Short chemoenzymatic azide-free synthesis of oseltamivir (tamiflu): Approaching the potential for process efficiency

Article abstract of DOI:10.1002/adsc.200900844

A short chemoenzymatic and azide-free synthesis of oseltamivir was attained with the key steps consisting of a one-pot Dauben-Michno oxidative transposition and animation and a reductive transposition of an acrylate.

Full text of DOI:10.1002/adsc.200900844

UPDATES
DOI: 10.1002/adsc.200900844
Short Chemoenzymatic Azide-Free Synthesis of Oseltamivir
(Tamiflu): Approaching the Potential for Process Efficiency
ACHTUNGTRENNUNG
Lukas Werner,a Ales Machara,a and Tomas Hudlickya,*
a
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario
L2S 3 A1, Canada
Fax : (+1)-905-984-4841; phone: (+1)-905-688-5550 ext. 4956; e-mail: thudlicky@brocku.ca
Received: November 11, 2009; Revised: December 5, 2009; Published online: December 30, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900844.
Abstract: A short chemoenzymatic and azide-free
synthesis of oseltamivir was attained with the key
steps consisting of a one-pot Dauben–Michno oxi-
dative transposition and amination and a reductive
transposition of an acrylate.
spectively. In our first- and second-generation efforts,
as well as in the above two preparations, additional
transformations were required in order to convert the
vinyl bromide functionality in 2 into the acrylate
moiety of oseltamivir. Such additional steps, as well
as protective and deprotective operations inherent in
most of the approaches to oseltamivir published to
date,[4] greatly detract from the overall efficiency and
hence limit the practicality component essential for a
large-scale industrial process.
Keywords: antiviral agents; asymmetric synthesis;
biotransformations; oxidative transposition; synthe-
sis design; tamiflu synthesis
The efficient and scaleable synthesis of tamiflu and/
or related, potentially active, compounds remains a
high priority in the event of a pandemic. Herein we
Recently we have reported a formal chemoenzymatic report a fourth-generation approach that is among
synthesis of oseltamivir (1) from ethyl benzoate in ten the shortest reported to date and which has the po-
steps compressed to just seven operations.[1] While tential for a very efficient process synthesis. The start-
this particular synthesis compared very favorably with ing material is ethyl benzoate, a commodity chemical
most preparations reported to date[2] it still relied on containing nine of the sixteen carbon atoms of oselta-
the use of azide as means of introduction of the C-5 mivir.
amino group. The synthesis represented a third-gener-
The synthesis begins with the whole-cell fermenta-
ation effort that evolved from our previous, and less tion of ethyl benzoate with E. coli JM109ACHTUNGTRENNUNG(pDTG
efficient, attempts, which utilized the cis-dihydrodiol 2 601), a recombinant organism developed by Gibson.[5]
derived enzymatically from bromobenzene as shown The over-expression of toluene dioxygenase, the
in Scheme 1.[3]
enzyme required for the cis-dihydroxylation of arenes,
This commercially available homochiral cis-dihy- facilitates the production of diol 3, which is isolated
drodiol was also used as a starting material in two by extraction from the fermentation broth in yields of
other syntheses, those of Fang[4p] and Banwell,[4o] re-
Scheme 1. Symmetry-based design for oseltamivir.
Adv. Synth. Catal. 2010, 352, 195 – 200
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195

Lukas Werner et al.
UPDATES
Scheme 2.
