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Studies towards Syntheses of Enantiopure 1-Azaadamantane-2-carboxylic AcidDerivatives.

Verhaar, M.T.

Publication date2000

Link to publication

Citation for published version (APA):Verhaar, M. T. (2000). Studies towards Syntheses of Enantiopure 1-Azaadamantane-2-carboxylic Acid Derivatives.

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Download date:24 May 2021

CHAPTERR 5

SYNTHESISS OF A 1-AZAADAMANTAN-4-ONE-2-CARBOXYLI C ESTER

5.11 Introductio n

Inn the early seventies research in the Speckamp group led to the synthesis of 1-

azaadamantan-4-one'' 3. One decade later, a more direct synthesis of the same molecule was

publishedd by Black2a (eq 5.1). The latter approach involved a very efficient double Mannich

reactionn of aminoketone 2 -formed in situ from the dioxolane 1- and formaldehyde under

acidicc conditions.

HoN N

H30+ +

O O

NH? ? (CH2Q)n n

H2S04 4

EtOH H O O

N N

33 (56%)

(5.1) )

Inspiredd by this result, we reasoned that such a process (eq 5.2) might allow a fast and

directt synthesis of enantiopure l-azaadamantan-6-one-2-carboxylic ester 4 via cyclisation of

aminoo ester 5. This enantiopure intermediate can be readily synthesised through partial

reductionn of p-methoxyphenylglycine 6, which is available in enantiopure form via the

selectivee enzymatic hydrolysis of the amino acid amide.3

OMe e

H H C02R R

^>^> J\ NH2 (5.2) )

Alternatively,, it might be possible to obtain the enantiopure l-azaadamantan-4-one-2-

carboxylicc ester 7 from the methylene-containing compounds 9 and 11 that were described in

Chapterss 2 and 4 (Scheme 5.1). Oxidative cleavage of the methylene group should allow access

too intermediates 8 and 10. In analogy with eq 5.1, a Mannich reaction of the bicyclic amino

esterr 10 with formaldehyde should lead stereoselectively to the formation of the target

moleculee 7, while amino ketone 8 in a reaction with a glyoxylic acid derivative, might give rise

too both diasteromers of 7.

97 7

ChapterChapter 5

Schem ee 5.1

4 / /

/ / [QQ "

77 C02R ^

0 ^ ^

0 ^ ^

hihi NH

8 8

100 C02R

\ \

<* *

\ ^~> N - -C0 2 Me e

9 9

8 ^ ^ 11 1

5.22 The/7-methoxyphenylgIycine approach

Thee syntheses of three />-mefhoxyphenylglycine-derived cyclisation precursors, viz. a

Boc-protectedd precursor of 5 for a double Mannich reaction (15) and two methyl carbamates 14

andd 16 for iV-acyliminium ion cyclisations, are outlined in Scheme 5.2. Racemic p-

Methoxyphenylglycinee 6 was converted in a one-pot procedure into 12 and 13 via a sequence

off steps involving subsequently (a) Birch reduction with Li/NH3, (b) protection of the nitrogen

withh either methyl chloroformate or di-fórf-butyl pyrocarbonate followed by (c) acidic

hydrolysiss of the methyl enol ether. Hydrogenation of the double bond using Pd on charcoal

followedd by esterification with either methanolic HC1 or diazomethane resulted in the

formationn of methyl carbamate 14 and fert-butyl carbamate 15 in good overall yields (64% and

59%,, respectively).

Schem ee 5.2 OMe (a)) Li, NH3 Ji (d) H2, Pd/C

(b)) CIC02Me, or Boc20 I I (e) HCI, MeOH, c)) H2S04 to pH = 2 N 5 ^ or CH2N2

14 4

HNN C02H HN C02Me

C02RR C02R 12(RR = Me) 14 (R = Me, 64%) 13(RR = fert-Bu) 15 (R = fert-Bu, 59%)

(f)) ethylene glycol, pTSA (9)) LIBH4 ^ (h)) CH2N2, silica (i)) acetone/H20, PPTS 1 QMe

HNN ^ ^

C02Mee 16

ReagentsReagents and conditions: (a) Li, NH3, THF, rerf-BuOH; then add H2S04 to pH = 9. (b) CIC02Me (3.4

equiv),, NaHC03 (1.1 equiv), H20; or (b) Boc20 (1.6 equiv), NaHC03 (1.1 equiv), H20. (c) add H2S04 to

pHH = 2. (d) H2, Pd/C, K2C03, EtOH. (e) (for R = Me) MeOH, HCI, rt, 64% over 5 steps; or (e) (for R =

fert-Bu)) CH2N2, Et20, 59% over 5 steps, (f) ethylene glycol (1.7 equiv), toluene, pTSA, Dean-Stark for 4

h,, 100%. (g) LiBH4, Et20, 96%. (h) CH2N2 [ca. 20 equiv), silica gel (0.5 mmol/g), Et20, 28%. (i) 10%

H200 in acetone, PPTS, reflux, 1 h, 86%.

98 8

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

Afterr protection of the ketone as a dioxolane the methyl ester 14 was reduced to the

correspondingg alcohol using L1BH4. The alcohol was selectively methylated using the non-

basicc diazomethane/silica procedure described by Nishiyama et al.4, after which the dioxolane

wass hydrolysed to liberate the ketone.

Withh the different cyclisation precursors (14, 15 and 16) in hand the cyclisations

towardss bi- and tricyclic systems were studied. However, none of the intended cyclisations

couldd be accomplished under various conditions (eq 5.3). The ferf-butyl carbamate 15 that

functionedd as the precursor for the in situ generation of 5 did not show any Mannich type

cyclisationn towards 4. For example, refluxing 15 in a solution of paraformaldehyde in

H2S04/EtOH22 resulted only in hydrolysis of the carbamate function and transesterification of

thee methyl ester. The treatment of methyl carbamates 14 and 16 with paraformaldehyde under

differentt conditions also did not lead to an intramolecular Af-acyliminium ion cyclisation to

bicyclicc systems of type 17. Apparently, the cyclisations are hindered by the presence of the R2

substituentt adjacent to the (iV-acyl)iminium ion centre. This in contrast to the unsubstituted

cyclisationn precursors, such as 2, which readily cyclise to bi- or tricyclic systems (see also

Sectionn 5.3, cyclisation of 21).

___ D double Mannich ?\ A/-acyliminium OU2HH reaction ^ " ^ ion cyclisation

-x-- O - * - ILk {:iSi

C02Me e 17 7

5.33 The bicyclic amino ketone approach

Thee Af-acyliminium ion cyclisation of allylsilane 18 was described in Chapter 2.

Oxidationn of the exocyclic double bond of 9 was effected by RuCb/NalCU oxidation5 in good

yield,, whereas ozonolysis led to complex mixtures.

SiPhMe,, (5.4) O AA RuCI3 (0.3 equiv)

ff B F * 0 E t * t ^ C O , M e N a l 4 e q " i v ) , t p N ^ C 0 2 M e 'NX02Mee i \ CCI4, CH3CN, H20 J \

188 z r 9 rt, 5h, 79% O 19

Withh a potential enantiopure synthesis of the bicyclic amino ketone6 19 in hand, a fast

synthesiss of the racemic material was desired. Therefore, p-methoxybenzylamine 20 was

99 9

ChapterChapter 5

convertedd into cyclisation precursor 21 via a sequence of steps (eq 5.5). A Birch reduction

followedd by treatment with methyl chloroformate, subsequent hydrolysis of the methyl enol

etherr and hydrogenation of the remaining double bond afforded 21 in good overall yield. The

N-acyliminiumm ion cyclisation to 19 was effected by refluxing a dilute solution of 21 and

paraformaldehydee in HCOOH. This cyclisation not only allowed fast access to 19 on gram

scale,, it also confirmed the fact that steric hindrance causes the failure of cyclisation of 16.

OMe e (a)) Li, NH3

(b)) CIC02Me (H2CO)n (1.1 equiv)

(c)) H2S04 to pH = 2 k / J HCOOH, reflux J \ ( 5 ' 5 ) Ye--C02Me e

(d)) H2, Pd/C

~NH2 2 X 0 2 M ee 19(78%)

200 21

ReagentsReagents and conditions: (a) Li, NH3, THF, fert-BuOH; then add H2S04 to pH = 9.5. (b) CIC02Me (2

equiv),, NaHC03 (2 equiv), H20. (c) add H2S04 to pH = 2. (d) H2, Pd/C, K2C03, EtOH, 72% over 4 steps.

Hydrolysiss of the methyl carbamate was effected by refluxing 19 in concentrated HC1

too give the HCl-salt 22. Remarkably, a Mannich reaction of this compound7 with a glyoxylic

acidd derivative could not be accomplished under several conditions (eq 5.6). For example, slow

syringee pump addition of a solution of methyl glyoxylate methyl hemiacetal in methanol to a

solutionn (at various temperatures) of 22 in methanolic HC1 or formic acid did not effect the

cyclisation. .

^ V c 0 2 M ee HCI(aq) < \ ^ N H 2 C , ) ( , V^N (5.6)

XJ~-AA reflux, quant. ^ ~ - \ x ? - V - - L 00 «« oo , C02Me

199 22 7

Thiss failure could possibly be attributed to the high reactivity of the iminium ion in

conjunctionn with the relatively low concentration of the nucleophile, the enol-form the ketone,

becausee a similar cyclisation with formaldehyde readily takes place (eq 5.1).

5.44 The bicyclic amino ester approach

Withh the above result in mind, the third approach, that utilises the bicyclic amino ester

10,, was investigated (eq 5.7). In this case, the final ring closure to the azaadamantane skeleton

iss comparable to the process that takes place during the synthesis of azaadamantanone by

Black22 (eq 5.1).

100 0

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

0 0

X. X. nn ? rnN„ v v

C02R R 1 0 C02R 11 1

(5.7) )

Inn order to arrive at a suitably protected form of intermediate 10, the tricyclic

compoundd 11 (available with both the equatorial (lleq) and axial (llax) oxazolidone ring, see

Sectionn 4.3) needs to undergo several transformations. The most important ones are (i)

oxidationn of the alcohol to the corresponding acid and (it) oxidative cleavage of the methylene

group.. The optimal sequence of these steps was studied.

5.4.11 Alcohol oxidation prior to oxidative cleavage

First,, the oxazolidinone ring of l leq was hydrolysed with NaOH in ethanol and the

nitrogenn protected as the corresponding rert-butyl carbamate 23. Then, the alcohol group was

efficientlyy oxidised using a Swern oxidation followed by NaClC>2 oxidation to furnish the acid,

whichh was methylated with diazomethane to give 24.

Schem ee 5.3

V j T \ N YY (a) NaOH, BOH V j ^ B o c <C> S w e m ,

J AA (b)BoczO J A 0 H (d)NaCI02

233 (96%) 11eq q

(f)fluCI3,, Nal04

(e)) CH2N2

^VtXN'Boc c i \\ C02Me

244 (57%) O O

1 \\ C02Me J \ C02Me

25(16%) ) 266 (23%)

ReagentsReagents and conditions: (a) NaOH, EtOH, reflux, 96%. (b) Boc20, Et3N, CH2CI2, rt, 100%. (c) Swern

oxidation:: (COCI)2, DMSO, Et3N, CH2CI2, -78 , 82%. (d) NaCI02, aqueous 1 M NaH2P04 buffer, tert-

BuOH,, 2-methyl-2-butene, 0 . (e) CH2N2, Et20, rt, 69% over 2 steps, (f) RuCI3 (0.3 equiv), Nal04 (4

equiv),, CCI„, MeCN, H20, rt, 5 h, 39%.

Oxidativee cleavage of the methylene group in compound 24 using the RuC^/NalCU

methode,55 however, resulted in the formation of both the desired product 25 in very low yield

togetherr with the overoxidised product 26 (23%). The formation of 26 is remarkable although

literaturee precedent exists for such an oxidation.9 The rather moderate yield and poor selectivity

off this last transformation prompted us not to pursue this sequence any further.

101 1

ChapterChapter 5

5.4.22 Oxidative cleavage and synthesis of racemic material

Inn order to produce 25 in higher yields the sequence that starts with the oxidative

cleavagee of the methylene group present in the cyclisation products l leq and l lax (see Section

4.3)) was studied. This oxidation was performed with RuCl3/NaI045 on both the racemic and

opticallyy active form of l leq and l lax to obtain the corresponding ketones 27 in good yield.

HH n

11eq(pH) ) 11ax(<xH) )

RuCI3(0.3equiv) ) Nal044 (4 equiv)

CCI4,, CH3CN, H20 rt,, 5 h

27eqq (87%) 27axx (74%)

(5.8) ) O O

Too have large quantities of 27 at our disposal, a fast racemic synthesis was desired

(Schemee 5.4). Therefore, alcohol 28, obtained from p-methoxybenzylalcohol via a literature

procedure,100 was coupled to oxazolidine-2,4-dione in good yield using di-wo-propyl

azodicarboxylatee and PPh3. Reduction of the oxazolidine-2,4-dione 29 with NaBH4 afforded

thee corresponding hydroxy oxazolidinone, that was deprotected upon reflux in 10% aqueous

acetonee in the presence of PPTS to yield the cyclisation precursor 30.

