Several generations of chemoenzymatic synthesis of oseltamivir (Tamiflu): Evolution of strategy, quest for a process-quality synthesis, and evaluation of efficiency metrics

Article

pubs.acs.org/joc

Several Generations of Chemoenzymatic Synthesis of Oseltamivir

(Tamiflu): Evolution of Strategy, Quest for a Process-Quality

Synthesis, and Evaluation of Efficiency Metrics

Lukas Werner, Ales Machara, Bradford Sullivan, Ignacio Carrera, Michael Moser, David R. Adams,

and Tomas Hudlicky*

Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines,

Ontario L2S 3A1, Canada

John Andraos*^,#

CareerChem, 504-1129 Don Mills Road, Don Mills, ON M3B 2W4, Canada

S

* Supporting Information

ABSTRACT: Four generations of chemoenzymatic approaches

to oseltamivir are presented. The first two generations relied

on the use of cyclohexadiene-cis-diol derived enzymatically

from bromobenzene. The third and fourth generation used the

corresponding diol obtained from ethyl benzoate by

fermentation with E. coli JM109(pDTG601a). Oseltamivir

was obtained from ethyl benzoate by intersecting intermediate 39 (third-generation synthesis) and intermediate 45 (fourth-

generation synthesis). Both of these advanced approaches benefited from symmetry considerations and translocation of the

acrylate double bond with concomitant elimination of the C-1 hydroxyl. The syntheses are evaluated for overall efficiency by the

use of efficiency metrics and compared with other syntheses of oseltamivir (both academic and industrial).

been reviewed as well as evaluated for overall effectiveness by

using green metrics.⁵

INTRODUCTION

■

Oseltamivir (1) is a direct precursor to the prodrug Tamiflu (2)

administered as a phosphate. Along with other inhibitors of

neuraminidase portrayed in Figure 1, it was developed based on

the understanding of the mechanism of hydrolysis of sialyl

glycosides. Neuraminidase is one of several essential surface

glycoproteins required for the efficient replication of the virus

and serves to cleave sialic acid from virions in order to avoid

their aggregation, which would make further progress in

replication inefficient. Thus, the mechanism-based inhibition of

the neuraminidase action would constitute an effective strategy

in combating influenza infections. The compounds pictured in

Figure 1 all act as transition-state mimic inhibitors of glycolysis

and appear to be effective to some degree in reducing the

spread of infection. The mechanism of influenza infection and

neuraminidase inhibition¹as well as effective pharmaceutical

approaches to drug development²have been reviewed on

numerous occasions.

From the perspective of a synthetic chemist, oseltamivir

should not present itself as a particularly challenging target. It is

a relatively simple molecule, yet a particularly efficient design

for its synthesis has not materialized despite numerous attempts

by academic researchers.³The current production route

employed by Roche seems to be the most efficient despite a

13-step preparation from shikimic acid, which provides the

necessary chirality. Other commercial routes exist⁴and have

Interest in the synthesis of oseltamivir continues despite the

fact that the compound seems to be less effective against recent

mutations of the influenza virus.⁶Thus, new approaches to this

molecule continue to appear regularly in the literature. In this

paper, we report the evolution of a chemoenzymatic strategy

toward oseltamivir through four generations of design. In

addition, an evaluation of overall efficiency and comparison

with existing syntheses is provided for the successful

approaches.

RESULTS AND DISCUSSION

■

The first-generation approach to oseltamivir was based on the

recognition that the structure represents a special case of a

“dideoxy diamino” analogue of a cyclitol.⁷Given the many

successful syntheses of amino cyclitols and amino inositols from

cyclohexadiene-cis-1,2-diols⁸via further stereoselective amina-

tions and/or hydroxylations, it seemed logical to approach

oseltamivir from acetonide 10,⁹obtained from the correspond-

ing diol, which is produced by fermentation of bromobenzene

with E. coli JM 109(pDTG601a) on a medium to large scale.¹⁰

Application of Corey’s protocol¹¹provided the acetamido

bromide 11, which was transformed to aziridine 12, as shown in

Received: September 16, 2011

Published: October 18, 2011

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Figure 1. Oseltamivir, Tamiflu, and other neuraminidase inhibitors based on the transition state for sialyl glycoside hydrolysis.

a

Scheme 1.

a

Abbreviations: DCM = dichloromethane, DME = dimethoxyethane, KHMDS = potassium hexamethyldisilazane, NBA = N-bromoacetamide.

Scheme 1. Opening of the aziridine ring with 3-pentanol provided

a 7:1 ratio of the trans- and cis-ethers 14 and 13, respectively, in a

combined yield of 87%. The major isomer 14 was subjected to

palladium-catalyzed carbonylation protocol to provide the acrylate

ester 15 in 68% yield. Acid-catalyzed hydrolysis yielded the free

diol 16, and a tosylation of the distal hydroxyl furnished tosylate

17a in 76% yield. Displacement of the tosyl group with azide gave

the azidohydrin 18, which was converted to the mesylate 19 in

anticipation of the reduction of azide as well as the regioselective

reduction of the mesylate to oseltamivir 1.

Unfortunately, all of our attempts to displace the mesylate

group with hydride reagents resulted only in the 1,4-displacement

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Figure 2. Symmetry analysis of oseltamivir.

a

Scheme 2.

a

Abbreviations: DMF = dimethylformamide, DMP = 2,2-dimethoxypropane, THF = tetrahydrofuran.

of the mesylate and the reduction of the azide. The major

product of these attempts was the fully reduced compound 21.

Amine 20 was isolated as a minor product along with at best

only traces of oseltamivir. On the basis of these disappointing

results, the approach was abandoned, despite the fact that azide

19 was obtained in only 10 steps from bromobenzene.

The second approach to oseltamivir also began with the

enzymatically derived diols 22 (X = Br or I) but would take

into account observation of latent symmetry in oseltamivir. As

noted above, the first-generation synthesis relied on the

reductive removal of the C-2 hydroxyl. The initial observation

of the 1,4-reduction of the mesylate in 19 and the concomitant

translocation of the olefin ultimately led to the recognition of

the latent symmetry and design of an approach that would take

advantage of a more flexible introduction of the nitrogen and

oxygen substituents.

Oseltamivir possesses a latent axis of functional symmetry

with respect to the carboxylate and acetamido groups, as shown

in Figure 2. This implies that the synthesis could start with

either diastereomer of vinyl aziridine, which could be opened

with either oxygen or nitrogen nucleophiles and lead to either

representation of 1 as depicted below.

The order of introduction of nucleophiles into either

aziridine 12 (Scheme 1) or 23 (Scheme 2) depends on the

eventual translocation of the olefin from the initial C-1/C-6

position to C-1/C-2 placement.

The known vinyl aziridine 23,¹²prepared in two steps from

diol 22, was treated with sodium azide to produce the vinyl

azide 24, whose Staudinger reduction followed by protection

furnished the Boc-protected amine 25 in 72% yield, as shown in

Scheme 2. Palladium-catalyzed carbonylation then provided the

acrylate 26 in 45% yield. Comparable results were also obtained

from the corresponding vinyl iodide derived from iodobenzene

by fermentation.

An alternative route to this compound was also developed

from diol 27, derived enzymatically from ethyl benzoate as

shown in Scheme 2. We thought that starting with ethyl

benzoate, which contains the carboxylate group of oseltamivir,

would avoid the carbonylation step and would ultimately be

shorter that the route utilizing either bromo- or iodobenzene.

However, the former route produced acrylate 26 in 23% yield

as compared to an overall yield of 10% for the route from ethyl

benzoate. Encouraged by the rapid access to the protected

diamine 26 (seven steps from bromobenzene), we attempted

the reductive removal exchange of the tosyl group. Acetylation

of 26 followed by the usual sodium naphthalide detosylation

was unsuccessful.

Hydrogenation of 26 provided the saturated esters 30a and

30b in an 8:1 ratio, and treatment of these esters with sodium

ethoxide in ethanol led cleanly to the allylic alcohol 31 in 76%

yield. When PtO₂was used as a catalyst in 95% EtOH only the

fully saturated alcohol resulting from the overhydrogenation of

31 was isolated in 92% yield, indicating that the collapse of

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a

Scheme 3.

a

Abbreviations: DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-N,N-dimethylaminopyridine, DMP = 2,2-dimethoxypropane.

the acetonide occurs under these conditions. The reductive

detosylation was attempted with this compound as well to no

avail. In addition, attempts to alkylate 31 with various

electrophilic reagents derived form 3-pentanol, such as the

trichloracetimidate reported by Fang,^3pwere unsuccessful, and

further efforts were abandoned.

The third-generation synthesis, which ultimately proved

successful, was also based on the recognition that oseltamivir

possesses a latent axis of functional symmetry with respect to

the carboxylate and acetamido groups, as shown in Figure 2,

and assumed the translocation of the acrylate olefin at a late

stage of synthesis.

To avoid potential issues inherent in the removal of the tosyl

group or reduction of C-2 hydroxyl, we decided to introduce

the acetamido group by a hetero-Diels−Alder cycloaddition

(inverse electron demand) of acyl nitroso group to the

polarized diene in diol 27. Thus, diol 27 was protected as an

acetonide and treated with acetylhydroxamic acid in the

presence of sodium periodate to afford cleanly the oxazine 32

as a single stereoisomer in 79% yield, as shown in Scheme 3.

Reduction of the oxazine with Mo(CO)₆¹³produced the allylic

alcohol 33 in 75% yield. Treatment of this alcohol with mesyl

chloride led to the allylic displacement to furnish oxazoline 34,

which was directly hydrolyzed with aqueous calcium carbonate

in ethanol to the amino alcohol derivative 35.

Hydrogenation over rhodium on alumina then provided the

fully saturated ester 36 in 95% yield. At this stage what

remained was the introduction of the remaining nitrogen

functionality, installation of pentan-2-ol moiety, and regener-

ation of the acrylate moiety. This was accomplished by

conversion of the alcohol to its mesylate 37 and displacement

of the mesylate with sodium azide in acetone to give azide 38 in

86% yield, Scheme 3. The formal synthesis of oseltamivir was

completed by treatment of ester 38 with DBU in methylene

chloride, leading to the elimination of the C-2 ether with

concomitant collapse of the acetonide to produce the

penultimate intermediate, the allylic alcohol 39, which was

reported by Fang in his synthesis of oseltamivir.¹⁴

The third-generation synthesis was relatively short and

reasonably efficient but still relied on the use of azide for the

introduction of the second nitrogen functionality. The

translocation of the acrylate double bond proved to be a

much more convenient way of removing the C-2 hydroxyl than

the attempted reduction during the first-generation synthesis.

In addition, starting the synthesis with the diol derived from

ethyl benzoate greatly improved the overall efficiency as the

three carbons of the ester are retained in the product. Thus, the

only further improvement sought was one that would avoid the

use of azide as means of introducing the nitrogen functionality.

The fourth-generation synthesis also began with diol 27¹⁵

derived by fermentation of ethylbenzoate with E. coli

JM109(pDTG601a)¹⁶leading to the diol in space−time yields

of 1 g/L/hour. The diol was converted in three steps to the

amino alcohol derivative 33 as described previously.¹⁷We have

discovered, quite fortuitously, that the well-known Dauben−

Michno oxidative transposition¹⁸(previously applied only to

allylic alcohols substituted with electron-donating groups)¹⁹

can also be used to convert allylic alcohols substituted with

electron-withdrawing groups to the corresponding enones.

Thus, treatment of alcohol 33 with chromium oxide and acetic

anhydride provided enone 40 in excellent yields, Scheme 4.

This reaction was found to be quite general and was later

exploited in the synthesis of β-cyanoenones from allylic

cyanohydrins in good yields.²⁰On a larger scale, the enone

was directly converted to oxime 41 in 75−82% yield from 33.

Hydrogenation of the oxime over rhodium on alumina

provided the saturated ester 42 along with ∼10% of the over-

reduced product lacking the C-2 oxygen functionality. Similar

results were also obtained when palladium on alumina and/or

Pd(OH)₂were used in the hydrogenation. This mixture was

converted to the Boc-protected derivatives 43 and 44 in 50%

yield over the two steps. Eventually, it was found that

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a

Scheme 4.

a

Abbreviations: DIAD = diisopropyl azodicarboxylate.

performing the hydrogenation in the presence of Boc anhydride

led directly to carbamate 44 in 93% yield, Scheme 4.

and side products (E-kernel), excess reagent consumption (E-

excess), and auxiliary material consumption arising from

reaction solvent, catalysts, all workup materials, and all

purification materials (E-aux). OP = oseltamivir phosphate.

The basis scale for all calculations is 1 mol of target

oseltamivir phosphate product so that standardized compar-

isons of plan performances can be made. Overall yields were

determined by multiplying all reported reaction yields along the

longest linear sequence of a plan. The list below shows in words

how each of the other metrics is evaluated. Masses of all

materials given here are appropriately scaled to meet the

objective of getting to the 1 mol basis scale of the final target

product. Hence, the E-factor values are interpreted formally as

mass units of associated waste per mol of target product. Using

the molecular weight of oseltamivir phosphate these are then

converted to standard E-factor units of mass of waste in grams

per gram of target product.

