A diastereodivergent strategy for the asymmetric syntheses of (-)-martinellic acid and (-)-4-epi-martinellic acid

Tetrahedron 69 (2013) 9779e9803

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Tetrahedron

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A diastereodivergent strategy for the asymmetric syntheses of

(ꢀ)-martinellic acid and (ꢀ)-4-epi-martinellic acid

*

Stephen G. Davies , Ai M. Fletcher, James A. Lee, Thomas J. A. Lorkin, Paul M. Roberts,

James E. Thomson

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansﬁeld Road, Oxford OX1 3TA, UK

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 23 July 2013

Accepted 3 September 2013

Available online 11 September 2013

Asymmetric syntheses of (ꢀ)-martinellic acid and (ꢀ)-4-epi-martinellic acid were achieved in 20 steps

from commercially available starting materials using a diastereodivergent strategy. The conjugate addition

of lithium (R)-N-allyl-N-(

bromophenyl]propenoate and alkylation of the resultant

a

-methyl-p-methoxybenzyl)amide to tert-butyl (E)-3-[2⁰-(N,N-diallylamino)-5⁰-

b-amino ester with methyl bromoacetate were

used as the key steps to install the C(9b) and C(3a) stereogenic centres, respectively. Subsequent cyclisation

to the corresponding pyrroloquinolin-2-one and reduction of the C(4)-carbonyl group was followed by

two complementary procedures for oleﬁnation and concomitant intramolecular Michael addition, which

gave both C(4)-epimers of this tricyclic molecular architecture in >99:1 dr. Subsequent elaboration

of these templates provided access to (ꢀ)-martinellic acid and, for the ﬁrst time, (ꢀ)-4-epi-martinellic acid.

Keywords:

(ꢀ)-Martinellic acid

Pyrroloquinoline

Lithium amide

Conjugate addition

Asymmetric synthesis

1. Introduction

In 1995 Witherup et al. isolated the highly functionalised pyr-

roloquinoline alkaloids (ꢀ)-martinellic acid 1 and (þ)-martinelline

2 from the species Martinella iquitoensis,¹a plant cultivated by

South American tribes for use as a treatment for eye ailments.²The

ground root extracts of these species are said to eventually cure

conjunctivitis,³an effect that was ﬁrst documented in 1791.^2,4The

individual biological activities of 1 and 2 have been assessed, and it

was noted that (þ)-martinelline 2 showed a much higher inhibitory

aptitude for bradykinin receptors compared to (ꢀ)-martinellic acid

1, as well as increased antimicrobial properties.¹The interesting

medicinal properties of 1 and 2 combined with their unique fused

pyrroloquinoline structure have spurred research into the synthesis

of this tricyclic molecular architecture,⁵as well as numerous ana-

logues,⁶with several total^7,8and formal^9,10syntheses of 1 and 2

having been reported to date (Fig. 1).¹¹

Fig. 1. The structures of (ꢀ)-martinellic acid 1 and (þ)-martinelline 2.

3$xHCl^7a,8awas identiﬁed as our initial target and we proposed that

a double aza-Michael strategy could be used to access the tricyclic

core within 3$xHCl. There are various reports in the literature

concerning the introduction of a C(4) sidechain into a pyrroloqui-

noline or pyrroloquinolin-4-one scaffold (such as 6), although in no

instance has the product been fully elaborated to either (ꢀ)-mar-

tinellic acid 1 or (þ)-martinelline 2.^5k,10a,c,14In our alternative

diastereodivergent approach both (ꢀ)-martinellic acid 1 and its

C(4)-epimer would both be accessible from 6: it was expected that

reduction of 6 would give the corresponding hemiaminal, which

upon reaction with a suitable oleﬁnation reagent would generate

As part of our ongoing research programme concerning the

conjugate addition of enantiopure secondary lithium amides

(derived from a-methylbenzylamines) to a,b

-unsaturated esters,¹²

and in particular the application of this methodology in the total

syntheses of natural products,¹³we became interested in the

tricyclic molecular architecture within (ꢀ)-martinellic acid 1. Upon

retrosynthetic analysis of (ꢀ)-martinellic acid 1, ‘Ma’s intermediate’

a,b-unsaturated ester 5, which would then undergo in situ intra-

molecular aza-Michael addition to generate the C(4) stereogenic

centre within 4. Furthermore, the resultant ester substituent within

4 would provide a functional handle for the construction of the

3-aminopropyl moiety found within 3$xHCl. It was envisaged that

* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).

http://dx.doi.org/10.1016/j.tet.2013.09.013

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S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

pyrroloquinoline 6 could be accessed via cyclisation of

b

-amino

puriﬁcation of aniline 11 after the Heck coupling was unnecessary

as a superior yield of 12 could be obtained if 11 was used directly in

the next step, without puriﬁcation.¹⁶In this case, bis-N-allylation of

11 was achieved by treatment with excess allyl iodide and K₃PO₄in

acetone at reﬂux for 48 h, which gave 12 in 89% isolated yield (from

10) and >99:1 dr; this method was amenable to the synthesis of

ester 7, which, in turn, could be produced from -unsaturated

a,b

ester 8 and enantiopure lithium amide 9 using our diaster-

eoselective aza-Michael reaction, followed by alkylation of the re-

sultant

b-amino ester, and therefore install the correct

stereochemistry at the C(3a) and C(9b) stereogenic centres within

the target molecules (Fig. 2). We describe herein our full in-

vestigations within this area, which culminate in the development

of asymmetric syntheses of (ꢀ)-martinellic acid 1 and its C(4)-

epimer, part of which has been communicated previously.¹⁵

a,b-unsaturated ester 12 in w25 g scale batches. Conjugate addition

of lithium (R)-N-benzyl-N-(

a

-methylbenzyl)amide to

a

,

b

-un-

saturated ester 12 in THF at ꢀ78 ^ꢁC gave

b-amino ester 13 in 97%

yield and >99:1 dr. The relative conﬁguration within 13 was

assigned by analogy to the established stereochemical outcome of

this class of conjugate addition reactions,¹²and by reference to our

transition state mnemonic, which was developed to rationalise the

diastereoselectivity observed upon conjugate addition of enantio-

pure lithium amides derived from

ment of -amino ester 13 with LDA, followed by addition of

a

-methylbenzylamine.¹⁷Treat-

b

bromoacetonitrile gave 14 in 80:20 dr, and 67% yield and >99:1 dr

after puriﬁcation via ﬂash column chromatography. Analogous al-

kylation of 13 with either tert-butyl bromoacetate or methyl bro-

moacetate gave 15 and 16 as single diastereoisomers (>99:1 dr),

which were isolated in quantitative and 82% yield, respectively.¹⁸

With a range of suitably functionalised substrates 14e16 in hand,

attention was turned to their deprotection and cyclisation to give

the corresponding dihydroquinolin-2-ones. N-Deallylation of

14e16 was achieved by employing a TsujieTrost reaction with

Pd(PPh₃)₄and N,N-dimethylbarbituric acid (DMBA) as the allyl

cation scavenger; DMBA is particularly effective for this purpose, as

excess DMBA can be removed from the crude reaction mixture by

extraction into aqueous solutions of K₂CO₃. Treatment of 14 with

5 mol % Pd(PPh₃)₄and DMBA in CH₂Cl₂at 35 ^ꢁC for 16 h gave 17,

which was isolated in 54% yield and >99:1 dr. Analogous reaction

of 15 and 16 gave 18, in 74% isolated yield and >99:1 dr, and 19 in

68% isolated yield and >99:1 dr, respectively (Scheme 1). The rel-

ative conﬁguration within 19 was established unambiguously by

single crystal X-ray diffraction analysis (Fig. 3),¹⁹and the absolute

(2R,3S,

aR)-conﬁguration within 19 was assigned relative to the

known (R)-conﬁguration of the

a

-methylbenzyl fragment; this

Fig. 2. Retrosynthetic analysis of (ꢀ)-martinellic acid 1.

2. Results and discussion

2.1. Model studies: introduction of the C(3a) and C(9b)

stereocentres

In the ﬁrst instance, an asymmetric synthesis of a model pyr-

roloquinoline scaffold which lacked the C(8)-carboxyl group was

investigated. Initial efforts were therefore directed at the optimi-

sation of the synthesis of a,b-unsaturated ester 12. Heck coupling of

commercially available 2-iodoaniline 10 and tert-butyl acrylate in

the presence of Pd(OAc)₂and P(o-Tol)₃in MeCN at 70 ^ꢁC for 16 h

proceeded to full conversion, to give 11^6gin >99:1 dr [(E)/(Z)]. An

analytically pure sample of 11 was obtained in 85% yield after pu-

riﬁcation of the crude reaction mixture; however, it was found that

Scheme 1. Reagents and conditions: (i) Pd(OAc)₂, P(o-Tol)₃, tert-butyl acrylate, Et₃N,

MeCN, 70 ^ꢁC, 16 h; (ii) allyl iodide, K₃PO₄, acetone, reﬂux, 48 h; (iii) lithium (R)-N-

benzyl-N-(

a

-methylbenzyl)amide, THF, ꢀ78 ^ꢁC, 2 h; (iv) LDA, THF, ꢀ78 ^ꢁC, 1 h then

RCH₂Br, ꢀ78 ^ꢁC to rt, 16 h; (v) Pd(PPh₃)₄, DMBA, CH₂Cl₂, 35 ^ꢁC, 16 h.

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9781

Fig. 4. X-ray crystal structure of 20 (selected H atoms are omitted for clarity).

Fig. 3. X-ray crystal structure of 19 (selected H atoms are omitted for clarity).

aldehyde 21, which was isolated in 76% yield and >99:1 dr, but

attempted hydrogenolysis of 21 (which was anticipated to effect

both N-debenzylation and reduction of the in situ formed imine

resulting from cyclisation of the primary amino group onto the

pendant aldehyde functionality)²⁰unfortunately gave only

returned starting material. All other attempts to form pyrroloqui-

nolin-4-one 22 from 21 were also unsuccessful (Scheme 2).

Attempted cyclisation of 18 upon treatment with PhCO₂H in THF

at 50 ^ꢁC resulted in returned starting material, and attempted

transesteriﬁcation of 18 to the corresponding bis-methyl ester with

SOCl₂/MeOH produced a complex mixture of products. However,

hydrogenolysis of 18 with Pd(OH)₂/C in MeOH under H₂(4 atm)

gave 23 in quantitative yield and >99:1 dr, and attempted chro-

matographic puriﬁcation of a portion of 23 resulted in partial cyc-

lisation to dihydroquinolin-2-one 24, which was isolated in 40%

yield and >99:1 dr (Scheme 3). The relative conﬁguration within 24

was established unambiguously by single crystal X-ray diffraction

analysis (Fig. 5);¹⁹these data also secured the assigned conﬁgura-

tions within 15, 18 and 23. However, all attempts at conversion of

24 to the corresponding pyrroloquinolin-4-one were unsuccessful:

substantial decomposition was observed upon treatment of 24 with

PhCO₂H, treatment of 24 with DBU (5.0 equiv) in CH₂Cl₂resulted in

analysis therefore also secured the assigned absolute (2R,3S,

aR)-

and (3S, R)-conﬁgurations within 16 and 13. The conﬁgurations

a

within 17 and 18 (and therefore also those within 14 and 15) were

assigned by analogy to those within 16 and 19; the similarities

between the ¹H NMR chemical shifts and ³J coupling constants

observed for both the C(3)H and C(1⁰)H protons within 14e19 were

consistent with this assumption, and in all cases these assignments

were later conﬁrmed unambiguously by single crystal X-ray

diffraction analyses of several derivatives.

With 17e19 in hand, attention was turned to their cyclisation to

give the corresponding dihydroquinolin-2-ones. Several sets of

conditions for the cyclisation of 17 were evaluated, and treating 17

with PhCO₂H (3.0 equiv) in THF at 50 ^ꢁC for 72 h was found to be the

optimal procedure, which gave 20 in quantitative yield (Scheme 2).

The relative conﬁguration within 20 was unambiguously estab-

lished by single crystal X-ray diffraction analysis (Fig. 4),¹⁹and the

absolute (3R,4S,

to the known (R)-conﬁguration of the

a

R)-conﬁguration within 20 was assigned relative

-methylbenzyl fragment;

a

this analysis also secured the assigned conﬁgurations within 14 and

17. Attention was next turned to the construction of the pyrrolidine

ring: reduction of the nitrile group within 20 with DIBAL-H gave

a

complex mixture of unidentiﬁed products, and attempted

Scheme 2. Reagents and conditions: (i) PhCO₂H, THF, 50 ^ꢁC, 72 h; (ii) DIBAL-H, CH₂Cl₂,

ꢀ78 ^ꢁC, 2 h.

Scheme 3. Reagents and conditions: (i) Pd(OH)₂/C, MeOH, H₂(4 atm), rt, 16 h; (ii)

attempted puriﬁcation; (iii) HCl (2.0 M in Et₂O), MeOH, reﬂux, 1 h.

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S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

Fig. 5. X-ray crystal structure of 24 (selected H atoms are omitted for clarity).

transesteriﬁcation of 24 to the corresponding methyl ester gave

only 25²¹which was isolated in 84% yield (Scheme 3).

Attempted cyclisation of 19 to the corresponding dihy-

droquinolin-2-one, upon treatment with PhCO₂H in PhMe at reﬂux

for 16 h, gave only tetrahydrobenzazepine 26 in 80% yield and

>99:1 dr (Scheme 4). The relative conﬁguration within 26 was

unambiguously established by single crystal X-ray diffraction

analysis (Fig. 6),¹⁹and the absolute (4R,5S,

a

R)-conﬁguration within

26 was assigned relative to the known (R)-conﬁguration of the

-methylbenzyl fragment. Furthermore, the determination of

Fig. 6. X-ray crystal structure of 26 (selected H atoms are omitted for clarity).

a

pyrroloquinolin-4-one and allow both rings to be formed in one

a Flack x parameter²²of ꢀ0.01(15) for the crystal structure of

26 allowed this assignment to be conﬁrmed unambiguously.

Meanwhile, hydrogenolytic N-debenzylation of 19 upon treatment

with Pd(OH)₂/C gave a 50:50 mixture of 27 and a product which

was tentatively assigned as pyrrolidin-2-one 28, based on ¹H NMR,

COSY and HSQC, and mass spectrometric analyses of the crude re-

action mixture (Scheme 4). Products arising from incomplete

step.

dition of lithium (R)-N-allyl-N-(

unsaturated ester 12, which gave

b

-Amino ester 29 was therefore prepared via conjugate ad-

-methylbenzyl)amide²³to

-amino ester 29 in 85% yield and

a

b

a,b-

>99:1 dr. Deprotonation of 29 with LDA followed by alkylation with

methyl bromoacetate proceeded to 84% conversion, giving 30 in

68% yield and >99:1 dr after puriﬁcation. N,N⁰-Deallylation of 30

was then achieved by treatment with Pd(PPh₃)₄and DMBA, which

gave 31 in 76% isolated yield and >99:1 dr. Subsequent treatment of

31 with PhCO₂H gave pyrroloquinolin-4-one 32 as the sole reaction

product, which was isolated in 80% yield and >99:1 dr (Scheme 5).

hydrogenolysis of the N-benzyl-N-(a-methylbenzyl) moiety were

also observed under these reaction conditions so the crude reaction

mixture was resubjected to the hydrogenolysis reaction conditions,

which gave a 39:61 mixture of 27 and 28, respectively. Heating

a solution of this mixture in PhMe at reﬂux, in an effort to drive the

cyclisation reaction to completion, resulted in substantial de-

composition to an intractable mixture of products.

Scheme 5. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methylbenzyl)-

amide, THF, ꢀ78 ^ꢁC, 2 h; (ii) LDA, THF, ꢀ78 ^ꢁC, 1 h then methyl bromoacetate, ꢀ78 ^ꢁC to

rt, 16 h; (iii) Pd(PPh₃)₄, DMBA, CH₂Cl₂, 35 ^ꢁC, 16 h; (iv) PhCO₂H, PhMe, reﬂux, 16 h.

Scheme 4. Reagents and conditions: (i) PhCO₂H, PhMe, reﬂux, 16 h; (ii) Pd(OH)₂/C, H₂

(1 atm), MeOH, rt, 16 h.