1–2 gLꢀ1 and immediately converted to its acetonide transposition, is well known for oxidations of tertiary
4, Scheme 2. alcohols containing electron-donating substituents or
Without further purification the acetonide is ex- cycloalkenes[7] but to the best of our knowledge has
posed to the in situ generated acylnitroso component no precedent for substrates with strong electron-with-
for the inverse-electron demand Diels–Alder cycload- drawing groups. We discovered that chromium triox-
dition, which provides oxazine 5 as a single isomer in ide dissolved in acetic anhydride (a variation to Fies-
an overall yield of 88% from diol 3. Reduction of the erꢁs reagent) is very suitable for this transformation
oxazine yields the allylic alcohol 6 (87%), which has while other oxidizing agents such as PDC, PCC, IBX,
been previously converted to oseltamivir in six steps. Dess–Martin periodate or TEMPO derivatives gave
At this point a new protocol was incorporated in only low yields of 7. Although the oxidative rear-
order to eliminate the use of azide in the introduction rangement proceeds at low temperature (48C) it is
of the remaining nitrogen functionality. The allylic al- necessary to prepare a homogeneous solution of the
cohol underwent a [3,3]oxidative rearrangement[6] to oxidizing agent by heating chromium trioxide in
enone 7 when exposed to chromium oxide. This type acetic anhydride at 808C prior to the reaction. After
of rearrangement, the Dauben–Michno oxidative complete dissolution of chromium trioxide the mix-
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Short Chemoenzymatic Azide-Free Synthesis of Oseltamivir (Tamiflu)
ture is cooled to room temperature, diluted with a were not successful (oxymercuration, for example)
small amount of dichloromethane, and cooled to 48C. and produced regioisomeric mixtures in low yields.
At higher temperatures we observed the formation of
In summary, we have provided a simplified prepa-
aromatic by-products or the C-4 epimer of enone 7. ration of the title compound in a manner that com-
Enone 7 was then converted to oxime 8 without isola- pares well in efficiency to all other preparations ac-
tion in 75–82% yield over the two steps.
cording to a recent analysis performed by Andraos
Hydrogenation of the unsaturated oxime isomers who provided the green chemistry metrics analysis of
produced the saturated amino ester 9, which was not most published syntheses for material efficiency.[9] Al-
isolated but converted directly to the Boc carbamate though our previous synthesis, published after An-
10 with Boc anhydride in 50% yield over the two draosꢁ review, was not yet subjected to the evaluation,
steps. However hydrogenation of unsaturated oxime 8 we plan to compare the efficacy of the current proce-
in aqueous ethanol in the presence of 2–3 equivalents dure with that of other published preparations in the
of Boc anhydride afforded directly Boc carbamate 10 near future. The attainment of alcohol 12 described in
in 90–93% yield. A small amount (~10%) of the fully this paper represents a substantial improvement over
saturated ester 11 was also observed probably as a other procedures: the allylic alcohol 12 is obtained
consequence of base-catalyzed elimination of the C-2 from diol 3 in just five operations and the entire se-
ether promoted by the presence of the primary quence (3 to 12) may be performed without chroma-
amine.
tography on a multi-gram scale! The overall yield of
Exposure of the saturated ester 10 to sodium ethox- 12 from diol 3 is 52% when chromatography is used
ide (0.5 equivalents) in ethanol resulted in the elimi- for purification at key steps (oxime 8 and ester 10).
nation of the C-2 ether moiety and generation of the With the purification of several intermediates by crys-
required allylic alcohol 12 in 94% yield. Thus, the tallization (oxime 8, ester 10, and alcohol 12) the
entire sequence from ethyl benzoate-derived cis-dihy- overall yield is lower as some product remains in the
drodiol 3 to alcohol 12 consists of seven chemical mother liquors. Furthermore, it is possible to use any
steps reduced to just five operations and proceeding in benzoate ester, or even a mixture of esters that are
an overall yield of 52% from diol 3.
substrates for the enzyme,[10] in the fermentation and
Attainment of the allylic alcohol constitutes a to carry such a mixture through the cycloaddition step
formal synthesis of oseltamivir as accomplished by where all components may easily be transesterified to
Shibasaki[4u] as well as Corey.[4g] The final step in the oxazine 5. The efficiency of the whole-cell fermenta-
synthesis requires the introduction of the 3-pentyl tion of benzoate esters with the recombinant organ-
ether and this may be accomplished by previously re- ism that over-expresses toluene dioxygenase requires
ported procedures, most notably by that of Corey.[4g] different metrics for evaluation than the synthetic
Repetition of Coreyꢁs procedure produced, in our transformations. The space-time yields of cis-dihydro-
hands, the Boc-protected oseltamivir 15 in 21% over- diols are expressed in grams/liter/hour. In the case of
all yield from the allylic alcohol 12. Aziridine forma- diol 3 the amounts obtained from a 15-L fermentor
tion proceeded in 35% yield from 12 at the expense (9–10 L
working
volume)
are
reproducibly
of the formation of the corresponding oxazoline 14 as 1 gLꢀ1 hour. The medium-scale procedure for this fer-
a by-product in 28% yield, Scheme 3.