Schemee 5.4

O ^ M ^ O O N N H H

(a)) DIAD, PPh3

(b)) NaBH4, MeOH, 0 C

OO (c) PPTS, acetone/H26

(d)) HCOOH, reflux

HO O *Ï5 5 31 1

o o 27(eq:ax=1:1) )

ReagentsReagents and conditions: (a) oxazolidine-2,4-dione, di-/so-propyl azodicarboxylate (DIAD), PPh3, THF,

63%.. (b) NaBH4, MeOH, 0 , 85%. (c) 10% H20 in acetone, PPTS, reflux, 43%. (d) HCOOH, reflux, 18

h,, 96%.

102 2

SynthesisSynthesis of a 1 -azaadamantan-4-one-2-carboxylic ester

Interestingly,, refluxing a solution of 30 in HCOOH resulted in the formation of an

unseparablee 1:1 mixture of the two diastereomers of 27. Apparently, the very reactive enol (31)

allowedd the formation of both the equatorial and the axial product in contrast to similar

cyclisationss with a double bond as the nucleophile (see also Section 4.3). Although this

sequencee directly leads to racemic 27eq and 27ax on multigram scale, separation of these

compoundss could not be accomplished using flash chromatography, which is a serious

drawbackk of this methodology.

5.4.33 Protection of the ketone before alcohol oxidation

Too prevent self-condensation during the opening of the oxazolidine ring the ketone

presentt in 27 had to be protected. Therefore, ketones 27eq and 27ax, obtained via oxidative

cleavagee were protected as the dioxolanes using ethylene glycol and PPTS (Scheme 5.5). Next,

thee oxazolidinone rings were hydrolysed followed by treatment with Boc20 to furnish the tert-

butyll carbamates 32eq and 32ax. Swern oxidation of these alcohols gave the corresponding

aldehydess in good yield. Remarkably, the subsequent oxidation of the material with the

equatoriall aldehyde only worked with a large excess of NaC102 to produce a low yield of the

correspondingg acid, which was methylated to give 33eq.

Schem ee 5.5 \~r^\~r^HH^^ (a) ethylene glycol ' i y C ^ N ^ B o c

J \\ (b)NaOH, EtOH P->A OH OO 2 7 e q (c)Boc20 < ^ 0 3 2 e q ( 5 9 % )

27axx 32ax (58%)

( d ) S w e r n ,, \pTN-Boc v , ^ V B O C (e)NaCI022 0 - ^ C 0 2 M e / x i \ C02Me (f)CH2N22 < n O

V - 00 33eq(l8%) 25 33axx (85%)

ReagentsReagents and conditions: (a) Ethylene glycol, toluene, PPTS, reflux, (b) NaOH, EtOH, reflux, (c) Boc20,

Et3N,, CH2CI2, rt. (d) Swern oxidation: (COCI)2, DMSO, Et3N, CH2CI2, -78 . (e) NaCI02, aqueous 1 M

NaH2P044 buffer, tert-BuOH, 2-methyl-2-butene, 0 C (for32e q 10 equiv NaCI02, rt). (f) CH2N2, Et20, rt.

Thiss poor reactivity is probably due to steric hindrance caused by the acetal. On the

otherr hand, the NaC102 oxidation of the axial aldehyde proceeded smoothly to give the

correspondingg acid, which was methylated to give ester 33ax in good yield. Unfortunately, the

deprotectionn of the cyclic acetal under hydrolytic11 or transacetalysation conditions failed.

103 3

ChapterChapter 5

Alternatively,, the acetal present in 32eq was easily deprotected (eq 5.9). This deprotection is

probablyy assisted by the neighbouring hydroxyl group, which is supported by the formation of

thee very stable hemiacetal 34.

yC^-N-Bocc acetone/H20 y C ^ N - B o c

/ H AA 0 H PPTS, reflux, l'h H o 4 A / (5-9) O O

32eqq 34(91%) a a Inn view of the unsatisfactory result of the dioxolane protective group, we turned our

attentionn to the dimethoxy acetal (eq 5.10). Thus, treatment of 27eq with trimethyl

orthoformatee in methanol, followed by hydrolysis of the oxazolidinone ring with NaOH in

ethanoll and treatment with di-ferf-butyl pyrocarbonate led to carbamate 35. A Swern oxidation

affordedd the aldehyde 36 in a quantitive yield. Remarkably, further oxidation of this aldehyde

withh NaC102 failed, in contrast to the aldehyde derived from 32eq which could be oxidised,

albeitt in low yield. The reason is probably steric hindrance caused by the freely rotating

methoxyy group.

(5.10) ) ^ ^ ^^ O (a) (MeO)3CH, MeOH, ^ ^ ^ ^ ^ ^ y u - > N - 77 pTSA Y p \ - N ' B o c ( d ) S w e r n y r \ - N - B o c

A ^ OO (b) NaOH. BOH' M e O ^ ^ - O H " M e O ^ A ) * 0 J~\J~\ (b) NaOH, EtOH OO (o) Boc20 MeÓ MeÓ H H

27eqq 35(38%) 36(100%)

ReagentsReagents and conditions: (a) trimethyl orthoformate, MeOH, pTSA, rt, 50%. (b) NaOH, EtOH, reflux, 81%.. (c) Boc20, Et3N, CH2CI2, rt, 93%. (d) (COCI)2, DMSO, Et3N, CH2CI2, -78 , 100%.

5.4.44 Functionalisation to a l-azaadamantanone-2-carboxylic ester

Inn a final attempt to obtain sizable amounts of 25 the ketone functionality in 27eq was

reducedd to the alcohol (Scheme 5.6). This mode of ketone protection should circumvent the

problemss caused by a protective group. On the other hand should it be possible to restore the

ketonee during a simultaneous Swern oxidation of both the primary and secundary hydroxyl

groups,, thus preventing the formation of a stable hemiacetal, such as 34. Therefore, racemic

ketonee 27eq was reduced with NaBH4 to give one stereoisomer, presumably the given structure

byy delivery of the hydride from the least hindred side of the ketone. Hydrolysis of the

oxazolidinonee ring with NaOH in ethanol and treatment with di-terf-butyl pyrocarbonate led to

thee N-Boc carbamate 37. A Swern oxidation of this diol resulted in the formation of an

104 4

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

approximatee 1:2 mixture of two aldehydes, in favour of the axial aldehyde. Thus, probably due

too the large excess of reagents an epimerisation occured during the Swern oxidation. However,

usingg flash chromatography the axial aldehyde 38 was obtained in pure form in 38%. This

aldehydee was oxidised with NaC102 to furnish the corresponding acid, which was methylated

withh diazomethane to give 25ax in a yield of 58%.

Schem ee 5.6

, 0 0 tf̂ -r(a)NaBH44

VPN-BOC i\\ N—O (b) NaOH, EtOH H - . ^ v—OH

(d)) Swern y C J O ^ B o c

(e)) chromatography

27eqq W " * " OH 37 (72%) ' 38(38%)

C02Me e (f)) NaCI02) V T O ^ B O C

(9)) CH2N2 j \ c r r

25axx (58%)

ReagentsReagents and conditions: (a) NaBH„, EtOH, 91%. (b) NaOH, EtOH, reflux, 100%. (c) Boc20, Et3N,

CH2CI2,, rt, 72%. (d) Swern oxidation: 12 equiv (COCI)2, 24 equiv DMSO, 24 equiv Et3N, CH2CI2, -78 .

(e)) Flash chromatography, 38% of 38. (f) NaCI02, aqueous 1 M NaH2P04 buffer, terf-BuOH, 2-methyl-

2-butene,, 0 . (g) CH2N2, Et20, rt, 58% over two steps.

Thee carbamate 25ax was treated with paraformaldehyde in formic acid (eq 5.11) which,

accordingg to 'H NMR of the crude reaction mixture, resulted in the formation of the 1-

azaadamantan-4-one-2-carboxylicc methyl ester 39 together with some minor impurities. Flash

chromatographyy (A1203, EtOAc containing 2% Et3N) afforded the product in pure form, albeit

withh a significant decrease of the yield (40%). This step concludes a stereoselective potentially

enantiopuree synthesis of the target l-azaadamantane-4-one-2-carboxylic ester 39 in 8 steps

fromm the cyclisation product 11. The structure was confirmed by 2D-NMR techniques, while

thee mass spectrrum showed a strong [M] + at m/z 209 (rel. int. = 100%) confirming the

molecularr formula of Ci iH|5N03.

C02Mee C02Me ^-r~^

v rb N , B o cc H2CO, HcooH W o N S rpN (511) J\J\ rt 1\J yX^C02Me

oo o o 25axx 39 (40%)

105 5

ChapterChapter 5

5.55 Concluding remarks

Inn this chapter, three routes that possibly lead to enantiopure azaadamantanone-2-carboxylicc esters have been detailed. The first two approaches did not afford any of the desired highlyy functionalised systems. The third approach on the other hand provided a straightforward entryy into several bicyclic amino esters. Moreover, a successful potentially enantioselective routee towards a l-azaadamantan-4-one-2-carboxylic ester has been detailed.

5.66 Acknowledgements

P.. N. M. Botman and H. W. Schakel are gratefully acknowledged for their contributions

too this chapter. R. H. Balk is kindly acknowledged for the large scale preparation of compound

21. .

5.77 A final word on 1-azaadamantanes

Duringg our investigations we have been frequently confronted with the recalcitrant characterr of the target molecules, the l-azaadamantane-2-carboxylic esters and the intermediatess towards these molecules. Adamantanes are sometimes referred to as diamond molecules,122 due to their conformationally rigid backbone (hardness) that consists of four perfectt all-chair six membered rings (facets). However, with three conformationally restricted sixx membered azacycles present in the 1-azaadamantanes considerable electronic effects13 are possible.. These electronic effects account for the surprising instability of the products when a leavingg group is present, due to facile Grob-fragmentations.14 Also the alignment of the atoms inn 1-azaadamantane and intermediates is ideal for rearrangements,15 such as the cationic azaCopee (see Sections 2.5 and 3.6), or the 1,2-H shift (see Sections 2.1.2, 2.4 and 4.3). Another characteristicc is the compact structure that can brings functional groups 'too' close together, resultingg in unexpected reactivity (see Section 5.4). Nevertheless, we have designed two straightforwardd stereoselective syntheses of l-azaadamantane-2-carboxylic esters using oxazolidinone-derivedd N-acyliminium ions as key intermediates.

5.88 Experimental section

Generall Information For general information, see Section 2.9. (I,4-Dioxa-spiro[4.5]dec-8-yl)-

methanoll 28 was synthesised from p-methoxy benzyl alcohol using a litrerature procedure.9

terf-Butoxycarbonylamino{4-oxocyclohex-l-enyl)aceticterf-Butoxycarbonylamino{4-oxocyclohex-l-enyl)acetic acid (13). A three neck flask was charged

withh THF (50 mL) and fórr-butanol (100 mL). The flask was cooled to -30 °C and liquid NH3 (ca 350

106 6

SynthesisSynthesis of a l-azjaadamantan-4-one-2-carboxylic ester

mL)) was condensed into it. Lithium granules (2.3 g, 0.33 mol) were added and the reactionn mixture was

stirredd for 0.5 h. To this solution p-methoxyphenylglycine (10 g, 55 mmol) was added, due to the low

solubility,, as a powdered solid. The mixture was stirred overnight. Volatiles were evaporated and the

resultingg residue was dissolved in water (200 mL). The solution was acidified to pH = 9.5 with 4 N

H2S044 and NaHC03 (5.0 g, 60 mmol) was added. Then Boc20 (19 g, 87 mmol) was added and the

mixturee was stirred for 1 h. The solution was acidified to pH = 2 with 4 N H2S04 and stirring was

continuedd for ca 1 h. The solution was transferred to a separating funnel and extracted with five

portionss of EtOAc. The combined organic layers were dried (MgS04) and concentrated in vacuo to

affordd 13 (11 g, 41 mmol, 75%) as a colourless oil: IR (film) v 3435, 2980, 1711, 1497, 1162, 1057,

860;; 'H NMR (400 MHz, CD3OD) 8 5.85 (br t, J = 4.2 Hz, 1 H, =CH), 4.68 (s, 1 H, NCH), 2.90 (d, J =

2.44 Hz, 2 H, =CHC#2), 2.54-2.45 (m, 4 H), 1.45 (s, 9 H, C(CH3)3); ,3C NMR (100 MHz) 8 212.0

(C=0),, 173.6 (OC=0), 157.6 (NC=0), 135.7 (C=CH), 124.3 (C=CH), 80.8 (C(CH3)3), 59.9 (NCH),

40.22 (CH2), 39.1 (CH2), 28.7 (C(CH3)3), 26.8 (CH2); HRMS (FAB) calculated for C13H20NO5 [M+H] +

270.13411 found 270.1344.