2.2. Model studies: introduction of the C(4) substituent

The formation of pyrrolidin-2-one 28 [i.e., cyclisation of a sub-

strate bearing a methyl ester on the C(2) substituent] during N-

deprotection of 19 suggested that this approach could be combined

with an acid promoted cyclisation to give the corresponding

With enantiopure pyrroloquinolin-4-one 32 in hand, attention

was turned to the introduction of the required stereochemistry at

the C(4) position. It was anticipated that in order to achieve che-

moselective reduction of 32 at C(4) [rather than at C(2)], the C(4)

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9783

carbonyl group would need to be activated by the introduction of

an electron withdrawing protecting group on the N(5) atom. Thus,

treatment of 32 with Boc₂O, DMAP and Et₃N in CH₂Cl₂gave 33 in

83% isolated yield (Scheme 6). The relative conﬁguration within 33

was determined unambiguously by single crystal X-ray diffraction

[of undetermined conﬁguration at C(4), >99:1 dr] in quantitative

yield, without any detectable reduction of the amide functionality

at C(2). Under optimised conditions, treatment of 34 with phos-

phorane 38 in PhMe at 80 ^ꢁC for 72 h effected both oleﬁnation and

in situ intramolecular aza-Michael addition to give 35 in >99:1 dr,

and 80% yield and >99:1 dr after puriﬁcation. Deprotection of the

N-Boc group within 35 was achieved by treatment with TFA in

CH₂Cl₂, which gave 36 in 58% yield and >99:1 dr. Subsequent re-

duction of 36 upon treatment with LiAlH₄gave 37 in 67% yield and

>99:1 dr (Scheme 6). The relative conﬁguration within 36 was

determined unambiguously by single crystal X-ray diffraction

analysis (Fig. 7),^19,24and the absolute (3aR,9bS,

aR)-conﬁguration

within 33 was assigned from the known (R)-conﬁguration of the a-

methylbenzyl fragment. Reduction of 33 with LiAl(O^tBu)₃H gave

complete conversion to hemiaminal 34 as a single diastereoisomer

analysis (Fig. 7),¹⁹and the absolute (3aS,4S,9bS,

within 36 was assigned from the known (R)-conﬁguration of the

aR)-conﬁguration

a

-

methylbenzyl fragment. This analysis therefore also established the

assigned conﬁgurations within 35 and 37.

2.3. Attempted elaboration to ‘Ma’s intermediate’

Initial attempts to activate the alcohol functionality within 37 as

the corresponding tosylate gave a mixture of products including

tosylate 39 and chloride 40, which were isolated in 41 and 23%

isolated yield, respectively. The formation of a chloride, such as 40,

from an alcohol upon attempted tosylation is unusual, although

this phenomenon has been noted in related systems.²⁵Alterna-

tively, subjecting 37 to an Appel reaction gave chloride 40 as the

sole product in 72% yield and >99:1 dr after puriﬁcation of the

crude reaction mixture. Initial attempts at the bromination of 40 at

the C(8) position, under the conditions reported by Miyata et al. for

the bromination of a related substrate,^10dresulted in a complex

mixture of products being formed, which included mono- and

dibrominated products 41 and 42.²⁶However, the slow addition of

a solution of NBS to a solution of 40, followed by stirring the re-

sultant mixture for 1 h at rt gave 41 and 42 in 68 and 6% isolated

yield, respectively, after puriﬁcation (Scheme 7). The aromatic

substitution pattern within 42 was assigned by ¹H NMR spectro-

scopic analysis, with the ¹H NMR ⁴J coupling constant (2.2 Hz)

between the C(7)H and C(9)H protons suggesting a meta relation-

ship between the protons on the aromatic ring, consistent with the

strong ortho and para directing ability of anilines.

It was anticipated that 3$xHCl could be obtained from 41 by (i)

methoxycarbonylation of the aryl bromide moiety; (ii) displace-

ment of the chloride by cyanide; and (iii) global hydrogenolysis

under acidic conditions. Thus, treatment of 41 with Pd(OAc)₂and

Xanpthos under CO (1 atm) at 70 ^ꢁC for 16 h proceeded to give

w50% conversion to 43. Resubjection of the crude reaction mixture

to the methoxycarbonylation reaction conditions proceeded with

full conversion to give 43; however, separation of 43 from the re-

sidual Xantphos ligand hindered the puriﬁcation and 43 was iso-

lated in only 17% yield. Subsequent treatment of 43 with NaCN in

DMSO at 90 ^ꢁC gave 44 in 79% yield and >99:1 dr. Typical

Scheme 6. Reagents and conditions: (i) Boc₂O, DMAP, Et₃N, CH₂Cl₂, 35 ^ꢁC, 16 h; (ii)

LiAl(O^tBu)₃H, THF, 0 ^ꢁC, 1 h; (iii) 38, PhMe, 80 ^ꢁC, 72 h; (iv) CH₂Cl₂/TFA (10:1), 35 ^ꢁC,

4 h; (v) LiAlH₄, THF, reﬂux, 16 h.

Fig. 7. X-ray crystal structures of 33 [left] and 36 [right] (selected H atoms are omitted for clarity).

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S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

In summary, our ﬁrst generation synthetic route enabled the

rapid and highly selective generation of the tricyclic molecular ar-

chitecture required for the synthesis of (ꢀ)-martinellic acid 1, al-

though this approach suffered

a number of drawbacks: (i)

dibromination of the aromatic ring was also observed, (ii)

methoxycarbonylation of the aryl bromide was incomplete and the

product was isolated in low yield, (iii) the N-a-methylbenzyl group

within 44 could not be deprotected by hydrogenolysis, and (iv) the

N(5) atom participated in a cyclisation during attempted reduction

of the nitrile group. It was hoped that issues (i), (ii) and (iv) could be

addressed by maintaining an N(5)-Boc protecting group until the

end of the synthesis, and it was thought that a differentially func-

tionalised N-

a-methylbenzyl group would allow deprotection

without recourse to hydrogenolysis. Numerous derivatives of

a

-

methylbenzylamine are commercially available as either enantio-

mer and have the advantage of being deprotected under a variety of

conditions.¹²In particular, derivatives of

a-methyl-p-methox-

ybenzylamine can be deprotected by treatment with acid,^13pCAN,²⁹

or DDQ.³⁰As it was ultimately desired to isolate 3 as the corre-

sponding hydrochloride salt, following reports of the instability of

the free base,^8aa strategy was adopted in which the ﬁnal steps

would be nitrile hydrogenolysis followed by global N-Boc depro-

tection under acidic conditions.

2.4. Model studies: alternative synthetic strategy

Conjugate addition of lithium (R)-N-allyl-N-(

a-methyl-p-

methoxybenzyl)amide³¹to

a,b

-unsaturated ester 12 gave 46 in 89%

Scheme 7. Reagents and conditions: (i) TsCl, DMAP, Et₃N, CH₂Cl₂, rt, 16 h; (ii) CCl₄,

PPh₃, Et₃N, MeCN, rt, 16 h; (iii) NBS, MeCN, 0 ^ꢁC to rt, 2 h.

yield and >99:1 dr. Deprotonation of 46 with LDA followed by

addition of methyl bromoacetate gave 47 in >98:2 dr, and 42% yield

and >99:1 dr after chromatographic puriﬁcation. However, a su-

perior yield of 47 was obtained when the two steps were run se-

quentially without puriﬁcation of 46; in this case 47 was isolated in

78% yield (from 12) and >99:1 dr. N,N⁰-Deallylation of 47, under the

previously optimised conditions, gave 48 in >99:1 dr, and treat-

ment of the crude reaction mixture with PhCO₂H in PhMe at reﬂux

resulted in cyclisation to give 49 in 52% yield. N-Boc protection of

49 upon treatment with Boc₂O and DMAP gave 50, which was

isolated in 78% yield and >99:1 dr after recrystallisation from

PhMe. However, when the synthesis was repeated (without puri-

ﬁcation of either 48 or 49), 50 was isolated in 57% overall yield

(from 47) for the three-step procedure (Scheme 9). The relative

conﬁguration within 50 was determined unambiguously by single

crystal X-ray diffraction analysis (Fig. 8),^19,24and the absolute

conditions for the deprotection of N-a-methylbenzyl groups are

treatment of the substrate with Pd(OH)₂/C in MeOH under H₂

(1 atm) for 16 h,¹²conditions which are also known to effect the

reduction of nitriles to the corresponding primary amines.²⁷It was

also desirable to trap the triamine product 3 as the corresponding

hydrochloride salt, as the free amine has been reported to be un-

stable and difﬁcult to handle.^8aHowever, treatment of 44 with

Pd(OH)₂/C in methanolic HCl under H₂(1 atm) gave a mixture of

products within which the major product was identiﬁed as tetra-

cycle 45. Puriﬁcation of the crude reaction mixture gave 45 in 30%

yield and w90% purity (Scheme 8).²⁸This route was therefore

abandoned in favour of a strategy which incorporated protection of

the N(5) atom.

(3aR,9bS,

aR)-conﬁguration within 50 was assigned by reference to

the known (R)-conﬁguration of the

a

-methyl-p-methoxybenzyl

fragment; this analysis also conﬁrmed the assigned conﬁgurations

within 46e49. Treatment of 50 with LiAl(O^tBu)₃H in THF at 0 ^ꢁC

gave hemiaminal 51 [of undetermined conﬁguration at C(4)] in

quantitative yield and >99:1 dr (Scheme 9).

Attention was next turned to the oleﬁnation and in situ intra-

molecular aza-Michael addition of 51. Treatment of 51 with excess

phosphorane 38 (3.0 equiv) in PhMe at 80 ^ꢁC proceeded within 72 h

to give 52 as the sole product, although 52 was found to be in-

separable from the remaining phosphorane 38 and Ph₃PO residues.

It was therefore decided to explore the corresponding oleﬁnation

protocol with phosphonate 54, which it was hoped would be more

readily separable from the reaction products. Reaction of 51 with

1.1 equiv of the anion derived from deprotonation of 54 with NaH

produced the corresponding 3a,4-syn-diastereoisomer as the major

product, giving a 76:24 mixture of 53 and 52, which were isolated

in 67 and 20% yield, respectively (Scheme 10). The conditions for

this reaction were then screened, varying the concentration, tem-

perature and number of equivalents of base used. Varying mixtures

of 52 and 53 were observed, although despite these efforts the

reaction could not be optimised further.

Scheme 8. Reagents and conditions: (i) Pd(OAc)₂, Xantphos, Et₃N, MeOH, 70 ^ꢁC, 16 h;

(ii) NaCN, DMSO, 90 ^ꢁC, 16 h; (iii) Pd(OH)₂/C, H₂(1 atm), HCl, MeOH, rt, 16 h.

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9785

Scheme 10. Reagents and conditions: (i) 38, PhMe, 80 ^ꢁC, 72 h; (ii) 54, NaH, THF, 0 ^ꢁC,

2 h [PMP¼p-methoxyphenyl].

diminished by the difﬁculty in separating 52 from the reaction by-

products. In contrast, the reaction of 51 with phosphonate 54

proceeds to give a 76:24 mixture of 53 and 52. As these diaster-

eoisomerically pure (>99:1 dr) samples of both 52 and 53 equili-

brate in the presence of NaH to give approximately 1:1 mixtures, it

is difﬁcult to draw any ﬁrm conclusions about the diaster-

eoselectivity of ring-closure with equilibration occurring in

tandem.

Scheme 9. Reagents and conditions: (i) lithium (R)-N-allyl-N-(a-methyl-p-methoxy-

benzyl)amide, THF, ꢀ78 ^ꢁC, 2 h; (ii) LDA, THF, ꢀ78 ^ꢁC, 1 h then methyl bromoacetate,

ꢀ78^ꢁC tort,16 h;(iii)Pd(PPh₃)₄, DMBA, CH₂Cl₂, 35^ꢁC,16h;(iv) PhCO₂H,PhMe, reﬂux,16 h;

(v)Boc₂O, DMAP, Et₃N, CH₂Cl₂, 35 ^ꢁC,16 h;(vi) LiAl(O^tBu)₃H, THF, 0 ^ꢁC,1 h [^aoverall yield for

thetwo-stepprocedure;^boverallyield for three-stepprocedure; PMP¼p-methoxyphenyl].

As this methodology provides access to both C(4)-epimers in

synthetically viable yields attention turned towards the elaboration

of the 3a,4-anti-diastereoisomer 52 to an analogue of 3, lacking

only the methyl ester substituent on the aromatic ring. Treatment

of 52 with CAN in MeCN/H₂O gave 55 in 57% isolated yield and

>99:1 dr, in addition to p-methoxyacetophenone, which was iso-

lated in 65% yield after puriﬁcation. Subsequent treatment of 55

with excess BH₃$THF gave a mixture of products, from which bo-

rane complex 56 was isolated in 57% yield and >99:1 dr. The

identity of 56 was conﬁrmed by ¹¹B NMR spectroscopic analysis (d_B

ꢀ14.9 ppm), the presence of characteristic BeH stretches in the IR

spectrum of 56 (n_max¼2361, 2370 cm^ꢀ1), and by high-resolution

þ

mass spectrometry {HRMS (ESI^þ) C₁₈H₂₉BN₂NaO₃([56þNa]^þ)

requires 355.2163; found 355.2162}. Decomplexation of 56 upon

treatment with Pd/C in MeOH^33,34proceeded to full conversion to

give amine 57. This simple decomplexation procedure was then

applied to the crude material from the borane reduction step, and

57 was isolated in 57% overall yield (from 52) and >99:1 dr

(Scheme 12).

Fig. 8. X-ray crystal structure of 50 (selected H atoms are omitted for clarity).

Efforts were next directed at the elaboration of 57 to 62$xHCl. N-

Boc protection of the N(1) atom within 57 gave 58 in >99:1 dr. The

crude product was tosylated to give 59 in 38% overall yield (from

57),³⁵and treatment of 59 with NaCN in N-methyl-2-pyrrolidinone

(NMP)³⁶gave 60 as a single diastereoisomer (>99:1 dr) in 70%

isolated yield. Reduction of the nitrile group within 60 and in situ

N-Boc protection of the resultant primary amino group was ach-

ieved upon treatment of 60 with NiCl₂$6H₂O, NaBH₄and Boc₂O,³⁷

which gave 61 in 71% isolated yield and >99:1 dr. Subsequent

global N-deprotection of 61 with methanolic HCl gave 62$xHCl (an

analogue of 3$xHCl, lacking only the methyl ester substituent on the

aromatic ring) in quantitative yield (Scheme 13).³⁸Modiﬁcation of

this route would enable the synthesis of 3$xHCl, which could then

be elaborated to (ꢀ)-martinellic acid 1 using literature conditions.^7a

It was envisaged that a C(8)-aryl bromide functionality could be

maintained from the start of the synthesis and this functionality

could be converted to a methyl ester upon methoxycarbonylation at

a late stage.

Treatment of either 52 or 53 in MeOH at reﬂux for 36 h resulted

in no loss of diastereoisomeric purity or decomposition, suggesting

that the equilibration of either diastereoisomer (via an E1_cb-type

process followed by intramolecular aza-Michael addition) requires

the presence of a strong base. Indeed, treatment of 53 (>99:1 dr)

with NaH (1.0 equiv) in THF at 0 ^ꢁC to rt for 16 h gave a 57:43

mixture of 53 and 52, which were isolated in 48 and 27% yield,

respectively. Treatment of 52 (>99:1 dr) under the same conditions

gave a 48:52 mixture of 52 and 53 (Scheme 11). In neither case was

there any evidence of oleﬁnic products in the ¹H NMR spectra of the

crude reaction mixtures.³²In summary, the reaction of 51 with

phosphorane 38 proceeded to give the 3,4-anti-diastereoisomer

exclusively. However, the synthetic utility of this reaction is

9786

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

Scheme 11. Reagents and conditions: (i) NaH (1.0 equiv), THF, 0 ^ꢁC to rt, 16 h [PMP¼p-methoxyphenyl].