The collapse of the acetonide and the generation of the

required acrylate unit was accomplished with sodium ethoxide

in ethanol to provide the allylic alcohol 45 in 94% yield, thus

formalizing the synthesis.²¹On a small scale, we have converted

this material to Boc-protected oseltamivir 46 in two ways: by

intersecting Corey’s^3gor Shibasaki’s^3uprotocols via aziridine 47

and its opening with 3-pentanol and by a low-yielding (∼10%)

alkylation with 3-iodopentane.²²In our hands, the repetition of

Corey’s procedure provided 46 in 21% yield from the allylic

alcohol. Repetition of Shibasaki’s protocol gave 46 in 47% yield.

Deprotection then provided the title compound matched by

TLC and HPLC with an authentic sample.

In summary, the fourth-generation approach provided for a

very efficient synthesis of allylic alcohol 45: 52% overall yield

from diol 27. The advantage of this latest design is, in addition

to brevity, the fact that the 10 chemical steps may be reduced to

just five operations, and on larger scales no chromatography is

needed. In any future ameliorations of this synthesis improve-

ments need to be discovered in the introduction of the 3-

pentanyl side chain. As of this writing there are no direct high-

yielding alkylation-based methods available for this trans-

formation.

Evaluation of Efficiency Metrics for Third- and Fourth-

Generation Synthesis. In order to better gauge the material

efficiencies of our two successful synthesis routes to oseltamivir

phosphate against published syntheses prior to ours we

determined their green metrics performances according to the

previously described Andraos algorithm which was used to test

the “greenness” of six industrial and nine academic plans to this

target molecule.⁵The essential metrics examined were as

follows: number of steps (N), number of input materials (I),

percent overall yield, percent overall atom economy (AE),²³

and overall E-factor.²⁴The overall E-factor in turn was

subdivided into its waste components arising from byproducts

(1) % overall AE = [molecular weight of OP/sum of

molecular weights of all stoichiometric reagents used] ×

100%

(2) E-kernel = [sum of masses of all stoichiometric reagents

− mass of 1 mol OP]/mass of 1 mol OP

(3) E-excess = sum of masses of excess reagents/mass of 1

mol OP

(4) E-aux = sum of masses of reaction solvents, catalysts, and

workup and purification materials/mass of 1 mol OP

(5) Overall E-factor = [sum of masses of all reagents,

catalysts, reaction solvents, and workup and purification

materials − mass of 1 mol OP]/mass of 1 mol OP =

E-kernel + E-excess + E-aux

The E-kernel contribution is a good metric to probe the

intrinsic chemical efficiency of synthesis plans since it depends

on the number of steps, reaction yields, and atom economies

for each step. These parameters are directly linked to the core

synthesis design strategy employed. An important insight

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Table 1. Comparison of Material Efficiency Green Metrics for Syntheses toward Fang’s Intermediate 39

plan

N

I

% yield

% AE

E-kernal

E-excess

E-aux

E-total

Scheme 3

7

11

8

15

18

17

29

27

17

11.6

26.5

6.9

17.1

14.7

16.8

8.6

28.5

12.6

34.3

32.0

124.7

37.3

109.5

59.1

1105.6

1656.7

1206.8

2342.5

7626.7

1243.6

1728.3

2482.5

2666.4

7930.2

11512.2

a

Fang

Scheme 3b

1241.4

291.8

178.8

5990.9

c

Fang

14

17

8

18.9

4.4

d

Chen−Liu

Scheme 3e

7.3

5.5

16.8

5484.1

a

b

See ref 3p; starting material is (S,S)-3-bromocyclohexa-3,5-diene-cis-1,2-diol; final target product is oseltamivir phosphate. Includes enzymatic cis-

dihydroxylation step to compound 27 from ethyl benzoate assuming maximum yield of 60% for this step, aqueous reaction solvent not included, and

c

d

e

10-fold reduction in ethyl acetate workup solvent. See ref 3j; starting material is D-xylose. See ref 3hh. Includes enzymatic cis-dihydroxylation step

to compound 27 from ethyl benzoate assuming: 48% yield for this step, all reaction and workup solvents included.

a

Table 2. Summary of Material Efficiency Green Metrics for Scheme 3 to Oseltamivir Phosphate

step

reaction

% yield

% AE

E-kernel

E-excess

E-aux

E-total

1

2

3

4

5

6

7

8

27 → 32

32 → 33

33 → 34

34 → 35

35 → 36

36 → 37

37 → 39

70

72

54

72

95

73

85

78

69

99

92

8.2

51

71

1.8

0.9

3.0

0.4

0.06

1.1

1.8

0.9

0.8

0.1

0.09

28

11.5

1.5

1.7

6.4

0.7

1.7

3.8

0.2

0.7

0.6

0.3

107

57.5

10.2

136.5

6.0

70.8

12.5

141.3

12.8

13.1

91.0

154.2

1.1

46

100

66

12.3

88.2

148.7

0

42

39 + 3-pentyl trichloroacetimidate

3-pentyl trichloroacetimidate synthesis

hydrogenation

68

8*

9

81

2.4

3.9

92

101.8

33.8

1137

102.5

34.1

1272

10

H₃PO₄salt formation

100

21

overall

a

Steps 8, 8*, 9, and 10 pertain to Fang’s synthesis (see ref 3j); the asterisk designates that this step was performed in the second branch of the

convergent synthesis.

concerning metrics analysis is that it is most useful in a

comparative rather in an absolute sense, that is, when various

plans to a common target molecule are compared head-to-head

according to some criteria. Such a comparison is fairest if such a

set of plans also begin from a common starting material;

however, this is a rare situation since most plans begin from

different kinds of starting materials. More importantly, the

recognition that true optimization has been achieved is realized

when “best values” of all metrics parameters gravitate to the

same synthesis plan.

We first examined the synthesis of Fang’s intermediate,

compound 39, according to Scheme 3 and two prior plans for

this target by Fang^3j,pand Chen-Liu^3hhwhose plans began from

D-xylose and D-glucal, respectively. The results are summarized

in Table 1 where the entries are ranked in ascending order with

respect to E-total. From these data we note that the plan given

in Scheme 3 is superior in material efficiency performance over

the others mainly because of a dramatic reduction in the

number of steps and a high overall atom economy. Though the

Fang plan had the highest overall yield at 19%, it had about the

same E-kernel value as the plan in Scheme 3 because its atom

economy was halved. This is a good example of non-

orchestrated optimization where a gain in one metric is offset

by a poorer performance in another. Overall, it is clear that the

best values of all eight metrics listed in Table 1 are linked to

Scheme 3 (see the first row), and hence, we may conclude that

this is indeed optimal relative to the other plans. However,

when the chemoenzymatic step to produce the cis-diol 27 is

included in the analysis for Scheme 3 so that the initial starting

material is now ethyl benzoate, the overall yield and E-factor

performances drop significantly (see the last row). The yield for

this chemoenzymatic step is 48%.¹⁷Since it is the lowest yield

in the sequence and it appears in the first step where the scale

of reaction is necessarily the highest in the plan, it results in a

31% increase in E-kernel compared to when this step is

excluded. Also, the greatest contributor to E-total arises from

the aqueous nutrient broth used as a reaction solvent. Both of

these apparent shortcomings in metrics performance can be

overcome on two fronts. First, the chemoenzymatic trans-

formation may be repeated over several cycles to convert as

much of the starting amount of ethyl benzoate as possible to

product. From a practical perspective three cycles are sufficient

to increase the reaction yield for this step to a maximum of

60%. This results in a best E-kernel value of 34.3 compared to

37.3. Second, the aqueous broth is relatively nontoxic compared

to other solvents used once it has been autoclaved prior to

disposal after the E. coli JM109(pDTG601a) cells are spent.

This type of evaluation conforms to the calculations of effective

mass yield (EMY) proposed by Hudlicky some time ago for

bioctalytic processes in which the mass of those components

judged benign do not enter into final calculations.²⁵If the mass

of solvent is not included in the calculation then the E-total

value improves to 3392, which is close in magnitude to Fang’s

value of 2666. A further 10-fold reduction in ethyl acetate

consumption as a workup solvent can potentially lead to a best

value of E-total of 2483, which surpasses the Fang performance.

Next, we examined in detail the green metrics performances

of Schemes 3 and 4 toward the oseltamivir phosphate target

product. In carrying out these calculations, the amounts of

purification materials, in particular chromatographic solvents

and silica gel, were not included since estimates of their masses

were not made consistently in all steps. Therefore, the E-aux

contributions arise from masses of catalysts, reaction solvents,

and workup extraction solvents/washes only. Tables 2 and 3

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Table 3. Summary of Material Efficiency Green Metrics for

Scheme 4 to Oseltamivir Phosphate

Scheme 5

step

reaction % yield % AE E-kernel E-excess E-aux

E-total

1

2

3

4

5

6

7

8

27 → 32

32 → 33

33 → 41

41 → 43

43 → 45

45 → 47

47 → 46

46 → 1

70

72

82

93

95

67

59

73

10.5

51

71

1.8

0.9

1.1

0.4

0.2

2.4

0.7

1.1

11.5

1.5

5.3

1.8

0

57.5

10.2

257.5

19.1

43.5

50.5

9.1

70.8

12.5

58

263.9

21.3

75

a

b

86

43.8

44

1.4

67.6

4.6

54.4

100

66

77.3

31.0

36.7

overall

22

24

183

1416

1623

a

b

See ref 21. See ref 3u.

summarize the results for each reaction in each scheme as well

as the overall performances. From these data, it is possible to

identify bottlenecks in each plan by pinpointing which steps

contribute the most waste and what parameters in particular are

responsible. This allows for further iterative improvements that

could be made to the plans so that the goal of orchestrated and

directed optimization is achieved. In effect, a metrics analysis

guides further meaningful optimization. Both plans were

evaluated from the common starting material cis-diol 27.

Since Scheme 3 represents a formal synthesis of 1, the

remaining steps from Fang’s plan were used to complete the

analysis from intermediate 39 to the final target product. From

Table 2 we observe that in Scheme 3, step 3 (33 → 34) has the

lowest yield and steps 1 (27 → 32), 3, and 7 (37 → 39) have

the lowest atom economies. With respect to E-factors, steps 1

and 3 contribute the largest E-kernel values, steps 1 and 4

(34 → 35) have the largest E-excess contributions, and steps 3,

7, and 9 (azide hydrogenation) have the largest auxiliary

material consumption. Overall, steps 3, 7, and 9 are the major

waste producers in this plan. We suggest the following

recommendations for further improvements: increase the yield

of step 3, reduce excess reagent consumption for steps 1 and 4,

and reduce solvent demand for steps 3 and 7. From Table 3 we

observe that in Scheme 4, step 7 (47 → 46) has the lowest yield

and steps 1 (27 → 32) and 6 (45 → 47) have the lowest atom

economies. Steps 1 and 6 contribute the most waste from

byproducts and side products. Steps 1 and 7 contribute the most

excess reagent consumption. Step 3 (33 → 41) has by far the

largest auxiliary material consumption. Overall, step 3 is the main

waste producer in this plan. As before, we may suggest the

following recommendations for further improvements: increase

the yield of step 7, reduce excess reagent consumption for steps 1

and 7, and reduce solvent demand for step 3. The first option

may be challenging due to the propensity of competing side

reactions as shown in Scheme 5. On comparing the overall

performances of plans in Schemes 3 and 4 we note that when all

auxiliary materials are excluded, the latter plan is indeed better

performing than the former one at the kernel level. This is

consistent with the Scheme 4 plan being shorter by two steps

and having a 3% higher overall yield (11% versus 8%). The

overall atom economies are about the same for both plans. This

result reinforces the conclusion that the synthesis strategy

employed in Scheme 4 is superior to that in Scheme 3. However,

when auxiliary materials are taken into account (reaction

solvents, catalysts, and workup materials) the overall E-factor

for Scheme 4 is now higher than that for Scheme 3 which goes

against the direction of optimization achieved by the intrinsic

chemical performance. Hence, further optimization of the plan in

Scheme 4 will necessarily involve auxiliary material reduction in

order to maintain its overall higher rank. Such a scenario is

confirmed when the workup solvent demand due to ethyl acetate

for step 3 is eliminated from the calculation of E-total. This

makes sense since that step was already identified as having the

largest E-aux contribution and largest E-total value overall (see

row 3 in Table 3). Indeed, a recalculation of E-total results in a

value of 1214 if this improvement were to be implemented,

corresponding to a 25% reduction in overall waste from an

original value of 1623. An E-total of 1214 is now less than the

estimate of 1272 for Scheme 3 if no further optimization is made

to that plan.