Methoxycarbonylamino(4-oxocyclohexyl)aceticc acid methyl ester (14). A three neck flask was

chargedd with THF (50 mL) and terf-butanol (100 mL). The flask was cooled to -30 °C and liquid NH3

(ca(ca 350 mL) was condensed into it. Lithium granules (2.3 g, 0.33 mol) were added and the reaction

mixturee was stirred for 0.5 h. To this solution p-methoxyphenylglycine (10 g, 55 mmol) was added as a

powderedd solid. The mixture was stirred overnight. Volatiles were evaporated and the resulting residue

waswas dissolved in water (300 mL). The solution was acidified with 4 N H2S04 aq to pH = 9.5 and

NaHC033 (5.0 g, 60 mmol) was added. Then methyl chloroformate (14.3 mL, 185 mmol) was added

dropwise.. The solution was further acidified to pH = 2 and after 2 h extracted with EtOAc (4 x). The

combinedd organic layers were dried (MgS04) and concentrated in vacuo. The residue was dissolved in

EtOHH and transferred to a Parr apparatus. After the addition of Pd on charcoal (100 mg) and K2C03 (0.9

g,, 4.2 mmol) the solution was degassed and placed under a H2 atmosphere (40-50 psi) with shaking for

244 h. The solution was filtrated over a path of Celite® and concentrated in vacuo. The residue was taken

upp in MeOH (200 mL) to which thionyl chloride (7.5 mL, 0.10 mol) had been added. After stirring

overnightt the solution was concentrated in vacuo to afford the crude product. Flash chromatography

(EtOAc/PEE 1:2) afforded 14 as a colourless oil (8.5 g, 35.0 mmol, 64%): IR (film) v 2953, 1722, 1699,

1538,, 1435, 1347, 1249, 1205; 'H NMR (400 MHz) 8 5.45 (s, 1 H, NH), 4.41 (br s 1 H, NCH), 3.72 (s,

33 H, OCH3), 3.64 (s, 3 H, OCH3), 2.39-2.24 (m, 5 H), 2.08-1.85 (m, 2 H), 1.54 (m, 2 H); l3C NMR

(1000 MHz) 5 210.1 (C=0), 171.8 (OC=0), 156.6 (NC=0), 57.1 (NCH), 52.3 (OCH3), 40.1, 40.0

(C(0)(CH2)2);; 39.1 (CH), 28.6, 27.4 (2xCH2); HRMS calculated for Ci,H17NOj 243.1107 found

243.1103. .

107 7

ChapterChapter 5

tert-Butoxycarbonylamino(4-oxocyciohexyl)acetictert-Butoxycarbonylamino(4-oxocyciohexyl)acetic acid methyl ester (15). A Parr apparatus was

chargedd with a solution of starting material 13 (7.4 g, 27.4 mmol) in EtOH (50 mL), Pd on charcoal

(1000 mg) and K2C03 (0.6 g, 4.3 mmol). The solution was degassed and placed under a H2 atmosphere

(40-500 psi) with shaking. After 24 h the solution was filtrated over a path of Celite® and evaporated.

Thee residue was dissolved in EtOAc and washed with an aqueous HC1 solution (pH 2.5). The aqueous

layerr was extracted with EtOAc (4x), The combined organic layers were dried (MgS04) and

concentratedd in vacuo to afford a colourless oil (7.4 g, 27.2 mmol, 99%): IR (KBr) v 3262, 2980, 1705,

1394,, 1365, 1165; lH NMR (400 MHz, CD3OD) 8 4.20 (d, J = 5.4 Hz, 1 H, NCH), 2.51-2.32 (m, 4 H),

2.08-1.944 (m, 2 H), 1.77-1.50 (m, 3 H), 1.44 (s, 9 H, C(CH3)3); ,3C NMR (50 MHz, CD3OD) 8 213.4

(C=0),, 175.2 (OC=0), 157.9 (NC=0), 80.3 (C(CH3)3), 58.9 (NCH), 40.4 (CH), 32.6 (C(0)(CH2)2),

28.66 (C(CH3)3), 26.6 (CH2), 25.4 (CH2); HRMS (FAB) calculated for C)3H22N05 [M+H] + 272.1500,

foundd 272.1498. To a solution of this N-Boc amino acid (1.2 g, 4.4 mmol) in ether (50 mL) was added

CH2N22 until the yellow colour persisted. The volatiles were evaporated and the residue was purified

usingg flash chromatography (EtOAc/PE 1:2, then EtOAc) to yield the methyl ester 15 (1.0 g, 3.5 mmol,

79%)) as a colourless oil: IR (film) v 2931, 1732, 1520, 1455, 1367, 1274, 1166; 'H NMR (400 MHz) 5

5.244 (d, J = 8.6 Hz, 1 H, NH), 4.29 (dd, J = 8.4, 5.2 Hz, 1 H, NCH), 3.65 (s, 3 H, OCH3), 2.31-2.15 (m,

55 H), 1.94-1.40 (m, 4 H), 1.32 (s, 9 H, C(CH3)3); 13C NMR (100 MHz) 8 210.1 (C=0), 172.0 (OC=0),

155.00 (NC=0), 79.8 (C(CH3)3), 56.5 (NCH), 52.1 (OCH3), 40.0 (C(0)(CH2)2), 39.1 (CH), 28.6 (CH2),

28.22 (C(CH3)3), 27.4 (CH2); HRMS calculated for C14H23N05 285.1576 found 285.1584.

[2-Methoxy«l-(4-oxocyclohexyl)ethyl]carbamicc acid methyl ester (16). A solution of 14 (1.0 g, 4.1

mmol),, ethylene glycol (0.4 mL, 7 mmol) and a few crystals of pTSA in toluene was refluxed in a

Dean-Starkk apparatus for 4 h. The solution was concentrated in vacuo and the residue taken up in

CH2C12.. Then aqueous saturated NaHC03 was added and the layers were separated. The organic layer

wass dried (MgS04) and concentrated in vacuo to afford the product (1.2 g, 4.1 mmol, 100%) as a

colourlesss oil: IR (film) v 2951, 1725, 1535, 1446, 1339, 1253; 'H NMR (400 MHz) 8 5.30 (d, J = 9.0

Hz,, 1 H, NH), 4.32 (dd, J = 9.0, 5.1 Hz, 1 H, NCH), 3.89 (t, J = 2.1 Hz, 4 H, 0(CH2)2), 3.72 (s, 3 Ht

OCH3),, 3.65 (s, 3 H, OCH3), 1.87-1.70 (m, 3 H), 1.70-1.60 (m, 1 H), 1.60-1.35 (m, 5 H); 13C NMR

(1000 MHz) 8 172.3 (OC=0), 156.7 (NC=0), 64.1 (0(CH2)2), 108.0 (Cq), 57.6 (NCH), 52.2, 52.1

(22 x OCH3), 39.5 (CH), 34.1 (Cq(CH2)2), 26.4, 25.0 (2 x CH2). To a solution of this dioxolane (0.69 g,

2.44 mmol) in ether (30 mL) was added LiBK j (0.11 g, 4.8 mmol). After stirring overnight aqueous

saturatedd NH4CI was added and the layers were separated. The aqueous layer was extracted with

CH2C122 (3 x). The combined organic layers were dried (MgS04) and concentrated in vacuo to afford a

colourlesss oil (0.60 g, 2.3 mmol, 96%): [l-(l,4-Dioxaspiro[4.5]dec-8-yl)-2-hydroxyethyl]carbamic

acidd methyl ester: IR (film) v 3333, 2947, 1699, 1539, 1447, 1255; 'H NMR (400 MHz) 8 5.22 (d, J =

108 8

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

8.99 Hz, 1 H, NH), 3.87 (s, 4 H, 0(CH2)2), 3.60 (br s, 5 H, OCHj+OCH2), 3.43 (br s, 1 H, NCH), 3.12

(brr s, 1 H, OH), 1.78-1.65 (m, 4 H), 1.58-1.40 (ra, 3 H), 1.40-1.22 (m, 2 H); 13C NMR (100 MHz) 5

157.55 (NC=0), 108.4 (Cq), 64.0 (0(CH2)2), 63.0 (CH2OH), 56.7 (NCH), 52.0 (OCH3), 37.4 (CH), 34.2,

34.11 (Cq(CH2)2), 26.7, 25.9 (2 x CH2); HRMS calculated for C,2H21NOj 259.1420, found 259.1416. To

aa solution of this alcohol (0.35 g, 1.3 mmol) in ether (60 mL) was added silica gel (2.4 g) followed by

CH2N22 (ca 20 equiv). The silica was filtered off and washed with EtOAc. The resulting solution was

concentratedd in vacuo and the residue applied to flash chromatography (EtOAc/PE 1:2) to yield the

productt (0.10 g, 0.37 mmol, 28%) as a colourless oil: [l-(l,4-Dioxaspiro[4.5]dec-8-yl)-2-

methoxyethyljcarbamicc acid methyl ester: IR (film) v 2941, 1720, 1532, 1446, 1244, 1092; *H NMR

(4000 MHz) 5 4.94 (d, / = 8.8 Hz, 1 H, NH), 3.88 (s, 4 H, 0(CH2)2), 3.61 (s, 3 H, C02CH3), 3.57 (br s, 1

H,, NCH), 3.45 (dd, J = 9.7,4.0 Hz, 1 H, CflHOMe), 3.31 (dd, J = 9.7,4.0 Hz, 1 H, CHflOMe), 3.28 (s,

33 H, OCH3), 1.78-1.61 (m, 4 H), 1.57-1.18 (m, 5 H); HRMS calculated for C13H23N05 273.1576, found

273.1570.. A solution of this compound (100 mg, 0.37 mmol) and PPTS (61 mg, 0.37 mmol) in acetone

containingg 10% H20 was refluxed for 1 h. The mixture was concentrated in vacuo and the residue taken

upp in CH2C12. The solution was washed with water, dried (MgSO-O and concentrated in vacuo. The

productt was purified with flash chromatography (EtOAc/PE 1:2) to give the product 16 (73 mg, 0.32

mmol,, 86%) as a colourless oil: IR (film) v 3331, 2954, 1699, 1539, 1242; 'H NMR (400 MHz) 8 5.21

(d,, J = 9.0 Hz, 1 H, NH), 3.67-3.56 (m, 1 H, NCH), 3.56 (s, 3 H, C02CH3), 3.45 (dd, J = 14.6, 3.6 Hz, 1

H,, C//HOMe), 3.31 (dd, J = 9.6, 3.8 Hz, 1 H, CH/ZOMe), 3.24 (s, 3 H, OCH3), 2.32-2.20 (m, 4 H,

C(0)(CH2)2),, 2.04-1.95 (m, 4 H), 1.46-1.40 (m, 1 H); ,3C NMR (100 MHz) 5 211.5 (C=0), 156.9

(NC=0),, 72.5 (OCH2), 59.0 (NCH), 53.9, 52.0 (2 x OCH3), 40.3 (C(0)(CH2)2), 37.6 (CH), 29.2, 28.7

(CH(CH2)2);; HRMS calculated for C H ^ C M 229.1314, found 229.1315.

6-Oxo-3-azabicyclo[3.3.1]nonane-3-carboxyIicc acid methyl ester (19). To a solution of 9 (10 mg,

0.055 mmol) in carbon tetrachloride (1 mL) and acetonitrile (1 mL) was added water (1.5 mL),

sodiummetaperiodatee (43 mg, 0.20 mmol) and rutheniumtrichloride hydrate (2.0 mg, 10 jimol). The

suspensionn was stirred vigorously for 1 h at rt. Then CH2C12 (5 mL) was added and the precipitate was

removedd using Celite® filtration. The organic layer was washed with water and the aqueous layer was

extractedd with CH2C12 (3 x). The combined organic layers were dried (MgS04) and concentrated in

vacuo.vacuo. The product was purified using flash chromatography (EtOAc/CHCl3 1:20), providing 19 (7.9

mg,, 0.05 mmol, 79%) as a colourless oil: IR (film) v 2923, 2864, 1700, 1448, 1225; 'H NMR (400

MHz)) (assignment with aid of HETCOR) (rotamers) 8 4.28-4.05 (m, 2 H, NC//H), 3.61 (s, 3 H,

OCHj),, 3.18-2.94 (m, 2 H, NCH//), 2.52-2.31 (m, 3 H), 2.05-1.86 (m, 5 H); 'H NMR (400 MHz,

C7D8,, 365 K) S 4.07 (d, J = 13.8 Hz, 1 H, NC//H), 4.03 (d, J = 12.8 Hz, 1 H, NC//H), 3.42 (s, 3 H,

OCH3),, 2.65 (br d, J = 13.1 Hz, 1 H, NCH//), 2.56 (dd, / = 13.3, 3.2 Hz, 1 H, NCH//), 2.22-2.07 (m, 3

109 9

ChapterChapter 5

H),, 1.67-1.58 (m, 1 H), 1.58-1.49 (m, 2 H), 1.49-1.33 (m, 2 H); l3C NMR (100 MHz) (rotamers) 5

199.11 (C=0), 156.0 (NC=0), 52.6 (OCH3), 46.6^6.2 (NCH2), 45.0 & 45.2 (CH, rotamers), 38.7

(C(0)CH2),, 31.6 (CH2), 29.5-29.0 (br CH2), 26.7 (CH); I3C NMR (100 MHz, C7D8, 365 K) 5 158.0

(NC=0),, 52.3 (OCH3), 50.2 (NCH2), 47.1 (NCH2), 45.8 (C-5), 38.7 (C(0)CH2), 32.0 (CH2), 29.2

(CH2),, 27.9 (C-l), (C=0 not observed); HRMS calculated for C10H,5NO3197.1052, found 197.1049.