64 followed by alkylation with methyl bromoacetate gave 65 in 81%

isolated yield (from 64) and >98:2 dr. N-Deallylation of 65 followed

by PhCO₂H-promoted ring-closure and subsequent N(5)-Boc pro-

tection gave 66 as a single diastereoisomer (>99:1 dr) in 49% yield

(from 65).⁴⁰Chemoselective reduction of 66 with LiAl(O^tBu)₃H

followed by reaction with phosphorane 70^41,42gave 67 as the sole

reaction product (>99:1 dr), and 67 was subsequently isolated in

75% yield (from 66) and >99:1 dr.⁴⁰N(1)-Deprotection of 67 upon

treatment with CAN, reduction with BH₃, N(1)-Boc protection, and

tosylation gave 68 in 41% overall yield (from 67). Treatment of 68

with NaCN in NMP, followed by methoxycarbonylation gave 69 as

a single diastereoisomer (>99:1 dr) in 59% yield (from 68). Sub-

sequent reduction of the nitrile group within 69, then deprotection

of the three N-Boc groups gave 3$xHCl in 91% yield (from 69) and

>99:1 dr (Scheme 14), completing a formal synthesis of (ꢀ)-mar-

tinellic acid 1 in 6.0% yield over 17 steps from commercially avail-

able starting materials. The spectroscopic data for our sample of

3$xHCl were in excellent agreement with literature values, as

communicated previously.¹⁵

Scheme 12. Reagents and conditions: (i) CAN, MeCN/H₂O (1:1), rt, 1 h; (ii) BH₃$THF,

THF, reﬂux, 4 h; (iii) Pd/C, MeOH, rt, 16 h [PMP¼p-methoxyphenyl].

A synthesis of the C(4)-epimer of 3$xHCl was targeted next.

Under optimised conditions, treatment of 71 [which was obtained

upon reduction of 66 with LiAl(O^tBu)₃H] with phosphonate 54

(1.1 equiv) and NaH in THF at 0 ^ꢁC for 2 h gave a 50:50 mixture of

C(4)-epimers 67 and 72, which were isolated in 38 and 36% yield,

respectively, as single diastereoisomers (>99:1 dr) after chro-

matographic puriﬁcation (Scheme 15).

Elaboration of the 3a,4-syn-diastereoisomer 72, following an

analogous series of steps to those used for the synthesis of 3$xHCl,

gave 79$xHCl in 18% overall yield: treatment of 72 with CAN in

MeCN/H₂O gave 73, which was reduced by treatment with BH₃$THF

at reﬂux to give 74 in 53% yield over three steps (from 72). N(1)-Boc

protection of 74 followed by O-tosylation gave 75 in 63% yield over

two steps (from 74). Displacement of the tosylate group within 75

with NaCN in NMP gave 76 in 87% yield. Repeated methox-

ycarbonylation of 76 using the Pd(OAc)₂/Xantphos catalyst system

gave 77 in 74% isolated yield and >99:1 dr. Reduction of the nitrile

functionality within 77 by hydrogenation with Ni₂B and H₂formed

in situ from NiCl₂$6H₂O and NaBH₄, and trapping of the primary

amine with Boc₂O gave 78 in 83% yield. Global N-deprotection of 78

was achieved by treatment with methanolic HCl for 6 h at rt, which

gave 79$xHCl in quantitative yield and >99:1 dr (Scheme 16). The

spectroscopic properties of (þ)-79$xHCl were in good agreement

with those previously reported for its antipode {[

a

]

²⁰þ93.7 (c 0.35,

D

16

MeOH); lit.^9cfor enantiomer [

a

]

D

ꢀ73.7 (c 0.34, MeOH)}.

Scheme 13. Reagents and conditions: (i) Boc₂O, Et₃N, DMAP, CH₂Cl₂, 35 ^ꢁC, 16 h; (ii)

TsCl, Et₃N, DMAP, CH₂Cl₂, 35 ^ꢁC, 16 h; (iii) NaCN, NMP, 60 ^ꢁC, 16 h; (iv) NiCl₂$6H₂O,

NaBH₄, Boc₂O, MeOH, 0 ^ꢁC to rt, 16 h; (v) HCl (1.25 M in MeOH), rt, 16 h.

Conversion of 3$xHCl and 79$xHCl into (ꢀ)-martinellic acid 1

and (ꢀ)-4-epi-martinellic acid 83, respectively, was achieved

according to a literature procedure:^7ain our hands, application of

this protocol to 3$xHCl gave 1$xTFA in 22% overall yield, as com-

municated previously (Scheme 17).¹⁵The spectroscopic data for

this sample of (ꢀ)-martinellic acid 1$xTFA, including its speciﬁc

2.5. Asymmetric syntheses of (L)-martinellic acid and (L)

-4-epi-martinellic acid

rotation {[

a

]

²⁰ꢀ118 (c 0.3, MeOH)}, were consistent with literature

D

data {lit.¹for sample isolated from natural source [

a

]

_Dꢀ8.5 (c 0.01,

a,b-Unsaturated ester 64 was prepared in 90% yield and >99:1

20

29

MeOH); lit.^7a

[

a

]

ꢀ112.7 (c 0.31 in MeOH); lit.^7b

[

a

]

D

ꢀ164.3 (c

dr upon Heck coupling of 2-iodo-4-bromoaniline 63³⁹with tert-

butyl acrylate, followed by bis-N-allyl protection. Conjugate addi-

D

23

0.14, MeOH); lit.^7c

[

a]

ꢀ164.8 (c 0.33, MeOH)}. Overall, (ꢀ)-mar-

D

tinellic acid 1 was isolated as its triﬂuoroacetate salt in 20 steps and

tion of lithium (R)-N-allyl-N-(a-methyl-p-methoxybenzyl)amide to

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9787

t

Br

I

Br

CO₂Bu

(i), (ii)

NH₂

NAllyl₂

64, 90% (from 63), >99:1 dr

(iii), (iv)

63

O

PMP

N

PMP

N

1

2

t

3

Br

CO₂Bu

(v)−(vii)

3a

4

5

CO₂Me

N

O

NAllyl₂

Boc

65, 81% (from 64), >98:2 dr

66, 49% (from 65), >99:1 dr

(viii), (ix)

N

P

CO₂Me

BocN

Ph₂

O

70

PMP

N

(x)−(xiii)

Br

CO₂Me

N

OTs

Boc

67, 75% (from 66), >99:1 dr

Boc

68, 41% (from 67), >99:1 dr

(xiv), (xv)

·xHCl

HN

BocN

(xvi), (xvii)

MeO₂C

NH₂

N

H

N

CN

Scheme 16. Reagents and conditions: (i) CAN, MeCN/H₂O (2:1), rt, 1 h; (ii) BH₃$THF,

THF, reﬂux, 4 h; (iii) MeOH, reﬂux, 48 h; (iv) Boc₂O, Et₃N, DMAP, CH₂Cl₂, 35 ^ꢁC, 16 h; (v)

TsCl, Et₃N, DMAP, CH₂Cl₂, 35 ^ꢁC, 16 h; (vi) NaCN, NMP, 60 ^ꢁC, 16 h; (vii) Pd(OAc)₂,

Xantphos, Et₃N, MeOH, CO (1 atm), 70 ^ꢁC, 48 h; (viii) NiCl₂$6H₂O, NaBH₄, Boc₂O,

MeOH, 0 ^ꢁC, 1 h; (ix) HCl (1.25 M in MeOH), rt, 6 h [PMP¼p-methoxyphenyl].

Boc

3·xHCl, 91% (from 69), >99:1 dr

69, 59% (from 68), >99:1 dr

Scheme 14. Reagents and conditions: (i) Pd(OAc)₂, P(o-Tol)₃, tert-butyl acrylate, Et₃N,

MeCN, 70 ^ꢁC, 16 h; (ii) K₃PO₄, allyl iodide, acetone, reﬂux, 48 h; (iii) lithium (R)-N-allyl-

N-(a

-methyl-p-methoxybenzyl)amide, THF, ꢀ78 ^ꢁC, 2 h; (iv) LDA, THF, ꢀ78 ^ꢁC, 1 h then

MeO₂CCH₂Br, ꢀ78 ^ꢁC to rt, 16 h; (v) Pd(PPh₃)₄, DMBA, CH₂Cl₂, 35 ^ꢁC, 16 h; (vi) PhCO₂H,

PhMe, reﬂux, 16 h; (vii) Boc₂O, DMAP, CH₂Cl₂, 35 ^ꢁC, 16 h; (viii) LiAl(O^tBu)₃H, THF, 0 ^ꢁC,

1 h; (ix) 70, PhMe, 80 ^ꢁC, 72 h; (x) CAN, MeCN/H₂O (1:1), rt, 1 h; (xi) BH₃$THF, reﬂux,

3 h then MeOH, reﬂux, 48 h; (xii) Boc₂O, Et₃N, DMAP, CH₂Cl₂, 35 ^ꢁC, 5 h; (xiii) TsCl,

Et₃N, DMAP, CH₂Cl₂, 35 ^ꢁC, 16 h; (xiv) NaCN, NMP, 60 ^ꢁC, 16 h; (xv) CO (1 atm),

Pd(OAc)₂, Xantphos, Et₃N, MeOH, 70 ^ꢁC, 48 h; (xvi) NiCl₂$6H₂O, NaBH₄, Boc₂O, MeOH,

1.3% yield from commercially available starting materials. However,

in the epimeric series, coupling of 79$xHCl (>99:1 dr) with thiourea

84, Et₃N and AgNO₃in MeCN/MeOH gave 81 in 45% yield and >99:1

dr after chromatographic puriﬁcation. Hydrolysis of 81 with NaOH

in H₂O/MeOH, followed by global N-Boc deprotection gave a mix-

ture of products, including 82$xTFA and 83$xTFA, which were iso-

lated in 16 and 2% yield, respectively (Scheme 17). Quinoline 82

could potentially arise from either oxidation of the N(5) atom, fol-

lowed by aromatisation, or elimination across the C(3a)eC(9b)

bond, followed by oxidation. Although it is notable that the C(4)eH

bond is relatively exposed for 81 (as opposed to 80), it is unclear

why there is such a difference in reactivity between these two

epimers, and why this fragmentation pathway was not observed for

any precursors to 81.⁴³

0

^ꢁC, 1 h; (xvii) HCl, MeOH, rt, 6 h [PMP¼p-methoxyphenyl].

Application of alternative literature conditions for the in-

troduction of the guanidine moieties was attempted next, following

the procedure reported by Snider et al.^8a,44Treatment of both

3$xHCl and 79$xHCl with BrCN gave bis-cyanamides 85 and 87,

respectively, then

a solution of prenylamine in 1,1,1,3,3,3-

hexaﬂuoroisopropanol (HFIP) was added, which gave 86 and 88.

Hydrolysis of 86 and 88 with 0.15 M aq NaOH at reﬂux in MeOH

proceeded to give (ꢀ)-martinellic acid 1 and (ꢀ)-4-epi-martinellic

acid 83, which were isolated as the corresponding triﬂuoroacetate

salts in 6 and 3% overall yield (from 3$xHCl and 79$xHCl), re-

spectively, after puriﬁcation via reverse phase HPLC (Scheme 18). In

both cases, ¹H NMR spectroscopic analysis of the crude reaction

mixtures indicated that quinoline by-products had not been

Scheme 15. Reagents and conditions: (i) 54, NaH, THF,

methoxyphenyl].

0

^ꢁC,

2

h

[PMP¼p-

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S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

Scheme 17. Reagents and conditions: (i) 84, AgNO₃, Et₃N, MeCN/MeOH (2:1), 40 ^ꢁC, 16 h; (ii) NaOH (0.2 M aq), MeOH, reﬂux, 16 h; (iii) TFA, anisole, CH₂Cl₂, rt, 16 h

[PMP¼p-methoxyphenyl].

formed; this route therefore offers a superior yield of (ꢀ)-4-epi-

martinellic acid 83$xTFA to that obtained using Ma’s procedure.

martinellic acid in 0.1% overall yield, from commercially available

starting materials in each case.

3. Conclusion

4. Experimental

In conclusion, a diastereodivergent strategy for the asymmetric

syntheses of both (ꢀ)-martinellic acid and (ꢀ)-4-epi-martinellic

acid has been developed. The conjugate addition of lithium (R)-N-

4.1. General experimental

All reactions involving organometallic or other moisture-

sensitive reagents were carried out under a nitrogen atmosphere

using standard vacuum line techniques and glassware that was

ﬂame dried and cooled under nitrogen before use. Solvents were

dried according to the procedure outlined by Grubbs et al.⁴⁵BuLi

was purchased as a solution in hexanes and titrated against

diphenylacetic acid before use. All other reagents were used as

supplied without prior puriﬁcation. Organic layers were dried over

MgSO₄. Thin layer chromatography was performed on aluminium

plates coated with 60 F₂₅₄silica. Plates were visualised using UV

light (254 nm), 1% aq KMnO₄or Dragendorff’s reagent. Flash col-

umn chromatography was performed on Kieselgel 60 silica. Melting

points are uncorrected. Speciﬁc rotations are reported in

allyl-N-(

(N,N-diallylamino)-5⁰-bromophenyl]propenoate and alkylation of

the resultant -amino ester have been used as the key steps to

a

-methyl-p-methoxybenzyl)amide to tert-butyl (E)-3-[2⁰-

b

install the C(9b) and C(3a) stereogenic centres, respectively. Sub-

sequent cyclisation to the corresponding dihydroquinolin-2-one

and reduction of the C(4) carbonyl group was followed by two

diastereodivergent procedures for the introduction of the C(4)-side

chain via oleﬁnation and concomitant intramolecular Michael ad-

dition, which gave both C(4)-epimers of this tricyclic molecular

architecture as single diastereoisomers (>99:1 dr). Subsequent

elaboration of these templates provided access to (ꢀ)-martinellic

acid in 1.3% overall yield and, for the ﬁrst time, (ꢀ)-4-epi-

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9789

Scheme 18. Reagents and conditions: (i) BrCN, NaHCO₃, MeOH, 0 ^ꢁC, 1 h; (ii) prenylamine, HFIP, 110 ^ꢁC, 5 days; (iii) NaOH (0.15 M aq), MeOH, reﬂux, 16 h.

10^ꢀ1deg cm²g^ꢀ1and concentrations in g/100 mL. IR spectra were

recorded using an ATR module. Selected characteristic peaks are

reported in cm^ꢀ1. NMR spectra were recorded in the deuterated

solvent stated. Spectra were recorded at rt unless otherwise stated.

The ﬁeld was locked by external referencing to the relevant deu-

teron resonance. ¹He¹H COSY, ¹He¹³C HMQC, and ¹He¹³C HMBC

analyses were used to establish atom connectivity. Accurate mass

measurements were run on a TOF spectrometer internally cali-

brated with polyalanine.

requisite electrophile (3.0 equiv) was then added slowly and the

reaction mixture was allowed to warm to rt over 16 h. Satd aq

NH₄Cl was then added. The reaction mixture was washed with 10%

aq citric acid (ꢂ2) and the combined aqueous layers were extracted

with Et₂O. The combined organic extracts were then washed se-

quentially with satd aq NaHCO₃and brine, then dried and con-

centrated in vacuo.

4.4. General procedure 3: N-deallylation

4.2. General procedure 1: conjugate addition of lithium am-

ides to a,b-unsaturated esters

A solution of the requisite substrate (1.0 equiv) in CH₂Cl₂and

DMBA (3.0 equiv per allyl group) was thoroughly purged with ar-

gon for w10 min. Pd(PPh₃)₄was then added in one portion under

a stream of argon. The resultant mixture was stirred at 35 ^ꢁC (in the

dark) for 16 h then concentrated in vacuo. The residue was dis-

solved in Et₂O and the resultant solution was washed with satd aq

K₂CO₃(ꢂ2). The combined aqueous layers were then extracted with

Et₂O and the combined organic extracts were dried and concen-

trated in vacuo.

BuLi was added to a solution of the requisite amine (1.6 equiv) in

THF at ꢀ78 ^ꢁC and the resultant mixture was stirred at ꢀ78 ^ꢁC for

30 min. A solution of the requisite a,b-unsaturated ester (1.0 equiv)

in THF at ꢀ78 ^ꢁC was added via cannula and the resultant mixture

was stirred at ꢀ78 ^ꢁC for 2 h. Satd aq NH₄Cl was then added and the

reaction mixture was allowed to warm to rt. The organic phase was

washed with 10% aq citric acid (ꢂ2) and the combined aqueous

layers were extracted with Et₂O. The combined organic layers were

washed sequentially with satd aq NaHCO₃and brine, then dried

and concentrated in vacuo.