Finally, we may examine the overall ranking of both plans in

Schemes 3 and 4 against all prior plans published to date

according to intrinsic chemical performance. The results shown

graphically in Figure 3 display E-kernel profiles in ascending

order for academic and industrial plans separately. This is an

update of the analysis from the previously published review⁵

and includes more recent plans from Chen−Liu,^3hhFang G2,^3p

Fang G3,^3pHayashi G1,^3tHayashi G2,³ⁱⁱHayashi G3,³ⁱⁱ

Kamimura,^3jjKo,^3kkKongkathip,³ⁿⁿLu,^3llMandai G1,^3vMandai

G2,^3vRoche G6,^3eeShibasaki G4,^3uShibasaki G5,^3xShiniogi &

Co., Ltd.,^3mmand Wu.^3ffSuperimposed on these bar graphs is

the fractional contribution to kernel waste from target bond

forming reactions and sacrificial reactions. Target bond forming

reactions pertain to those in a synthesis plan that are involved

in the skeletal building up of the target molecule structure.

Sacrificial reactions, on the other hand, are those in a plan that

involve protection group chemistry, redox adjustments to

atoms for further elaboration in subsequent target bond

forming steps, and chiral directing group chemistry. Low

overall E-kernel factor values and a lower proportion of waste

arising from sacrificial reactions characterize well-strategized

plans. An interesting case comparison is that between the

Banwell^3oplan and our own, which utilizes the same

chemoenzymatic dihydroxylation reaction, albeit the starting

material in the Banwell plan is bromobenzene instead of ethyl

benzoate. In our plans, about 40% of the kernel waste arises

from sacrificial reactions, whereas the Banwell strategy affords

70%, yet both plans have similar E-kernel values between 21

and 28. Among academic plans, Schemes 3 and 4 rank among

the best disclosed so far; however, there is little difference in

E-kernel performance between the top ranking dozen plans in

this group. For example, the E-kernel values range from 7 (Shi)

to 24 (Hayashi G2). However, the overall yields range from

48% over eight steps (Shi, linear) to 31% over four steps

(Hayashi G2, convergent) corresponding to average yields per

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in all steps, which is also true of the majority of academic plans.

This means that the E-total value of 465 for the Shi plan should

be considered a lower limit of the true E-total value. In general

the details of overall solvent usage for the industrial plans was

better disclosed in published procedures. Another important

point is that none of the published academic plans were

conducted on a scale large enough to demonstrate their

feasibility for industrial processes. It remains to be seen whether

their performances can be replicated at larger kilogram scales

comparable to those used in the best performing industrial plan

(Roche G3 plan from shikimic acid).^3d,fOf particular note in

this regard is the extreme telescoping of reaction steps without

isolation of intermediates achieved by the Hayashi plans.^3t,ii

The Roche G3 plan requires 446 g of shikimic acid starting

material to produce 1 mol or 410 g of oseltamivir phosphate

along with 95 kg of total waste and was conducted on a 5 mol

scale of shikimic acid. The Hayashi G2 plan, on the other hand,

requires 289 g of starting 3-pentanol to produce 1 mol or 312 g

of oseltamivir along with 191 kg of total waste and was

conducted on a 46 mmol scale of 3-pentanol. By comparison,

our Scheme 4 plan requires 1.8 kg of cis-diol 27 to produce

1 mol or 410 g of oseltamivir phosphate along with 666 kg of

total waste and was conducted on 27 mmol scale of cis-diol.

Clearly, these results show that in principle telescoping of steps

can go a long way in reducing overall waste. In terms of

strategy, 69% of the kernel waste generated in the Roche G3

plan originates from target bond forming reactions whereas the

comparable value for our Scheme 4 plan is 65% which indicates

that they are evenly matched. Buoyed by the results of the

green metrics analysis described in this work we are confident

that further directed optimizations as described earlier for key

steps, are possible using our synthesis strategy, particularly at

higher scale and using telescoping techniques.

CONCLUSION

■

We have described four generations of approaches to

oseltamivir, two of which were successful and two of which

resulted in oseltamivir derivatives and/or isomers. The

successful syntheses were analyzed in terms of efficiency

metrics and compared with other academic as well as industrial

preparations of this important compound. Our latest synthesis

compared well with academic efforts in terms of overall

efficiency. The metrics calculations were in each case based on

conditions and yield values as reported in the literature. It

should be noted that yield values reported in publications from

academic groups are frequently subject to wide fluctuations for

a variety of reasons that have recently been analyzed.²⁶Thus

only the industrial protocols that have been subjected to

focused optimization and have been performed on large scales

can be taken as reliable in terms of the reported values. We

continue to address further improvements in our quest for a

truly practical synthesis of oseltamivir and will report on future

accomplishments in due course.

Figure 3. E-kernel profiles for various academic and industrial

synthesis plans to oseltamivir phosphate showing proportion of

waste originating from target bond forming and sacrificial reactions.

step of 91 and 75%, respectively. A caveat is that all estimates of

metrics are based on the veracity of reported reaction yields in

the literature for these plans.²⁶Despite these advances and

claims, the industrial plans are still well ahead in performance as

evidenced by the 5-fold decrease in the scale of the E-kernel

axis for the industrial plan profile. The best performing Roche

G3 plan from shikimic acid has 13 steps, an overall yield of

39%, and an E-kernel value of 8. When reaction solvents,

catalysts, and auxiliaries are included the E-total is 231, which

is half the value of the best performing academic Shi plan

(E-total =465). It should be noted that the solvent demand for

chromatographic purification in the Shi plan was not disclosed

EXPERIMENTAL SECTION

■

All nonaqueous reactions were conducted in an inert (nitrogen or

argon) atmosphere using standard Schlenk techniques for the

exclusion of moisture and air. All solvents were distilled unless

otherwise noted. Analytical thin-layer chromatography was performed

on silica gel 60 Å 250 μm TLC plates with F-254 indicator. Flash

column chromatography was performed using silica gel (230−400

mesh). Melting points are uncorrected. IR spectra were obtained on a

FT-IR spectrometer. Optical rotation was measured on a polarimeter

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1

at a wavelength of 589 nm. H and ¹³C spectra were recorded on 300

The crude material was purified by flash column chromatog-

raphy with a solvent gradient of 2:1 then 1:1 (hexanes−ethyl

acetate) to afford 12 (9.21 g, 67%) as colorless crystals: R_f0.44

(1:1, hexanes−ethyl acetate); mp 128 °C; [α]²³_D−57.6 (c 0.75,

CHCl₃); IR (film) ν 3017, 2938, 1704, 1423, 1383, 1372, 1289,

1267, 1216, 1161, 1063, 994, 967, 894, 868, 819, 756, 668, 619,

MHz and/or 600 MHz spectrometers. All chemical shifts are

referenced to TMS or residual nondeuterated solvent. Data for proton

spectra are reported as follows: chemical shift (multiplicity [singlet (s),

doublet (d), triplet (t), quartet (q), quintet (quint), and multiplet (m)],

coupling constants [Hz], integration). Carbon spectra were recorded

with complete proton decoupling and the chemical shifts are reported

in ppm (C). Mass spectra and high resolution mass spectra were

performed by the analytical division at Brock University. Combustion

analyses were performed by Atlantic Microlabs, Atlanta, GA.

1

554, 510, 485, 468 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 6.70

(d, J = 4.8 Hz, 1H), 4.72 (dd, J = 0.9, 6.9 Hz, 1H), 4.46 (dd, J =

4.2, 6.9 Hz, 1H), 3.19 (dd, J = 5.1, 6.0 Hz, 1H), 3.11 (ddd, J =

0.9, 6.0, 6.1 Hz, 1H), 2.17 (s, 3H), 1.56 (s, 3H), 1.41 (s, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 181.7, 129.9, 122.8, 108.5, 76.6,

71.9, 39.6, 36.7, 27.0, 24.9, 23.2; MS (EI) m/z 272 (M⁺− CH₃),

232 (9), 230 (9), 208 (5), 190 (9), 189 (8), 188 (9), 187 (7),

172 (6), 170 (5), 160 (13), 158 (13), 150 (18), 109 (18), 108

(45), 100 (23), 85 (10), 84 (5), 81 (9), 80 (17), 79 (7), 78 (7),

59 (9), 53 (7), 52 (6), 51 (10), 43 (100), 42 (6), 41 (6);

HRMS (EI) calcd for C₁₁H₁₄O₃NBr 287.0157, found 287.0161.

N-[(3aR,4R,5S,7aS)-4,7-Dibromo-2,2-dimethyl-3a,4,5,7a-

tetrahydro-1,3-benzodioxol-5-yl]acetamide (11).

To a solution of N-bromoacetamide (309 mg, 2.25 mmol) in

40 mL of acetonitrile was added 0.28 mL SnBr₄(0.4 M

in CH₂Cl₂, 0.11 mmol) at −40 °C in the dark. Diene 10⁹

(432 mg; 1.87 mmol) in acetonitrile (20 mL) was added slowly

to the reaction mixture by syringe pump at the same temperature

over 4 h. The resulting reaction mixture was stirred for 1 h,

before saturated aqueous NaHCO₃(10 mL) and Na₂SO₃(10 mL)

were carefully added. The phases were separated and the

aqueous phase was extracted with CH₂Cl₂(3 × 100 mL). The

combined organic extracts were washed with brine (10 mL),

dried over MgSO₄, and concentrated under reduced pressure.

The residue was purified by flash column chromatography on

neutral alumina (CH₂Cl₂) to afford bromo amide 11 (526 mg,

76%) as colorless crystals: R_f0.71 (CH₂Cl₂/MeOH 96:4); mp

181 °C; [α]²³_D+188.2 (c 0.50, CHCl₃); IR (film) ν 3684, 3019,

2400, 1676, 1498, 1425, 1216, 1064, 929, 757, 669, 497, 478,

472 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.21 (d, J = 9.0 Hz,

1H), 4.93 (m, 1H), 4.68 (d, J = 5.1 Hz, 1H), 4.60 (t, J = 4.5 Hz,

1H), 4.21 (t, J = 3.6 Hz, 2H), 1.97 (s, 3H), 1.51 (s, 3H), 1.42

(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 169.0, 128.0, 124.7,

112.0, 77.8, 75.8, 50.3, 44.4, 27.8, 26.5, 23.3; MS (EI) m/z 366

(M), 354(6), 313 (6), 294 (6), 255 (6), 253 (12), 251 (7), 232

(33), 230 (34), 190 (11), 189 (6), 188 (12), 187 (5), 174 (6),

173 (10), 172 (8), 171 (9), 165 (8), 163 (8), 151 (6), 109

(22), 108 (9), 93 (7), 81 (8), 80 (10), 65 (8), 59 (11), 55 (8),

43 (100), 42 (11), 41 (6); HRMS (EI) calcd for C₁₁H₁₅O₃NBr₂

366.9419, found 366.9418. Anal. Calcd: C, 35.80; H, 4.10.

Anal. Calcd: C, 45.85; H, 4.90. Found: C, 45.84; H, 4.95.

N-((3aS,4S,5R,7aS)-7-Bromo-2,2-dimethyl-5-(pentan-3-

yloxy)-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)acetamide

(14) and N-((3aS,4S,5S,7aS)-7-Bromo-2,2-dimethyl-5-(pentan-

3-yloxy)-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)-

acetamide (13).

To a solution of aziridine 12 (7.78 g, 27.0 mmol) in 3-pentanol

(30 mL) was added copper(II) trifluoromethanesulfonate (976 mg,

2.70 mmol) at 0 °C. The reaction mixture was stirred for 16 h

before being concentrated under reduced pressure. The crude

residue was dissolved in methylene chloride (20 mL), washed

with satd NaHCO₃(3 × 5 mL) and brine (1 × 10 mL), and

then dried over Na₂SO₄. The residue was purified by flash

column chromatography with a solvent gradient of 3:1 then 1:1

(hexanes−diethyl ether) to afford 13 (1.09 g, 11%) and 14

(7.64 g, 76%) as clear oils.

13: R_f0.45 (diethyl ether); [α]²³_D+41.5 (c 1.0, CHCl₃); IR (film) ν

3439, 3019, 2971, 2936, 2879, 1675, 1514, 1463, 1384, 1373, 1342,

1514, 1463, 1384, 1373, 1342, 1216, 1163, 1095, 1046, 965, 931, 888,

865, 758, 669, 502 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 6.35 (d, J =

8.7 Hz, 1NH), 6.31 (d, J = 5.3 Hz, 1H), 4.57 (d, J = 5.3 Hz, 1H),

4.40−4.44 (m, 2H), 3.90 (t, J = 5.3 Hz, 1H), 3.19 (quint, J = 5.8 Hz,

1H), 2.03 (s, 3H), 1.41−1.55 (m, 4H), 1.46 (s, 3H), 1.36 (s, 3H), 0.88

(t, J = 7.6 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 169.6, 129.0,

127.5, 111.1, 81.6, 76.7, 75.3, 70.6, 46.6, 27.5, 26.6, 26.4, 25.9, 23.3,

9.8, 9.6; MS (EI) m/z 375 (M), 232 (8), 231 (7), 230 (9), 229 (5),

190 (21), 189 (16), 188 (22), 187 (13), 166 (6), 164 (6), 143 (22),

142 (100), 137 (9), 136 (8), 126 (6), 125 (6), 110 (5), 109 (32), 108

(7), 100 (30), 85 (6), 84 (61), 83 (9), 80 (9), 71 (8), 70 (9), 60 (9),

59 (12), 43 (73), 41 (7); HRMS (EI) calcd for C₁₆H₂₆BrNO₄

375.1045, found 375.1045.

