Amino-2-hydroxy Compounds; General Procedure:
To a stirred solution of the cis-1-azido-2-hydroxy compound
(0.25 mmol) in THF/MeOH (1:1, 4 mL) was added 5% Pd-C (25.7 mg).

SYNTHESIS
September 1998
1355
The mixture was hydrogenated under 1 atm hydrogen pressure (using
a balloon) at r.t. for 4 h. The mixture was filtered through Celite and
the residue was thoroughly washed with MeOH. Evaporation of the
filtrate afforded the crude amino alcohol which was subjected to col-
umn chromatography (silica gel, 10% MeOH/CH2Cl2).
1H NMR: δ = 7.79, 7.66 (2s, 2H5,10); 7.87–7.75, 7.50–7.43 (m, 4H,
Ar); 4.89 (d, 1H1, J = 3.7 Hz); 4.18 (app quint, 1H2, Japp ~ 4.5 Hz);
3.23 (dt, 1H4, J = 4.9; 17.2 Hz); 3.04 (m, 1H4); 2.15–2.06 (m, 2H3).
HRMS Calcd for C14H13N3O (M+): 239.1059; found: 239.1009.
cis-(1R,2S)-1-Amino-2-hydroxy-1,2,3,4-tetrahydroanthracene (15):
colorless powder that turns yellow rather quickly; yield: 92%.
1H NMR (CDCl3 + 1 drop CD3OD): δ = 7.83, 7.59 (2s, 2H5,10); 7.79–
7.71, 7.42–7.39 (m, 4H, Ar); 4.19 (d, 1H1, J = 4.5 Hz); 4.06 (dt, 1H2,
J = 4.1; 9.7 Hz); 3.16 (dt, 1H4, J = 5.4; 16.9 Hz); 2.96 (m, 1H4); 2.08–
1.87 (m, 2H3).
Indane Derivatives 5 → 9 → 13:
cis-(1R,2S)-2-Acetoxy-1-azido-2,3-dihydro-1H-indene (5): conver-
sion to the azido acetate took 24 h. Colorless oil; yield: 69%.
1H NMR: δ = 7.43–7.25 (m, 4H, Ar); 5.52 (q, 1H2, J = 5.8 Hz); 4.86
(d, 1H1, J = 5.6 Hz); 3.23 (dd, 1H3, J = 6.6; 16.3 Hz); 3.12 (dd, 1H3,
J = 5.9; 16.3 Hz); 2.14 (s, 3H, OAc).
HRMS Calcd for C14H16NO (M+ + 1): 214.1232; found: 214.1235.
HRMS Calcd for C9H7N3 (M+ – CH3CO2H): 157.0640; found:
157.0633.
Benzocycloheptene Derivatives 4 → 8 → 12 → 16:
(±)-cis-5,6-Dihydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene
(4):
NMR data for the (1S,2R)-isomer is identical; yield: 67%.
cis-(1R,2S)-1-Azido-2-hydroxy-2,3-dihydro-1H-indene (9): colorless
oil; quantitative yield.
1H NMR (proton assignments by COSY, HMQC and DEPT, in
CD3COCD3): δ = 7.33 (m, 1H, Ar); 7.12 (m, 2H, Ar); 7.04 (m, 1H,
Ar); 4.86 (d, 1H5, J = 3.7 Hz); 4.15 (d, 1H5–OH, J = 4.1 Hz); 3.83 (m,
1H6); 3.39 (d, 1H6–OH, J = 5.5 Hz); 3.07 (dd, 1H9, J = 10.7; 12.6 Hz);
2.61 (dd, 1 H9, J = 8.5; 13.8 Hz); 2.16 (m, 1H7); 1.89 (m, 1H7); 1.81
(m, 1H8); 1.50 (m, 1H8).
1H NMR: δ = 7.40–7.25 (m, 4H, Ar); 4.78 (d, 1H1, J = 5.4 Hz); 4.60
(m, 1H2); 3.16 (dd, 1H3, J = 6.3; 16.0 Hz); 2.94 (dd, 1H3, J = 6.0;
16.0 Hz); 2.39 (br s, 1HOH).
HRMS Calcd for C9H9N3O (M+): 175.0746; found: 175.0752.
NMR data for the (1S,2R)-isomer is identical; yield: 93%.
cis-(1R,2S)-1-Amino-2-hydroxy-2,3-dihydro-1H-indene (13): color-
less powder; yield: 76%.
cis-(5R,6S)-6-Acetoxy-5-azido-6,7,8,9-tetrahydro-5H-benzocyclo-
heptene (8): conversion to the azido acetate took 42 h and chromatog-
raphy was performed on silica gel using 5% MeOH/benzene. Color-
less solid; yield: 61%.