mentation has been described in detail[11] and the iso-
However, our repetition of Shibasakiꢁs conditions[4u] lated yields of 3 are currently 9–10 grams per fermen-
provided aziridine 13 in 70–78% yield with only trace tation in which ~20 grams of ethyl benzoate are intro-
amounts of oxazoline 14. Aziridine 13 was converted duced to the cells grown to maximum density. There
to the Boc-protected oseltamivir 15 by copper triflate- are no by-products observed in this fermentation and
catalyzed opening of the aziridine in 60% yield.
~10 grams of ethyl benzoate are recovered. Thus the
Attempts at direct alkylation of the allylic alcohol “chemical yield” of this transformation based on re-
in 12 with 3-iodopentane in the presence of silver car- covered starting material would approach a quantita-
bonate[8] produced 15 in low yields (<10%). Other tive conversion. For eventual large-scale commercial
methods of direct introduction of the 3-pentyl ether application the titers could be improved further by di-
rected evolution of the organism. Finally, the chal-
lenge for future generations of oseltamivir synthesis
that use the allylic alcohol 12 as an intermediate
would certainly be the invention of a new method for
introduction of the ether moiety onto the allylic alco-
hol in 12 (as well as other alcohols not responding
well to standard SN2-type ether formation).
Scheme 3. Oxazoline formation during the Mitsunobu reac-
tion.
Adv. Synth. Catal. 2010, 352, 195 – 200
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197

Lukas Werner et al.
UPDATES
stirred for additional 16 h. The mixture was then diluted
with ethyl acetate (130 mL) and extracted 4ꢃ8 mL with sa-
turated NaHCO3 solution. The combined aqueous layers
were re-extracted with ethyl acetate (30 mL). The combined
organic layer was dried with MgSO4 and evaporated. Chro-
matography of the residue [hexane-ethyl acetate (1:1)!
ethyl acetate, 30 mL (15 g) silica] afforded oxime 8 as a
greenish oil which solidified on trituration with 2-propanol;
yield: 860 mg (82%). Recrystallization from 2-propanol-
hexane provided 8 as a white solid; mp 106–1168C; Rf 0.30
(ethyl acetate); [a]2D0: ꢀ52.63 (c 1, CHCl3); IR (KBr): n=
1H NMR (300 MHz, CDCl3): d=9.65 (bs, 1H), 7.77 (s, 1H),
6.29 (d, J=8.4 Hz, 1H), 5.04 (d, J=5.4 Hz, 1H), 5.02 (dd,
J=8.4, 8.1 Hz, 1H), 4.32 (m, 1H), 4.30 (m, 2H), 2.06 (s,
3H), 1.49 (s, 3H), 1.44 (s, 3H), 1.36 (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=171.2, 165.4, 148.9, 132.4,
124.8, 111.1, 76.0, 70.6, 61.7, 49.9, 27.9, 26.4, 23.3, 14.1; MS
(FAB+): m/z (%)=313 (M+H)+, 255 (73), 195 (76), 150
(16), 43 (38); HR-MS: m/z=313.14056, calcd. for
C14H21N2O6: 313.13996; anal. calcd. for C14H21N2O6: C 53.84,
H 6.45; found: C 54.80,H 7.52; the crystals contain 15 mol%
of 2-propanol.