Found: C, 35.77; H, 4.11.

(3aS,4S,5S,7aS)-8-Acetyl-7-bromo-2,2-dimethyl-3a,4,5,7a-

tetrahydro-4,5-epimino-1,3-benzodioxole (12).

14: R_f0.40 (diethyl ether); [α]²³_D−100.0 (c 1.0, CHCl₃); IR (film)

ν 3439, 3019, 2971, 2936, 2879, 1675, 1514, 1463, 1384, 1373, 1342,

1514, 1463, 1384, 1373, 1342, 1216, 1163, 1095, 1046, 965, 931, 888,

865, 758, 669, 502 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 6.14 (d, J =

1.5 Hz, 1H), 5.83 (d, J = 9.0 Hz, 1H), 4.57 (dd, J = 1.5, 5.3 Hz, 1H),

4.40 (dd, J = 2.4, 5.1 Hz, 1H), 4.30 (dt, J = 2.4, 8.9 Hz, 1H), 3.89 (dd,

J = 1.5, 8.9 Hz, 1H), 3.24 (quint, J = 5.6 Hz, 1H), 2.00 (s, 3H), 1.43−

1.49 (m, 4H), 1.38 (s, 3H), 1.34 (s, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.85

(t, J = 7.4 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 169.9, 132.5,

122.7, 110.2, 82.4, 77.3, 76.0, 73.6, 51.2, 27.4, 26.3, 26.1, 25.6, 23.5, 9.6,

9.2; MS (EI) m/z 375 (M), 232 (8), 231 (7), 230 (9), 229 (5), 190

To a solution of amide 11 (17.61 g, 47.72 mmol) in dimeth-

oxyethane (400 mL) was added n-Bu₄NBr (16.33 g, 52.49 mmol)

at 0 °C under argon. At this temperature, potassium

bis(trimethylsilyl)amide (100 mL, 0.5 M in toluene, 52.49 mmol)

was added dropwise. The reaction mixture was stirred for 3 h at

0 °C and then quenched by the addition of potassium

phosphate monobasic sodium hydroxide (350 mL, set to pH 7).

The two-phase mixture was extracted with ethyl acetate

(3 × 150 mL), and then the combined organic phases were

dried over MgSO₄and concentrated under reduced pressure.

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(21), 189 (16), 188 (22), 187 (13), 166 (6), 164 (6), 143 (22), 142

(100), 137 (9), 136 (8), 126 (6), 125 (6), 110 (5), 109 (32), 108 (7),

100 (30), 85 (6), 84 (61), 83 (9), 80 (9), 71 (8), 70 (9), 60 (9), 59 (12),

43 (73), 41 (7); HRMS (EI) calcd for C₁₆H₂₆BrNO₄375.1045, found

375.1045. Anal. Calcd: C, 51.07; H, 6.96. Found: C, 51.07; H, 6.98.

Ethyl (3aR,6R,7S,7aS)-7-Acetamido-2,2-dimethyl-6-(pentan-

3-yloxy)-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-4-carboxy-

late (15).

(c 0.47, CHCl₃); mp 154 °C; IR (film) ν 3380, 3020, 2970,

2937, 2879, 1715, 1661, 1576, 1464, 1374, 1244, 1217, 1094,

1

1060, 929, 756, 667 cm⁻¹; H NMR (600 MHz, (CD₃)₂CO) δ

7.36 (d, J = 6.4 Hz, 1NH), 6.78 (d, J = 3.8 Hz, 1H), 4.86 (d, J =

4.2 Hz, 1OH), 4.64 (t, J = 3.9 Hz, 1H), 4.21−4.25 (m, 1H) 4.21

(dq, J = 1.1, 7.2 Hz, 2H), 4.01−4.15 (m, 2H), 3.96 (dd, J = 4.3,

6.6 Hz, 1H), 3.56 (quin, J = 5.8 Hz, 1H), 1.87 (s, 3H), 1.44−

1.58 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.6 Hz, 3H),

0.87 (t, J = 7.6 Hz, 3H); ¹³C NMR (150 MHz, (CD₃)₂CO) δ

169.2, 165.9, 137.7, 132.6, 81.4, 73.4, 67.0, 65.7, 60.4, 53.1, 26.1,

26.0, 22.4, 13.6, 9.2, 8.8; MS (FAB) m/z 330 (M⁺), 260 (21),

242 (25), 224 (13), 182 (23), 178 (14), 152 (11), 136 (13), 112

(11), 110 (21), 109 (16), 81 (13), 71 (13), 69 (17), 67 (10), 60

(19), 57 (19), 55 (31), 43 (100), 41 (34), 39 (16), 29 (45);

+

HRMS calcd for C₁₆H₂₈NO₆330.1917, found 330.1919.

To a solution of vinyl bromide 14 (6.50 g, 17.3 mmol) in

toluene (300 mL) and ethanol (82 mL) was passed CO gas

(1 atm). After 10 min, triethylamine (84.2 mL, 604.6 mmol)

was added followed by tetrakis(triphenylphosphine)palladium(0)

(998 mg, 0.864 mmol) at room temperature. The resulting

solution was heated to 60 °C while a continuous flow of CO

gas (1 atm) was passed. After 2 h, dichlorobis(triphenylphos-

phine)palladium(II) (1.21 g, 1.73 mmol) was added in two

portions over 15 min. The reaction mixture was brought to

reflux for 4 h, cooled to room temperature, and filtered through

a plug of Celite. The crude material was purified by flash

column chromatography with a solvent gradient of 2:1 then 1:1

(hexanes-ethyl acetate) to yield 15 (4.34 g, 68%) as a colorless

solid: R_f0.22 (96:4, methylene chloride/methanol); mp 112−

115 °C; [α]²³_D−122.7 (c 1.0, CHCl₃); IR (film) ν 3383, 3022,

2975, 2879, 1711, 1663, 1576, 1464, 1374, 1254, 1218, 1094,

1068, 929, 776, cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 6.90 (d,

J = 1.9 Hz, 1H), 5.82 (d, J = 8.7 Hz, 1NH), 5.03 (dd, J = 0.76,

5.7 Hz, 1H), 4.49 (dd, J = 2.6, 5.7 Hz, 1H), 4.22−4.31 (m, 3H),

4.04 (d, J = 9.0 Hz, 1H), 3.34 (quint, J = 5.6 Hz, 1H), 2.03 (s,

3H), 1.48−1.56 (m, 4H), 1.37 (s, 3H), 1.34 (s, 3H), 1.30 (t, J =

7.0 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H); ¹³C

NMR (150 MHz, CDCl₃) δ 169.9, 165.5, 141.1, 129.9, 109.5,

82.6, 74.7, 72.0, 71.6, 61.1, 51.9, 27.3, 26.1, 25.9, 25.5, 23.6, 14.2,

9.6, 9.3; MS (EI) m/z (%) 369 (M⁺-CH₃), 228 (10), 182 (12),

181 (11), 154 (6), 153 (8), 143 (8), 142 (88), 136 (10), 112 (8),

110 (7), 109 (7), 100 (17), 88 (6), 87 (13), 86 (32), 85 (8), 84

(100), 83 (9), 80 (6), 71 (12), 70 (11), 69 (5), 60 (8), 59 (13), 58

(5), 57 (11), 55 (11), 49 (10), 47 (11), 43 (87), 42 (6), 41 (13);

HRMS (EI) calcd for C₁₈H₂₈NO₆354.1917, found 354.1919.

Ethyl (3R,4R,5S,6R)-4-Acetamido-5,6-dihydroxy-3-(pentan-

3-yloxy)cyclohex-1-enecarboxylate (16).

Ethyl (3R,4S,5S,6R)- 4-Acetamido-6-hydroxy-3-(pent-3-

yloxy)-5-(tosyloxy)cyclohex-1-enecarboxylate (17a).

To a solution of diol 16 (2.32 g, 7.04 mmol) in dry pyridine (15

mL) was added 4-toluenesulfonyl chloride (1.48 g, 7.74 mmol)

portionwise over 5 min. The reaction mixture was stirred at

room temperature for 48 h and then diluted with methylene

chloride (10 mL). The organic layer was washed with cold 1 N

HCl (3 × 5 mL) and brine (1 × 10 mL) and dried over Na₂SO₄.

The crude mixture was purified by flash column chromatography

with a solvent system gradient of 99:1 then 96:4 (methylene

chloride/methanol) to yield 17 (1.76 g, 76%, based on 0.587 g

of recovered starting material) as a clear oil: R_f0.71 (96:4,

methylene chloride/methanol); [α]²³_D−36.6 (c 2.5, CHCl₃); IR

(film) ν 3375, 2971, 2937, 2879, 2733, 2458, 2252, 1920, 1716,

1660, 1598, 1527, 1463, 1444, 1372, 1248, 1218, 1190, 1178,

1121, 1096, 1059, 1002, 970, 915, 848, 815, 769, 704, 666, 556,

1

486 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.81 (d, J = 8.3 Hz,

2H), 7.35 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 6.8 Hz, 1NH), 6.87

(d, J = 4.9 Hz, 1H), 4.95 (t, J = 3.5 Hz, 1H), 4.76 (t, J = 3.8 Hz,

1H), 4.26 (q, J = 7.2 Hz, 2H), 4.15 (dt, J = 3.2, 6.8 Hz, 1H), 4.08

(dd, J = 2.6, 4.9 Hz, 1H), 3.45 (quint, J = 5.8 Hz, 1H), 3.25 (d,

J = 3.4 Hz, 1OH), 2.45 (s, 3H), 1.92 (s, 3H), 1.45−1.51 (m,

2H), 1.34−1.40 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.24−1.26

(m, 1H), 0.84 (t, J = 7.4, 3H), 0.70 (t, J = 7.2 Hz, 3H); ¹³C

NMR (150 MHz, CDCl₃) δ 170.3, 165.3, 145.4, 137.4, 132.9,

131.2, 130.1 (2 × C), 128.0 (2 × C), 82.2, 74.6, 72.6, 64.6, 61.6,

50.9, 26.3, 25.9, 23.4, 21.7, 14.2, 9.8, 8.9; MS (FAB) m/z 484

(M⁺), 29 (13), 39 (10), 41 (13), 43 (27), 55 (12), 57 (8), 69

(6), 77 (5), 91 (8), 136 (8), 178 (5), 224 (7), 396 (5); HRMS

(FAB) calcd for C₂₃H₃₄NO₈S 484.2005, found 484.1998.

Ethyl (3R,4S,5S,6R)-4-Acetamido-6-hydroxy-5-(methylsulfo-

nyloxy)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (17b).

To a solution of ester 15 (1.13 g, 3.06 mmol) in ethanol (20 mL)

was added 6 M HCl (500 μL) at room temperature. The

resulting solution was stirred for 5 h at 60 °C before the addition

of H₂O (500 μL). The reaction was stirred for an additional 1 h at

60 °C before being cooled to room temperature and concentrated

under reduced pressure. The crude material was purified by

flash column chromatography with a solvent system of 24:1

(methylene chloride/methanol) to yield 16 (715 mg, 71%) as white

To a stirred solution of 16 (20 mg, 0.061 mmol) in pyridine

(0.5 mL) was added mesyl chloride (5 μL, 0.06 mmol) at 0 °C.

solid: R_f0.71 (9:1, methylene chloride/methanol); [α]²³−44.1

D

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The resulting solution was stirred for 24 h before being diluted

with Et₂O (1 mL) and H₂O (1 mL). The layers were separated,

and the aqueous layer was extracted with Et₂O (10 × 0.2 mL).