1H NMR: δ = 7.32–7.21 (m, 4H, Ar); 4.38 (dt, 1H2, J = 3.0; 5.4 Hz);
4.30 (d, 1H1, J = 5.4 Hz); 3.09 (dd, 1H3, J = 5.5; 16.4 Hz); 2.93 (dd,
1H3, J = 2.9; 16.4 Hz); 2.38 (br s, 3HOH,NH).
1H NMR (proton assignments by DQF-COSY, and HMQC): δ =
7.27–7.10 (m, 4H, Ar); 4.98 (ddd, 1H6, J = 1.8; 3.6; 11.3 Hz); 4.77 (br
s, 1H5); 3.10 (t, 1H9, J = 13.5 Hz); 2.66 (dd, 1H9, J = 6.5; 14.5 Hz);
2.31 (m, 1H7); 2.10 (s, 3H, OAc); 1.97 (m, 2H7,8); 1.52 (m, 1H8).
HRMS Calcd for C13H15NO2 (M+ – N2): 217.1103; found: 217.1113.
HRMS Calcd for C9H11NO (M+): 149.0841; found: 149.0847.
NMR data for the (1S,2R)-isomer is identical; yield: 90%.
Naphthalene Derivatives 6 → 10 → 14:
cis-(1R,2S)-2-Acetoxy-1-azido-1,2,3,4-tetrahydronaphthalene (6):
pale yellow, oily product; yield: 71%.
cis-(5R,6S)-5-Azido-6-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclo-
heptene (12): colorless, oily product; yield: 93%.
1H NMR: δ = 7.29–7.25, 7.19–7.16 (m, 4H, Ar); 5.23 (dt, 1H2, J = 3.5;
11.0 Hz); 4.74 (d, 1H1, J = 3.5 Hz); 3.07–2.85 (m, 2H4); 2.32–2.20
(m, 1H3); 2.16 (s, 3H, OAc); 2.04–1.95 (m, 1H3).
1H NMR: δ = 7.29–7.09 (m, 4H, Ar); 4.83 (br s, 1H5); 3.89 (m, 1H6);
3.03 (t, 1H9, J = 13.0 Hz); 2.66 (dd, 1H9, J = 7.2; 14.4 Hz); 2.15 (m,
1H7); 2.05–1.77 (m, 2H7,8); 1.54 (m, 1H8).
HRMS Calcd for C12H14N3O2 (M+ + 1): 232.1086; found: 232.1068.
HRMS Calcd for C11H13NO (M+ – N2): 175.0997; found: 175.1002.
cis-(1R,2S)-1-Azido-2-hydroxy-1,2,3,4-tetrahydronaphthalene (10):
pale yellow, oily product; quantitative yield.
cis-(5R,6S)-5-Amino-6-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclo-
heptene (16): colorless powder; yield: 72%.
1H NMR: δ = 7.31–7.26, 7.20–7.18 (m, 4H, Ar); 4.68 (d, 1H1, J =
3.8 Hz); 4.12–4.03 (m, 1H2); 3.01 (dt, 1H4, J = 4.9; 17.3 Hz); 2.88 (m,
1H4); 2.13 (d, 1HOH, J = 9.0 Hz); 2.04–1.97 (m, 2H3).
1H NMR (CDCl3/CD3OD): δ = 7.30–7.03 (m, 4H, Ar); 4.16 (br s,
1H5); 3.90 (ddd, 1H6, J = 1.9; 4.1; 8.1 Hz); 2.92 (ddd, 1H9, J = 2.2;
9.7; 14.6 Hz); 2.76 (ddd, 1H9, J = 2.2; 8.5; 14.6 Hz); 2.10–1.75 (m,
3H7,8); 1.59 (m, 1H8).
HRMS Calcd for C10H11N3O (M+): 189.0902; found: 189.0903.
cis-(1R,2S)-1-Amino-2-hydroxy-1,2,3,4-tetrahydronaphthalene (14):
colorless powder; yield: 80%.
HRMS Calcd for C11H15NO: 177.1154; found: 177.1161.
1H NMR: δ = 7.40–7.37, 7.22–7.19, 7.13–7.10 (m, 4H, Ar); 4.11 (d,
1H1, J = 4.7 Hz); 3.98 (dt, 1H2, J = 4.5; 10.4 Hz); 2.93 (dt, 1H4, J =
4.7; 16.7 Hz); 2.79 (m, 1H4); 1.97–1.80 (m, 2H3).