Experimental Section
All non-aqueous reactions were conducted in an argon at-
mosphere using standard Schlenk techniques for the exclu-
sion of moisture and air. Dichloromethane was distilled
from calcium hydride, THF and toluene were dried over po-
tassium/benzophenone. Analytical thin layer chromatogra-
phy was performed on Silicycle 60 ꢂ 250 mm TLC plates
with F-254 indicator. Flash column chromatography was per-
formed using Kieselgel 60 (230–400 mesh). Melting points
were recorded on a Hoover Unimelt apparatus and are un-
corrected. IR spectra were obtained on a Perkin–Elmer One
FT-IR spectrometer. Optical rotation was measured on a
Perkin–Elmer 341 polarimeter at a wavelength of 589 nm.
1H and 13C spectra were recorded on a 300 MHz and
600 MHz spectrometer. All chemical shifts are referenced to
TMS or residual undeuterated solvent. Data of proton spec-
tra are reported as follows: chemical shift (multiplicity [sin-
glet (s), doublet (d), triplet (t), quartet (q) and multiplet
(m)], coupling constants [Hz], integration). Carbon spectra
were recorded with complete proton decoupling and the
chemical shifts are reported in ppm (d) relative to solvent
resonance as internal standard. Mass spectra and high reso-
lution mass spectra were performed by the analytical divi-
sion at Brock University.
3367, 2988, 1720, 1659, 1547, 1382, 1246, 1069, 1023 cmꢀ1
;
(3aR,6S,7R,7aS)-7-Acetylamino-6-tert-butoxycarbon-
ylamino-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo
dioxole-4-carboxylic Acid Ethyl Sster (10)
ACHTUNGTRENNUNG[1,3]-
(3aR,7R,7aS)-Ethyl-7-acetamido-6-(hydroxyimino)-
2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[d]ACTHNUGTRNEUNG[1,3]-
dioxole-4-carboxylate (8)
Procedure
A (“stepwise”): A suspension of oxime 8
(400 mg; 1.27 mmol) and 100 mg Rh/Al2O3 (5%) in EtOH
(96%, 45 mL) was hydrogenated in the Parr apparatus (60
pound/inch2). After 16 h the reaction mixture was filtered
through short bed of celite and evaporated.
On a preparative scale the amine (3aR,4R,6S,7R,7aS)-
ethyl-7-acetamido-6-amino-2,2-dimethylhexahydrobenzo[d]-
The oxidizing agent was prepared by stirring CrO3 (835 mg;
8.35 mmol) in Ac2O (2 mL) at 808C. After 7 min the result-
ing slurry was allowed to cool to room temperature diluted
with 6 mL of dichloromethane and cooled in an ice bath.
This solution was added over 30 seconds to a cooled (48C)
solution of tertiary alcohol 6 (1 g; 3.34 mmol) in dichlorome-
thane (20 mL). After 5 min of stirring the reaction was
quenched by addition of 8 mL EtOH, pyridine (0.4 mL) and
solid NaHCO3 (2 g). The reaction mixture was then stirred
for additional 5 min in an ice bath and 30 min at room tem-
perature.
AHCTUNGTREG[NNUN 1,3]dioxole-4-carboxylate (9) was not isolated but taken di-
rectly to the next step. An analytical sample was purified via
flash column chromatography [dichloromethane-methanol
(1:1)] to yield amine 9 as colorless oil: Rf 0.26 (1:1 dichloro-
methane-methanol); [a]2D0: ꢀ11.54 (c 1, CHCl3); IR (KBr):
n=3445, 2984, 1733, 1654, 1556, 1384, 1222, 1144, 1049 cmꢀ1
;
On
(3aR,7S,7aS)-ethyl-7-acetamido-2,2-dimethyl-6-oxo-3a,6,7,7a-
tetrahydrobenzo[d][1,3]dioxole-4-carboxylate (7) was not
a
preparative scale the intermediate enone
1H NMR (600 MHz, CDCl3): d=5.52 (d, J=8.4 Hz, 1H),
4.58 (dd, J=4.8, 4.2 Hz, 1H), 4.28 (m, 1H), 4.19 (m, 1H),
4.05 (dd, J=8.4, 4.8 Hz, 1H), 3.56 (dd, J=10.8, 8.4 Hz, 1H),
2.81 (ddd, J=13.2, 4.2, 4.2 Hz, 1H), 2.76 (m, 1H), 2.06 (s,
3H), 2.04 (m, 1H), 1.85 (ddd, J=13.2, 11.9, 11.9 Hz, 1H),
1.55 (s, 3H), 1.36 (s, 3H), 1.28 (t, J=7.2, 3H); 13C NMR
(75 MHz, CDCl3): d=171.1, 170.8, 109.7, 77.9, 74.0, 60.9,
59.7, 50.8, 41.4, 30.9, 28.1, 26.2, 23.8, 14.1; MS (FAB): m/z
(%)=301 (M+ +H), 273 (8), 226 (7), 184 (13), 151 (7), 110
(9), 43 (13); HR-MS: m/z=300.1800, calcd. for C14H24N205:
300.1685.