(4-Oxocyclohexylmethyl)carbamicc acid methyl ester (21). A three neck flask was charged with THF

(1000 mL) and rm-butanol (33 mL). The flask was cooled to -30 °C and liquid NH3 (ca 300 mL) was

condensedd into it. Lithium granules (2.3 g, 0.33 mol) were added and the reaction mixture was stirred

forr 0.5 h. To this solution p-methoxybenzylamine (7.9 g, 57 mmol) was added as a solution in THF (15

mL).. The mixture was stirred for 1 h. Methanol was added to destroy the excess Li , then the volatiles

weree evaporated and the resulting residue was dissolved in water (150 mL). The solution was acidified

withh 4 N H2S04 to pH = 9.5 and NaHC03 (5.0 g, 60 mmol) was added. Then methyl chloroformate (6.6

mL,, 86 mmol) was added dropwise and stirring was continued for ca 1 h. The solution was further

acidifiedd to pH = 2 and after 2 h extracted with CH2C12 (4 x). The combined organic layers were dried

(MgS04)) and concentrated in vacuo. The residue was dissolved in EtOH (20 mL) and transferred to a

Parrr apparatus. After the addition of Pd on charcoal (100 mg) and K2C03 (0.8 g, 6 mmol) the solution

wass degassed and placed under a H2 atmosphere (40-50 psi) with shaking for 24 h. The solution was

filtratedd over a path of Celite® and concentrated in vacuo. Flash chromatography (EtOAc/PE 1:2)

affordedd the product 21 (7.6 g, 41 mmol, 72%) as a white solid: mp 45-48 °C; IR (film) v 1715, 1539;

'HH NMR (250 MHz) 5 4.85 (br s, 1 H, NH), 3.65 (s, 3 H, OCH3), 3.12 (t, J = 6.4 Hz, 2 H, NCH2), 2.44-

2.233 (m, 4 H, C(0)(CH2)2), 2.09-1.87 (m, 3 H), 1.52-1.31 (m, 2 H); 13C NMR (50 MHz) 8 211.0

(C=0),, 156.9 (NC=0), 51.9 (OCH3), 45.5 (NCH2), 40.0 (C(0)CH2), 36.4 (CH), 29.8 (CH2); HRMS

calculatedd for C9H,5N03185.1052, found 185.1046.

Cyclisationn of 21 with paraformaldehyde in HCOOH. A solution 21 (1.5 g, 7.8 mmol) in HCOOH

(300 mL) was slowly (1.5 h) added to a stirred solution of paraformaldehyde (0.35 g, 1.8 mmol) in

HCOOHH (400 mL) which was heated at 50 °C. The resulting solution was remained at that temperature

forr 12 h. The formic acid was destilled off and the residue subjected to flash chromatography

(EtOAc/CHCl33 1:20) to provide 19 (1.2 g, 6.0 mmol, 79%) as a colourless oil. For spectral data vide

supra. supra.

3-Azabicyclo[3.3.1]nonan-6-onee HCL salt (22). A solution of bicyclic carbamaat 19 (0.72 mg, 3.7

mmol)) in aqueous concentrated HC1 (40 mL) was refluxed for 15 h. The volatiles were removed in

vacuovacuo to afford the HC1 salt of the bicyclic amine 22 (0.65 g, 3.7 mmol, 100%) as a slightly coloured

110 0

SynthesisSynthesis of a l-azjaadamantan'4-one-2-carboxylic ester

amorphouss solid: IR (KBr) 3387-2300, 1711, 1587, 1453; 'H NMR (400 MHz, D20) 8 3.48 (d, J = 15.9

Hz,, 1 H, NC//H), 3.41 (d, / = 12.8 Hz, 1 H, NC//H), 3.39-3.28 (m, 2 H, NCH//), 2.83-2.73 (m, 1 H),

2.60-2.488 (m, 2 H), 2.49-2.36 (m, 1 H), 2.26 (br d, J = 14.1 Hz, 1 H), 2.06 (br d, J = 14.1 Hz, 1 H),

1.93-1.822 (m, 2 H); 13C NMR (50 MHz, D20) 8 198.6 (C=0), 51.3 (NCH2), 47.1 (NCH2), 43.5 (C-5),

28.33 (CH2), 25.4 (C-l), 25.3 (2 x CH2); HRMS (FAB) calculated for CgHl4NO [M+H] + 140.1075,

foundd 140.1077.

(//?,2S,5S)-2-Hydroxymethyl-8-methyIene-3-azabicyclo[33JJnonane-3-carboxylicc acid terf-butyl

esterr (23). According to general procedure C of Section 4.9, oxazolidinone l leq (0.87 g, 4.5 mmol)

wass converted into the corresponding aminoalcohol (0.73 g, 4.3 mmol, 96%): (i/f,25,5S)-(8-

Methylene-3-azabicyclo[3.3.1]non-2-yl)methanol:: Colourless oil; [a]o +76.9 (c 1.8, CH2C12); IR

(film)) v 3333, 2916, 1444; 'H NMR (400 MHz) 8 4.67 (t, J = 1.8 Hz, 1 H, =C//H), 4.57 (t, J = 1.8 Hz, 1

H,, =CH//), 3.51 (dd, J = 10.9,4.5 Hz, 1 H, OCHH), 3.39 (dd, J = 10.8,4.5 Hz, 1 H, OCH//), 3.09 (m, 2

H,, NCH2), 2.94 (m, 1 H, NCH), 2.88 (m, 1 H, H-7), 2.65 (br s, 1 H, OH), 2.27-2.13 (m, 2 H, H-7 and

H-l) ,, 1.85-1.69 (m, 5 H); 13C NMR (100 MHz in CM 8 151.5 (C=CH2), 108.9 (C=CH2), 67.2

(OCH2),, 61.4 (NCH), 52.8 (NCH2), 42.3 (C-l), 37.1 (CH2), 33.9 (C-7), 32.7 (CH2), 29.7 (C-5); HRMS

calculatedd for CioH17NO 167.1310, found 167.1312. According to general procedure D of Section 4.9,

thee aminoalcohol (0.71 mg, 4.2 mmol) was treated with Boc20 to afford the pure product (1.1 g, 4.2

mmol,, 100%) after flash chromatography (EtOAc/PE 2:5) as a colourless oil: [a]D +89.3 (c 1.1,

CHC13);; IR (film) v 3457, 2930, 1681; 'H NMR (400 MHz) (assignment with aid of COSY and

HETCOR)) 8 4.71 (t, J = 1.9 Hz, 1 H, =C//H), 4.63 (t, 7 = 1.8 Hz, 1 H, =CH//), 4.60 (br s, 1 H, OH),

4.055 (dt, J = 12.8, 1.7 Hz, 1 H, NC//H), 3.93 (ddd, J = 15.9, 8.8,4.1 Hz, 1 H, OC//H), 3.51-3.46 (m, 1

H,, OCH//), 3.46-3.40 (m, 1 H, NCH), 3.15 (ddd, J = 13.4, 4.0, 1.6 Hz, 1 H, NCH//), 2.49-2.39 (m, 2

H,, H-l and H-7), 2.19 (dd, / = 14.6, 6.8 Hz, 1 H, H-7), 1.90 (s, 1 H, H-5), 1.85-1.78 (m, 2 H,

CHC//HCHH and H-6), 1.70-1.63 (m, 2 H CHCH//CH and H-6), 1.45 (s, 9 H, (C(CH3)3); 13C NMR

(1000 MHz) (assignment with aid of HETCOR) 155.0 (NC=0), 147.9 (C=CH2), 109.9 (C=CH2), 80.2

(C(CH3)3),, 65.6 (OCH2), 63.3 (NCH), 51.3 (NCH2), 42.4 (C-l), 35.1, 31.2 (2 x CH2), 30.0 (C-7), 28.4

(C(CH3)3),, 27.6 (C-5); HRMS calculated for C . jH^Oj 267.1835 found 267.1816.

(/J?^54S)-8-Methylene-3-azabicydo[3J.l]nonane-2r3-dicarboxylicc acid 2-methyl ester 3-tert-

butytt ester (24). According to general procedure E of Section 4.9, alcohol 23 (100 mg, 0.38 mmol) was

submittedd to the Swem oxidation to yield the corresponding aldehyde (82 mg, 0.31 mmol, 82%) as a

whitee solid: (2i{^S^S)-2-Formyl-8-methylene-3-azabicycIo[33.1]nonane-3-carboxyUc acid tert-

butyll ester, mp 73 °C; [afo -9.0 (c 0.6, CH2C12); IR (film) v 2928, 2959, 1731, 1682; lH NMR (400

MHz)) 8 9.18 (d, J = 4.7 Hz, 1 H, C(O)H), 4.74 (s, 1 H, =C//H), 4.64 (s, 1 H, =CH//), 3.86 (m, 1 H,

111 1

ChapterChapter 5

NCHH),NCHH), 3.63 (t, J = 4.3 Hz, I H, NCH), 3.20 (dd, J = 12.8, 2.9 Hz, 1 H, NCHH), 2.68 (s, 1 H, H-l )

2.70-2.611 (m, 1 H), 2.28 (dd, J = 13.7, 6.1 Hz, 1 H), 2.09 (br s, 1 H), 1.90 (m, 1 H), 1.77 (s, 1 H, H-5),

1.70-1.666 (m, 2 H), 1.44 (s, 9 H, (C(CH3)3); 13C NMR (100 MHz) 8 194.8 (HC=0), 157.0 (NC=0),

145.55 (C=CH2), 111.3 (C=CH2), 80.4 (C(CH3)3), 64.9 (NCH), 49.5 (NCH2), 41.0 (C-l), 32.6, 32.4,

31.33 (3 x CH2), 28.1 (C(CH3)3) 26.9 (C-5); HRMS (FAB) calculated for C15H24N03 [M+Hf 266.1756,

foundd 266.1755. According to general procedure F of Section 4.9, this aldehyde (78 mg, 0.29 mmol)

waswas oxidised with NaC102. After work up the crude acid was taken up in ether and treated with CH2N2

untill the yellow colour persisted. The solution was concentrated in vacuo and the residue was applied to

flashh chromatography (EtOAc/PE 2:3) providing the methyl ester 24 (60 mg, 0.20 mmol, 69%) as a

colourlesss oil: [oc]D +66.8 (c 3.0, CHC13); IR (film) v 2977, 2930, 1759 1700; 'H NMR (400 MHz) 8

4.599 (t, J = 2.0 Hz, 1 H, =C//H), 4.53 (t, J = 2.0 Hz, 1 H, =CHH), 4.15 (d, J = 6.0 Hz, 1 H, NCH), 3.62

(d,, J = 12.9 Hz, 1 H, NCHH), 3.58 (s, 3 H, OCH3), 3.45-3.39 (m, 1 H, NCH//), 2.79 (s, 1 H, H-l) ,

2.68-2.066 (m, 3 H), 1.77-1.67 (m, 3 H), 1.56-1.42 (m, 1 H), 1.38 (s, 9 H, C(CH3)3); l3C NMR (100

MHz)) 8 171.0 (OC=0), 148.9 (C=CH2), 109.4 (C=CH2), 80.3 (br, C(CH3)3), 61.2 (br, NCH), 51.2

(OCH3),, 48.6 (br, NCH2), 39.8 (C-l), 32.9, 30.9, 28.9 (3 x CH2), 28.1 (C(CH3)3>, 26.4 (C-5) (NC=0

nott observed); HRMS calculated for C6H25NO4 295.183, found 295.1774.