The combined organic layers were washed with brine (1 × 1 mL)

and dried over Na₂SO₄. The crude material was purified via

flash column chromatography with a solvent gradient of 1:20

then 1:10 (hexane−ethyl acetate) to yield mesylate 17b

(21 mg, 86%) as a white solid: R_f0.47 (1:15 hexanes−ethyl

(1 mL), extracted into methylene chloride (3 × 1 mL), and

dried over Na₂SO₄. The crude material was purified by flash

column chromatography with a solvent gradient of 2:1 and then

1:1 (hexanes−ethyl acetate) to yield 19 (21 mg, 75%) as a

white solid: R_f0.40 (1:1 hexanes−ethyl acetate); [α]²³_D−3.88 (c

0.50, CHCl₃); mp 96−98 °C; IR (film) ν 3345, 2968, 2932,

2877, 1717, 1655, 1558, 1362, 1264 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 7.15 (d, J = 3.4 Hz, 1H), 6.14 (d, J = 8.5 Hz, 1NH),

5.65 (d, J = 4.14 Hz, 1H), 4.73 (dd, J = 4.2, 5.8 Hz, 1H), 4.26−

4.31 (m, 3H), 4.22 (ddd, J = 3.4, 5.3, 8.5 Hz, 1H), 3.58−3.62

(m, 1H), 3.18 (s, 3H), 2.00 (s, 3H), 1.49−1.56 (m, 4H), 1.34

(t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H), 0.91 (t, J = 7.4 Hz,

3H); ¹³C NMR (150 MHz, CDCl₃) δ 169.7, 164.4, 143.1,

125.5, 82.5, 72.4, 65.8, 61.9, 54.5, 53.4, 38.9, 26.1, 25.8, 23.4,

14.1, 9.9, 9.2; MS (EI) m/z 425 (M⁺− 7), 43 (100), 55 (11),

1

acetate); H NMR (300 MHz, CDCl₃) δ 6.91 (d, J = 4.1 Hz,

1H), 6.83 (d, J = 6.8 Hz, 1NH), 5.09 (t, J = 3.6 Hz, 1H), 4.95

(d, J = 4.2 Hz, 1H), 4.42 (dt, J = 3.7, 7.3 Hz, 1H), 4.28 (q, J =

7.1 Hz, 2H), 4.14 (t, J = 4.2 Hz, 1H), 3.69 (br s, 1OH), 3.53

(qn, J = 5.7 Hz, 1H), 3.13 (s, 3H), 1.98 (s, 3H), 1.48−1.60 (m,

4H), 1.33 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H), 0.89 (t,

J = 7.5 Hz, 3H); MS (EI) m/z 362 (M − C₂H₅O⁺), 43 (100),

112 (66), 136 (39), 149 (25), 158 (32), 181 (29), 182 (21), 228

79 (12), 120 (15), 136 (37), 152 (29), 201 (40), 224 (21), 242

(79), 300 (17), 329 (7), 360 (5).

(44); HRMS calcd for C₁₅H₂₄NO₇S 362.1270, found 362.1278.

Ethyl (3R,4R,5R,6R)-4-Acetamido-5-azido-6-hydroxy-3-(pentan-

3-yloxy)cyclohex-1-enecarboxylate (18). A. From Tosylate 17a.

Ethyl (3S,4R,5R)-4-Acetamido-3-amino-5-(pentan-3-yloxy)-

cyclohex-1-enecarboxylate (20).

To a stirred solution of tosylate 17a (24 mg, 0.049 mmol) in

dimethoxyethane (2 mL) was added tetrabutylammonium azide

(141 mg, 0.49 mmol). The resulting suspension was heated to

reflux for 16 h, cooled, and concentrated under reduced

pressure. The crude material was purified by flash column

chromatography with a solvent system of 2:1 (hexanes−ethyl

acetate) to yield 18 (12 mg, 69%) as a pale yellow oil.

B. From Mesylate 17b. A similar protocol from mesylate 17b

furnished 18 in comparable yield.

A 32 mg portion of carboxylate 19 (0.07 mmol) was dissolved in

0.5 mL of ethanol and 0.1 mL of THF. Sodium borohydride (14

mg, 0.37 mmol) was added in small portions at rt. The reaction

was stirred for 12 h, concentrated on high vacuum, and partitioned

between CH₂Cl₂and water. The organic phase was dried over

MgSO₄, filtered, and evaporated. After a pipet column (CH₂Cl₂/

MeOH 96:4 to 8:2), 2 mg of the double bond regioisomer of

oseltamivir was isolated (0.01 mmol, 9%): R_f0.40 (8:2 CH₂Cl₂/

1

MeOH); H NMR (600 MHz, MeOD-d₄) δ 6.61 (s, 1 H), 4.15

18: R_f0.27 (1:1 hexanes−ethyl acetate); [α]²³−39.71 (c 1.00,

D

(q, J = 7.2 Hz, 2 H), 3.83 (m, 1H), 3.72 (m, 1H), 3.68 (m, 1H),

3.39 (quint, J = 5.7 Hz, 1 H), 2.87 (dd, J = 5.1 Hz, J = 17.1 Hz, 1

H), 2.25 (m, 1H), 1.96 (s, 3H), 1.40 (m, 4H), 1.19 (t, J = 7.2 Hz,

3H), 0.76 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H).

N-[(3aS,4R,5S,7aS)-5-Azido-7-bromo-2,2-dimethyl-3a,4,5,7a-

tetrahydro-1,3-benzodioxol-4-yl]-4-methylbenzenesulfona-

mide (24, X = Br) and N-[(3aS,4R,5S,7aS)-5-Azido-7-iodo-2,2-

dimethyl-3a,4,5,7a-tetrahydro-1,3-benzodioxol-4-yl]-4-meth-

ylbenzenesulfonamide (24, X = I).

CHCl₃); mp 112−115 °C (hexanes−ethyl acetate); IR (film) ν 3382,

1

2966, 2927, 2863, 1719, 1653 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

6.87 (dd, J = 0.94, 2.8 Hz, 1H), 6.10 (d, J = 7.9 Hz, 1NH), 4.71 (ddd,

J = 0.94, 1.1, 6.4 Hz, 1H), 4.48 (dd, J = 6.4, 9.4 Hz, 1H), 4.43 (ddd, J =

2.1, 2.7, 6.8 Hz, 1H), 4.28 (dq, J = 2.7, 7.1 Hz, 2H), 3.82 (ddd, J =

6.7, 7.9, 9.4 Hz, 1H), 3.47 (quint, J = 5.8 Hz, 1H), 2.01 (s, 3H),

1.48−1.56 (m, 4H), 1.33 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H),

0.91 (t, J = 7.5 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.2,

166.0, 139.4, 130.3, 82.5, 73.0, 71.3, 61.5, 58.9, 55.9, 26.1, 25.8, 23.5,

14.2, 9.6, 9.4; MS (FAB) m/z 348 (M⁺− 7), 29 (57), 43 (100), 77

(27), 107 (16), 136 (26), 172 (15), 224 (23), 242 (31), 260 (64),

278 (26).

Ethyl (3R,4R,5R,6R)-4-Acetamido-5-azido-6-(methylsulfonyl-

oxy)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (19).

To a stirred solution of aziridine 23 (X = Br)¹²(200 mg, 0.499

mmol) in DMF (2 mL) was added NH₄Cl (400 mg) and NaN₃

̊

(324 mg, 4.99 mmol) at 0 C. The reaction mixture was stirred

for 12 h, extracted into Et₂O (5 × 1 mL), washed with H₂O (20 ×

0.5 mL), washed with brine (1 × 1 mL) and dried over Na₂SO₄.

The crude material was recrystallized from CHCl₃-hexanes to

yield 24 (X = Br) (203 mg, 92%) as a white solid: R_f0.53 (2:1

hexanes-ethyl acetate); mp 119−120 °C (CHCl₃−hexanes);

[α]²³_D+82.36 (c 3.5, CHCl₃); IR (film) ν 3435, 2108, 1645, 1599,

To a stirred solution of alcohol 18 (23 mg, 0.065 mmol) in

methylene chloride (1 mL) was added triethylamine (72 mL,

0.52 mmol). The resulting solution was cooled to −78 °C prior

to the addition of methanesulfonyl chloride (15 mL, 0.19

mmol). The reaction mixture was allowed to warm to 15 °C

slowly over 3 h, quenched by the addition of satd NaHCO₃

1

1219, 1159 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.80 (d, J =

8.3 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 6.14 (d, J =

3.4 Hz, 1H), 5.61 (d, J = 8.3 Hz, 1H), 4.58 (d, J = 5.6 Hz, 1H),

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Article

B. From Azide 29.

4.19 (dd, J = 5.8, 6.9 Hz, 1H), 3.73 (dd, J = 3.0, 6.4 Hz, 1H),

3.56 (q, J = 7.5 Hz, 1H), 2.45 (s, 3H), 1.37 (s, 3H), 1.34 (s,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 143.8, 137.6, 129.7, 128.9,

127.2, 124.2, 111.4, 75.9, 75.7, 60.5, 55.2, 27.5, 25.9, 21.6; MS

(EI) m/z 442 (M), 43 (47), 91 (100), 155 (35); HRMS calcd

for C₁₅H₁₆N₄O₄BrS^•442.0076, found 442.0072.

tert-Butyl (3aS,4R,5S,7aS)-7-Bromo-2,2-dimethyl-4-([ (4-methyl-

phenyl)sulfonyl]amino)-3a,4,5,7a-tetrahydro-l,3-benzodioxol-

5-yl)carbamate (25, X = Br) and tert-Butyl (3aS,4R,5S,7aS)-7-

Bromo-2,2-dimethyl-4-([ (4-methylphenyl)sulfonyl]amino)-

3a,4,5,7a-tetrahydro-l,3-benzodioxol-5-yl)carbamate (25, X = I).

To a stirred solution of 29 (110 mg, 0.252 mmol) in 12:1

THF/H₂O (1.5 mL) was added triphenylphosphine (132 mg,

0.504 mmol). The reaction mixture was stirred for 12 h,

extracted into Et₂O (3 × 1 mL), washed with brine (1 × 1 mL),

and dried over Na₂SO₄. To a stirred solution of the crude

Staudinger intermediate (0.252 mmol) in DCM (1.5 mL) and

triethylamine (200 μL) was added (Boc)₂O (275 mg, 1.26

mmol) at 0 °C. The reaction mixture was stirred for 16 h,

extracted into CHCl₃(5 × 1 mL), washed with satd NH₄Cl

(2 × 1 mL), washed with brine (1 × 1 mL), and then dried

over Na₂SO₄. The crude material was purified by flash column

chromatography to yield 26 (41 mg, 32%).

To a stirred solution of azide 24 (X = Br) (41 mg, 0.092 mmol)

in 12:1 THF/H₂O (1 mL) was added triphenylphosphine

(48 mg, 0.18 mmol). The reaction mixture was stirred for 12 h,

extracted into Et₂O (5 × 0.5 mL), washed with brine (1 × 1 mL),

and dried over Na₂SO₄. To a stirred solution of the crude

Staudinger intermediate (0.092 mmol) in DCM (1 mL) and

triethylamine (50 μL) was added (Boc)₂O (29 mg, 0.14 mmol)

at 0 °C. The reaction mixture was stirred for 12 h, extracted

into CHCl₃(5 × 0.5 mL), washed with satd NH₄Cl (2 × 1

mL), washed with brine (1 × 1 mL), and then dried over

Na₂SO₄. The crude material was purified by flash column

chromatography with a solvent gradient of 10:1, 6:1 then 3:1

(hexane−ethyl acetate) to yield 25 (X = Br) (36 mg, 77%): R_f

0.31 (2:1 hexanes−ethyl acetate); mp 153−154 °C (EtOAc−

26: R_f0.46 (1:1 hexanes−ethyl acetate); [α]²³−11.77 (c 0.72,

D

1

CHCl₃); IR (film) ν 3434, 2099, 1647, 1160 cm⁻¹; H NMR (300

MHz, CDCl₃) δ 7.78 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H),

6.89 (d, J = 2.2 Hz, 1H), 5.36 (d, J = 8.2 Hz, 1H), 5.23 (d, J = 8.3 Hz,

1H), 4.92 (d, J = 5.6 Hz, 1H), 4.23 (q, J = 7.0 Hz, 2H), 4.10 (dd, J =

6.0, 8.9 Hz, 1H), 3.38 (q, J = 8.7 Hz, 1H), 2.39 (s, 3H), 1.46 (s, 9H),

1.29 (t, J = 7.1 Hz, 3H), 1.26 (s, 3H), 1.05 (s, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 171.1, 143.5, 136.7, 129.6, 127.6, 109.5, 78.3, 74.0,

60.7, 42.9, 28.7, 27.4, 26.0, 21.5, 20.5, 14.1; MS (EI) m/z 510 (M),

43(100), 57(52), 84(54); HRMS calcd for C₂₄H₃₄N₂O₈S 510.2036,

found 510.2038.

Ethyl (3aR,4R,6S,7R,7aS)-6-[(tert-Butoxycarbonyl)amino]-

2,2-dimethyl-7-{[(4-methylphenyl)sulfonyl]amino}hexahydro-

l,3-benzodioxole-4-carboxylate (30a).

hexanes); [α]²³+15.467 (c 2.1, CHCl₃); IR (film) ν 3408,

D

1

2090, 1642, 1161 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 7.77

(d, J = 7.9 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 6.17 (d, J =

3.4 Hz, 1H), 5.32 (d, J = 8.9 Hz, 1H), 5.26 (d, J = 8.2 Hz,

1H), 4.60 (d, J = 5.6 Hz, 1H), 4.23 (dd, J = 6.2, 6.9 Hz, 1H),

4.08−4.13 (m, 1H), 3.46 (q, J = 7.4 Hz, 1H), 2.40 (s, 3H),

1.43 (s, 9H), 1.29 (s, 3H), 1.18 (s, 3H); ¹³C NMR (150 MHz,

CDCl₃) δ 155.6, 143.5, 137.5, 132.7, 129.6, 127.32, 121.4,

110.9, 80.3, 76.4, 76.3, 55.0, 51.2, 28.3, 27.3, 25.9, 21.5; MS

(EI) m/z 516 (M), 57 (46), 91 (81), 98 (62), 99 (97), 139

(48), 254 (100); HRMS calcd for C₂₁H₂₉N₂O₆SBr 516.0930,

found 516.0940.