ACHTUNGTRENNUNG
isolated and taken directly to the next step. An analytical
sample was purified via flash column chromatography (ethyl
acetate) Analytical data for intermediary enone 7: Colorless
oil: Rf 0.6 (ethyl acetate); [a]2D0: +19.35 (c 1, CHCl3); IR
(KBr): n=3385, 2988, 1724, 1712, 1662, 1543, 1383, 1253,
1077, 1024 cmꢀ1 1H NMR (300 MHz, CDCl3): d=6.94 (s,
;
1H), 6.10 (d, J=5.4 Hz, 1H), 5.13 (d, J=4.8 Hz, 1H), 4.82
(m, 1H), 4.39 (m, 1H), 4.35 (q, J=7.2 Hz, 1H), 2.10 (s, 3H),
1.61 (s, 3H), 1.48 (s, 3H), 1.36 (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=195.0, 170.8, 164.5, 140.7, 134.5, 112.0,
70.3, 62.3, 58.3, 27.7, 26.4, 23.2, 14.0; MS (EI): m/z (%)=
297 (M+), 239 (4), 221 (4), 197 (14), 175 (13), 151 (11), 84
(100), 43 (34); HR-MS: m/z=297.1218, calcd. for
C14H19N06: 297.1212.
The above reaction mixture was again cooled in an ice
bath and NH2OH·HCl (2.32 g; 33.43 mmol) was added in
one portion. After 1 h of stirring in the ice bath the reaction
mixture was allowed to warm to room temperature and
Minor over-hydrogenated product (1R,3S,4R,5R)-ethyl 4-
acetamido-3-amino-5-hydroxycyclohexanecarboxylate: white
solid: mp 158–1628C (CHCl3); Rf 0.10 (1:1 dichlorome-
thane-methanol); [a]D20: dynamic ꢀ12 to +7 (c 1, CHCl3/
MeOH 1:1); IR (KBr): n=3444, 3422, 3279, 3093, 2982,
2932, 2900, 2865, 2846, 2798, 1731, 1640, 1592, 1562, 1453,
1383, 1320, 1276, 1244, 1222, 1191, 1155, 1101, 1048, 1031,
977, 956, 855, 744, 609 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d=4.15 (q, J=7.2 Hz, 2H), 3.50–3.42 (m, 2H), 3.33 (dddd,
J=4ꢃ~1.5 Hz, 1H) 2.62 (m, 1H), 2.50 (dddd, J=3.3, 3.3,
198
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Short Chemoenzymatic Azide-Free Synthesis of Oseltamivir (Tamiflu)
12.6, 12.6 Hz, 1H) 2.27–2.16 (m, 2H), 2.05 (s, 3H), 1.57–1.48
(m, 1H), 1.44 (ddd, J=6.3, 6.3, 6.3 Hz, 1H), 1.27 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=174.10, 173.47,
70.35, 60.82, 60.49, 52.01, 38.68, 36.06, 35.11, 21.80, 13.21;
MS (FAB+): m/z (%)=245 (100), 168 (12); HR-MS: m/z=
245.15013, calcd. for C11H21N2O4: 245.14667.
concentrated. Chromatography [ethyl acetate, 6 mL silica]
afforded the amide 10 as a white solid; yield: 87 mg (93%).