Oxidationn of 24 with RuCl3, NaI04. To a solution of compound 24 (50 mg, 0.17 mmol) in carbon

tetrachloridee (1 mL) and acetonitrile (1 mL) was added water (1.5 mL), sodiummetaperiodate (1.45 g,

0.688 mmol) and rutheniumtrichloride hydrate (10 mg, 0.05 mmol). The suspension was stirred

vigorouslyy for 1 h at it. Then CH2C12 (5 mL) was added and the precipitate was removed using Celite®

filtration.. The organic layer was washed with water and the aqueous layer was extracted with CH2CI2

(33 x). The combined organic layers were dried (MgS04) and concentrated in vacuo. The product was

purifiedd using flash chromatography (EtOAc/PE 2:3), providing two fractions. The first fraction

consistedd of (/JRr25^S)-8-Oxo-3-azabicyclo[3.3.1]nonane-2,3-dicarboxylic acid 2-methyl ester 3-

tert-butyltert-butyl ester 25 (8.0 mg, 0.027 mmol, 16%) as a colourless glass: [cc]D 55.5 (c 0.4, CHC13); IR (film)

vv 2923, 1749, 1702; 'H NMR (400 MHz) (assignment with aid of COSY) 8 4.03 (d, / = 5.0 Hz, 1 H,

NCH),, 3.95 (d, J = 12.9 Hz, 1 H, NCHH), 3.66 (s, 3 H, OCH3), 3.37 (dd, J = 12.9,5.0 Hz, 1 H, NCHH),

3.066 (m, 1 H, H-7), 2.79 (d, J = 1.9 Hz, 1 H, H-l) , 2.40 (dd, J = 14.8, 5.9 Hz, 1 H, H-7), 2.22 (br s, 1

H,, H-5), 2.08 (m, 1 H, H-6), 1.98 (m, 2 H, H-9), 1.91 (m, 1 H, H-6), 1.43 (s, 9 H, C(CH3)3); 13C NMR

(1000 MHz) 8 210.4 (C=0), 170.5 (OC=0), 81.3 (C(CH3)3), 59.6 (NCH), 51.7 (OCH3), 49.3 (NCH2),

47.11 (C-l), 38.6, 31.4, 30.9 (3xCH2), 27.9 (C(CH3)3), 26.2 (C-5) ((NC=0) not observed); HRMS

calculatedd for Cl5H23N05 297.1576, found 297.1572. The second fraction consisted of (i/f,2S,5S)-4,8-

dioxo-3-azabicyclo[3.3.1]nonane-2,3-dicarboxylicc acid 2-methyl ester 3-terf-butyl ester 26 (12 mg,

0.0388 mmol, 23%) as a colourless glass: [a]D 78.5 (c 0.6, CHC13); IR (film) v 2954, 1780, 1751, 1715;

112 2

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxyiic ester

lHH NMR (400 MHz) (assignment with aid of COSY, HETCOR) 8 4.72 (d, J = 5.9 Hz, 1 H, NCH), 3.70

(s,, 3 H, OCH3), 3.15 (m, 1 H, H-l) , 2.95 (d, J = 1.5 Hz, 1 H, H-5), 2.65 (m, 1 H, H-7), 2.48 (m, 2 H,

H-66 + H-7), 2.34 (m, 1 H, H-9), 2.08 (m, 1 H, H-9), 1.90 (m, I H, H-6), 1.43 (s, 9 H, C(CH3)3); 13C

NMRR (100 MHz) 8 207.7 (C=0), 171.4 (OC=0), 169.5 (C=0), 151.1 (C=0), 84.6 (C(CH3)3), 61.7

(NCH),, 52.7 (OCH3), 47.6 (C-l), 39.0 (CH), 37.9, 29.7, 28.8 (3 x CH2), 27.8 (C(CH3)3); HRMS

calculatedd for C15H2IN06 311.1369, found 311.1377.

(IR(IR^S^S)-4-Oxa-6-azatricyclo[63.1.0^S^S)-4-Oxa-6-azatricyclo[63.1.02,62,6]dodecane-5,ll-dione]dodecane-5,ll-dione (27eq). To a solution of compound

l leqq (0.52 g, 2.7 mmol) in carbon tetrachloride (16 mL) and acetonitrile (16 mL) was added water (25

mL),, sodiummetaperiodate (2.31 g, 10.8 mmol) and rutheniumtrichloride hydrate (170 mg, 0.80 mmol).

Thee suspension was stirred vigorously for 5 h at rt. Then CH2C12 (80 mL) was added and the percipitate

wass removed using Celite8 filtration. The organic layer was washed with water and the aqueous layer

wass extracted with CH2C12 (3 x). The combined organic layers were dried (MgS04) and concentrated in

vacuo.vacuo. The product was purified using flash chromatography (EtOAc/PE 1:1), providing the product

(0.466 g, 2.4 mmol, 87%) as a white solid: mp 107-109 °C; [a]D +25.1 (c 1.8, CHC13); IR (film) v 2930,

2869,, 1747, 1702; 'H NMR (400 MHz) 8 4.36 (t, J = 9.0 Hz, 1 H, OCHH), 4.01 (dt, J = 7.5, 3.5 Hz, 1

H,, NCH), 3.91 (d, J = 13.0 Hz, 1 H, NCtfH), 3.85 (dd, J = 7.5, 9.0 Hz, 1 H, OCHH), 3.27 (ddd, J =

13.00 , 3.9, 1.8 Hz, 1 H, NCHW), 2.52-2.46 (m, 2 H, C(0)CH2), 2.27 (ddd, J = 17.6, 12.4, 8.1 Hz, 1 H),

2.18-1.900 (m, 5 H); l3C NMR (100 MHz) 8 210.3 (C=0), 156.5 (NC=0), 64.7 (OCH2), 56.9 (NCH),

47.22 (C-l), 46.6 (NCH2), 39.4 (C-10), 31.3, 29.6 (2xCH2), 25.6 (C-8); HRMS calculated for

CioHi3N033 195.0893, found 195.0894. In a similar experiment racemic product was obtained: mp 133—

1355 °C.

(//i^if»«S)-4-Oxa-6-azatricyclo[6J.1.02,6]dodecane-5,ll-dionee (27ax). To a solution of compound

l la xx (0.26 g, 1.3 mmol) in carbon tetrachloride (5 mL) and acetonitrile (5 mL) was added water (7.5

mL),, sodiummetaperiodate (1.15 g, 5.4 mmol) and rutheniumtrichloride hydrate (62 mg, 0.3 mmol).

Thee suspension was stirred vigorously for 5 h at rt. Then CH2C12 was added and the precipitate was

removedd using Celite® filtration. The organic layer was washed with water and the aqueous layer was

extractedd with CH2C12 (3 x). The combined organic layers were dried (MgS04) and concentrated in

vacuo.vacuo. The product was purified using flash chromatography (EtOAc/PE 1:1), providing the product

(0.200 g, 1.0 mmol, 74%) as a colourless oil: [a]D +82.4 (c 1.8, CHC13); IR (film) v 2951, 1747, 1712,

1420;; 'H NMR (400 MHz) 5 4.54 (t, J = 7.3 Hz, 1 H, OCHH), 4.25 (dd, J = 11.0, 14.2 Hz, 1 H,

NCWH),, 4.02-3.89 (m, 2 H, OCHW + NCH), 3.07 (dd, J = 14.2, 2.4 Hz, 1 H, NCHfl), 2.79-2.70 (m, 1

H),, 2.57-2.40 (m, 3 H), 2.15-1.94 (m, 3 H), 1.80 (dt, / = 13.9, 2.9 Hz, 1 H); l3C NMR (100 MHz) 8

113 3

ChapterChapter 5

209.99 (C=0), 158.8 (NC=0), 68.6 (OCH2), 53.4 (NCH), 50.3 (C-l), 42.4 (NCH2), 34.0 (CH2), 31.3

(CH2),, 25.8 (CH2), 24.1 (C-8).

3-(l,4-Dioxaspiro[4.5]dec-8-ylmethyl)oxazo]idine-2,4-dionee (29). According to general procedure A

off Section 4.9, (l,4-Dioxaspiro[4.5]dec-8-yl)methanol 28 (6.0 g, 35 mmol) was coupled to oxazolidine-

2,4-dionee to afforded the product 29 (5.6 g, 22 mmol, 63%) as a white solid after flash chromatography

(EtOAc/PEE 1:2): mp 98-99 °C ; IR (film) v 2937, 1734, 1445; 'H NMR (400 MHz) 5 4.70 (s, 2 H,

C(0)CH2),, 3.93 (s, 4 H, (OCH2)2), 3.45 (d, J = 7.1 Hz, 2 H, NCH2), 1.85-1.30 (m, 9 H); I3C NMR (100

MHz)) 8 170.5 (C=0), 156.0 (NC=0), 108.1 (Cq), 67.4 (OCH2), 64.0 (OCH2), 45.1 (NCH2), 34.7 (CH),

33.77 (CH2), 27.4 (CH2); HRMS calculated for C,2H17N05 255.1107, found 255.1115.

4-Hydroxy-3-(4-oxo-cyclohexylmethvl)-oxazolidine-2-onee (30). To a cooled (0 °C) solution of

oxazolidinedionee 29 (5.0 g, 20 mmol) in MeOH (100 mL) was added NaBti, (1.5 g, 39 mmol). The

mixturee was allowed to warm to it and left stirring for 2.5 h. The reaction was quenched by the addition

acetonee and stirring was continued for 1 h. After evaporation of the solvent in vacuo the residue was

takenn up in CH2C12 and the remaining inorganic salts were removed by filtration through Celite®. The

organicc solution was washed with water. The aqueous layer was extracted with CH2C12 (3 x). The

combinedd organic layers were dried (MgS04) and concentrated in vacuo, yielding the product (4.3 g, 17

mmol,, 85%) as a white solid (1:1 mixture of diastereomers): IR (film) v 3333, 2931, 1755, 1528; 'H

NMRR (200 MHz) 8 5.22 (br t, J = 6.0 Hz, 1 H, NCH), 4.68 (br d, J = 9.0 Hz, 1 H, OH), 4.39 (dd, J =

10.1,, 6.2 Hz, 1 H, OC//H), 4.15 (dd, J = 10.1, 1.7 Hz, 1 H, OCH//), 3.93 (s, 4 H, (OCH2)2), 3.25-3.10

(m,, 2 H, NCH2), 1.90-1.15 (m, 9 H); l3C NMR (100 MHz) 8 158.0 (NC=0), 108.6 (C-4), 82.4 (NCH),

70.66 (OCH2), 64.1 (OCH2), 46.0 (NCH2), 34.8 (CH), 33.9 & 33.7 (CH2), 27.7 & 27.5 (CH2). A solution

off this compound (2.6 g, 10 mmol) and PPTS (50 mg, 0.2 mmol) in acetone (100 mL) containing 10%

H200 was refluxed for 2 h. The mixture was concentrated in vacuo and the residue was subjected to flash

chromatographyy (EA) to give the product 30 (0.92 g, 4.3 mmol, 43%) as a white solid: mp 106-

1077 °C ; IR (film) v 3333, 2933, 1714, 1433, 1244; 'H NMR (400 MHz) 8 5.30 (br s, 1 H, OH), 5.28

(dd,, J = 6.8, 1.8 Hz, 1 H, NCH), 4.38 (dd, J = 10.5,7.4 Hz, 1 H, OC//H), 4.13 (dd, J = 10.4, 1.6 Hz, 1

H,, OCH//), 3.23 (d, J = 7.6 Hz, 2 H, NCH2), 2.43-2.21 (m, 4 H), 2.00-1.94 (m, 3 H), 1.50-1.32 (m, 2

H);; 13C NMR (100 MHz) 8 211.9 (C=0), 158.2 (NC=0), 80.0 (NCH), 70.7 (OCH2), 45.5 (NCH2), 40.0,

39.99 (2 xCH2), 34.5 (CH), 30.0, 39.9 (2 xCH2); HRMS calculated for C,oH15N04 213.1001, found

213.1000. .

Cyclisationn of 30 in HCOOH at rt . A solution of hydroxyoxazolidinone 30 (12 mg, 0.056 mmol) in

HCOOHH (2 mL) was stirred overnight at ambient temperature. The reaction mixture was concentrated

114 4

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

inin vacuo. To remove residual formic acid toluene was added and evapotated in vacuo to yield 3-(4-

oxocyclohexylmethyl)-3H-oxazol-2-onee (11 mg, 0.056 mmol, 100%) as a colourless oil: 'H NMR (400

MHz)) 8 6.81 (d, J = 1.3 Hz, 1 H, =CH), 6.51 (d, J = 1.3 Hz, 1 H, =CH), 3.52 (d, J = 7.1 Hz, 2 H,

NCH2),, 2.60-2.00 (m, 7 H), 1.55-140 (m, 2 H).