4.5. General procedure 4: cyclisation of aniline derivatives

PhCO₂H was added to a solution of the requisite substrate

(1.0 equiv) in either THF or PhMe, as stated. The resultant mixture

was heated at 50 ^ꢁC or reﬂux for either 16 or 72 h, as stated. The

reaction mixture was then concentrated in vacuo. The residue was

dissolved in CH₂Cl₂and the resultant solution was washed with

satd aq K₂CO₃(ꢂ2). The combined aqueous layers were then

extracted with CH₂Cl₂and the combined organic extracts were

dried and concentrated in vacuo.

4.3. General procedure 2: b-amino ester alkylation

BuLi was added to a solution of ⁱPr₂NH (1.5 equiv) in THF at 0 ^ꢁC.

The resultant mixture was stirred for 15 min at 0 ^ꢁC then cooled to

ꢀ78 ^ꢁC and stirred at ꢀ78 ^ꢁC for 30 min. A solution of the requisite

b

-amino ester (1.0 equiv) in THF at ꢀ78 ^ꢁC was then added via

cannula and the resultant mixture was stirred at ꢀ78 ^ꢁC for 1 h. The

9790

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

4.6. General procedure 5: oxidative N-debenzylation with CAN

(C]O); d_H(400 MHz, CDCl₃) 1.55 (9H, s, CMe₃), 3.65 (4H, d,

N(CH₂CH]CH₂)₂), 5.12e5.21 (4H, m, N(CH₂CH]CH₂)₂), 5.77e5.87

(2H, m, N(CH₂CH]CH₂)₂), 6.31 (1H, d, J 16.2, C(2)H), 7.00e7.05

(2H, m, Ar), 7.25e7.31 (1H, m, Ar), 7.51e7.55 (1H, m, Ar), 8.04

(1H, d, J 16.2, C(3)H); d_C(100 MHz, CDCl₃) 28.2 (CMe₃), 56.1

(N(CH₂CH]CH₂)₂), 80.2 (CMe₃), 117.6 (N(CH₂CH]CH₂)₂), 119.6

(C(2)), 121.5, 122.6, 127.8 (Ar), 129.7 (C(1⁰)), 129.8 (Ar), 134.6

(N(CH₂CH]CH₂)₂), 141.4 (C(3)), 150.8 (C(2⁰)), 166.7 _þ(C(1)); m/z

(ESI^þ) 300 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₉H₂₆NO₂([MþH]^þ)

requires 300.1958; found 300.1967.

Method Bdstep 1: P(o-Tol)₃(725 mg, 2.38 mmol), Et₃N (33.1 mL,

238 mmol), tert-butyl acrylate (19.2 mL, 131 mmol) and Pd(OAc)₂

(267 mg, 1.19 mmol) were added sequentially to a solution of 10

(26.0 g, 119 mmol) in degassed MeCN (300 mL) under an argon

atmosphere, and the resultant solution was stirred at 70 ^ꢁC for 16 h.

The reaction mixture was then allowed to cool to rt and concen-

trated in vacuo. The residue was dissolved in CH₂Cl₂(300 mL) and

the resultant solution was washed with H₂O (2ꢂ200 mL). The

aqueous layer was extracted with CH₂Cl₂(2ꢂ150 mL), and the

combined organic extracts were then dried and concentrated in

vacuo to give 11 (26.0 g, >99:1 dr).

Method Bdstep 2: Allyl iodide (27.0 mL, 298 mmol) was added to

a solution of K₃PO₄(76.0 g, 357 mmol) and 11 (26.0 g, >99:1 dr) in

acetone (250 mL) and the resultant mixture was heated at reﬂux for

48 h. The reaction mixture was allowed to cool to rt then diluted

with H₂O (100 mL) and Et₂O (200 mL). The aqueous layer was

extracted with Et₂O (2ꢂ100 mL) and the combined organic extracts

were then dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 92:8) gave

12 as a yellow oil (31.6 g, 89% from 10, >99:1 dr).

A solution of CAN (3.0 equiv) in H₂O (10 mL mmol^ꢀ1of sub-

strate) was added dropwise to a solution of the requisite substrate

(1.0 equiv) in MeCN (10 mL mmol^ꢀ1of substrate) and the resultant

mixture was stirred at rt for 1 h. MeCN was then removed in vacuo

and the resultant mixture was partitioned between brine and

CHCl₃/IPA (3:1). The organic layer was washed with brine (ꢂ2) and

the combined aqueous layers were extracted with CHCl₃/IPA (3:1,

ꢂ5). The combined organic extracts were then dried and concen-

trated in vacuo.

4.7. General procedure 6: palladium-catalysed

methoxycarbonylation

A ﬂask containing the requisite substrate (1.0 equiv) was evac-

uated using a vacuum manifold and was backﬁlled with N₂(ꢂ3).

The requisite phosphine ligand and palladium source were added

sequentially. Degassed Et₃N then degassed MeOH were added via

syringe. The resultant mixture was stirred at rt and the apparatus

was carefully evacuated using a vacuum manifold, and was then

backﬁlled with N₂; the process was then repeated (ꢂ2). The re-

action mixture was purged for w30 min with CO, then the appa-

ratus was carefully evacuated using a vacuum manifold, and was

then backﬁlled with CO; the process was then repeated (ꢂ2). The

resultant mixture was submerged in a preheated oil bath at 70 ^ꢁC

and was vigorously stirred under CO for 16 h. The reaction mixture

was then ﬁltered through Celite^Ò(eluent MeOH/Et₃N, 100:1) and

concentrated in vacuo.

4.8. tert-Butyl (E)-3-(2⁰-aminophenyl)propenoate 11

4.10. tert-Butyl (3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)

P(o-Tol)₃(3.77 g, 12.4 mmol), Et₃N (32.0 mL), tert-butyl acrylate

(18.4 mL, 125 mmol) and Pd(OAc)₂(1.28 g, 5.70 mmol) were added

sequentially to a solution of 10 (25.0 g, 114 mmol) in degassed

MeCN (250 mL) under an argon atmosphere, and the resultant

solution was stirred at 70 ^ꢁC for 16 h. The reaction mixture was then

allowed to cool to rt and concentrated in vacuo. The residue was

dissolved in CH₂Cl₂(300 mL) and the resultant solution was

washed with H₂O (2ꢂ200 mL). The aqueous layer was extracted

with CH₂Cl₂(2ꢂ150 mL), and the combined organic extracts were

then dried and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 1:1) gave 11 as

a yellow solid (21.5 g, 85%, >99:1 dr); C₁₃H₁₇NO₂requires C, 71.2; H,

7.8; N, 6.4%; found: C, 71.2; H, 7.8; N, 6.4%; mp 76e77 ^ꢁC; n_max(ATR)

1695 (C]O); d_H(400 MHz, CDCl₃) 1.54 (9H, s, CMe₃), 3.97 (2H, br s,

NH₂), 6.29 (1H, d, J 15.7, C(2)H), 6.70 (1H, dd, J 8.2,1.0, Ar), 6.74e6.78

(1H, m, Ar), 7.14e7.18 (1H, m, Ar), 7.36e7.38 (1H, m, Ar), 7.74 (1H, d, J

15.7, C(3)H); d_C(100 MHz, CDCl₃) 28.2 (CMe₃), 80.5 (CMe₃), 116.7,

119.1 (Ar), 120.3 (C(2)), 128.1, 130.9_þ(Ar), 139.0 (C(3)), 139.0 (C(1⁰)),

145.1 (C(2⁰)), 166.6 (C(1)); m/z (ESI ) 220 ([MþH]^þ, 100%); HRMS

amino]-3-(2⁰-N,N-diallylaminophenyl)propanoate 13

Following general procedure 1, BuLi (2.25 M in hexanes, 16.9 mL,

38.0 mmol), (R)-N-benzyl-N-(a

-methylbenzyl)amine¹²(8.57 g,

25.4 mmol, >99:1 er) and 12 (7.61 g, 25.4 mmol, >99:1 dr) were

reacted in THF (300 mL) to give 13 in >99:1 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 5:1) gave 13

as a yellow oil (12.6 g, 97%, >99:1 dr); C₃₄H₄₂N₂O₂requires C, 80.0;

25

H, 8.3; N, 5.5%; found C, 79.8; H, 8.1; N, 5.45%; [

a

]

ꢀ9.5 (c 1.1,

D

CHCl₃); n_max(ATR) 1727 (C]O); d_H(400 MHz, CDCl₃) 1.28 (9H, s,

CMe₃), 1.33 (3H, d, J 6.8, C( )Me), 2.45 (1H, dd, J 15.5, 6.6, C(2)H_A),

a

2.68 (1H, dd, J 15.5, 7.6, C(2)H_B), 3.52 (2H, dd, J 14.2, 6.3,

N(CH_AH_BCH]CH₂)₂), 3.61 (2H, dd, J 14.2, 6.7, N(CH_AH_BCH]CH₂)₂),

3.74 (1H, d, J 15.1, NCH_AH_BPh), 3.86 (1H, d, J 15.1, NCH_AH_BPh), 3.98

(1H, q, J 6.8, C(

5.75e5.90 (2H, m, N(CH₂CH]CH₂)₂), 7.07e7.37 (13H, m, Ar, Ph),

7.56 (1H, d, J 7.3, Ar); d_C(100 MHz, CDCl₃) 14.4 (C( )Me), 27.9

(CMe₃), 40.2 (C(2)), 49.9 (NCH₂Ph), 53.6 (C(3)), 56.8 (C( )) 57.0

a)H), 5.08e5.24 (5H, m, C(3)H, N(CH₂CH]CH₂)₂),

a

(N(CH₂CH]CH₂)₂), 80.0 (CMe₃), 117.6 (N(CH₂CH]CH₂)₂), 123.6,

124.0, 126.1, 126.5, 127.1, 127.8, 127.8, 127.9, 128.1, 129.0 (Ar, Ph),

135.0 (N(CH₂CHCH₂)₂), 139.3, 142.9, 144.3, 149.9 (C(1⁰), C(2⁰), i-Ph),

171.5 (C(1))_þ; m/z (ESI^þ) 511 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

(ESI^þ) C₁₃H₁₈NO₂([MþH]^þ) requires 220.1332; found 220.1330.

4.9. tert-Butyl (E)-3-(2⁰-N,N-diallylaminophenyl)propenoate

12

C

₃₄H₄₃N₂O₂([MþH]^þ) requires 511.3319; found 511.3315.

Method A: Allyl iodide (1.87 mL, 20.0 mmol) was added to

a mixture of K₃PO₄(18.0 g, 84.6 mmol) and 11 (6.07 g, 27.7 mmol,

>99:1 dr) in acetone (50 mL) and the resultant mixture was heated

at reﬂux for 48 h. The reaction mixture was allowed to cool to rt

then diluted with H₂O (50 mL) and Et₂O (100 mL). The aqueous

layer was extracted with Et₂O (2ꢂ50 mL) and the combined organic

extracts were dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 95:5) gave

12 as a yellow oil (2.00 g, 73%, >99:1 dr); C₁₉H₂₅NO₂requires C,

76.2; H, 8.4; N, 4.7%; found: C, 76.05; H, 8.4; N, 4.6%; n_max(ATR) 1708

4.11. tert-Butyl (2R,3S,aR)-2-(cyanomethyl)-3-[N-benzyl-N-(a-

methylbenzyl)amino]-3-(2⁰⁰-N,N-diallylaminophenyl)prop-

anoate 14

i

Following general procedure 2, Pr₂NH (0.43 mL, 3.09 mmol),

BuLi (2.3 M in hexanes, 1.34 mL, 3.09 mmol), 13 (1.05 g, 2.06 mmol,

>99:1 dr) and bromoacetonitrile (0.43 mL, 6.18 mmol) were reac-

ted in THF (20 mL) to give 14 in 80:20 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N,

89:11:1) gave 14 as a yellow oil (765 mg, 67%, >99:1 dr); [

a]

²⁵ꢀ8.7

D

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9791

(c 1.9, CHCl₃); n_max(ATR) 2978, 2933, 2821 (CeH), 2249 (C^N),1728

4.14. tert-Butyl (2R,3S,

a

R)-2-cyanomethyl-3-[N-benzyl-N-(

a

-

(C]O); d_H(400 MHz, CDCl₃) 1.20 (3H, d, J 6.6, C(a)Me), 1.60 (9H, s,

methylbenzyl)amino]-3-(2⁰⁰-aminophenyl)propanoate 17

CMe₃), 2.19 (1H, dd, J 16.4, 3.4, C(1⁰)H_A), 2.38 (1H, dd, J 16.4, 11.5,

C(1⁰)H_B), 3.40 (1H, app td, J 11.5, 3.4, C(2)H), 3.52e3.68 (5H, m,

NCH_AH_BPh, N(CH₂CH]CH₂)₂), 3.84 (1H, d, J 14.4, NCH_AH_BPh), 4.19

Following general procedure 3, 14 (371 mg, 0.67 mmol, >99:1 dr),

DMBA (627 mg, 4.02 mmol) and Pd(PPh₃)₄(46 mg, 40.4 mol) were

m

(1H, q, J 6.6, C(

5.77e5.90 (2H, m, N(CH₂CH]CH₂)₂), 7.07e7.39 (14H, m, Ar, Ph); d_C

(100 MHz, CDCl₃) 17.3 (C(

)Me),19.1 (C(1⁰)), 28.2 (CMe₃), 46.9 (C(2)),

)), 82.4

a

)H), 5.13e5.25 (5H, m, C(3)H, N(CH₂CH]CH₂)₂),

reacted in CH₂Cl₂(10 mL) to give 17 in >99:1 dr. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N,

75:25:1/50:50:1) gave 17 as a white foam (169 mg, 54%, >99:1 dr);

a

51.6 (NCH₂Ph), 57.5 (N(CH₂CH]CH₂)₂), 57.7, 57.8 (C(3), C(

a

[a]

²⁵þ21.7 (c 1.8, CHCl₃); n_max(ATR) 3443, 3374 (NeH), 2977, 2935

D

(CMe₃), 117.7 (C(2⁰)), 118.8 (N(CH₂CH]CH₂)₂), 124.6, 125.2, 126.3,

126.5, 127.6, 128.3, 128.4, 128.8, 129.2, 133.6, 134.0, 140.9, 143.9,

151.5 (Ar, Ph, N(CH₂CH]CH₂)₂), 172.1 (C(1)); m/z (ESI^þ) 572

(CeH), 2248 (C^N), 1725 (C]O); d_H(400 MHz, CDCl₃) 1.31 (3H, d, J

6.8, C(

(1H, dd, J 16.4, 11.1, C(1⁰)H_B), 3.31e3.38 (1H, m, C(2)H), 3.63 (1H, d, J

14.9, NCH_AH_BPh), 4.03e4.24 (4H, m, C( )H, NCH_AH_BPh, NH₂), 4.40

(1H, d, J 6.8, C(3)H), 6.65 (1H, d, J 7.8, Ar), 6.76 (1H, app t, J 7.5, Ar),

7.08e7.46 (12H, Ar, Ph); d_C(100 MHz, CDCl₃) 11.3 (C( )Me), 17.0

)), 62.0

a

)Me),1.48 (9H, s, CMe₃), 2.14 (1H, dd, J 16.4, 3.3, C(1⁰)H_A), 2.26

([MþNa]^þ, 100%), 550 ([MþH]^þ, 25%); HRMS (ESI^þ)

a

þ

C

₃₆H₄₃N₃NaO₂([MþNa]^þ) requires 572.3247; found 572.3240.

a

4.12. tert-Butyl (2R,3S,

a

R)-2-(2⁰-tert-butoxy-2⁰-oxoethyl)-3-

(C(1⁰)), 27.9 (CMe₃), 47.2 (C(2)), 51.6 (NCH₂Ph), 57.0 (C(

a

[N-benzyl-N-(

a

-methylbenzyl)amino]-3-(2⁰⁰-N,N-dia-

(C(3)), 82.8 (CMe₃), 117.1, 118.4 (Ar), 118.4 (C(2⁰)), 121.8, 127.1, 127.2,

128.2, 128.3, 128.4, 128.6, 128.9, 129.8, 140.7, 143.5, 145.6 (Ar, Ph),

171.0 (C(1)); m/z (ESI^þ) 961 ([2MþNa]^þ, 53%), 492 ([MþNa]^þ, 30%),

llylaminophenyl)propanoate 15

þ

Following general procedure 2, ⁱPr₂NH (4.25 g, 20.2 mmol), BuLi

(1.6 M in hexanes, 18.3 mL, 29.3 mmol), 13 (10.3 g, 20.2 mmol,

>99:1 dr) and tert-butyl bromoacetate (9.85 g, 50.5 mmol) were

reacted in THF (300 mL) to give 15 in >95:5 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 5:1) gave 15

as a yellow oil (16.3 g, >99:1 dr, quant); C₄₀H₅₂N₂O₄requires C,

470 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₀H₃₅N₃NaO₂([MþNa]^þ) re-

quires 492.2621; found 492.2622.