(±)-trans-5-Azido-6-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohep-
tene:
1H NMR: δ = 7.40 (m, 1H, Ar); 7.24 (m, 2H, Ar); 7.14 (m, 1H, Ar);
4.74 (d, 1H5, J = 7.8 Hz); 3.75 (m, 1H6); 2.92 (ddd, 1H9, J = 2.2; 8.8;
14.3 Hz); 2.73 (ddd, 1H9, J = 2.3; 9.2; 14.3 Hz); 2.17 (m, 1H7); 2.08
(br s, 1HOH); 1.84 (m, 2H7,8); 1.57 (m, 1H8).
HRMS Calcd for C10H14NO (M+ + 1): 164.1075; found: 164.1052.
Anthracene Derivatives 7 → 11 → 15:
HRMS Calcd for C11H13N3O (M+): 203.1059; found: 203.1057.
cis-(1R,2S)-2-Acetoxy-1-azido-1,2,3,4-tetrahydroanthracene
(7):
yellow, oily product; yield: 62%.
1H NMR: δ = 7.80, 7.66 (2s, 2H5,10); 7.86–7.45, 7.50–7.43 (m, 4H,
Ar); 5.33 (dt, 1H2, J = 3.5; 10.4 Hz); 4.93 (d, 1H1, J = 3.5 Hz); 3.24
(dt, 1H4, J = 5.8; 17.2 Hz); 3.09 (m, 1H4); 2.41–2.28 (m, 1H3); 2.17
(s, 3H, OAc); 2.13–2.04 (m, 1H3).
This work was supported by NCI contract NO1-CB-61004
(M.K.L), the Ministry of Science and Technology of Slovenia (B.Z),
in part by GM29909 from NIGMS (D.T.G), and a predoctoral fel-
lowship (S.M.R) through the Iowa Center for Biocatalysis and
Bioprocessing (University of Iowa) and USPHS training grant T32
GM8365 from NIGMS. We thank Drs. Bogdan Kralj and Dusˇan
HRMS Calcd for C16H15N3O2 (M+): 281.1164; found: 281.1150.
cis-(1R,2S)-1-Azido-2-hydroxy-1,2,3,4-tetrahydroanthracene (11):
yellow, oily product that solidifies slowly in the refrigerator; yield:
96%.
ˇ
Zigon at the Joˇzef Stefan Institute, Slovenia, for mass spectral
measurements.

SYNTHESIS
Papers
1356
† Present address: Department of Chemistry, University of North
Dakota, Grand Forks, ND 58202 USA, E-mail: mlaksh-
man@mail.chem.und.nodak.edu, tel +1(701)777-2495, fax
+1(701) 777-2331.
(9) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2810.
Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2813.
‡ Present address: PE Applied Biosystems, 850 Lincoln Center
Drive, Foster City, CA 94404, USA.
§ Present address: Swiss Federal Institute for Environmental Sci-
ence and Technology (EAWAG), Department of Microbiology,
Ueberlandstrasse 133, CH-8600 Dübendorf, Switzerland, E-mail:
resnick@eawag.ch
(10) Senanayake, C. H.; Roberts, F. E.; DiMichele, L. M.; Ryan, K.
M.; Liu, J.; Fredenburgh, L. E.; Foster, B. S.; Douglas, A. W.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett.
1995, 36, 3993.
(11) Senanayake, C. H.; DiMichele, L. M.; Liu, J.; Fredenburgh, L.
E.; Ryan, K. M.; Roberts, F. E.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7615.
(12) For an excellent review see: Hudlicky, T.; Entwistle, D. A.; Pit-
zer, K. K.; Thorpe, A. J. Chem. Rev. 1996, 96, 1195.
(13) Lakshman, M. K.; Zajc, B. Tetrahedron Lett. 1996, 37, 2529.
(14) Boyd, D. R.; Sharma, N. D.; Bowers, N. I.; Goodrich, P. A.;
Groocock, M. R.; Blacker, A. J.; Clarke, D. A.; Howard, T.;
Dalton, H. Tetrahedron: Asymmetry 1996, 7, 1559.
(15) Resnick, S. M.; Torok, D. S.; Gibson, D. T. J. Org. Chem. 1995,
60, 3546.
(1) Roxburgh, C. J. Synthesis 1996, 307.
(2) A class of HIV type 1 protease inhibitors, L-735,524, L-
704,486, L-685,434, L-689,502, utilizes the (1S,2R)-1-amino-
2-hydroxyindane core: Vacca, J. P.; Dorsey, B. D.; Schleif, W.
A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quin-
tero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach,
A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.;
Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Anderson, P. S.;
Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. 1994, 91, 4096.
(3) Radesca, L.; Bowen, W. D.; Di Paolo, L.; de Costa, B. R.
J. Med. Chem. 1991, 34, 3058.
(16) Resnick, S. M.; Gibson, D. T. Appl. Environ. Microbiol. 1996,
62, 1364.