Cyclisationn of 30 in HCOOH at 100 °C. A solution of hydroxyoxazolidinone 30 (128 mg, 0.60 mmol)

inn HCOOH (4 mL) was stirred overnight at 100 °C. The reaction mixture was concentrated in vacuo. To

removee residual formic acid toluene was added and evapotated in vacuo to yield a 1:1 mixture (114 mg,

0.588 mmol, 96%) of (ilï*^S*^S*)-4-Oxa-6-azatricyclo[63.1.02'']dodecane-5,ll-dione (27eq) and

(l/f*^/i*^S*)-4-Oxa-6-azatricyclo[6J.1.0 2'6]dodecane-5,ll-dionee (27ax): for spectral data vide

supra. supra.

(i/?r2S^S)-2-Hydroxymethyl-8-oxo-3-azabicyclo[33.1]nonane-3-carboxylicc acid tert-butyl ester

ethylenee glycol acetal (32eq). A solution of ketone 27eq (0.39 g, 2.0 mmol), ethylene glycol (0.56 mL,

100 mmol) and pTSA (10 mg) in toluene (100 mL) was refluxed for 2 h in a Dean-Stark apparatus. The

reactionn mixture was cooled to rt and water was added. The layers were separated and the aqueous layer

wass extracted with CH2C12 (3 x). The combined organic layers were dried (MgS04) and concentrated in

vacuo.vacuo. The product was purified using flash chromatography (EtOAc/PE 1:1), providing the product

(0.422 g, 1.8 mmol, 88%) as a white solid: (i/c^S^S)-4-Oxa-6-azatricyclo[63.02'^dodecane-5,ll-

dionee ethylene glycol acetal: mp 144-146 °C; [cc]D +73.0 (c 1.0, CHC13); IR (film) v 2921, 1742,

1436,, 1245; 'H NMR (400 MHz) 6 4.86 (t, J = 8.6 Hz, 1 H, OCHH), 4.25 (t, J = 8.6 Hz, 1 H, OCHtf),

3.97-3.833 (m, 5 H, (OCH2)2 +NCH), 3.73 (d, J = 12.9 Hz, 1 H, NC//H), 3.09 (dd, J = 12.8,4.8 Hz, 1 H,

NCHtf),, 2.24 (br d, J = 13.3 Hz, 1 H), 1.85 (s, 1 H, H-l) , 1.80-1.74 (m, 4 H), 1.66-1.61 (m, 2 H);13C

NMRR (100 MHz) 8 157.3 (NC=0), 109.7 (C-l l ) , 65.4 (OCH2), 64.8 (OCH2), 63.2 (OCH2), 57.1

(NCH),, 47.0 (NCH2), 37.8 (C-l), 31.1 (CH2), 30.6 (CH2), 28.6 (CH2), 25.6 (C-8); HRMS calculated for

Ci2H|7N044 239.1158, found 239.1150. In a similar experiment racemic product was obtained: mp 116-

1199 °C. According to general procedure C of Section 4.9, the enantiopure oxazolidine (0.50 g, 2.0

mmol)) was converted into the corresponding aminoalcohol (0.33 g, 1.6 mmol, 78%): (2JÏ,2S,#S)-4-

Hydroxymethyl-3-azabicyclo[3.3.1]nonane-6-onee ethylene glycol acetal: colourless oil; [cc]D +29.2

(cc 2.4, CHC13); IR (film) v 3400, 2918, 1445, 1116, 1035; 'H NMR (400 MHz, Q A J) 8 3.86 (dd, J

=11.1,, 6.7 Hz, 1 H, OCHH), 3.75 (dd, J =11.1, 6.7 Hz, 1 H, OCHH), 3.47-3.32 (m, 4 H, (OCH2)2),

2.88-2.844 (m, 3 H, NCH+NCHz), 2.70 (dt, / = 12.9,6.6 Hz, 1 H), 2.28 (ddt, J = 12.4, 3.2, 1.4 Hz, I H),

2.022 (m, 2 H), 1.90-1.82 (m, 1 H), 1.69-1.62 (m, 3 H), 1.54-1.47 (m, 1 H), 1.46 (br s, 1 H); 13C NMR

(500 MHz, CeD6) 8 111.4 (C-6), 65.8 (OCH2), 64.0 (OCH2), 62.8 (OCH2), 60.9 (NCH), 52.3 (NCH2),

39.99 (C-5), 33.3 (CH2), 33.2 (CH2), 28.1 (C-l). According to general procedure D of Section 4.9, the

115 5

ChapterChapter 5

aminee (0.70 g, 3.3 mmol) was treated with Boc20 to afford N-Boc amine 32eq (0.89 g, 2.8 mmol,

86%)) after flash chromatography (EtOAc/PE 1:2) as a colourless oil: [a]D +55.5 (c 1.3, CHC13); IR

(film)) v 3478, 2926, 1677; 'H NMR (400 MHz) 8 4.60-4.54 (m, 1 H, OC//H), 4.13 (br s, 1 H, OH),

4.07-3.844 (m, 5 H, (OCH2)2 + OCH//), 3.54-3.48 (m, 2 H, NCH + NC//H), 3.15 (dd, J = 13.4, 3.3 Hz,

11 H, NCH//), 2.06 (d, J = 14.7 Hz, 1 H), 1.94 (ddd, J = 13.3, 11.9, 8.1 Hz, 1 H), 1.80-1.73 (m, 3 H),

1.66-1.577 (m, 3 H), 1.47 (s, 9 H, C(CH3)3); 13C NMR (100 MHz) 8 155.2 (NC=0), 110.5 (C-8), 80.2

(C(CH3)3),, 64.8 (NCH), 64.7 (OCH2), 64.3 (OCH2), 63.6 (OCH2), 51.5 (NCH2), 40.4 (C-l), 32.6 (CH2),

30.99 (CH2), 30.7 (CH2), 28.5 (C(CH3)3), 27.3 (C-5).

(//?^/?,5S)-2-Hydroxymethyl-8-oxo-3-azabicyclo[3J.l]nonane-3-carboxylicc acid tert-butyl ester

onee ethylene glycol acetaJ (32ax). A solution of ketone 27ax (195 mg, 1.0 mmol), ethylene glycol

(0.300 mL, 5.3 mmol) and pTSA (10 mg) in toluene (50 mL) was refluxed for 2 h. The reaction mixture

wass cooled to rt and water was added. The layers were separated and the aqueous layer was extracted

withh CH2CI2 (3 x). The combined organic layers were dried (MgSO.*) and concentrated in vacuo

providingg the product (219 mg, 0.92 mmol, 92%) as a colourlesss oil: (lR£RftS)-4-Oxa-6-

azatricyclo[6.3.02,6]dodecane-5,ll-dionee ethylene glycol acetal: [rx]D +0.54 (c 10.9, CHC13); IR (film)

vv 2944, 1757, 1420; 'H NMR (400 MHz) 8 4.48 (t, J = 8.5 Hz, 1 H, OC//H), 4.04 (t, J = 8.2 Hz, 1 H,

OCH//),, 4.00-3.91 (m, 4 H, (OCH2)2), 3.85-3.80 (m, 2 H, NC//H+NC//), 2.88 (dd, J = 13.8, 1.6 Hz, 1

H,, NCH//), 2.21-2.19 (m, 1 H, H-l) , 1.87 (dd, J = 13.6, 4.7 Hz, 1 H), 1.80-1.72 (m, 3 H), 1.66-1.60

(m,, 2 H), 1.56-1.51 (m, 1 H); 13C NMR (100 MHz) 8 157.8 (NC=0), 108.7 (C-l l ) , 69.3 (OCH2), 64.3

(OCH2),, 64.0 (OCH2), 52.9 (NCH), 42.5 (NCH2), 42.4 (C-l), 28.9 (CH2), 27.0 (CH2), 23.6 (C-8), 23.0

(CH2).. According to general procedure C of Section 4.9, the oxazolidine (219 mg, 0.92 mmol) was

convertedd into the corresponding aminoalcohol (195 mg, 0.92 mmol, 100%): (7S,4i?,5/ï)-4-

Hydroxymethyl-3-azabicyclo[3.3.1]nonane-6-onee ethylene glycol acetal. colourless oil; [a]D + 10.0

(cc 6.4, CHCI3); IR (film) v 3355, 2944, 1452; 'H NMR (400 MHz) 8 3.99-3.83 (m, 4 H, (OCH2)2), 3.68

(t.. J = 10.3 Hz, 1 H, OC//H), 3.33 (dd, J = 10.3, 5.2 Hz, 1 H, OCH//), 3.11 (dd, J = 10.5, 5.3 Hz, 1 H,

NCH),, 3.02 (ddd, J = 11.1, 2.6, 1.2 Hz, 1 H, NC//H), 2.76 (dt, J = 10.6, 2..0 Hz, 1 H, NCH//), 2.22-

2.177 (m, 1 H), 2.02-1.74 (m, 6 H), 1.62 (s, 1 H), 1.47 (s, 1 H); 13C NMR (100 MHz) 8 110.2 (C-6),

64.00 (OCH2), 63.4 (OCH2), 61.6 (OCH2), 53.1 (NCH), 46.1 (NCH2), 37.8 (C-5), 31.6 (CH2), 28.1

(CH2),, 26.6 (C-l), 25.7 (CH2). According to general procedure D of Section 4.9, the aminoalcohol (195

mg,, 0.92 mmol) was treated with Boc20 to afford JV-BOC amine 32ax (181 mg, 0.58 mmol, 63%) after

flashflash chromatography (EtOAc/PE 1:1): Colourless oil; [a]D +13.2 (c 2.2, CHC13); IR (film) v 3442,

2969,, 2929, 1681, 1415; *H NMR (400 MHz) (rotamers) 8 4.44 & 4.31 (t, / = 7.1 Hz, 1 H, OC//H),

4.033 (d, J = 13.2 Hz, V2 H, OCH//), 3.96-3.80 (m, 5Yi H, OCH//+(OCH2)2+NCH), 3.76-3.53 (m, 1 H,

NC//H),, 3.08 & 2.97 (d, J = 13.1 Hz, 1 H, NCH//), 1.84-1.59 (m, 7 H), 1.57-1.51 (m, 1 H), 1.43 &

116 6

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

1.411 (s, 9 H, C(CH3)3); l3C NMR (100 MHz) (rotamers) 8 156.2 & 156.3 (C=0), 109.7 & 109.5 (C-6),

79.88 (C(CH3)3), 64.2 & 64.1 (OCH2), 62.3 & 61.4 (OCH2), 53.3 & 52.5 (NCH), 46.5 & 45.4 (NCH2),

36.66 & 36.3 (C-5), 30.7 & 30.6 (CH2), 28.3 (C(CH3)3), 28.2 & 28.1 (CH2), 26.7 (C-l), 25.1 & 25.0

(CH2). .

(7fi,2S,£S)-8-Oxo-3-azabicycIo[3.3.1]nonane-2,3-dicarboxylicc acid 2-methyI ester 3-tert-butyl ester

ethylenee glycol acetal (33eq). According to general procedure E of Section 4.9, the alcohol 32eq (226

mg,, 0.72 mmol) was subjected to the Swem oxidation (with 4 equiv oxalyl chloride, 8 equiv DMSO, 16

equivv Et3N) to afford the aldehyde (200 mg, 0.64 mmol, 89%) as a slightly coloured oil (some minor

imputitiess according to 'H NMR): (l/?^S^S)-2-Formyl-8-oxo-3-azabicyclo[3.3.1]nonane-3-

carboxylicc acid terf-butyl ester ethylene glycol acetal: IR (film) v 2926, 1749, 1718, 1683, 1370,

11622 ; 'H NMR (400 MHz) (rotamers) 8 9.48 (d, J = 4.1 Hz, 1 H, C(O)H), 3.93-3.63 (m, 6 H), 3.12

(dd,, J = 12.7, 4.7 Hz, 1 H, NCHtf), 2.74 (s, 1 H), 2.28-2.23 (m, 1 H), 2.06 (d, J = 12.8 Hz, 1 H), 2.00

(s,, 1 H, H-l) , 1.85-1.80 (m, 2 H), 1.69-1.64 (m, 1 H), 1.59 (d, J = 12.8 Hz, 1 H), 1.45 (s, 9 H,

C(CH3)3);; ,3C NMR (100 MHz) (rotamers) 8 197.3 (C=0), 157.5 (NC=0), 108.9 (C-8), 80.3 (C(CH3)3),

65.00 (NCH), 64.0 (OCH2), 63.0 (OCH2), 50.2 (NCH2), 40.8 & 39.9 (C-l), 31.9 (CH2), 29.3 (CH2), 28.7

(CH2),, 27.9 (C(CH3)3), 26.2 (C-5). According to general procedure F, the aldehyde (0.20 g, 0.64 mmol)

wass oxidised to the acid using NaC102 (10 equiv, at rt). After work up the crude acid was taken up in

etherr and treated with CH2N2 until the yellow colour persisted. The solution was concentrated in vacuo

andd the residue was applied to flash chromatography (EtOAc/PE 1:2) to afford the methyl ester 33eq

(466 mg, 0.13 mmol, 20%) as a colourless oil: [a]D +26.9 (c 2.3, CHC13); IR (film) v 2931, 1759, 1697,

13688 ; 'H NMR (400 MHz) (assignment with aid of COSY) 5 4.18 (d, J = 7.2 Hz, 1 H, NCH), 3.95-

3.877 (m, 2 H, OCH2), 3.85-3.75 (m, 2 H, OCH2), 3.66 (s, 3 H, OCH3), 3.51-3.45 (m, 2 H, NCH2), 2.37

(s,, 1 H, H-l) , 2.28-2.20 (m, 1 H), 2.09 (s, 1 H), 2.02-1.99 (m, 1 H), 1.76 (tt, J = 9.5, 4.3 Hz, 1 H),

1.69-1.644 (m, 1 H), 1.58 (d, J = 12.9 Hz, 1 H), 1.48 (d, J = 13.6 Hz, 1 H), 1.39 (s, 9 H, C(CH3)3); 13C

NMRR (100 MHz) 8 172.0 (C=0), 155.1 (NC=0), 109.1 (C-8), 80.3 (C(CH3)3), 64.1 (OCH2), 63.6

(OCH2),, 58.3 (NCH), 51.3 (OCH3), 48.6 (NCH2), 37.4 (C-l), 29.7 (CH2), 28.9 (CH2), 28.1 (C(CH3)3),

26.88 (CH2), 25.3 (C-5); HRMS calculated for C17H27N06 341.1838, found 341.1823.