AHCTUNGTREG(NNUN 3R,4R,5S)-4-Acetylamino-5-tert-butoxycarbonyl-
amino-3-hydroxy-cyclohex-1-enecarboxylic Acid
Ethyl Ester (12)
The crude mixture containing 9 was dissolved in dichloro-
methane (20 mL) and Boc2O (800 mg; 3.66 mmol) was
added and the mixture stirred at room temperature. The
progress of the reaction was monitored by TLC (ethyl ace-
tate-hexane 1:1). After 6 h the reaction mixture was diluted
with dichloromethane (45 mL) and washed with a saturated
solution of NaHCO3 (5 mL+1 g of solid NaHCO3). The or-
ganic layer was dried with MgSO4 and evaporated. Chroma-
tography of the residue [ethyl acetate-hexane (3:1)!ethyl
acetate, 15 g silica] afforded protected amide 10 as a white
solid (yield: 260 mg, 50%) and ~10% of over-hydrogenated
by-product (1R,3S,4R,5R)-ethyl 4-acetamido-3-(tert-butoxy-
carbonylamino)-5-hydroxycyclohexanecarboxylate (11).
Analytical data for major product 10: white solid; mp
174–1758C (ethyl acetate-hexane); Rf =0.3 (ethyl acetate);
[a]2D0: ꢀ33.51 (c 1, CHCl3); IR (KBr): n=3349, 2978, 2930,
2885, 2360, 2340, 1731, 1682, 1656, 1528, 1459.87, 1384, 1371,
1346, 1289, 1253, 1219, 1166, 1120, 1092, 1064, 1044, 1024,
1008, 988, 969, 958, 929, 905, 870, 800, 781, 755, 715, 696,
Acetonide 10 (534 mg; 1.33 mmol) was dissolved in EtOH
(10 mL) and 12.4 mL of ethanolic sodium ethoxide solution
(0.05M) were added dropwise over a period of 1 min. After
5 min of stirring at room temperature reaction mixture was
quenched by addition of 1 g of silica and then filtered and
evaporated. Chromatography [ethyl acetate!ethyl acetate-
ethanol (1:1), 5 g silica] of the residue afforded allyl alcohol
12 as a white solid; yield: 432 mg (94%); mp 177–1788C
(ethyl acetate-hexane); Rf =0.2 (ethyl acetate); [a]2D0: ꢀ9.14
(c 1, CHCl3); IR (KBr): n=3341, 2926, 2854, 2360, 2326,
1726, 1680, 1654, 1626, 1530, 1460, 1319, 1295, 1249, 1165,
1127, 1091, 1046, 1025, 992, 946, 908, 863, 782, 755, 735, 644,
1
607, 590, 571, 543, 491, 460, 437 cmꢀ1; H NMR (CDCl3, 600
MHz): d=7.35 (d, J=5.8 Hz, 1H), 6.83 (dd, J=2.4, 2.4 Hz,
1H), 5.07 (bs, 1H), 4.92 (d, J=7.9 Hz, 1H), 4.36–4.29 (m,
1H), 4.27–4.16 (m, 2H), 3.85–3.83 (m, 1H), 3.77–3.73 (m,
1H), 2.84 (dd, 1H, J=17.4, 5.1 Hz, 1H), 2.21 (dddd, J=
17.4, 11.0, 2 x ꢁ 3 Hz, 1H), 2.03 (s, 3H), 1.47 (s, 9H), 1.30
(t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d=173.61,
165.86, 157.64, 139.05, 127.65, 80.87, 73.60, 61.05, 60.55,
48.05, 30.83, 28.23, 23.09, 14.17; MS (FAB+): m/z (%)=343
(M+ +H), 287 (100), 243 (25), 208 (30); HR-MS; m/z=
343.18417, calcd. for C16H27N2O6: 343.18691; anal. calcd. for
C16H27N2O6: C 56.13, H 7.65, N 8.18; found: C 56.31, H 7.83,
N 8.17.