4.15. tert-Butyl (2R,3S,

[N-benzyl-N-(

-methylbenzyl)amino]-3-(2⁰⁰-aminophenyl)

propanoate 18

a

R)-2-(2⁰-tert-butoxy-2⁰-oxoethyl)-3-

a

76.9; H, 8.4; N, 4.5%; found C, 76.7; H, 8.4; N, 4.4%; [

CHCl₃); n_max(ATR) 3004, 2977, 2933 (CeH), 1731 (C]O), 1642, 1596

a

]

²⁵ꢀ9.6 (c 1.0,

D

Following general procedure 3, 15 (1.59 g, 2.54 mmol, >99:1 dr),

DMBA (1.23 g, 7.87 mmol) and Pd(PPh₃)₄(147 mg, 0.13 mmol) were

reacted in CH₂Cl₂(50 mL) to give 18 in >99:1 dr. Puriﬁcation via

(C]C); d_H(400 MHz, CDCl₃) 1.19 (3H, d, J 6.6, C(a)Me), 1.38 (9H, s,

CMe₃), 1.51 (9H, s, CMe₃), 2.13 (1H, dd, J 15.4, 2.8, C(1⁰)H_A), 2.37 (1H,

dd, J 15.4, 11.4, C(1⁰)H_B), 3.44e3.69 (6H, m, C(2)H, N(CH₂CH]CH₂)₂,

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 5:1)

25

NCH_AH_BPh), 3.92 (1H, d, J 14.7, NCH_AH_BPh), 4.23 (1H, q, J 6.6, C(

a

)H),

gave 18 as a yellow oil (1.02 g, 74%, >99:1 dr); [

a

]

D

þ11.7 (c 0.9,

5.08e5.22 (5H, m, C(3)H, N(CH₂CH]CH₂)₂), 5.71e5.86 (2H, m,

N(CH₂CH]CH₂)₂), 6.95e7.42 (14H, m, Ar, Ph); d_C(100 MHz, CDCl₃)

CHCl₃); n_max(ATR) 2977 (CeH), 1727 (C]O); d_H(400 MHz, CDCl₃)

1.24e1.32 (12H, m, C(a)Me, CMe₃), 1.34 (9H, s, CMe₃), 2.03 (1H, dd, J

18.2 (C(

a

)Me), 28.0, 28.1 (2ꢂCMe₃), 37.4 (C(1⁰)), 46.4 (C(2)), 51.2

17.2, 2.8, C(1⁰)H_A), 2.31 (1H, dd, J 17.2, 11.6, C(1⁰)H_B), 3.37e3.47 (1H,

m, C(2)H), 3.63 (1H, d, J 14.9, NCH_AH_BPh), 4.02e4.18 (2H, br s, NH₂),

(NCH₂Ph), 57.0 (N(CH₂CH]CH₂)₂), 57.6 (C(a)), 58.1 (C(3)), 80.8, 80.5

(2ꢂCMe₃), 118.3 (N(CH₂CH]CH₂)₂), 124.1, 124.4, 125.8, 126.1, 127.3,

127.3, 127.6, 128.5, 128.7, 129.5, 134.2, 134.3, 141.5, 143.9, 151.4

(N(CH₂CH]CH₂)₂, Ar, Ph), 171.0, 173.9 (C(1), C(2⁰)); m/z (ESI^þ) 64_þ7

([MþNa]^þ, 100%), 625 ([MþH]^þ, 73%); HRMS (ESI^þ) C₄₀H₅₃N₂O₄

([MþH]^þ) requires 625.4000; found 625.3999.

4.15e4.23 (2H, m, NCH_AH_BPh, C(a)H), 4.37 (1H, d, J 6.3, C(3)H), 6.62

(1H, d, J 7.8, Ar), 6.71 (1H, app t, J 7.5, Ar), 7.06 (1H, t, J 7.5, Ar),

7.09e7.37 (9H, m, Ar, Ph), 7.47 (2H, d, J 7.6, Ph); d_C(100 MHz, CDCl₃)

11.4 (C(

(NCH₂Ph), 57.0 (C(

a

)Me), 27.8, 28.0 (2ꢂCMe₃), 33.5 (C(1⁰)), 46.4 (C(2)), 51.9

a

), C(3)), 79.7, 80.9 (2ꢂCMe₃), 116.7, 118.0, 126.6,

126.9, 128.1, 128.1, 128.1, 128.2, 128.5, 130.1, 141.5, 141.5, 144.1, 145.5

4.13. tert-Butyl (2R,3S,

a

R)-2-(2⁰-methoxy-2⁰-oxoethyl)-3-[N-

(Ar, Ph), 171.1, 171.4 (C(1), C(2⁰)); m/z (ESI^þ) 567 ([MþNa]^þ, 100%),

þ

benzyl-N-(

a

-methylbenzyl)amino]-4-(2⁰⁰-N,N-dia-

545 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₄H₄₄N₂NaO₄([MþNa]^þ) re-

llylaminophenyl)propanoate 16

quires 567.3193; found 567.3187.

Following general procedure 2, ⁱPr₂NH (0.44 mL, 3.14 mmol), BuLi

(2.3 M in hexanes,1.37 mL, 3.14 mmol),13 (1.07 g, 2.09 mmol, >99:1

dr) and methyl bromoacetate (0.59 mL, 6.27 mmol) were reacted in

THF (20 mL) to give 16 in >95:5 dr. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N, 89:11:1) gave

16 as a yellow oil (1.00 g, 82%, >99:1 dr); C₃₇H₄₆N₂O₄requires C,

4.16. tert-Butyl (2R,3S,

benzyl-N-(

anoate 19

a

R)-2-(2⁰-methoxy-2⁰-oxoethyl-)-3-[N-

a

-methylbenzyl)amino]-4-(2⁰⁰-aminophenyl)prop-

Following general procedure 3, 16 (528 mg, 0.91 mmol, >99:1 dr),

DMBA (848 mg, 5.43 mmol) and Pd(PPh₃)₄(31 mg, 27.0 mol) were

m

76.3; H, 8.0; N, 4.8%; found C, 76.3; H, 8.1; N, 4.8%; [

a]

²⁵ꢀ16.2 (c 2.0,

reacted in CH₂Cl₂(10 mL) to give 19 in >99:1 dr. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N,

66:34:1) gave 19 as a white solid (310 mg, 68%, >99:1 dr); mp

D

CHCl₃); n_max(ATR) 3062, 3027, 2977 (CeH), 1741 (C]O), 1666, 1642,

1597, 1485 (C]C); d_H(400 MHz, CDCl₃) 1.19 (3H, d, J 6.6, C(a)Me),

1.49 (9H, s, CMe₃), 2.21 (1H, dd, J 15.4, 2.8, C(1⁰)H_A), 2.46 (1H, dd, J

15.4,11.5, C(1⁰)H_B), 3.45e3.68 (9H, m, C(2)H, OMe, N(CH₂CH]CH₂)₂,

147e150 ^ꢁC; [

a

]

D

²⁵þ11.7 (c 1.3, CHCl₃); n_max(ATR) 3061, 3027 (NeH),

2975, 2949 (CeH), 1736 (C]O); d_H(400 MHz, CDCl₃) 1.30 (3H, d, J

NCH_AH_BPh), 3.93 (1H, d, J 14.4, NCH_AH_BPh), 4.22 (1H, q, J 6.6, C(

a

)H),

6.8, C(a

)Me), 1.36 (9H, s, CMe₃), 2.18 (1H, dd, J 17.1, 2.7, C(1⁰)H_A), 2.40

5.10e5.20 (5H, m, C(3)H, N(CH₂CH]CH₂)₂), 5.72e5.85 (2H, m,

N(CH₂CH]CH₂)₂), 6.96e7.41 (14H, m, Ar, Ph); d_C(100 MHz, CDCl₃)

(1H, dd, J 17.1, 11.2, C(1⁰)H_B), 3.41e3.50 (1H, m, C(2)H), 3.42 (3H, s,

OMe), 3.65 (1H, d, J 14.9, NCH_AH_BPh), 4.02e4.23 (2H, br s, NH₂),

17.8 (C(

a

)Me), 28.1 (CMe₃), 36.0 (C(1⁰)), 46.3 (C(2)), 51.3 (NCH₂Ph),

4.14e4.25 (2H, m, C(

(1H, d, J 8.1, Ar), 6.71 (1H, app t, J 7.3, Ar), 7.06 (1H, app t, J 7.3, Ar),

7.11e7.49 (11H, m, Ar, Ph); d_C(100 MHz, CDCl₃) 11.5 (C( )Me),

27.8 (CMe₃), 32.5 (C(1⁰)), 46.4 (C(2)), 51.2 (OMe), 51.9 (NCH₂Ph), 57.0

(C( )), 60.3 (C(3)), 81.2 (CMe₃), 116.8, 118.0, 123.1, 126.5, 126.9, 128.1,

a)H, NCH_AH_BPh), 4.40 (1H, d, J 6.3, C(3)H), 6.62

51.6 (OMe), 57.0 (N(CH₂CH]CH₂)₂), 57.4 (C(

a

)), 58.0 (C(3)), 80.9

(CMe₃), 118.4 (N(CH₂CH]CH₂)₂), 124.2, 124.5, 125.9, 126.2, 127.3,

127.4, 127.7, 128.5, 128.7, 129.4, 134.1, 134.2, 141.4, 143.8, 151.4

(N(CH₂CH]CH₂)₂, Ar, Ph), 172.1, 173.5 (C(1), C(2⁰)); m/z (ESI^þ) 60_þ5

([MþNa]^þ, 100%), 583 ([MþH]^þ, 95%); HRMS (ESI^þ) C₃₇H₄₇N₂O₄

([MþH]^þ) requires 583.3530; found 583.3532.

a

128.1, 128.3, 128.3, 128.5, 1_þ29.9, 141.4, 144._þ0, 145.5 (Ar, Ph), 172._þ4,

172.8 (C(1), C(2⁰)); m/z (ESI ) 525 ([MþNa] , 100%), 503 ([MþH] ,

9792

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

þ

100%); HRMS (ESI^þ) C₃₁H₃₈N₂NaO₄

525.2724; found 525.2723.

([MþNa]^þ) requires

m/z (ESI^þ) 351 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₉H₃₁N₂O₄

([MþH]^þ) requires 351.2278; found 351.2277.

4.17. (3R,4S,

aR)-3-(Cyanomethyl)-4-[N-benzyl-N-(a-methyl-

4.20. (3R,4S)-3-(2⁰-tert-Butoxy-2⁰-oxoethyl)-4-amino-3,4-

dihydro-1H-quinolin-2-one 24

benzyl)amino]-3,4-dihydro-1H-quinolin-2-one 20

Following general procedure 4, 17 (580 mg, 1.23 mmol, >99:1 dr)

and PhCO₂H (452 mg, 3.70 mmol) in THF (7.5 mL) was heated at

50 ^ꢁC for 72 h. Puriﬁcation via ﬂash column chromatography (el-

Attempted puriﬁcation of a portion of 23 (231 mg, 0.66 mmol,

>99:1 dr) on silica (eluent EtOAc/Et₃N, 100:1) gave 24 as a white

25

solid (74 mg, 40%, >99:1 dr); mp 144e146 ^ꢁC; [

a]

ꢀ16.0 (c 1.0,

uent 30e40 ^ꢁC petrol/Et₂O/Et₃N, 50:50:1/25:75:1) gave 20 as

D

25

CHCl₃); n_max(ATR) 3029 (NeH), 2778, 2929 (CeH), 1725 [C]O

(ester)], 1680 [C]O ( lactam)]; d_H(400 MHz, CDCl₃) 1.31 (2H, br s,

a white solid (488 mg, quant, >99:1 dr); mp 158e163 ^ꢁC; [

a]

D

d

ꢀ28.4 (c 2.5, CHCl₃); n_max(ATR) 3061, 3027, 2977, 2933 (CeH), 2247

NH₂), 1.49 (9H, s, CMe₃), 2.55 (1H, dd, J 16.4, 7.7, C(1⁰)H_A), 3.06 (1H,

dd, J 16.4, 6.5, C(1⁰)H_B), 3.19e3.26 (1H, m, C(3)H), 4.09 (1H, d, J 4.1,

C(4)H), 6.86 (1H, d, J 7.9, Ar), 7.02 (1H, app t, J 7.5, Ar), 7.19e7.25 (2H,

m, Ar), 9.22 (1H, d, N(1)H); d_C(100 MHz, CDCl₃) 28.1 (CMe₃), 32.0

(C(1⁰)), 43.2 (C(3)), 51.3 (C(4)), 80.8 (CMe₃), 116.0, 123.4, 126.7, 128.1,

128.7,136.1 (Ar),171.4,171.7 (C(2), C(2⁰)); m/z (ESI^þ) 575 ([2MþNa]^þ,

(C^N), 1680 (C]O); d_H(400 MHz, CDCl₃) 0.99 (3H, d, J 6.8, C(a)Me),

2.35 (1H, dd, J 16.9, 6.8, C(1⁰)H_A), 2.68e2.97 (1H, m, C(3)H), 3.14 (1H,

dd, J 16.9, 6.8, C(1⁰)H_B), 3.64 (1H, d, J 14.0, NCH_AH_BPh), 3.71 (1H, d, J

14.0, NCH_AH_BPh), 4.05 (1H, q, J 6.8, C(

6.99 (1H, d, J 7.8, Ar), 7.10e7.43 (13H, m, Ar, Ph), 9.65 (1H, s, NH); d_C

(100 MHz, CDCl₃) 14.2 (C(1⁰)), 14.8 (C(

)Me), 43.0 (C(3)), 50.2

(NCH₂Ph), 55.6 (C(4)), 56.9 (C( )), 116.8 (Ar), 119.5, 122.7, 123.5,

a)H), 4.20 (1H, d, J 6.6, C(4)H),

a

100%), 299 ([MþNa]^þ, 62%), 277 ([MþH]^þ, 84%); HRMS (ESI^þ)

a

þ

C

₁₅H₂₀N₂NaO₃([MþNa]^þ) requires 299.1366; found 299.1366.

127.3,127.5,127.7,128.6,128.6,129.2,129.4,129.5,137.2,_þ139.2,143.5

(C(2⁰), Ar, Ph), 170.2 (C(2)); m/z (ESI^þ) 813 ([2MþNa] , 84%), 418

([MþNa]^þ, 49%), 396 ([MþH]^þ, 10%); HRMS (ESI^þ) C₂₆H₂₅N₃NaO^þ

([MþNa]^þ) requires 418.1890; found 418.1887.