A hydrogenation vial was charged with acrylate 26 (240 mg,

0.470 mmol), 5% Rh/Al₂O₃(60 mg), and 85% ethanol (1.5 mL)

before evacuation with H₂. The reaction was stirred at room

temperature and 55 psi for 144 h before filtering through a plug

of SiO₂and concentrating. The crude material was purified via

flash column chromatography with a solvent gradient of 3:1

then 1:1 (hexanes−ethyl acetate) to yield 30a and 30b (8:1)

(228 mg, 95%) as a white solid:

Ethyl (3aR,6S,7R,7aS)-6-[(tert-Butoxycarbonyl)amino ]-2,2-

dimethyl-7-{ [(4-methylphenyl)sulfonyl]amino}-3a,6,7,7 a-tet-

rahydro-l,3-benzodioxole-4-carboxylate (26). A. From Vinyl

Bromide 25. A solution of vinyl bromide 25 (X = Br, I) (2.00 g,

Major isomer 30a: R_f0.49 (1:1 hexanes−ethyl acetate); mp 246−

247 °C (CHCl₃); IR (film) ν 3434, 2099, 1647, 1160 cm⁻¹; ¹H NMR

(600 MHz, CDCl₃) δ 7.78 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz,

2H), 5.30 (d, J = 8.6 Hz, 1H), 5.12 (d, J = 8.3 Hz, 1H), 4.46 (t, J =

4.3 Hz, 1H), 4.18−4.25 (m, 1H), 4.09−4.15 (m, 1H), 3.86 (dd, J =

5.1, 8.8 Hz, 1H), 3.40 (dq, J = 1.3, 10.2 Hz, 1H), 3.21 (q, J = 9.3 Hz,

1H), 2.81 (dt, J = 3.8, 12.6 Hz, 1H), 2.42 (s, 3H), 2.13 (dt, J = 3.7,

13.5 Hz, 1H), 1.80 (q, J = 12.8 Hz, 1H), 1.45 (s, 9H), 1.22 (t, J = 6.9

Hz, 3H), 1.18 (s, 3H), 1.16 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ

170.3, 156.4, 142.8, 138.6, 129.1, 127.4, 109.4, 80.1, 79.2, 73.8, 60.9,

60.2, 50.4, 41.2, 28.5, 28.4, 27.7, 26.0, 21.4, 14.1; MS (EI) m/z 497

(M − CH₃), 41 (52), 43 (44), 57 (100), 91 (99), 100 (35), 155 (44),

182 (46), 240 (47), 257 (79); HRMS calcd for C₂₃H₃₃N₂O₈S

497.1958, found 497.1962.

3.86 mmol), ethanol (15 mL), and triethylamine (15 mL) in toluene

(70 mL) was purged with CO (g) for 10 min. The solution was

charged with CO(g) and Pd(PPh₃)₄(223 mg, 0.193 mmol) and then

heated to 60 °C for 1 h before the addition of Pd[(PPh₃)₂(Cl)₂] (271 mg,

0.386 mmol). The reaction was then heated to reflux for 6 h, cooled to

room temperature, and filtered through a plug of SiO₂. The crude

material was purified by flash column chromatography to yield acrylate

26 (888 mg, 45%) as a yellow oil.

The minor isomer 30b was not fully characterized, identified only

by NMR in the mixtures. In preparative runs, the mixture of the two

isomers was used in the next step without separation.

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Article

Ethyl (3R,4R,5S)-5-((tert-Butoxycarbonyl)amino)-3-hydroxy-

4-(4-methylphenylsulfonamido)cyclohex-1-ene carboxylate (31).

(300 MHz, CDCl₃) δ 7.83 (d, J = 8.3 Hz, 2H), 7.30 (d,

J = 8.3 Hz, 2H), 6.87 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 7.8 Hz,

1H), 4.91 (d, J = 5.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.10

(dd, J = 5.7, 9.1 Hz, 1H), 3.93 (dd, J = 2.6, 9.0 Hz, 1H),

3.45−3.54 (m, 1H), 2.42 (s, 3H), 1.32−1.37 (m, 4H), 1.28−

1.32 (m, 5H); MS (FAB) m/z 437 (M + H⁺), 43 (18), 91

(100), 136 (20), 139 (39), 152 (23), 155 (72), 167 (24), 168

(22), 181 (27), 196 (38), 437 (27); HRMS calcd for

C₁₉H₂₅N₄O₆S 437.1495, found 437.1494

Ethyl (3aS,4S,7R,7aS)-8-Acetyl-2,2-dimethyl-7,7a-dihydro-

4,7-(epoxyimino)-1,3-benzodioxole-4(3aH)-carboxylate (32).

The allylic alcohol 31 was generated on a small scale by base-

catalyzed elimination (EtOH, EtONa, room temperature).

Ethyl (3aS,4R,5R,7aR)-2,2-Dimethyl-8-[(4-methylphenyl)-

sulfonyl]-3a,4,5,7a-tetrahydro-4,5-epimino-1,3-benzodioxole-

7-carboxylate (28).

To a stirred solution of cis-dihydrodiol 27¹⁵(5.00 g, 27.1 mmol)

in 2,2-dimethoxypropane (80 mL) was added p-toluenesulfonic

acid (catalytic amount) at room temperature. After complete

consumption of starting material (TLC analysis), the

solution was cooled 0 °C before the addition of H₂O (10 mL).

On a preparative scale, the intermediate acetonide was not

isolated (analytical samples were purified via flash column

chromatography with a solvent system of 3:1 (hexanes−

ethyl acetate)).

To a stirred solution of acetonide 27 (500 mg, 2.23 mmol) and

Cu(acac)₂(58 mg, 0.22 mmol) in MeCN (1 mL) was added

PhINTs (832 mg, 2.23 mmol) at 0 °C. The resulting

solution was stirred for 5 h before being filtered through SiO₂

and concentrated. The crude material was purified via flash

column chromatography with a solvent gradient of 10:1, 6:1,

then 3:1 (hexane−ethyl acetate) to yield aziridine 28 (359 mg,

41%) as colorless crystals: R_f0.46 (2:1 hexanes−ethyl

Data for the intermediate acetonide, ethyl (3aR,7aS)-2,2-

dimethyl-3a,7a-dihydro-1,3-benzodioxole-4-carboxylate:¹⁵colorless

oil; R_f0.56 (1:1 hexanes/ethyl acetate); [α]²³+74.6 (c 4.02,

acetate); mp 106−107 °C (MeOH−hexanes); [α]²³−52.5

D

(c 0.62, CHCl₃); IR (film) ν 3434, 2099, 1647, 1160 cm⁻¹; ¹H

NMR (600 MHz, (CO(CD₃)₂) δ 7.86 (d, J = 8.3 Hz, 2H),

7.48 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 4.5 Hz, 1H), 4.73 (d, J =

6.9 Hz, 1H), 4.62 (dd, J = 0.9, 6.9 Hz, 1H), 4.14−4.21 (m,

2H), 3.56 (dd, J = 4.5, 6.2 Hz, 1H), 3.34 (dd, J = 1.1, 6.4 Hz,

1H), 2.45 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H), 1.23 (t, J = 7.1

Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 164.6, 145.2, 134.7,

134.1, 131.2, 130.0 (2 × C), 127.9 (2 × C), 110.3, 70.0, 68.6,

60.7, 37.5, 35.3, 27.0, 24.9, 20.8, 13.6; MS (EI) m/z 393 (M),

43 (38), 47 (29), 49 (24), 47 (100), 86 (80), 91 (20); HRMS

calcd for C₁₉H₂₃NO₆S 393.1246, found 393.1239.

CHCl₃); IR (film) ν 3018, 2987, 2936, 1712, 1651, 1425, 1380, 1259,

1

1155, 1031, 917, 856, 697, 667, 512 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 7.06 (dd, J = 5.3, J = 3.1 Hz, 1H), 4.84 (d, J = 5.7 Hz, 1H),

4.28−4.41 (m, 1H), 4.07−4.26 (m, 2H), 2.21−2.45 (m, 1H), 1.99−

2.16 (m, 1H), 1.86−1.99 (m, 1H), 1.58−1.72 (m, 1H), 1.33 (d, J =

10.2 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 166.2, 142.3, 130.0, 108.5, 72.6, 70.4, 60.5, 27.8, 26.2, 25.1, 20.9,

14.2; MS (EI) m/z 226 (M⁺− CH₃), 211 (77), 181 (15), 169 (17),

123 (100), 105 (17), 95 (13), 83 (11), 79 (76), 67 (14), 59 (10), 55

(11), 43 (82), 41 (14); HRMS (M⁺− CH₃) calcd for C₁₂H₁₆O₄

211.0970, found 211.0969. Anal. Calcd: C, 64.27; H, 7.19. Found: C,

64.52; H, 7.08.

Ethyl (3aR,6S,7R,7aS)-6-Azido-2,2-dimethyl-7-{[ (4-

methylphenyl)sulfonyl]amino}-3a,6,7,7a-tetrahydro-l,3-benzo-

dioxole-4-carboxylate (29).

NaIO₄(5.80 g, 27.1 mmol) was added to the reaction vessel prior to

the addition of a solution of acetohydroxamic acid (2.03 g, 27.1 mmol)

in MeOH (25 mL) dropwise over 5 min. The resulting solution was

stirred at room temperature for 16 h, quenched by the slow addition of

satd NaHSO₃(10 mL) and extracted into Et₂O (3 × 100 mL). The

combined organic layers were washed with brine (2 × 30 mL) and

dried over Na₂SO₄. The crude material was purified via flash column

chromatography with a solvent system of 2:8 (hexanes−ethyl acetate)

to yield 32 (5.65 g, 70% over two steps) as a white solid: R_f0.33 (3:7

hexanes−ethyl acetate); mp 89−90 °C (hexanes−ethyl acetate);

To a stirred solution of 28 (25 mg, 0.064 mmol) and NH₄Cl

(51 mg, 0.95 mmol) in DMF (0.5 mL) was added NaN₃(8 mg,

0.127 mmol) at 0 °C. The resulting suspension was stirred

for 3 h before being diluted with Et₂O (1 mL) and H₂O

(1 mL). The layers were separated, and the aqueous layer

was extracted with Et₂O (10 × 0.2 mL). The combined

organic layers were washed with brine (1 × 1 mL) and dried

over Na₂SO₄. The crude material was purified via flash

column chromatography with a solvent gradient of 4:1 then

2:1 (hexane−ethyl acetate) to yield 29 (22 mg, 79%) as a

[α]²³−18.0 (c 0.54, CHCl₃); IR (film) ν 3466, 2938, 2987, 1747,

D

1684, 1620, 1372, 1275, 1086 cm⁻¹; H NMR (600 MHz, CDCl₃) δ

1

6.57−6.65 (m, 2H), 5.47−5.52 (m, 1H), 4.71 (d, J = 6.8 Hz, 1H), 4.56

(dd, J = 4.7, 6.6 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.01 (s, 3H), 1.38

(t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.30 (s, 3H); ¹³C NMR (150 MHz,

CDCl₃) δ 173.9, 166.6, 132.4, 128.4, 111.7, 79.2, 76.1, 72.8, 62.7, 50.0,

25.6, 25.4, 21.7, 14.1; MS (EI) m/z 297 (M), 43(100), 96(30),

100(32), 105(35), 124(52); HRMS calcd for C₁₄H₁₉NO₆297.1212,

found 297.1215. Anal. Calcd: C, 56.56; H, 6.44. Found: C, 56.67;

H, 6.45.

1

white solid: R_f0.43 (1:1 hexanes−ethyl acetate); H NMR

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+

Ethyl (3aS,4S,7R,7aS)-7-(Acetylamino)-4-hydroxy-2,2-dimethyl-

(M − CH₃), 43 (52), 136 (19), 266 (100); HRMS calcd for

C₁₃H₁₆NO₅266.1028, found 266.1032.

3a,4,7,7a-tetrahydro-1,3-benzodioxole-4-carboxylate (33).

Ethyl (3aR,6R,7R,7aS)-7-(Acetylamino)-6-hydroxy-2,2-dimeth-

yl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-4-carboxylate (35).

To a stirred solution of oxazine 32 (955 mg, 3.21 mmol) in

15:1/CH₃CN:H₂O (10 mL) was added molybdenum

hexacarbonyl (848 mg, 3.21 mmol) at room temperature.