(17) Induced cells of strain PpF39/D (300 mL) incubated for 24 h
with 300 mg 2-indanol yielded 217 mg of crude products. Radi-
al dispersion chromatography was used to isolate (–)-(1S,2R)-
1,2-dihydroxyindane [(–)-1, 92% ee, 110 mg, >85% relative
product yield], trans-1,2-dihydroxyindane (13 mg), and 2-hy-
droxyindan-1-one (<2 mg). The enantiomeric purity of (–)-1
was determined by chiral stationary phase HPLC.
(18) Ghosh, A. K.; Kincaid, J. F.; Haske, M. G. Synthesis 1997, 541.
(19) Igarashi, Y.; Otsutomo, S.; Harada, M.; Nakano, S.; Watanabe,
S. Synthesis 1997, 549.
Rajagopalan, P.; Scribner, R. M.; Pennev, P.; Schmidt, W. K.;
Tam, S. W.; Steinfels, G. F.; Cook, L. Bioorg. Med. Chem. Lett.
1992, 2, 715.
Rajagopalan, P.; Scribner, R. M.; Pennev, P.; Mattei, P. L.; Ke-
zar, H. S.; Cheng, C. Y.; Cheeseman, R. S.; Ganti, V. R.; John-
son, A. L.; Wuonola, M. A.; Schmidt, W. K.; Tam, S. W.;
Steinfels, G. F.; Cook, L. Bioorg. Med. Chem. Lett. 1992, 2,
721.
(4) For some examples on the synthesis of the taxol C-13 side-chain
see: Hönig, H.; Seufer-Wasserthal, P.; Weber, H. Tetrahedron
1990, 46, 3841.
(20) Lakshman, M.; Nadkarni, D. V.; Lehr, R. E. J. Org. Chem.
1990, 55, 4892.
(21) Resnick, S. M.; Lee, K.; Gibson, D. T. J. Indust. Microbiol.
1996, 17, 438.
(22) Burgess, K.; Porte, A. M. Angew. Chem., Int. Ed. Engl. 1994,
33, 1182.
(23) Gibson, D. T.; Zylstra, G. J.; Chauhan, S. In Pseudomonas: Bio-
transformations, Pathogenesis, and Evolving Biotechnology;
Silver, S.; Chakrabarty, A. M.; Iglewski, B.; Kaplan, S., Eds.;
American Society for Microbiology: Washington, D.C., 1990;
pp 121.
Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1991, 56,
6939.
Georg, G. I.; Mashava, P. M.; Akgün, E.; Milstead, M. W.
Tetrahedron Lett. 1991, 32, 3151.
Holton, R. A.; Liu, J. H. Bioorg. Med. Chem. Lett. 1993, 3,
2475.
Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 1994,
59, 5104.
(5) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
(6) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 6811.
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron Lett.
1996, 37, 3815.
(24) Boyd, D. R.; Sharma, N. D.; Dalton, H. In Organic Reactivity:
Physical and Biological Aspects; Golding, B. T.; Griffin, R. J.;
Maskill, H., Eds.; The Royal Society of Chemistry: Cambridge,
UK, 1995; pp 130.
(25) Gibson, D. T.; Resnick, S. M.; Lee, K.; Brand, J. M.; Torok, D.
S.; Wackett, L. P.; Schocken, M. J.; Haigler, B. E. J. Bacteriol.
1995, 177, 2615.
(26) Imuta, M.; Ziffer, H. J. Org. Chem. 1978, 43, 4540.
(27) Jerina, D. M.; Daly, J. W.; Jeffrey, A. M.; Gibson, D. T. Arch.
Biochem. Biophys. 1971, 142, 394.
(28) Jerina, D. M.; Selander, H.; Yagi, H.; Wells, M. C.; Darvey, J.
F.; Mahadevan, V.; Gibson, D. T. J. Am. Chem. Soc. 1976, 98,
5988.
Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527.
Davies, I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J.
J. Org. Chem. 1996, 61, 9629.
Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.;
Wald, S. A. Tetrahedron Lett. 1997, 38, 1125.
Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800.
Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62,
5226.
(7) Bellucci, C. M.; Bergamini, A.; Cozzi, P. G.; Papa, A.; Taglia-
vini, E.; Umani-Ronchi, A. Tetrahedron: Asymmetry 1997, 8,
895.
(8) Sharpless, K. B.; Chong, A. O.; Oshima, K. J. Org. Chem. 1976,
41, 177.
(29) Since submission of this manuscript other authors have reported
difficulties in derivatizing propranolol, a β-amino alcohol, with
phenylboronic acid: Hori, M.; Janda, K. D. J. Org. Chem. 1998,
63, 889.
Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544.