4.21. 3-(2⁰-Methoxy-2⁰-oxoethyl)-1H-quinolin-2-one 25

A solution of 24 (84 mg, 0.30 mmol, >99:1 dr) in MeOH (4 mL)

and HCl (2.0 M in Et₂O, 4 mL) was heated at reﬂux for 1 h. The

reaction mixture was then allowed to cool to rt and concentrated in

vacuo. The residue was dissolved in CH₂Cl₂(5 mL) and the resultant

solution was washed with satd aq NaHCO₃(5 mL), then dried and

concentrated in vacuo to give 25 as a white solid (56 mg, 84%); mp

176e178 ^ꢁC; n_max(ATR) 2952, 2857 (CeH), 1736 [C]O (ester)], 1665

[C]O (quinolinone)]; d_H(400 MHz, CDCl₃) 3.73 (2H, s, C(1⁰)H₂),

3.75 (3H, s, OMe), 7.17e7.22 (1H, m, Ar), 7.38e7.57 (3H, m, Ar), 7.78

(1H, s, Ar), 12.52 (1H, br s, N(1)H); d_C(100 MHz, CDCl₃) 35.7 (C(1⁰)),

52.2 (OMe), 116.0, 119.9, 122.6, 126.5, 127.5, 130.2, 138.1, 139.4 (Ar),

163.9 (C(2)), 171.5 (C(2⁰)); m/z (ESI^þ) 457 ([2MþNa]^þ, 100%), 240

4.18. (3R,4S,

benzyl)amino]-3,4-dihydro-1H-quinolin-2-one 21

a a-methyl-

R)-3-(2⁰-Oxoethyl)-4-[N-benzyl-N-(

DIBAL-H (1.0 M in CH₂Cl₂, 0.62 mL, 0.62 mmol) was added to

a stirred solution of 20 (81.4 mg, 0.21 mmol, >99:1 dr) in CH₂Cl₂

(2.0 mL) at ꢀ78 ^ꢁC and the resultant mixture was stirred at ꢀ78 ^ꢁC

for 2 h. Satd aq Rochelle’s salt (5 mL) was added and the resultant

mixture was stirred vigorously at rt for 5 min. The aqueous layer

was extracted with EtOAc (2ꢂ5 mL) and the combined organic

extracts were dried and concentrated in vacuo. The residue was

passed through a short plug of silica (eluent 30e40 ^ꢁC petrol/EtOAc/

Et₃₂N₅, 50:50:1) to give 21 as a yellow oil (63 mg, 76%, >99:1 dr);

þ

([MþNa]^þ, 75%); HRMS (ESI^þ) C₁₂H₁₁NNaO₃([MþNa]^þ) requires

[

a]

ꢀ78.3 (c 1.0, CHCl₃); n_max(ATR) 3061 (CeH), 1721 [C]O (al-

D

240.0631; found 240.0630.

dehyde)], 1673 [C]O (lactam)]; d_H(400 MHz, CDCl₃) 0.89 (3H, d, J

6.8, C(

)Me), 2.59e2.69 (1H, m, C(1⁰)H_A), 3.26e3.37 (2H, m, C(1⁰)H_B,

C(3)H), 3.59 (1H, d, J 13.8, NCH_AH_BPh), 3.73 (1H, d, J 13.8,

NCH_AH_BPh), 4.00e4.08 (2H, m, C(4)H, C( )H), 6.93 (1H, d, J 8.1, Ar),

7.00e7.17 (3H, m, Ar), 7.18e7.40 (10H, m, Ph), 9.48 (1H, s, C(2⁰)H),

9.52 (1H, br s, NH); d_C(100 MHz, CDCl₃) 14.0 (C(

)Me), 39.5 (C(1⁰)),

39.6 (C(3)), 50.3 (NCH₂Ph), 55.5, 56.1 (C( ), C(4)), 116.5, 123.1, 123.7,

a

4.22. tert-Butyl (4R,5S,aR)-2-oxo-5-[N-benzyl-N-(a-methyl-

benzyl)amino]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-

carboxylate 26

a

PhCO₂H (2 mg, 18.0 mmol) was added to a solution of 19

126.9, 127.2, 127.9, 128.3, 128.4, 129.0, 129.3, 129.5, 137.5, 139._þ6,

(90.4 mg, 0.18 mmol, >99:1 dr) in PhMe (2 mL) and the resultant

solution was heated at reﬂux for 16 h. The reaction mixture was

then allowed to cool to rt and diluted with Et₂O (10 mL). The re-

sultant mixture was washed with satd aq K₂CO₃(2ꢂ5 mL) and the

aqueous layer was extracted with Et₂O (5 mL). The combined or-

ganic extracts were then dried and concentrated in vacuo. Puriﬁ-

cation via ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/

144.0 (Ar, Ph), 172.4 (C(2)), 200.2 (C(2⁰)); m/z (ESI^þ) 819 ([2MþNa] ,

100%), 421 ([MþNa]^þ, 40%), 399 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₆H₂₆N₂NaO₂([MþNa]^þ) requires 421.1886; found 421.1883.

4.19. tert-Butyl (2R,3S)-2-(2⁰-tert-butoxy-2⁰-oxoethyl)-3-

amino-3-(2⁰⁰-aminophenyl)propanoate 23

EtOAc/Et₃N, 50:50:1) gave 26 as a colourless oil (68 mg, 80%, >99:1

25

Pd(OH)₂/C (100 mg) was added to a solution of 18 (200 mg,

0.36 mmol, >99:1 dr) in MeOH (15 mL) and the resultant mixture

was vigorously stirred under H₂(4 atm) for 16 h. The resultant

suspension was passed through a pad of Celite^Ò(eluent MeOH/

dr); mp 129e132 ^ꢁC; [

a

]

ꢀ1.50 (c 1.1, CHCl₃); n_max(ATR) 3207

D

(NeH), 3028, 2976, 2932 (CeH), 1729 [C]O (ester)], 1677 [C]O

(lactam)]; d_H(400 MHz, CDCl₃) 1.28 (3H, d, J 6.8, C( )Me), 1.39

(9H, s, CMe₃), 2.48 (1H, dd, J 14.4, 5.6, C(3)H_A), 2.71 (1H, dd, J 14.4,

8.1, C(3)H_B), 3.28e3.35 (1H, m, C(4)H), 3.68 (1H, d, J 15.2,

NCH_AH_BPh), 3.78 (1H, d, J 15.2, NCH_AH_BPh), 4.12 (1H, q, J 6.8, C(a)H),

4.56 (1H, d, J 5.8, C(5)H), 6.86 (1H, d, J 7.6, Ar), 7.09e7.32 (11H, m, Ar,

Ph), 7.41e7.47 (2H, m, Ar), 8.14 (1H, s, N(1)H); d_C(100 MHz, CDCl₃)

)Me), 27.9 (CMe₃), 34.6 (C(3)), 48.4 (C(4)), 52.7 (NCH₂Ph),

)), 66.1 (C(5)), 81.3 (CMe₃), 121.9, 124.5, 126.5, 126.9,

128.0, 128.0, 128.0, 128.2, 128.8, 130.9, 132.2, 137.4, 141.1, 143.2

a

Et₃N, 100 mL) and the ﬁltrate was concentrated in vacuo to give 23

25

as a colourless oil (120 mg, quant, >99:1 dr); [

a

]

þ1.2 (c 1.0,

D

CHCl₃); n_max(ATR) 3429, 3383, 3311 (NeH), 2978, 2932 (CeH), 1728

(C]O); d_H(400 MHz, CDCl₃) 1.39 (9H, s, CMe₃), 1.48 (9H, s, CMe₃),

1.69e1.87 (2H, br s, NH₂), 2.25 (1H, dd, J 16.9, 5.3, C(1⁰)H_A), 2.31 (1H,

dd, J 16.9, 8.2, C(1⁰)H_B), 3.27e3.35 (1H, m, C(2)H), 4.23 (1H, d, J 9.4,

C(3)H), 4.76e4.86 (2H, m, NH₂), 4.76e4.86 (2H, m, Ar), 6.95e7.00

(1H, m, Ar), 7.04e7.09 (1H, m, Ar); d_C(100 MHz, CDCl₃) 28.0, 28.1

(2ꢂCMe₃), 35.9 (C(1⁰)), 45.4 (C(2)), 57.4 (C(3)), 80.1, 80.5 (2ꢂCMe₃),

116.7, 117.5, 125.2, 128.5, 129.7, 146.3 (Ar), 171.1, 173.7 (C(1), C(2⁰));

14.9 (C(

a

57.5 (C(

a

^þ) 963 ([2MþNa]^þ, 40%),

^tBu); m/z (ESI

(Ar, Ph), 171.9, 173.2 (C(2), CO₂

493 ([MþNa]^þ, 25%), 471 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₃₀H₃₄N₂NaO₃([MþNa]^þ) requires 493.2462; found 493.2465.

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9793

4.23. tert-Butyl (3S,

a

R)-3-[N-allyl-N-(

a

-methylbenzyl)

s, NH₂), 6.51 (1H, d, J 7.8, Ar), 6.62 (1H, app t, J 7.3, Ar), 6.92 (1H, d, J

6.8, Ar), 7.03 (1H, app td, J 7.6, 1.5, Ar), 7.15e7.29 (5H, m, Ph); d_C

(100 MHz, CDCl₃) 21.0 (C(

(C(2)), 51.5 (OMe), 54.5 (C(a)), 62.7 (C(3)), 81.4 (CMe₃), 116.5, 117.4,

amino]-3-(2⁰-N,N-diallylaminophenyl)propanoate 29

a

)Me), 28.1 (CMe₃), 34.7 (C(1⁰)), 44.5

Following general procedure 1, BuLi (2.1 M in hexanes), (R)-N-allyl-

N-(a

-methylbenzyl)amine²³(1.20 g, 7.42 mmol, >99:1 er) and 12

122.4, 126.3, 126.6, 128.2, 128.5, 130.8, 145._þ8, 146.6 (Ar, Ph), 172._þ3,

(1.39 g, 4.64 mmol, >99:1 dr) were reacted in THF (50 mL) to give 29

in >99:1 dr. Puriﬁcation via ﬂash column chromatography (eluent

173.6 (C(1), C(2⁰)); m/z (ESI^þ) 413 ([MþH] , 100%); HRMS (ESI )

þ

C

₂₄H₃₃N₂O₄([MþH]^þ) requires 413.2435; found 413.2443.

30e40 ^ꢁC petrol/Et₂O, 5:1) gave 29 as a yellow oil (1.80 g, 85%, >99:1

25

dr); [

a

]

þ8.71 (c 2.1, CHCl₃); n_max(ATR) 3073, 3025, 3004, 2877,

4.26. (3aR,9bS,aR)-N(1)-(a-Methylbenzyl)-2,3,3a,4,5,9b-hex-

ahydro-1H-pyrrolo[3,2-c]quinoline-2,4-dione 32

D

2931, 2816, 2349 (CeH),1728 (C]O),1640,1596 (C]C); d_H(400 MHz,

CDCl₃) 1.23 (3H, d, J 6.8, C( )Me), 1.36 (9H, s, CMe₃), 2.57 (1H, dd,

a

J 15.3, 6.2, C(2)H_A), 2.92 (1H, dd, J 15.3, 8.5, C(2)H_B), 3.20 (1H, dd, J 15.7,

4.7, NCH_AH_BCH]CH₂), 3.39 (1H, dd, J 15.7, 6.7, NCH_AH_BCH]CH₂),

Following general procedure 4, 31 (280 mg, 0.68 mmol, >99:1 dr)

and PhCO₂H (9 mg, 68 mmol) were reacted in PhMe (5 mL) at reﬂux

3.49e3.76 (4H, m, N(CH₂CH]CH₂)₂), 3.98 (1H, q, J 6.8, C(

a)H),

for 16 h to give 32. Puriﬁcation via ﬂash column chromatography

4.90e5.26 (7H, m, C(3)H, NCH₂CH]CH₂, N(CH₂CH]CH₂)₂),

5.73e5.96 (3H, m, NCH₂CH]CH₂, N(CH₂CH]CH₂)₂), 7.07e7.31 (6H,

m, Ar, Ph), 7.38 (2H, d, J 7.6, Ph), 7.55 (1H, d, J 7.6, Ar); d_C(100 MHz,

(eluent EtOAc/Et₃N, 100:1) gave 32 as a white solid (166 mg, 80%,

20

>99:1 dr); mp 174e177 ^ꢁC; [

a

]

þ86.8 (c 0.7, CHCl₃); n_max(ATR)

D

3216 (NeH), 3061, 2988, 2924 (CeH), 1682 [C]O (

[C]O ( -lactam)]; d_H(400 MHz, CDCl₃) 1.04 (3H, d, J 7.1, C(

2.81 (1H, dd, J 16.7, 8.1, C(3)H_A), 3.06e3.14 (1H, m, C(3a)H), 3.31 (1H,

d, J 16.7, C(3)H_B), 4.72 (1H, d, J 5.6, C(9b)H), 5.49 (1H, q, J 7.1, C( )H),

g

-lactam)], 1616

CDCl₃) 15.7 (C(a)Me), 28.0 (CMe₃), 40.4 (C(2)), 49.2 (NCH₂CH]CH₂),

d

a

)Me),

53.6 (C(3)), 56.3 (C(a)), 57.0 (N(CH₂CH]CH₂)₂), 80.1 (CMe₃), 114.5,

117.7 (NCH₂CH]CH₂, N(CH₂CH]CH₂)₂), 123.7, 124.1, 126.3, 127.1,

127.8, 127.8, 128.9, 135.0, 139.2, 140.0, 145.2, 150.0 (NCH₂CH]CH₂,

N(CH₂CH]CH₂)₂, Ar, Ph),171.6 (C(1)); m/z (ESI^þ) 483 ([MþNa]^þ, 98%),

a

6.29 (1H, d, J 7.3, Ar), 6.85 (1H, app t, J 7.4, Ar), 6.93 (2H, d, J 7.8, Ph),

7.26e7.40 (5H, m, Ar, Ph), 10.04 (1H, br s, N(5)H); d_C(100 MHz,

CDCl₃) 16.7 (C(a)Me), 34.3 (C(3)), 38.6 (C(3a)), 49.1 (C(a)), 57.7

þ

461 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₀H₄₁N₂O₂([MþH]^þ) requires

461.3163; found 461.3163.

(C(9b)), 116.0, 117.3, 122.7, 127.3, 127.5, 128.5, 130.7, 131.6, 137.3,

139.0 (Ar, Ph), 171.0, 173.6 (C(2), C(4)); m/z (ESI^þ) 635 ([2MþNa]^þ,

4.24. tert-Butyl (2R,3S,

a

R)-2-(2⁰-methoxy-2⁰-oxoethyl)-3-[N-

100%), 613 ([2MþH]^þ, 30%), 329 ([MþNa]^þ, 55%); HRMS (ESI^þ)

þ

allyl-N-(

a

-methylbenzyl)amino]-3-(2⁰⁰-N,N-dia-

C

₁₉H₁₈N₂NaO₂([MþNa]^þ) requires 329.1260; found 329.1261.

llylaminophenyl)propanoate 30

4.27. (3aR,9bS,aR)-N(1)-(a-Methylbenzyl)-N(5)-(tert-butox-

ycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quino-

lin-2,4-dione 33

Following general procedure 2, ⁱPr₂NH (11.5 mL, 82.0 mmol), BuLi

(2.5 M in hexanes, 31.7 mL, 79.3 mmol), 29 (25.2 g, 54.7 mmol,

>99:1 dr) and methyl bromoacetate (15.5 mL, 164 mmol) were

reacted in THF (500 mL) to give 30 in >95:5 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N,

Boc₂O (6.68 g, 30.6 mmol), Et₃N (6.40 mL, 45.9 mmol) and DMAP

(93 mg, 0.78 mmol) were added sequentially to a stirred solution of

32 (4.69 g, 15.3 mmol, >99:1 dr) in CH₂Cl₂(150 mL) and the re-

sultant mixture was stirred at 35 ^ꢁC for 16 h. The reaction mixture

was then washed with 1.0 M aq HCl (100 mL) and the aqueous layer

was extracted with CH₂Cl₂(50 mL). The combined organic extracts

were washed sequentially with satd aq NaHCO₃(50 mL) and brine

(50 mL), then dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N,

50:50:1/0:100:1) gave 33 as a yellow solid (5.14 g, 83%, >99:1 dr);

86:14:1) gave 30 as a yellow oil (20.0 g, 68%, >99:1 dr); [

a]

²⁰þ5.76

D

(c 1.2, CHCl₃); n_max(ATR) 3073, 2978, 2820 (CeH), 1742 (C]O); d_H

(400 MHz, CDCl₃) 1.04 (3H, app dd, J 6.6, 1.3, C(a)Me), 1.50 (9H, s,

CMe₃), 2.20 (1H, dd, J 15.7, 3.0, C(1⁰)H_A), 2.50 (1H, dd, J 15.7,

11.5, C(1⁰)H_B), 3.10e3.19 (1H, m, NCH_AH_BCH]CH₂), 3.21e3.30

(1H, m, NCH_AH_BCH]CH₂), 3.45e3.67 (8H, m, C(2)H, CO₂Me,

N(CH₂CH]CH₂)₂), 4.16 (1H, q, J 6.6, C(a)H), 4.77e4.89 (2H, m,

NCH₂CH]CH₂), 5.03 (1H, d, J 11.6, C(3)H), 5.12e5.22 (4H, m,

N(CH₂CH]CH₂)₂), 5.61e5.73 (1H, m, NCH₂CH]CH₂), 5.81e5.94

(2H, m, N(CH₂CH]CH₂)₂), 7.10e7.31 (8H, m, Ar, Ph), 7.35e7.40 (1H,

C

₂₄H₂₆N₂O₄requires C, 70.9; H, 6.45; N, 6.9%; found C, 70.8; H, 6.6;

N, 7.0%; mp 155e168 ^ꢁC; [

a

]

D

²⁰þ53.3 (c 2.1, CHCl₃); n_max(ATR) 2981,

m, Ar); d_C(100 MHz, CDCl₃) 18.7 (C(

46.6 (OMe), 49.9 (NCH₂CH]CH₂), 51.6 (C(2)), 56.5 (C(

a

)Me), 28.0 (CMe₃), 35.9 (C(1⁰)),

)), 57.3

2936 (CeH), 1766, 1694 [C]O (d lactam)], 1608 [C]O (carbamate)];

a

d_H(400 MHz, CDCl₃) 1.06 (3H, d, J 7.3, C(a)Me), 1.61 (9H, s, CMe₃),

(C(3)), 57.4 (N(CH₂CH]CH₂)₂), 80.7 (CMe₃), 114.8 (NCH₂CH]CH₂),

118.4 (N(CH₂CH]CH₂)₂), 124.4, 124.5, 126.0, 127.6, 127.7,

127.9, 129.1, 134.3, 134.6, 138.7, 145.4, 151.4 (NCH₂CH]CH₂,

N(CH₂CH]CH₂)₂, Ar, Ph), 172.1, 173.7 (C(1), C(2⁰)); m/z (ESI^þ) 55_þ5

([MþNa]^þ, 35%), 533 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₃H₄₅N₂O₄

([MþH]^þ) requires 533.3374; found 533.3377.