The reaction was brought to reflux for 3 h and then cooled

before the addition of activated charcoal (spatula tip). The

resulting suspension was stirred for 30 min and then filtered

through a plug of Celite. The crude material was purified via

flash column chromatography with a solvent system of 1:9

(hexanes−ethyl acetate) to yield 33 (720 mg, 75%) as a white

solid: R_f0.20 (ethyl acetate); mp 97−99 °C (hexanes−ethyl

To a stirred solution of oxazoline 34 (800 mg, 2.86 mmol) in

1:1/ethanol/water (8 mL) was added calcium carbonate (570

mg, 5.69 mmol) at room temperature. The reaction mixture

was brought to reflux for 48 h before concentrating. The crude

residue was dissolved in ethyl acetate and then filtered through

a plug of Celite. The crude material was purified via flash

column chromatography with a solvent system of 1:4 (hexanes−

ethyl acetate) to yield 35 (616 mg, 72%) as a white solid: R_f

0.23 (96:4 methylene chloride−methanol); mp 115−118 °C

acetate); [α]²³−94.3 (c 0.79, CHCl₃); IR (film) ν 3433,

(hexanes−ethyl acetate); [α]²³−54.33 (c 1.7, CHCl₃); IR

D

1

D

2094, 1644, 1271, 1217, 1060 cm⁻¹; H NMR (600 MHz,

(film) ν 3307, 2624, 2247, 1718, 1655, 1541, 1247, 1069

CDCl₃) δ 6.25 (d, J = 8.7 Hz, 1NH), 5.98 (dd, J = 3.8, 9.8 Hz,

1H), 5.94 (dd, J = 0.9, 9.9 Hz, 1H), 4.77−4.81 (m, 1H), 4.37

(t, J = 8.3 Hz, 1H), 4.34 (dd, J = 4.3, 7.7 Hz, 1H), 4.22−4.29

(m, 2H), 4.12 (s, 1OH), 1.99 (s, 3H), 1.35 (s, 3H), 1.32 (t,

J = 7.4 Hz, 3H), 1.28 (s, 3H); ¹³C NMR (150 MHz, CDCl₃)

δ 172.7, 170.0, 132.9, 129.6, 109.3, 81.0, 76.3, 74.5, 62.8, 48.8,

1

cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.01 (d, J = 3.1 Hz,

1NH), 5.76 (br s, 1NH), 5.01 (d, J = 5.6 Hz, 1H), 4.73 (t, J =

3.4 Hz, 1H), 4.53 (q, J = 5.9 Hz, 1H), 4.47 (t, J = 5.8 Hz,

1H), 4.26−4.31 (m, 2H), 3.07 (bs, 1OH), 2.04 (s, 3H), 1.42

(s, 6H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz,

CDCl₃) δ 171.6, 165.4, 141.0, 130.3, 109.9, 73.8, 69.8, 68.8,

61.3, 52.3, 27.48, 25.7, 23.4, 14.2; MS (FAB) m/z 299 (M⁺),

29(34), 43(71), 136(29), 182(23), 242(100); MS (EI) m/z

284 (M⁺− CH₃), 43 (100), 84 (25), 142 (23), 284 (17);

HRMS calcd for C₁₃H₁₈NO₆284.1134, found 284.1132.

Anal. Calcd for C₁₄H₂₁NO₆: C, 56.18; H, 7.07. Found: C,

56.22; H, 7.17.

+

26.2, 24.2, 23.5, 14.0; MS (EI) m/z 284 (M − CH₃), 43

(90), 83 (47), 84 (100), 86 (61), 96 (37), 125 (36), 153

(38), 199 (99); HRMS calcd for C₁₃H₁₈NO₆284.1130, found

284.1137. Anal. Calcd: C, 56.18; H, 7.07. Found: C, 56.27; H,

7.11.

Ethyl (3aR,5aR,8aR,8bS)-2,2,7-Trimethyl-3a,5a,8a,8b-tetra-

hydro[1,3]dioxolo[4,5-e][1,3]benzoxazole-4-carboxylate (34).

Ethyl (3aR,4R,6R,7R,7aS)-7-(Acetylamino)-6-hydroxy-2,2-

dimethylhexahydro-1,3-benzodioxole-4-carboxylate (36).

To a stirred solution of allylic alcohol 33 (400 mg, 1.33 mmol)

in methylene chloride (5 mL) was added NEt₃(0.74 mL, 4.0 mmol),

DMAP (catalytic amount) and methanesulfonyl chloride

(0.16 mL, 2.1 mmol) at room temperature. The resulting

solution was stirred for 4 h before being quenched by the slow

addition of sat. NaHCO₃(5 mL), and then extracted into

ethyl acetate (3 × 5 mL). The combined organic layers were

washed with brine (1 × 2 mL), dried over Na₂SO₄and

concentrated under reduced pressure. The crude material was

purified via flash column chromatography with a solvent

system of 1:2 (hexanes−ethyl acetate) to yield 34 (204 mg,

54%) as a white yellow solid: R_f0.40 (1:4 hexanes−ethyl

acetate); mp 54−55 °C (hexanes−ethyl acetate); [α]²³_D+150.4

(c 1.25, CHCl₃); IR (film) ν 3543, 2986, 1722, 1667,

1372, 1218 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 6.56

(d, J = 3.0 Hz, 1H), 5.14 (dd, J = 2.9, 8.5 Hz, 1H), 4.93 (d, J =

5.2 Hz, 1H), 4.86 (dd, J = 2.7, 5.1, Hz, 1H), 4.58 (d, J = 8.4

Hz, 1H), 4.27−4.34 (m, 2H), 1.97 (d, J = 1.3 Hz, 3H), 1.42 (s,

3H), 1.34 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H); ¹³C NMR (150

MHz, CDCl₃) δ 165.9, 165.6, 133.3, 130.5, 109.1, 73.6, 73.2,

68.9, 64.3, 61.2, 27.8, 26.3, 14.2, 14.1; MS (EI) m/z 266

A hydrogenation vial was charged with ethyl acrylate 35

(150 mg, 0.501 mmol), 5% Rh/Al₂O₃(60 mg), and 85%

ethanol (2 mL) before evacuation with H₂. The reaction was

stirred at room temperature and 60 psi for 144 h before being

filtered through a plug of SiO₂and concentrated. The crude

material was purified via flash column chromatography with a

solvent gradient of 1:1 (hexanes−ethyl acetate) and then

methanol to yield 36 (143 mg, 95%) as a white solid: R_f0.66

(90:10 CHCl₃−methanol); mp 156−158 °C (CHCl₃); [α]²³_D−90.15

(c 1.1, CHCl₃); IR (film) ν 3305, 2986, 1722, 1666, 1553,

1374, 1219, 1066, 771 cm⁻¹

;

¹H NMR (600 MHz,

CO(CD₃)₂) δ 7.17 (d, J = 7.7 Hz, 1NH), 4.59 (t, J = 4.1

Hz, 1H), 4.38 (br s, 1OH), 4.21 (dq, J = 7.2, 10.9 Hz, 1H), 4.14

(dd, J = 4.6, 9.0 Hz, 1H), 4.11 (dq, J = 3.3, 7.0 Hz, 1H), 4.00−

4.03 (m, 1H), 3.85 (td, J = 2.2, 4.5 Hz, 1H), 3.24 (dt, J = 4.3,

12.6 Hz, 1H), 1.92(s, 3H), 1.88−2.00 (m, 2H), 1.42 (s, 3H),

1.28 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); MS (EI) m/z 301 (M),

43 (38), 47 (29), 49 (24), 47 (100), 86 (80), 91 (20); HRMS

calcd for C₁₄H₂₃NO₆301.1525, found 301.1524.

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Article

Ethyl (3aR,4R,6R,7S,7aS)-7-(Acetylamino)-2,2-dimethyl-6-

[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-4-carboxy-

late (37).

was purified by flash column chromatography with a solvent system of

1:7 (hexanes−ethyl acetate) to yield 39 (15 mg, 86% over two steps)

as a yellow oil: R_f0.22 (1:10 hexanes−ethyl acetate); [α]²³+44.3 (c

D

0.65, CHCl₃); IR (film) ν 3509, 2103, 1701, 1690, 1510, 1214 cm⁻¹

;

¹H NMR (600 MHz, CDCl₃) δ 6.83 (t, J = 2.4 Hz, 1H), 5.96 (br s,

1NH), 5.28 (br s, 1OH), 4.39 (d, J = 2.8 Hz, 1H), 4.22 (q, J = 7.2 Hz,

2H), 3.59−3.66 (m, 2H), 2.98 (dd, J = 4.3, 15.9 Hz, 1H), 2.42−2.49

(m, 1H), 2.10 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz,

CDCl₃) δ 173.6, 165.6, 138.1, 127.6, 71.2, 61.4, 57.9, 57.6, 29.5, 23.2,

14.1; MS (FAB) m/z 269 (M + H⁺), 41 (44), 43 (100), 56 (54), 57

(46), 84 (22), 227 (55); HRMS calcd for C₁₁H₁₇N₄O₄269.1250,

found 269.1248.

Ethyl (3aR,7R,7aS) 7-Acetamido-6-(hydroxyimino)-2,2-

dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-4-carboxy-

late (41).

To a stirred solution of alcohol 36 (50 mg, 0.17 mmol) and

triethylamine (93 μL, 0.66 mmol) in methylene chloride (100 μL)

was added methanesulfonic anhydride (58 mg, 0.33 mmol) at

0 °C. The reaction temperature was slowly raised to room

temperature over 24 h before the solution was diluted with

methylene chloride (500 μL) and then washed with 1 N HCl

(2 × 500 μL), satd NaHCO₃(2 × 500 μL), and brine (1 × 1 mL).

The crude material was purified via flash column chromatog-

raphy with a solvent gradient of 1:2 then 1:5 (hexanes−ethyl

acetate) to yield 37 (46 mg, 73%) as a white solid: R_f0.47 (1:10

hexanes−ethyl acetate); mp 101−102 °C (CHCl₃); [α]²³_D−49.91

(c 1.21, CHCl₃); IR (film) ν 3307, 2628, 1719, 1651, 1361 cm

The oxidizing agent was prepared by stirring CrO₃(835 mg;

8.35 mmol) in Ac₂O (2 mL) at 80 °C. After 7 min the resulting

slurry was allowed to cool to room temperature diluted with 6

mL of DCM and cooled in ice-bath. This solution was added

over 30 s to a cooled (4 °C) solution of tertiary alcohol 33 (1 g;

3.34 mmol) in DCM (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). Reaction mixture was then

stirred additional 5 min in ice bath and 30 min at room

temperature. On a preparative scale the intermediate enone

ethyl (3aR,7S,7aS) −7-acetamido-2,2-dimethyl-6-oxo-

3a,6,7,7a-tetrahydrobenzo[d]-[1,3]dioxole-4-carboxylate

(40) was not isolated and taken directly to the next step.

Analytical sample was purified via flash column chromatog-

raphy (ethyl acetate). Analytical data for intermediary enone

1

cm⁻¹; H NMR (600 MHz, CDCl₃) δ 5.15−5.17 (m, 1H),

4.74 (d, J = 8.9 Hz, 1NH), 4.62 (t, J = 4.1 Hz, 1H), 4.22−4.28

(m, 1H), 4.15−4.19 (m, 1H), 4.03 (dd, J = 4.6, 8.6 Hz, 1H),

3.58 (dt, J = 2.7, 8.8 Hz, 1H), 3.12 (s, 3H), 2.92 (dt, J =

4.2, 13.3 Hz, 1H), 2.25 (dt, J = 4.2, 14.9 Hz, 1H), 2.09−2.13

(m, 1H), 2.08 (s, 3H), 1.55 (s, 3H), 1.37 (s, 3H), 1.26 (t, J =

7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.6, 169.7,

109.9, 77.7, 73.8, 73.3, 61.1, 56.4, 42.6, 37.6, 28.1, 26.2, 25.2,

21.0, 14.1; MS (FAB) m/z 380 (M + H⁺), 43(23), 257(100);

HRMS calcd for C₁₅H₂₆NO₈S⁺380.1379, found 380.1366.

Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-hydroxycyclo-

hex-1-ene-1-carboxylate (39).

40: Colorless oil: R_f0.6 (ethyl acetate); [α]²⁰+19.35 (c 1,

D

CHCl₃); IR (KBr, cm⁻¹) ν 3385, 2988, 1724, 1712, 1662, 1543,

1

1383, 1253, 1077, 1024; H NMR (300 MHz, CDCl₃) δ 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) δ 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); HRMS calcd for C₁₄H₁₉NO₆297.1212, found 297.1218.

The above reaction mixture was again cooled in 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 stirred for additional 16 h. The mixture

was then diluted with ethyl acetate (130 mL) and extracted 4 × 8 mL

with saturated NaHCO₃solution. Combined aqueous layers were re-

extracted with ethyl acetate (30 mL). The combined organic layer was

dried with MgSO₄and evaporated. Chromatography of residue

[hexane−ethyl acetate (1:1) → ethyl acetate, 30 g silica] afforded 860

mg (82%) of oxime 41 as a greenish oil which solidified on trituration

with 2-propanol. Recrystallization from 2-propanol−hexane provided

41 as white solid: mp 106−116 °C (2-propanol); R_f0.30 (ethyl

To a stirred solution of 37 (25 mg, 0.066 mmol) in acetone/

H₂O 10:1 (0.5 mL) was added sodium azide (43 mg, 0.66 mmol).