(2/ï^/ï^5)-8-Oxo-3-azabicyclot33.1]nonane-2^-dicarboxylicc acid 2-methyl ester 3-tert-butyl

esterr ethylene glycol acetal (33ax). According to general procedure E of Section 4.9, the alcohol 32ax

(800 mg, 0.26 mmol) was subjected to the Swern oxidation to afford the crude aldehyde (110 mg,

137%!)) as a yellowish oil (some imputities according to 'H NMR): (I/t,2/?,5S)-2-Fonnyl-8-oxo-3-

azabicyclo[3J.l]nonane-3-carboxylicc acid tert-butyl ester: IR (film) v 2928, 1733, 1693; 'H NMR

(4000 MHz) (rotamers) 8 9.55 & 9.53 (s, 1 H, C(O)H), 4.91 & 4.71 (s, 1 H, NCH), 4.05-3.85 (m, 5 H),

117 7

ChapterChapter 5

3.19-3.088 (m, 1 H, NCHH), 2.30 & 2.28 (s, 1 H, H-l) , 1.95-1.60 (m, 7 H), 1.46 & 1.42 (s, 9 H,

C(CH3)3);; l3C NMR (100 MHz) (rotamers) 8 201.0 & 200.9 (HC=0), 155.2 (NC=0), 109.0 & 108.9

(C-8),, 80.3 & 80.1 (C(CH3)3), 64.5 & 64.4 (OCH2), 62.7 & 61.6 (NCH), 47.1 & 45.7 (NCH2), 35.5 &

35.00 (C-l), 30.8 (CH2), 28.2 & 28.1 (C(CH3)3), 28.1 (CH2), 26.1 (C-5), 26.0 (CH2). According to

generall procedure F, the crude aldehyde (0.26 mmol theoretical) was oxidised to the acid using

Na002.. After work up the crude acid was taken up in ether and treated with CH2N2 until the yellow

colourr persisted. The solution was concentrated in vacuo and the residue was applied to flash

chromatographyy (EtOAc/PE 1:1) to afford the methyl ester 33ax (75 mg, 0.22 mmol, 85% from the

alcohol)) as a colourless oil: [<x]D +21.3 (c 2.5, CHC13); IR (film) v 2928, 1745, 1693; 'H NMR (400

MHz)) (assignment with aid of COSY) (rotamers) 8 4.98 & 4.81 (s, 1 H, NCH), 4.01-3.95 (m, 4 H,

(OCH2)2),, 3.89 & 3.82 (d, J = 13.0 Hz, 1 H, NC//H), 3.73 & 3.72 (s, 3 H, OCH3), 3.32 & 3.24 (dd, J =

12.9,, 3.8 Hz, 1 H, NCHtf), 2.28 & 2.21 (s, 1 H, H-l) , 2.00-1.54 (m, 7 H), 1.47 & 1.42 (s, 9 H,

C(C//3)3);; l3C NMR (100 MHz) (rotamers) 8 173.0 & 172.9 (C=0), 165.0 (NC=0), 109.0 & 108.9 (C-

8),, 80.0 & 79.9 (C(CH3)3), 64.4 (OCH2), 60.8 (OCH2), 56.4 & 55.3 (NCH), 51.9 (OCH3), 47.7 & 46.8

(NCH2),, 38.4 & 38.3 (C-l), 30.7 & 30.6 (CH2), 28.6 & 28.5 (CH2), 28.3 & 28.2 (C(CH3)3), 26.2 & 26.1

(C-5),, 26.0 & 25.9 (CH2).

7-Hydroxy-6-oxo-3-azatricyclo[5JtJ.04,8]undecane-3-carboxylicc acid fórr-butyl ester (34). A

solutionn of 32eq (350 mg, 1.1 mmol) and pTSA (10 mg, 0.37 mmol) in acetone containing 10% H20

wass refluxed for 1 h. The mixture was concentrated in vacuo and the residue taken up in CH2C12. The

solutionn was washed with water, dried (MgSO,») and concentrated in vacuo to give the product (270 mg,

1.00 mmol, 91%) as a colourless oil: IR (film) v 3394, 2930, 1691, 1367, 1170; 'H NMR (400 MHz)

(rotamers)) 8 4.19-4.10 (m, 2 H, OCH2), 4.08-3.85 (m, 1 H, NCH), 3.47-3.28 (m, 2 H, NCH2), 2.69 (s,

11 H, NCHCW), 2.40-2.30 (m, 1 H), 2.12 (s, 1 H), 2.03-1.89 (m, I H), 1.85-1.79 (m, 2 H), 1.76-1.56

(m,, 3 H), 1.45 (s, 9 H, C(CH3)3); ,3C NMR (100 MHz) (rotamers) 8 157.5 & 157.0 (NC=0), 105.5 &

105.22 (C-7), 79.9 & 79.6 (C(CH3)3), 72.9 & 72.3 (OCH2), 56.4 & 56.2 (NCH), 50.5 & 49.8 (NCH2),

42.11 & 41.8 (CH), 31.1 & 30.9 (CH2), 29.4 (C(CH3)3), 25.7 & 24.9 (CH2), 23.7 (C-l), 22.2 (CH2);

HRMSS calculated for C14H23N04 269.1627, found 269.1627.

(7/i^S^S)-2-Hydroxymethyl-8,8-dimethoxy-3-azabicyclo[3.3.1]nonane-3-carboxylicc acid tert-

butyll (35). To a solution of bicyclic ketone 27eq (0.86 g, 4.4 mmol) in dry methanol (70 mL) was

addedd trimethoxyorthoformate (3.0 mL, 18 mmol) and pTSA (170 mg, 0.98 mmol). After stirring

overnightt NaOMe (65 mg, 1.2 mmol) was added and the volatites were removed. The residue was

subjectedd to flash chromatography (EtOAc/PE 1:1) to afford the product (0.52 mg, 2.2 mmol, 50%) as

ann amorphous white solid: (i/Ï^S^S)-ll,ll-Dimethoxy-4-oxa-6-azatricyc!o[6.3.1.02'6]dodecane-5-

118 8

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

one:: [a]D +43.3 (c 9.4, CHC13); IR (film) v 2928, 1745, 1453; lH NMR (400 MHz) 8 4.82 (t, J = 8.4

Hz,, 1 H, OCWH), 4.26 (t, J = 8.7 Hz, 1 H, OCHtt), 3.98 (dt, J = 8.6, 3.4 Hz, 1 H, NCtfH), 3.74 (d, J =

12.88 Hz, 1 H, NCH), 3.16 (s, 3 H, OCH3), 3.14 (s, 3 H, OCH3), 3.13-3.08 (m, 1 H, NCHtf), 2.14-2.06

(m,, 2 H), 1.96-1.84 (m, 2 H), 1.80-1.62 (m, 3 H), 1.54 (dd, J = 12.5, 2.2 Hz, 1 H); 13C NMR (100

MHz)) 8 157.1 (NC=0), 100.8 (C-l l) , 65.3 (OCH2), 56.9 (NCH), 46.9 (NCH2), 46.8 (OCH3), 46.4

(OCH3),, 33.3 (C-l), 29.1, 28.7, 27.5 (3xCH2), 25.7 (C-5). According to general procedure C of

Sectionn 4.9, this oxazolidine (0.52 mg, 2.2 mmol) was converted into the corresponding aminoalcohol

(0.388 mg, 1.8 mmol, 81%): (2/f^S4S)-(8,8-Dimethoxy-3-azabicyclo[33.1]non-2-yl)methanol:

Colourlesss oil; [a]D +56.8 (c 0.5, CHC13); IR (film) v 3350, 2920, 1111, 1044; 'H NMR (400 MHz) 5

3.677 (dd, J = 11.4, 5.8 Hz, 1 H, OCtfH), 3.58 (dd, J = 11.4, 6.2 Hz, 1 H, OCH//), 3.20 (s, 3 H, OCH3),

3.133 (s, 3 H, OCH3), 3.10-2.96 (m, 4 H, NCH+NCH2+OH), 2.20 (dt, J = 13.1, 7.0 Hz, 1 H), 2.01 (s, 1

H),, 2.00-1.88 (m, 2 H), 1.83-1.64 (m, 3 H), 1.54 (dd, J = 12.4, 2.4 Hz, 1 H); 13C NMR (100 MHz) S

102.11 (Cq), 65.2 (OCH2), 60.3 (NCH), 52.1 (NCH2), 47.0 (OCH3), 46.7 (OCH3), 35.3 (CH), 31.5, 31.0,

27.99 (3 x CH2), 27.7 (C-5). According to general procedure D of Section 4.9, the amine (0.38 mg, 1.8

mmol)) was treated with Boc20 to afford N-Boc amine 35 (0.52 g, 1.6 mmol, 93%) after flash

chromatographyy (EtOAc/PE 1:1): colourless oil; [a]D +30.7 (c 5.0, CHC13); IR (film) v 2936, 1680,

1365,, 1160, 1110, 1051; 'H NMR (400 MHz) 8 4.53 (dd, J = 12.1, 9.3 Hz, 1 H, OCflH), 4.06 (dt, J =

13.4,, 2.1 Hz, 1 H, OCHH), 3.57-3.44 (m, 2 H, NCH+NCHH), 3.15 (s, 3 H, OCH3), 3.12 (s, 3 H,

OCH3),, 3.11-3.05 (m, 1 H, NCHW), 2.15 (s, 1 H), 1.93-1.76 (m, 7 H), 1.46 (s, 9 H, C(CH3)3); ,3C NMR

(1000 MHz) 8 154.6 (NC=0), 101.4 (C-8), 79.6 (C(CH3)3), 65.1 (NCH), 64.1 (OCH2), 51.9 (NCH2),

46.99 (OCH3), 46.5 (OCH3), 36.4 (C-l), 31.7 & 28.7 (2 x CH2), 28.2 (C(CH3)3), 27.5 (C-5), 27.3

(CH2);; HRMS calculated for C,5H26N04 [M-OMe]+ 284.1862, found 284.1873.

(7«,2S,5S)-2-Fonnyl-8,8-dimethoxy-3-azabicyclo[3J.l]nonane-3-carboxyIicc acid terf-butyl ester

(36).. According to general procedure E of Section 4.9, alcohol 35 (359 mg, 1.14 mmol) was subjected

too the Swem oxidation (3 equiv oxalyl chloride, 6 equiv DMSO, 6 equiv Et3N) to afford the crude

aldehydee 36 (359 mg, 1.14 mmol, 100%) as a yellowish oil: 'H NMR (400 MHz) 8 9.34 (d, J = 4.1 Hz,

11 H, C(O)H), 3.75 (d, J = 12.4 Hz, 1 H, NCtfH), 3.68 (t, / = 4.6 Hz, 1 H, NCH), 3.16-3.13 (m, 1 H,

NCHtf),, 3.12 (s, 3 H, OCH3), 3.04 (s, 3 H, OCH3), 2.51 (s, 1 H, H-l) , 2.03-1.94 (m, 4 H), 1.75-1.66

(m,, 3 H), 1.46 (s, 9 H, C(CH3)3).