2.73 (1H, dd, J 16.4, 7.5, C(3)H_A), 3.08e3.14 (1H, m, C(3a)H), 3.28

(1H, d, J 16.4, C(3)H_B), 4.63 (1H, d, J 5.3, C(9b)H), 5.48 (1H, q, J 7.3,

C(

(2H, d, J 7.8, Ph), 7.28e7.39 (5H, m, Ar, Ph); d_C(100 MHz, CDCl₃) 16.7

(C( )Me), 27.6 (CMe₃), 34.5 (C(3)), 39.5 (C(3a)), 48.9 (C( )), 57.4

a)H), 6.26 (1H, d, J 7.6, Ar), 6.87e6.95 (1H, m, Ar), 7.04e7.10

a

(C(9b)), 85.8 (CMe₃), 116.1, 118.6, 123.7, 127.4, 127.4, 128.5, 130.6,

131.9, 137.1, 138.9 (Ar, Ph), 150.8 (NCO), 167.7, 173.2 (C(2), C(4)); m/z

þ

4.25. tert-Butyl (2R,3S,

a

R)-2-(2⁰-methoxy-2⁰-oxoethyl)-3-[N-

(ESI^þ) 429 ([MþNa]^þ, 100%); HRMS (ESI^þ) C₂₄H₂₆N₂NaO₄

(a

-methylbenzyl)amino]-3-(2⁰⁰-aminophenyl)propanoate 31

([MþNa]^þ) requires 429.1785; found 429.1782.

Following general procedure 3, 30 (1.07 g, 2.02 mmol, >99:1 dr),

4.28. (3aR,4R,9bS,aR)- or (3aR,4S,9bS,aR)-N(1)-(a-Methyl-

DMBA (1.42 g, 9.09 mmol) and Pd(PPh₃)₄(350 mg, 0.30 mmol) were

reacted in CH₂Cl₂(20 mL) to give 31 in >99:1 dr. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N,

benzyl)-4-hydroxy-N(5)-(tert-butoxycarbonyl)-2,3,3a,4,5,9b-

hexahydro-1H-pyrrolo[3,2-c]quinolin-2-one 34

66:34:1) gave 31 as a yellow oil (631 mg, 76%, >99:1 dr); [

a]

²⁰ꢀ1.6

LiAl(O^tBu)₃H (5.44 g, 21.4 mmol) was added to a stirred solution

of 33 (4.35 g, 10.7 mmol, >99:1 dr) in THF (100 mL) at 0 ^ꢁC and the

resultant mixture was stirred at 0 ^ꢁC for 1 h. H₂O (1 mL) was then

added dropwise, EtOAc (20 mL) was added, and the resultant

mixture was allowed to stir at rt for 10 min. The reaction mixture

was then ﬁltered through a pad of Celite^Ò(eluent EtOAc), then

D

(c 1.15, CHCl₃); n_max(ATR) 3428, 3298 (NeH), 3027, 2974, 2930

(CeH), 1728 (C]O); d_H(400 MHz, CDCl₃) 1.38 (3H, d, J 6.6, C(a)Me),

1.50 (9H, s, CMe₃), 2.21 (1H, dd, J 16.9, 4.6, C(1⁰)H_A), 2.45 (1H, dd, J

16.9, 9.8, C(1⁰)H_B), 3.43 (1H, app td, J 9.8, 4.6, C(2)H), 3.58 (3H, s,

OMe), 3.62 (1H, q, J 6.6, C(a)H), 4.08 (1H, d, J 9.6, C(3)H), 4.76 (2H, br

9794

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

dried and concentrated in vacuo to give 34 as a white foam (4.40 g,

quant, >99:1 dr). An aliquot was puriﬁed via ﬂash column chro-

Ph), 172.5, 173.5 (C(2), C(2⁰)); m/z (ESI^þ) 751 ([2MþNa]^þ, 100%), 387

([MþNa]^þ, 90%); HRMS (ESI^þ) C₂₂H₂₄N₂NaO₃^þ([MþNa]^þ) requires

387.1679; found 387.1665.

matography (eluent EtOAc/Et₃N, 100:1) to give an analytically pure

20

sample of 34 as a white foam (>99:1 dr);⁴⁶

[

a]

þ68.6 (c 1.6,

D

CHCl₃); n_max(ATR) 3429 (OeH), 3032, 2951 (CeH), 1695 [C]O

(carbamate)], 1664 [C]O lactam)]; d_H(400 MHz, CDCl₃)

0.94 (3H, d, J 7.3, C( )Me), 1.47 (9H, s, CMe₃), 2.54 (1H, dd, J 16.8, 1.9,

C(3)H_A), 2.76e2.92 (2H, m, C(3)H_B, C(3a)H), 3.74 (1H, br s, OH), 4.48

(1H, d, J 7.3, C(9b)H), 5.38 (1H, s, C(4)H), 5.47 (1H, q, J 7.3, C( )H),

6.38 (1H, dd, J 7.6, 1.0, Ar), 6.93 (1H, td, J 7.5, 1.3, Ar), 7.05 (2H, d, J 7.8,

Ph), 7.24e7.38 (5H, m, Ar, Ph); d_C(100 MHz, CDCl₃) 16.5 (C( )Me),

28.3 (CMe₃), 36.1 (C(3)), 42.2 (C(3a)), 49.8 (C( )), 56.9 (C(9b)), 81.9,

4.31. (3aS,4S,9bS,aR)-N(1)-(a

-Methylbenzyl)-4-(2⁰-hydrox-

yethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

37

(g

a

LiAlH₄(2.0 M in Et₂O, 8.40 mL, 16.8 mmol) was added to a so-

lution of 36 (1.53 g, 4.20 mmol, >99:1 dr) in THF (60 mL) at 0 ^ꢁC. The

resultant mixture was heated at reﬂux for 16 h, then allowed to cool

to rt and subsequently cooled to 0 ^ꢁC. Aq NaOH (2.0 M, 5.0 mL) was

carefully added then the reaction mixture was diluted with EtOAc

(20 mL) and the resultant mixture was stirred at rt for 20 min. The

reaction mixture was then ﬁltered through a pad of Celite^Ò(eluent

EtOAc/Et₃N, 100:1, 150 mL), then dried and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 90:10, CHCl₃/

a

81.9 (C(4), CMe₃), 124.3, 126.0, 127.3, 127.8, 128.2, 129.1, 130.4, 137.4,

138.6 (Ar, Ph), 152.7 (NCO), 173.5 (C(2)); m/z (ESI^þ) 839 ([2MþNa]^þ,

þ

100%), 431 ([MþNa]^þ, 76%); HRMS (ESI^þ) C₂₄H₂₈N₂NaO₄

([MþNa]^þ) requires 431.1941; found 431.1937.

4.29. (3aS,4S,9bS,

a

R)-N(1)-(

a

-Methylbenzyl)-4-[2⁰-methoxy-

MeOH) gave 37 as a yellow oil (898 mg, 67%, >99:1 dr); [

(c 1.2, CHCl₃); n_max(ATR) 3390 (OeH), 3025, 2965, 2934, 2876

a

]

²⁰ꢀ99.1

D

2⁰-oxoethyl]-N(5)-(tert-butoxycarbonyl)-2,3,3a,4,5,9b-hexahy-

dro-1H-pyrrolo[3,2-c]quinolin-2-one 35

(CeH); d_H(400 MHz, CDCl₃) 1.54 (3H, d, J 6.6, C(a)Me), 1.55e1.73

(2H, m, C(3)H_A, C(1⁰)H_A), 1.79e1.91 (1H, m, C(1⁰)H_B), 1.92e2.10 (2H,

m, C(3)H_B, C(3a)H), 2.58e2.72 (2H, m, C(2)H₂), 3.41 (1H, dt, J 8.6,

2.2, C(4)H), 3.71 (1H, d, J 5.3, C(9b)H), 3.73e3.82 (1H, m, C(2⁰)H_A),

Phosphorane 38 (7.15 g, 21.4 mmol) was added to a solution of

34 (4.40 g, 10.7 mmol) in PhMe (100 mL) and the resultant mixture

was stirred at 80 ^ꢁC for 72 h. The reaction mixture was then con-

centrated in vacuo to give 35 in >99:1 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N,

75:25:1) followed by trituration with Et₂O to gave 35 as a yellow oil

3.85e3.93 (1H, m, C(2⁰)H_B), 4.34 (1H, q, J 6.6, C(

a

)H), 6.62 (1H, d, J

7.8, Ar), 6.67e6.72 (1H, m, Ar), 7.06e7.12 (1H, m, Ar), 7.17e7.34 (4H,

m, Ar, Ph), 7.41 (2H, d, J 7.3, Ph); d_C(100 MHz, CDCl₃) 11.2 (C( )Me),

26.1 (C(3)), 35.6 (C(1⁰)), 39.6 (C(3a)), 42.9 (C(2)), 52.3 (C(4)), 53.7

a

(3.97 g, 80%, >99:1 dr); [

2934 (CeH), 1739 [C]O (ester)], 1695 [C]O (carbamate, lactam)];

a

]

²⁰þ96.8 (c 0.7, CHCl₃); n_max(ATR) 2976,

(C(a

)), 58.7 (C(9b)), 61.5 (C(2⁰)), 114.6, 116.6, 120.6, 126.4, 127.5,

D

127.9, 128.1, 131.1, 144.7, 144.9 (Ar, Ph); m/z (ESI^þ) 323 ([MþH]^þ,

100%); HRMS (ESI^þ) C₂₁H₂₇N₂O^þ([MþH]^þ) requires 323.2118;

found 322.2108.

d_H(400 MHz, CDCl₃) 0.91 (3H, d, J 7.1, C(a)Me), 1.50 (9H, s, CMe₃),

2.04e2.17 (2H, m, C(1⁰)H₂), 2.65e2.78 (2H, m, C(3)H_A, C(3a)H),

2.85e2.99 (4H, m, C(3)H_B, OMe), 4.44 (1H, d, J 7.8, C(9b)H),

4.80e4.93 (1H, br m, C(4)H), 5.46 (1H, q, J 7.1, C(

7.3, Ar), 6.92e6.99 (1H, m, Ar), 7.07 (2H, d, J 7.8, Ph), 7.25e7.40 (5H,

m, Ar, Ph); d_C(100 MHz, CDCl₃) 16.6 (C( )Me), 28.3 (CMe₃), 38.4, 39.1

(C(3), C(1⁰)), 39.8 (C(3a)), 49.7 (C(

)), 51.7 (OMe), 56.0 (C(4)), 56.7

a)H), 6.38 (1H, d, J

4.32. (3aS,4S,9bS,

nesulfonyloxy)ethyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-

aR)-N(1)-(a

-Methylbenzyl)-4-[2⁰-(4⁰⁰-tolue-

a

c]quinoline 39 and (3aS,4S,9bS,aR)-N(1)-(a-methylbenzyl)-4-

a

(2⁰-chloroethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]

(C(9b)), 81.5 (CMe₃), 124.5, 126.7, 127.3, 127.8, 128.3, 129.0, 129.2,

quinoline 40

130.3,138.6,138.7 (Ar, Ph),152.8 (NCO),170.8,173.7 (C(2), C(2⁰)); m/z

(ESI^þ) 951 ([2MþNa]^þ, 99%), 487 ([MþNa]^þ, 100%); HRMS (ESI^þ)

Method A: CCl₄(0.78 mL, 7.80 mmol) was added to a solution of

37 (257 mg, 0.80 mL, >99:1 dr), PPh₃(523 mg, 2.00 mmol) and Et₃N

(1.11 mL, 7.80 mmol) in MeCN (10 mL) at 0 ^ꢁC. The resultant mixture

was stirred at rt for 16 h then was concentrated in vacuo. Puriﬁ-

þ

C

₂₇H₃₂N₂NaO₅([MþNa]^þ) requires 487.2203; found 487.2199.

4.30. (3aS,4S,9bS,aR)-N(1)-(a

-Methylbenzyl)-4-(2⁰-methoxy-

2⁰-oxoethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quino-

cation via ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/

20

lin-2-one 36

EtOAc, 75:25) gave 40 as a yellow oil (196 mg, 72%, >99:1 dr); [a]

D

ꢀ64.9 (c 1.3, CHCl₃); n_max(ATR) 3410 (NeH), 2965, 2931, 2875

TFA (6.0 mL) was added to a stirred solution of 35 (3.97 g,

8.54 mmol, >99:1 dr) in CH₂Cl₂(60 mL) at rt and the resultant

mixture was stirred at 35 ^ꢁC for 4 h. The reaction mixture was then

allowed to cool to rt and neutralised carefully with satd aq K₂CO₃.

The resultant solution was washed with satd aq K₂CO₃(2ꢂ50 mL)

and the combined aqueous layers were extracted with CH₂Cl₂

(50 mL). The combined organic extracts were then dried and con-

centrated in vacuo to give 36 as a pale yellow solid. Puriﬁcation via

(CeH); d_H(500 MHz, CDCl₃); 1.50 (3H, d, J 6.6, C(a)Me), 1.62e1.72

(1H, m, C(3)H_A), 1.90e2.14 (4H, m, C(3)H_B, C(3a)H, C(1⁰)H₂),

2.59e2.72 (2H, m, C(2)H₂), 3.48 (1H, td, J 7.9, 3.2, C(4)H), 3.65e3.74

(3H, m, C(9b)H, C(2⁰)H₂), 4.08 (1H, br s, N(5)H), 4.20 (1H, q, J 6.6,

C(

(3H, m, Ar, Ph), 7.26e7.31 (2H, m, Ph), 7.38 (2H, d, J 7.6, Ph); d_C

(125 MHz, CDCl₃) 12.9 (C(

)Me), 26.5 (C(3)), 36.6 (C(1⁰)), 39.3

(C(3a)), 42.2 (C(2⁰)), 43.6 (C(2)), 50.8 (C(4)), 54.9 (C(

)), 58.3 (C(9b)),

a)H), 6.57 (1H, d, J 7.9, Ar), 7.05 (1H, app td, J 7.6, 1.3, Ar), 7.17e7.22

a

recrystallisation (CH₂Cl₂/pentane) gave 36 as a white solid (1.61 g,

114.4, 117.1, 121.3, 126.4, 127.4, 128.0, 128.0, 130.8, 144.0, 145.0 (A_þr,

Ph); m/z 341 ([M(³⁵Cl)þH]^þ, 100%); HRMS (ESI^þ) C₂₁H₂₆³⁵ClN₂

([M(³⁵Cl)þH]^þ) requires 341.1779; found 341.1778.