The resulting solution was stirred at room temperature for 12 h

and then concentrated under reduced pressure to provide azide

ethyl (3aR,4R,6S,7R,7aS)-7-(acetylamino)-6-azido-2,2-dime-

thylhexahydro-1,3-benzodioxole-4-carboxylate (38), which

was used without further purification. Data for 38: R_f0.41

(1:10 hexanes−ethyl acetate); IR (film) ν 3583, 3284, 2987,

2108, 1720, 1655, 1540, 1372, 1248, 1072 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 5.77 (d, J = 7.5 Hz, 1NH), 4.58 (dd, J = 4.0,

4.8 Hz, 1H), 4.43 (dd, J = 4.8, 8.6 Hz, 1H), 4.13−4.29 (m, 2H),

3.91 (dt, J = 3.4, 11.7 Hz, 1H), 3.20 (dd, J = 8.1, 11.1 Hz, 1H),

2.85 (dt, J = 3.9, 13.2 Hz, 1H), 2.17 (dt, J = 3.9, 13.2 Hz, 1H),

2.02 (s, 3H), 1.91 (q, J = 13.1 Hz, 1H), 1.51 (s, 3H), 1.34 (s,

3H), 1.26 (s, 3H); MS (FAB) m/z 327 (M+ H⁺), 43(23),

257(100), 299 (33); HRMS calcd for C₁₄H₂₃N₄O₅327.1668,

found 327.1670.

acetate); [α]²⁰−52.63 (c 1, CHCl₃); IR (KBr, cm⁻¹) ν 3367, 2988,

D

1720, 1659, 1547, 1382, 1246, 1069, 1023; ¹H NMR (300 MHz,

CDCl₃) δ 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) δ 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

To a stirred solution of crude azide 38 in methylene chloride (150 μL)

was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15 μL, 0.1 mmol) at

0 °C. The resulting solution was stirred until complete consumption of

starting material (TLC analysis, ∼12 h). The reaction was diluted with

methylene chloride (500 μL), washed with 1 N HCl (3 × 250 μL) and

brine (1 × 500 μL), and then dried over Na₂SO₄. The crude material

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Article

313 (M + H)⁺, 255 (73), 195 (76), 150 (16), 43 (38); HRMS calcd

for C₁₄H₂₁N₂O₆[M⁺+ 1] 313.1400, found 313.1406. Anal. Calcd for

C₁₄H₂₀N₂O₆: C, 53.84; H, 6.45. Found: C, 54.80; H, 7.52 (crystals

contain 15 mol % of 2-propanol).

(3aR,6S,7R,7aS)-7-Acetylamino-6-tert-butoxycarbonylami-

no-2,2-dimethyl-3a,6,7,7a-tetrahydrobenzo[1,3]dioxole-4-

carboxylic Acid Ethyl Ester (43). Procedure A (“Stepwise”).

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, 653, 624, 586, 545, 514, 464, 431; H NMR (600

1

MHz, CDCl₃) δ 5.63 (d, J = 9.3 Hz, 1H), 4.96 (d, J = 8.7 Hz, 1H),

4.57 (dd, 2 × 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 (150 MHz,

CDCl₃) δ 171.3, 170.4, 109.9, 79.7, 78.7, 73.8, 61.0, 55.2, 50.8, 41.4, 29.7,

28.3, 28.0, 26.2, 23.4, 14.2; MS (EI+) m/z (M⁺−CH₃) 385(3), 341(11),

329(15), 311(20); HRMS calcd for C₁₈H₂₉N₂O₇385.1975, found

385.1983. Anal. Calcd for C₁₉H₃₂N₂O₇: C, 56.99; H, 8.05; N, 7.00.

Found: C, 57.13; H, 8.19; N, 6.93.

Ethyl (1R,3S,4R,5R)- 4-acetamido-3-(tert-butoxycarbonyl-

amino)-5-hydroxycyclohexanecarboxylate (44). Analytical data

for minor product 44: waxy solid; mp 180 °C (ethyl acetate−hexane);

R_f0.1 (ethyl acetate); [α]²⁰_D−90.0 (c 1, CHCl₃); IR (KBr, cm⁻¹) ν 3357,

2979, 2936, 2871, 1725, 1686, 1654, 1569, 1559, 1526, 1457, 1384, 1340,

Suspension of oxime 41 (400 mg; 1.27 mmol) and 100 mg of

Rh/Al₂O₃(5%) in EtOH (96%, 45 mL) was hydrogenated in

the Parr apparatus (60 pound/in.²). After 16 h, the reaction

mixture was filtered through a short bed of Celite and

evaporated. On a preparative scale, the amine ethyl

(3aR,4R,6S,7R,7aS)-7-acetamido-6-amino-2,2-

dimethylhexahydrobenzo[d][1,3]dioxole-4-carboxylate (42)

was not isolated but taken directly to the next step. The

analytical sample was purified via flash column chromatography

[dichloromethane−methanol (1:1)] to yield amine 42 as

colorless oil: R_f0.26 (1:1 dichloromethane−methanol);

1

1328, 1317, 1284, 1244, 1171, 1129, 1079, 1023, 999; H NMR (600

MHz, CDCl₃) δ 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 (150 MHz, CDCl₃) δ 173.64,

173.5, 80.4, 73.4, 62.0, 60.9, 50.6, 38.7, 36.2, 33.6, 28.3, 23.2, 14.1; MS

(FAB+) m/z 345 (M⁺+ H), 289 (45), 245 (100), 168 (26); HRMS calcd

for C₁₆H₂₉N₂O₆345.2053, found 345.2026. Anal. Calcd for C₁₆H₂₈N₂O₆:

C,55.80; H, 8.19; N, 8.13. Found: C, 55.25; H, 8.24; N, 7.56.

Procedure B (“One Pot”). A suspension of oxime 41 (73 mg; 0.24

mmol), Boc₂O (0.105 mg; 0.48 mmol) and 20 mg of Rh/Al₂O₃(5%) in

EtOH (96%, 2 mL) was hydrogenated in a Parr apparatus (60 pound/

in.²). After 16 h, the reaction mixture was filtered through a short bed of

Celite and concentrated. Chromatography (ethyl acetate, 6 mL of silica)

yield 87 mg (93%) of amide 43 as a white solid.

[α]²⁰−11.54 (c 1, CHCl₃); IR (KBr, cm⁻¹) ν 3445, 2984,

D

1

1733, 1654, 1556, 1384, 1222, 1144, 1049; H NMR (600

MHz, CDCl₃) δ 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) δ 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); HRMS calcd for

Ethyl (3R,4R,5S)-4-Acetylamino-5-tert-butoxycarbonylami-

no-3-hydroxycyclohex-1-enecarboxylate (45).

C₁₄H₂₄N₂O₅300.1685, found 300.1800.

Minor overhydrogenated product: ethyl (1R,3S,4R,5R)-4-acet-

amido-3-amino-5-hydroxycyclohexanecarboxylate: white solid;

mp 158−162 °C (CHCl₃); R_f0.10 (1:1 dichloromethane−methanol);

[α]²⁰dynamic −12 to +7 (c 1, CHCl₃/MeOH 1:1); IR (KBr, cm⁻¹)

Acetonide 43 (534 mg; 1.33 mmol) was dissolved in EtOH (10 mL),

and 12.4 mL of ethanolic sodium ethoxide solution (0.05 M)

was added dropwise over period 1 min. After 5 min of

stirring at room temperature, the 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 of silica] of the residue afforded 432 mg

(94%) of allyl alcohol 45 as a white solid: mp 177−178 °C

D

ν 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; ¹H NMR (300 MHz,

CDCl₃) δ 4.15 (q, J = 7.2 Hz, 2H), 3.50−3.42 (m, 2H), 3.33 (dddd,

J = 4 × ∼1.5 Hz, 1H), 2.62 (m, 1H), 2.50 (dddd, J = 3.3, 3.3, 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, 1H), 1.27 (t, J = 7.2 Hz, 3H); ¹³C NMR

(75 MHz, CDCl₃) δ 174.1, 173.5, 70.4, 60.8, 60.5, 52.0, 38.7, 36.1,

35.1, 21.8, 13.2; MS (FAB+) m/z 245 (100), 168 (12); HRMS calcd

for C₁₁H₂₁N₂O₄245.1467, found 245.1501.

The crude mixture containing 42 and the minor overhydrogenated

product was dissolved in dichloromethane (20 mL), Boc₂O (800 mg;

3.66 mmol) was added, and the mixture was stirred at room

temperature. The progress of the reaction was monitored by TLC

(ethyl acetate−hexane 1:1). After 6 h, the reaction mixture was diluted

with DCM (45 mL) and washed with saturated solution of NaHCO₃

(5 mL + 1 g of solid NaHCO₃). The organic layer was dried with

MgSO₄and evaporated. Chromatography of residue [ethyl acetate−

hexane (3:1)→ ethyl acetate, 15 g silica] afforded 260 mg (50%) of

protected amide 43 as white solid and ∼10% of overhydrogenated

byproduct ethyl (1R,3S,4R,5R)-4-acetamido-3-(tert-butoxycarbony-

lamino)-5-hydroxycyclohexanecarboxylate (44).

(ethyl acetate−hexane); R_f0.2 (ethyl acetate); [α]²⁰−9.14

D

(c 1, CHCl₃); IR (KBr, cm⁻¹) ν 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,

607, 590, 571, 543, 491, 460, 437; ¹H NMR (600 MHz,

CDCl₃) δ 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 × ≈ 3 Hz, 1H), 2.03 (s, 3H), 1.47 (s, 9H), 1.30 (t,

J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 173.6, 165.9,

157.6, 139.1, 127.7, 80.9, 73.6, 61.1, 60.6, 48.1, 30.8, 28.2, 23.1,

14.2; MS (FAB+) m/z 343 (M⁺+ H), 287(100), 243(25),

208(30); HRMS calcd for C₁₆H₂₇N₂O₆343.1870, found

343.1842. Anal. Calcd for C₁₆H₂₇N₂O₆: C, 56.13; H, 7.65; N,

8.18. Found: C, 56.31; H, 7.83; N, 8.17.

Analytical data for major product 43: white solid; mp 174−175 °C

(ethyl acetate−hexane); R_f0.3 (ethyl acetate); [α]²⁰−33.5 (c 1,

D

CHCl₃); IR (KBr, cm⁻¹) ν 3349, 2978, 2930, 2885, 2360, 2340, 1731,

10065

dx.doi.org/10.1021/jo2018872|J. Org. Chem. 2011, 76, 10050−10067

The Journal of Organic Chemistry

Article

Ethyl (3R,4R,5S)-4-Acetamido-5-(tert-butoxycarbonylami-

no)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (46).

AUTHOR INFORMATION

Corresponding Authors

■

*E-mail: thudlicky@brocku.ca (T.H.); c1000@careerchem.com

(J.A.).

^#To whom correspondence regarding the efficiency metrics

should be addressed.

ACKNOWLEDGMENTS

■

We are grateful to the following agencies for financial support

of this work: Natural Sciences and Engineering Research

Council of Canada (NSERC) (Idea to Innovation and

Discovery Grants), TDC Research, Inc., TDC Research

Foundation, Brock University, Research Corporation, and the

Ontario Partnership for Innovation and Commercialization

(OPIC). We also thank the following persons for their

assistance with parts of the earlier syntheses: Melisa Drouin,

Amy English, Dr. Mohamed Hague, and Robert Giacometti.

To a solution of aziridine 47 (16 mg; 0.05 mmol) in 3-pentanol

(1 mL) was added Cu(OTf)₂(3 mg; 0.008 mmol). After 16 h,

the reaction mixture was quenched by addition of saturated

solution of NaHCO₃(0.1 mL) and concentrated. Chromatog-

raphy of the residue [hexane−ethyl acetate (3:1) → (2:1), 4.5

mL of silica] afforded 12 mg (60%) of compound 46 as a white

solid: mp 144−145 °C (CHCl₃); R_f0.3 (ethyl acetate−hexane

1:2); [α]²⁰−21.54 (c 0.5, CHCl₃); IR (KBr, cm⁻¹) ν 3324,

D

2976, 3966, 2933, 2877, 2855, 1720, 1687, 1658, 1587, 1536,

1459, 1384, 1297, 1250, 1176, 1146, 1130, 1086, 1054, 1019,

948; H NMR (600 MHz, CDCl₃) δ 6.81 (s, 1H), 5.80 (d,

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ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra. This material is available free of

charge via the Internet at http://pubs.acs.org.

10066

dx.doi.org/10.1021/jo2018872|J. Org. Chem. 2011, 76, 10050−10067

The Journal of Organic Chemistry

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10067

dx.doi.org/10.1021/jo2018872|J. Org. Chem. 2011, 76, 10050−10067

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Several generations of chemoenzymatic synthesis of oseltamivir (Tamiflu): Evolution of strategy, quest for a process-quality synthesis, and evaluation of efficiency metrics

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