(iJ?VS*^S%£K*)-2-Hydroxymethyl-8-hydroxy-3-azabi^ ^ ^

butyll ester (37). To a cooled (0 °C) solution of the racemic tricyclic ketone 27eq (384 mg, 1.97 mmol)

inn EtOH (20 mL) was added NaBRt (107 mg, 2.84 mmol). The mixture was allowed to warm to rt and

leftt stirring for 1.3 h. The reaction was quenched by the addition of acetone. After evaporation of the

119 9

ChapterChapter 5

solventt in vacuo the residue was taken up in CH2CI2 and the remaining inorganic salts were removed by

filtrationn through Celite®. The organic solution was washed with water. The aqueous layer was

extractedd with CH2C12 (3 x). The combined organic layers were dried (MgS04) and concentrated in

vacuo,vacuo, yielding the product (347 mg, 1.79 mmol, 91%) as a white solid: (1R*JS*£S*,11R*)-11-

Hydroxy-4-Oxa-6-azatricyclo[63.1.02'6]dodecane-5-one:: mp 138 °C; IR v 3131, 2931, 3014, 2865,

1739,, 1435, 1245; 'H NMR (400 MHz) 8 5.15 (t, J = 8.4 Hz, 1 H, OCHR), 4.25 (t, J = 8.8 Hz, 1 H,

OCHH),OCHH), 4.02-3.93 (m, 2 H, NCH + OCH), 3.67 (d, J = 12.9 Hz, 1 H, NC//H), 3.08 (dd, J = 12.9 , 2.1

Hz,, I H, NCH#), 2.99 (s, 1 H, OH), 2.08 (t, J = 3.2 Hz, 1 H, H-l) , 1.80-1.64 (m, 7 H); 13C NMR (50

MHz)) 8 157.5 (C=0), 73.1 (OCH), 65.5 (OCH2), 57.6 (NCH), 46.8 (NCH2), 34.5 (C-l), 31.8, 29.7,

29.55 (3 x CH2), 25.6 (C-8); HRMS calculated for CoH^NOj 197.1052, found 197.1046. According to

generall procedure C of Section 4.9, this oxazolidine (347 mg, 1.76 mmol) was converted into the

correspondingg aminoalcohol (301 mg, 1.76 mmol, 100%) as a colourless oil: (lS*,4S*£R*,6R*)-4-

Hydroxymethyl-3-azabicyclo[3.3.1]nonane-6-ol:: IR (film) v 3350, 3004, 2931; 'H NMR (200 MHz) 8

4.599 (br s, 2 H, OH), 3.68-3.52 (m, 1 H, OCH), 3.52-3.40 (m, 2 H, OCH2), 2.83- 2.75 (m, 2 H), 2.75-

2.655 (m, 1 H), 1.85- 1.30 (m, 8 H); HRMS calculated for C9H17N02 171.1259, found 171.1245.

Accordingg to general procedure D of Section 4.9, the aminoalcohol (301 mg, 1.76 mmol) was treated

withh Boc20 to afford N-Boc amine 37 (379 mg, 1.40 mmol, 79%) as a colourless oil: IR v 3304, 2932,

1666;; 'H NMR (400 MHz) 8 6.05 (br s, 2 H, OH), 4.28 (dd, J = 13.0, 3.1 Hz, 1 H, OC#H), 4.14 (d, J =

13.44 Hz, 1 H, NC//H), 3.75-3.70 (m, 1 H, OCH), 3.63 (dd, J = 13.0, 2.5 Hz, 1 H, OCHH), 3.39 (d, J =

2.55 Hz, 1 H, NCH), 3.03 (d, J = 13.2 Hz, 1 H, NCHtf), 2.02-1.99 (m, 1 H), 1.84-1.68 (m, 7 H), 1.44 (s,

99 H, C(CH3)3); l3C NMR (50 MHz) S 154.8 (C=0), 80.4 (C(CH3)3), 71.9 (OCH), 63.8 (NCH), 62.7

(OCH2),, 52.8 (NCH2), 41.3 (C-5), 36.0, 30.5, 29.4 (3 xCH2), 28.1 (C(CH3)3), 27.6 (C-l); HRSM

(FAB)) calculated for Cl4H26N04 [M+H] + 272.1862, found 272.1858.

(i/?*,2/f*,55*)-2-Formyl-8-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylicc acid tert-buty] ester (38).

Accordingg to general procedure E of Section 4.9, diol 37 (379 mg, 1.40 mmol) was subjected to the

Swernn oxidation (12 equiv oxalyl chloride, 24 equiv DMSO, 24 equiv Et3N) to afford the crude reaction

productt mixture, which consisted of a 2:1 mixture of aldehydes together with minor impurities. From

thiss mixture aldehyde 38 (143 mg, 0.53 mmol, 38%) was isolated in pure form using flash

chromatographyy (EtOAc/PE 1:2): IR v 3009, 2983, 1740, 1690; 'H NMR (200 MHz) (rotamers) 5 9.56

&& 9.54 (s, 1 H, C(O)H), 4.77 & 4.56 (s, 1 H, NCH), 4.20-4.03 (m, 1 H, NC//H), 3.30 & 3.17 (dd, J =

13.3,, 2.6 Hz, 1 H, NCH//), 3.02 (s, 1 H, H-l) , 2.57- 2.44 (m, 2 H), 2.10-1.70 (m, 5 H), 1.46 & 1.39 (s,

99 H, C(CH3)3); l3C NMR (50 MHz) (rotamers) 8 210.9 & 210.1 (C=0), 198.4 & 198.3 (HC=0), 155.5

&& 155.0 (NC=0), 81.1 & 80.8 (C(CH3)3), 63.1 & 61.6 (NCH), 50.3 & 48.4 (NCH2), 42.9 & 42.7 (C-l),

38.33 (CH2), 29.1 & 28.6 (CH2), 28.4 & 28.2 (C(CH3)3), 28.1 & 27.9 (CH2), 25.7 & 24.9 (C-5).

120 0

SynthesisSynthesis of a l-azaadamantan-4-one-2-carboxylic ester

(i/f*^/f* r5S*)-8-Oxo-3-azabicyclo[33.1]nonane-2^-dicarboxylicc acid 2-methyl ester 3-tert-butyl

esterr (25ax). According to general procedure F, the aldehyde 38 (125 mg, 0.47 mmol) was oxidised to

thee acid using NaC102. After work up the crude acid was taken up in ether and treated with CH2N2 until

thee yellow colour persisted. The solution was concentrated in vacuo and the residue was applied to flash

chromatographyy (EtOAc/PE 1:2) to afford the methyl ester 25ax (80.6 mg, 0.27 mmol, 58%) as a

colourlesss oil: IR v 2933, 1742, 1696, 1212; 'H NMR (200 MHz) (rotamers) 8 4.81 & 4.66 (d, J = 1.5

Hz,, 1 H, NCH), 4.06 & 3.97 (d, J = 13.4, 1 H, NCtfH), 3.75 & 3.73 (s, 3 H, OCH3), 3.45 & 3.32 (d, J =

13.4,, 1 H, NCH//), 3.01 & 2.97 (s, 1 H, H-l) , 2.60-2.40 (m, 2 H), 2.17-1.80 (m, 5 H), 1.46 & 1.39 (s, 9

H,, C(CH3)3); 13C NMR (100 MHz) (rotamers) 8 211.2 & 210.4 (C=0), 170.7 (OC=0), 155.5 & 155.2

(NC=0),, 80.9 (C(CH3)3), 57.0 & 55.7 (NCH), 52.4 (OCH3), 48.0 & 47.0 (NCH2), 46.1 (C-l), 38.2

(CH2),, 29.7 & 29.2 (CH2), 28.4 & 28.2 (C(CH3)3), 28.1 & 27.9 (CH2), 26.2 & 26.0 (C-5); HRMS

calculatedd for CsH^NOj 297.1577, found 297.1575.

(2R*,3R*,(2R*,3R*,5S*,5S*,7S*)-4-oxo-l-azatricyclo[33.1.17S*)-4-oxo-l-azatricyclo[33.1.13,23,2]decane-2-carboxyUc]decane-2-carboxyUc acid methyl ester (39). A

solutionn of 25ax (70.5 mg, 0.267 mmol) and formaldehyde (71 mg, 2.37 mmol) in formic acid (5 mL)

waswas stirred at it for 48 h. The mixture was concentrated and residual formic acid removed by

azeotropicall destination of toluene. The crude product was purified using flash chromatography

(aluminumm oxide, EtOAc containing 2% Et3N) to yield the product 39 (19.9 mg, 0.095 mmol, 40%) as a

colourlesss glass: IR v 2938, 1737, 1704, 1212; 'H NMR (400 MHz, C6D6) (assignment with aid of

COSYY and HETCOR) 8 3.45 (dd, / = 13.8, 2.0 Hz, 1 H, NCtfH), 3.41 (s, 1 H, NCH), 3.33 (s, 3 H,

OCH3),, 3.03 (s, 1 H, H-3), 2.94 (dd, J = 13.2, 1.1 Hz, 1 H, NC*#H), 2.73 (dd, J = 13.2, 1.8 Hz, 1 H,

NCHH),NCHH), 2.66 (d, J = 13.8 Hz, 1 H, NC*H#), 2.24 (s, 1 H, H-5), 2.14 (dd, J = 13.2, 2.8 Hz, 1 H, CHH),

1.63-1.588 (m, 3 H, CHH + CH2), 1.04 (s, 1 H, H-7) 13C NMR (100 MHz, QD6) 8 211.0 (C=0), 170.4

(OC=0),, 67.4 (NCH), 62.4 (NC*H2), 53.3 (NC°H2), 52.2 (OCH3), 49.3 (C-2), 47.7 (C-5), 37.9 (CH2),

34.66 (CH2), 26.7 (C-7); HRMS calculated for C,1H15N03 209.1052, found 209.1046.

5.99 References and notes

1.. (a) Speckamp, W. N.; Dijkink, J.; Huisman, H. O. J. Chem. Soc, Chem. Commun. 1970, 197.

(b)) Dekkers, A. W. J. D.; Verhoeven, J. W.; Speckamp, W. N. Tetrahedron 1973,29, 1691.

2.. (a) Black, R. M. Synthesis 1981,829. (b) Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080.

3.. Schoemaker, H. E.; Boesten, W. H. J.; Broxterman, Q. B.; Roos, E. C; Kaptein, B.; Van der

Tweel,, W. J. J.; Kamphuis, J.; Rutjes, F. P. J. T. Chimia, 1997,51, 308.

4.. Ohno, K.; Nishiyama, H.; Nagase, H. Tetrahedron Lett. 1979,4405.

5.. Mehta, G.; Murthy, A. N. /. Org. Chem. 1987,52, 2875.

121 1

ChapterChapter 5

6.. Interestingly, a similar tricyclic amino ketone has been synthesised using an enzymatic

oxidation,, however, no enantioselectivity was observed: Johnson, R. A.; Herr, M. E.; Murray,

H.. C; Reineke, L. M.; Fonken, G. S. /. Org. Chem. 1968,33,3195.

7.. The free amino ketone 8 undergoes rapid self-condensation.

8.. Os04 oxidation or ozonolysis of the double bond did not lead to the desired compound 25.

9.. (a) Berkowitz, W. F.; Amarasekara, A. S.; Perumattam, J. J. J. Org. Chem 1987, 52, 1119. (b)

Isobe,, M.; Iio, H.; Kawai, T.; Goto, T. Tetrahedron 1979, 35, 941.

10.. Davies, C. E.; Heightman, T. D.; Hermitage, S. A.; Moloney, M. G. Synth. Commun. 1996, 687.

11.. The dioxolane remained intact in refluxing concentrated methanolic and aqueous HC1 solutions.

12.. Fort, R. C. jr. Adamantane. The chemistry of diamond molecules, vol. 5 of Studies in Organic

Chemistry,, Marcel Dekker Inc., New York, 1976.

13.. (a) Dekkers, A. W. J. D.; Verhoeven, J. W.; Speckamp, W. N. Tetrahedron 1973, 29, 1691. (b)

Worrell,, C; Verhoeven, J. W.; Speckamp, W. N. Tetrahedron 1974, 30, 3525.

14.. (a) Grob, C. A.; Kiefer, H. R. Lutz, H. J.; Wilkens, H. J. Helv. Chim. Act. 1967, 50, 416. (b)

Gleiter,, R.; Stohrer, W.-D.; Hoffman, R. Helv. Chim. Act. 1972, 55, 893. (c) Grob, C. A.;

Bolleter,, M. Kunz, W. Angew, Chem. 1980, 92, 734.

15.. (a) Delpech, B.; Khuong-Huu, Q. J. Org. Chem. 1978,43,4898. (b) Pancrazi, A.; Kabore, I.;

Delpech,, B.; Khuong-Huu, Q. Tetrahedron Lett. 1979, 3729. (c) Risch, N.; Molm, D. Liebigs

Ann.Ann. 1995, 1901.

122 2