653, 624, 586, 545, 514, 464, 431 cmꢀ1 1H NMR (CDCl3,
;
600 MHz): d=5.63 (d, J=9.3 Hz, 1H), 4.96 (d, J=8.7 Hz,
1H), 4.57 (dd, 2 x J=3.9, 3.9 Hz, 1H), 4.33–4.18 (m, 2H),
4.00 (ddd, J=11.4, 9.3, 9.0 Hz, 1H), 3.86 (dd, J=4.5, 9.0 Hz,
1H), 3.38 (m, 1H), 2.83 (ddd, J=4.2, 4.2, 8.7 Hz, 1H), 2.12
(ddd, J=3.9, 3.9, 9.6 Hz, 1H), 2.01 (s, 3H), 1.92 (ddd, J=
13.2, 13.2, 13.2 Hz, 1H), 1.43 (s, 9H), 1.36 (s, 3H), 1.28 (s,
3H), 1.27 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d=171.27, 170.40, 109.93, 79.73, 78.66, 73.76, 61.03, 55.22,
50.78, 41.38, 29.71, 28.33, 27.99, 26.23, 23.43, 14.16; MS
(EI+): m/z (%)=385 (3) (M+ꢀCH3), 341 (11), 329 (15),
311 (20); HR-MS: m/z=385.19829, calcd. for C18H29N2O7:
385.19748; anal. calcd. for C19H32N2O7: C 56.99, H 8.05, N
7.00; found: C 57.13, H 8.19, N, 6.93.
Supporting Information
1
Experimental procedures and H- and 13C NMR spectra for
compounds 3–15 are available as Supporting Information.
Acknowledgements
Analytical data for minor product 11 [(1R,3S,4R,5R)-
Ethyl 4-Acetamido-3-(tert-butoxycarbonylamino)-5-hydroxy-
cyclohexanecarboxylate]: gel-like solid; mp 1808C (ethyl
acetate-hexane); RF =0.1 (ethyl acetate); [a]2D0: ꢀ90.0 (c 1,
CHCl3); IR (KBr): n=3357, 2979, 2936, 2871, 1725, 1686,
1654, 1569, 1559, 1526, 1457, 1384, 1340, 1328, 1317, 1284,
The authors are grateful to the following agencies for finan-
cial support of this work: Natural Sciences and Engineering
Research Council of Canada (NSERC), (Idea to Innovation
and Discovery Grants), TDC Research, Inc., Brock Universi-
ty, Research Corporation, and the Ontario Partnership for In-
novation and Commercialization (OPIC).
1244, 1171, 1129, 1079, 1023, 999 cmꢀ1 1H NMR (CDCl3,
;
600 MHz): d=6.91 (bs, 1H), 5.01 (d, J=7.2 Hz, 1H), 4.16–
4.11 (m, 2H), 3.55 (m, 2H), 3.48 (m, 1H), 2.44 (dddd, J=
12.0, 12.0, 3.6, 3.6 Hz, 1H), 2.34 (m, 1H), 2.18 (m, 1H), 2.00
(s, 3H), 1.56–1.50 (m, 2H), 1.49 (s, 9H), 1.45 (t, J=7.2 Hz,
3H); 13C NMR (CDCl3, 150 MHz): d=173.64, 173.46, 80.38,
73.35, 62.01, 60.88, 50.61, 38.70, 36.16, 33.58, 28.26, 23.15,
14.14; MS (FAB+): m/z (%)=345 (M+ +H), 289 (45), 245
(100), 168 (26); HR-MS: m/z=345.20256, calcd. for
C16H29N2O6: 345.20525; anal. calcd. for C16H28N2O6: C5 5.80,
H 8.19, N 8.13; found: C 55.25, H 8.24, N 7.56.
Procedure B (“One-Pot”): A suspension of oxime 8
(73 mg; 0.24 mmol), Boc2O (0.105 mg; 0.48 mmol) and
20 mg Rh/Al2O3 (5%) in EtOH (96%, 2 mL) was hydrogen-
ated in a Parr apparatus (60 pound/inch2). After 16 h the re-
action mixture was filtered through a short bed of celite and
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