20

58%, >99:1 dr); mp 150e155 ^ꢁC; [

a

]

ꢀ31.7 (c 1.01, CHCl₃); n_max

D

(ATR) 3392, 3338 (NeH), 3029, 2973, 2847 (CeH), 1731 [C]O (es-

ter)], 1678 [C]O ( lactam)]; d_H(400 MHz, CDCl₃) 1.33 (3H, d, J 7.3,

C(

)Me), 2.17e2.25 (1H, m, C(3a)H), 2.32 (1H, dd, J 16.7,1.5, C(1⁰)H_A),

g

Method B: DMAP (11 mg, 91 mmol), Et₃N (0.19 mL, 1.36 mmol)

a

and TsCl (208 mg, 1.09 mmol) were added sequentially to a stirred

solution of 37 (293 mg, 0.91 mmol) in CH₂Cl₂(20 mL) and the re-

sultant mixture was stirred at rt for 16 h. The reaction mixture was

washed with 1.0 M aq HCl (20 mL) and the aqueous layer was

extracted with CH₂Cl₂(20 mL). The combined organic extracts were

washed sequentially with satd aq NaHCO₃(10 mL) and brine

(10 mL), then dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N,

66:34:1) gave 40 as a yellow oil (72 mg, 23%, >99:1 dr). Further

2.39 (1H, dd, J 16.2, 10.1, C(3)H_A), 2.65 (1H, dd, J 16.2, 2.5, C(3)H_B),

2.73 (1H, dd, J 16.7, 7.0, C(1⁰)H_B), 3.47 (1H, br t, C(4)H), 3.72 (3H, s,

OMe), 4.63 (1H, app d, J 5.1, C(9b)H), 4.91 (1H, s, N(5)H), 5.38 (1H, q,

J 7.3, C(

6.56 (1H, dd, J 8.1, 0.8, Ar), 7.08 (1H, app td, J 7.6, 1.5, Ar), 7.12e7.37

(5H, m, Ph); d_C(100 MHz, CDCl₃) 16.6 (C(

)Me), 35.9 (C(1⁰)), 36.0

(C(3a)), 38.2 (C(3)), 48.1 (C(4)), 49.3 (C( )), 52.0 (OMe), 56.7 (C(9b)),

115.0, 115.6, 117.0, 126.9, 127.3, 128.3, 129.9, 132.4, 140.1, 144.3 (Ar,

a)H), 6.40 (1H, dd, J 7.8, 1.1, Ar), 6.51 (1H, app td, J 7.3, 1.0, Ar),

a

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9795

20

elution gave 39 as a yellow oil (180 mg, 41%, w90% purity); [

a

]

30e40 ^ꢁC petrol/Et₂O, 75:25) gave 43 as a colourless oil (35 mg,

D

ꢀ82.2 (c 1.2, CHCl₃); n_max(ATR) 3401 (NeH), 3055, 3026, 2966,

17%, >99:1 dr); [

a]

²⁰ꢀ73.5 (c 1.06, CHCl₃); n_max(ATR) 3371 (NeH),

D

2931, 2876 (CeH); d_H(400 MHz, CDCl₃) 1.48 (3H, d, J 6.6, C(

a

)Me),

2950, 2876, 2839 (CeH), 1689 (C]O); d_H(400 MHz, CDCl₃) 1.50

1.52e1.64 (1H, m, C(3)H_A), 1.70e1.81 (1H, m, C(1⁰)H_A), 1.86e2.06

(3H, m, C(3)H_B, C(3a)H, C(1⁰)H_B), 2.45 (3H, s, C(4⁰⁰)Me), 2.52e2.71

(2H, m, C(2)H₂), 3.36 (1H, td, J 8.0, 2.8, C(4)H), 3.66 (1H, d, J 5.3,

(3H, d, J 6.8, C(a)Me), 1.57e1.68 (1H, m, C(3)H_A), 1.87e2.14 (4H, m,

C(3)H_B, C(3a)H, C(1⁰)H₂), 2.61e2.70 (2H, m, C(2)H₂), 3.45e3.58 (1H,

m, C(4)H), 3.63e3.74 (3H, m, C(2⁰)H₂, C(9b)H), 3.85 (3H, s, OMe),

C(9b)H), 4.12e4.29 (3H, m, C(

a

)H, C(2⁰)H₂), 6.46 (1H, d, J 7.3, Ar),

4.13 (1H, q, J 6.8, C(a)H), 4.64 (1H, s, N(5)H), 6.51 (1H, d, J 8.2, C(6)H),

6.66 (1H, app td, J 7.3, 1.0, Ar), 7.03 (1H, app td, J 7.6, 1.4, Ar), 7.16 (1H,

d, J 6.6, Ar), 7.20 (1H, t, J 7.0, Ph), 7.28 (2H, app t, J 7.0, Ph), 7.32e7.40

(4H, m, C(3⁰⁰)H, C(5⁰⁰)H, Ph), 7.83 (2H, d, J 8.3, C(2⁰⁰)H, C(6⁰⁰)H); d_C

7.13e7.20 (1H, m, Ph), 7.22e7.29 (2H, m, Ph), 7.32 (2H, d, J 7.5, Ph),

7.71 (1H, dd, J 8.2, 1.7, C(7)H), 7.84 (1H, d, J 1.7, C(9)H); d_C(125 MHz,

CDCl₃) 13.0 (C(

a

)Me), 26.4 (C(3)), 36.6 (C(1⁰)), 38.8 (C(3a)), 42.1

(100 MHz, CDCl₃) 12.8 (C(

a

)Me), 21.7 (C(4⁰⁰)Me), 26.3 (C(3)), 32.9

)), 58.2 (C(9b)),

(C(2⁰)), 43.6 (C(2)), 50.8 (C(4)), 51.6 (OMe), 55.0 (C(

a)), 58.5 (C(9b)),

(C(1⁰)), 39.3 (C(3a)), 43.5 (C(2)), 49.9 (C(4)), 54.8 (C(

a

113.4, 118.0, 119.5, 126.5, 127.4, 128.0, 130.1, 133.4, 144.9, 148.0 (Ar,

Ph), 167.4 (CO₂Me); m/z (ESI^þ) 399 ([M(³⁵Cl)þH]^þ, 100%); HRMS

68.1 (C(2⁰)), 114.4, 117.0, 121.0, 126.4, 127.4, 127.9, 128.0, 130.0,_þ130.8,

132.9, 143.8, 145.0 (C(2⁰⁰), C(3⁰⁰), C(5⁰⁰), C(6⁰⁰), Ar, Ph); m/z (ESI ) 477

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₈H₃₃N₂O₃S^þ([MþH]^þ) requires

477.2206; found 477.2206.

þ

(ESI^þ) C₂₃H₂₈³⁵ClN₂O₂([M(³⁵Cl)þH]^þ) requires 399.1834; found

399.1820.

4.35. (3aS,4S,9bS,aR)-N(1)-(a

-Methylbenzyl)-4-(2⁰-cya-

noethyl)-8-(methoxycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-

pyrrolo[3,2-c]quinoline 44

4.33. (3aS,4S,9bS,

oethyl)-8-bromoe2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]

quinoline 41 and (3aS,4S,9bS, R)-N(1)-(

-methylbenzyl)-4-(2⁰-

a

R)-N(1)-(

a

-Methylbenzyl)-4-(2⁰-chlor-

a

chloroethyl)-6,8-dibromo-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo

[3,2-c]quinoline 42

NaCN (10 mg, 0.19 mmol) was added to a solution of 43 (50 mg,

0.13 mmol, >99:1 dr) in DMSO (1.0 mL) and the resultant mixture

was heated at 90 ^ꢁC for 16 h. The reaction mixture was allowed to

cool to rt and was then partitioned between H₂O (10 mL) and EtOAc

(20 mL). The organic layer was washed with H₂O (3ꢂ10 mL) and the

combined aqueous layers were extracted with EtOAc (3ꢂ10 mL).

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

then dried and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/EtOAc, 50:50) gave 44 as

A solution of NBS (39.0 mg, 0.22 mmol) in MeCN (0.6 mL) was

added to a solution of 40 (71 mg, 0.21 mmol, >99:1 dr) in MeCN

(1 mL) at 0 ^ꢁC over a period of 10 min. The resultant mixture was

stirred at rt for 2 h, then diluted with CHCl₃(50 mL) and washed

with H₂O (2ꢂ10 mL). The combined aqueous layers were extracted

with CHCl₃(20 mL) and the combined organic extracts were washed

with brine (2ꢂ20 mL), then dried and concentrated in vacuo. Puri-

ﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/

Et₂₂O₀, 60:40) gave 42 as a colourless oil (6.2 mg, 6%, w90% purity);

a pale brown oil (38 mg, 79%, >99:1 dr); [

a

]

D

²⁰ꢀ70.0 (c 0.96, CHCl₃);

n_max(ATR) 3374 (NeH), 2949, 2876, 2849 (CeH), 2247 (C^N), 1703

(C]O); d_H(500 MHz, CDCl₃) 1.50 (3H, d, J 6.6, C(a)Me), 1.57e1.66

[

a

]

ꢀ47.8 (c 0.37, CHCl₃); n_max(ATR) 3396 (NeH), 2962, 2928

(1H, m, C(3)H_A), 1.87e2.07 (4H, m, C(3)H_B, C(3a)H, C(1⁰)H₂), 2.44

(1H, dd, J 17.0, 7.3, C(2⁰)H_A), 2.51 (1H, dd, J 17.0, 7.6, C(2⁰)H_B),

2.62e2.72 (2H, m, C(2)H₂), 3.47e3.56 (1H, br m, C(4)H), 3.70 (1H, d,

D

(CeH); d_H(400 MHz, CDCl₃) 1.38 (3H, d, J 6.6, C(a)Me), 1.54e1.66

(1H, m, C(3)H_A), 1.75e2.06 (4H, m, C(3)H_B, C(3a)H, C(1⁰)H₂),

2.59e2.69 (2H, m, C(2)H₂), 3.43e3.51 (1H, m, C(4)H), 3.54e3.65 (3H,

J 4.1, C(9b)H), 3.86 (3H, s, OMe), 4.13 (1H, q, J 6.6, C(a)H), 4.49 (1H, br

m, C(9b)H, C(2⁰)H₂), 3.93 (1H, q, J 6.6, C(

a

)H), 4.68 (1H, br s, N(5)H),

7.10e7.17 (2H, Ar, Ph), 7.18e7.29 (4H, m, Ph), 7.32 (1H, d, J 2.2, Ar); d_C

(100 MHz, CDCl₃) [selected peaks] 15.1 (C( )Me), 26.8 (C(3)), 28.0

)), 58.6 (C(9b)),

s, N(5)H), 6.54 (1H, d, J 8.5, C(6)H), 7.13e7.19 (1H, m, Ph), 7.21e7.34

(4H, m, Ph), 7.72 (1H, d, J 8.5, C(7)H), 7.84 (1H, s, C(9)H); d_C

a

(125 MHz, CDCl₃) 12.9 (C(a

)Me), 13.2 (C(2⁰)), 26.1 (C(3)), 29.3 (C(1⁰)),

(C(3a)), 36.6 (C(1⁰)), 42.0 (C(2⁰)), 44.7 (C(2)), 56.9 (C(

a

37.8 (C(3a)), 43.4 (C(2)), 51.2 (C(4)), 51.7 (OMe), 54.8 (C(a)), 58.5

126.8, 127.3, 128.2, 132.4, 132.9, 144.6 (Ar, Ph); m/z (ESI^þ) 49_þ9

([M(⁷⁹Br⁸¹Br³⁵Cl)þH]^þ, 100%); HRMS (ESI^þ) C₂₁H₂₄⁷⁹Br⁸¹Br³⁵ClN₂

([M(⁷⁹Br⁸¹Br³⁵Cl)þH]^þ) requires 498.9969; found 498.9957. Further

(C(9b)),113.7 (C(6)), 118.4, 119.5 (Ar), 119.7 (C(3⁰)),126.5, 127.3, 128.0

(Ph), 130.2 (C(7)), 133.4 (C(9)), 144.7, 147.9 (Ar, Ph), 167.3 (CO₂Me);

m/z (ESI^þ) 412 ([MþNa]^þ, 25%), 390 ([MþH]^þ, 100%); HMRS (ESI^þ)

þ

elution gave 41 as a yellow oil (60 mg, 68%, >99:1 dr); [

a]

²⁰ꢀ65.2

C

₂₄H₂₈N₃O₂([MþH]^þ) requires 390.2176; found 390.2164.

D

(c 1.55, CHCl₃); n_max(ATR) 3416 (NeH), 3058, 3025, 2964, 2932, 2874

(CeH); d_H(300 MHz, CDCl₃) 1.37 (3H, d, J 6.7, C(

a

)Me), 1.47e1.64

4.36. (3aS,3bS,11bS,aR)-N(1)-(a

-Methylbenzyl)-10-(1⁰-oxo-1⁰-

(1H, m, C(3)H_A), 1.70e2.02 (4H, m, C(3)H_B, C(3a)H, C(1⁰)H₂),

2.52e2.64 (2H, m, C(2)H₂), 3.29e3.40 (1H, m, C(4)H), 3.49e3.59

methoxy)-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-

a:3⁰,2⁰-c]quinoline 45

(3H, m, C(9b)H, C(2⁰)H₂), 3.96 (1H, q, J 6.7, C(

a

)H), 6.31 (1H, d, J 8.5,

C(6)H), 6.99 (1H, dd, J 8.5, 2.3, C(7)H), 7.06e7.32 (6H, m, C(9)H, Ph);

d_C(100 MHz, CDCl₃) 14.6 (C(

)Me), 26.8 (C(3)), 36.6 (C(1⁰)), 39.2

(C(3a)), 42.1 (C(2⁰)), 44.5 (C(2)), 50.7 (C(4)), 56.4 (C(

)), 58.2 (C(9b)),

Pd(OH)₂/C (5 mg) was added to a stirred, degassed solution of 44

(10 mg, 0.1 mmol, >99:1 dr) in HCl (0.4 M in MeOH, 2 mL). The

resultant mixture was purged with H₂and stirred vigorously under

H₂(1 atm) at rt for 16 h. The mixture was then purged with N₂,

ﬁltered through a short pad of Celite^Ò(eluent MeOH/Et₃N, 100:1,

10 mL) and concentrated in vacuo. The residue was dissolved in

EtOAc (10 mL) and the resultant solution was washed with 2.0 M aq

NaOH (2ꢂ10 mL). The organic layer was then dried and concen-

trated in vacuo. Puriﬁcation via ﬂash column chromatography

(eluent EtOAc/Et₃N, 100:1) gave 45 as a colourless oil (3 mg,

30%, w90% purity); n_max(ATR) 2360, 2341 (CeH), 1703 (C]O);

d_H(400 MHz, C₆D₆) 1.00e1.14 (1H, m, C(4)H_A), 1.23e1.34 (1H, m,

a

108.7, 116.0, 123.8, 126.7, 127.4, 128.2, 130.6, 133.1, 142.8, 144.9 (Ar,

Ph); m/z (ESI^þ) _þ421 ([M(⁸¹Br³⁵Cl)þH]^þ, 100%); HRMS (ESI^þ)

C

₂₁H₂₅⁸¹Br³⁵ClN₂([M(⁸¹Br³⁵Cl)þH]^þ) requires 421.0864; found

421.0849.

4.34. (3aS,4S,9bS,aR)-N(1)-(a

-Methylbenzyl)-4-(2⁰-chlor-

oethyl)-8-(methoxycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyr-

rolo[3,2-c]quinoline 43

Following general procedure 6, Pd(OAc)₂(11.4 mg, 51

mmol),

C(5)H_A), 1.36e1.53 (5H, m, C(3)H_A, C(3a)H, C(a)Me), 1.57e1.65 (1H,

Xantphos (59 mg, 0.10 mmol), 41 (213 mg, 0.51 mmol) and Et₃N

(3.4 mL) were reacted in MeOH (0.6 mL) at 70 ^ꢁC for 16 h. The re-

action mixture was resubjected to the reaction conditions once

more, then puriﬁcation via ﬂash column chromatography (eluent

m, C(3)H_B), 1.65e1.74 (1H, m, C(5)H_B), 1.77e1.85 (1H, m, C(4)H_B),

2.42e2.51 (1H, m, C(6)H_A), 2.60 (1H, td, J 8.9, 4.7, C(6)H_B), 2.87e2.95

(1H, m, C(2)H_A), 3.06 (1H, td, J 9.5, 1.6, C(2)H_B), 3.40 (1H, td, J 10.4,

5.0, C(3b)H), 3.58 (1H, d, J 4.4, C(11b)H), 3.78 (3H, s, OMe), 4.60 (1H,

9796

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

q, J 6.6, C(

a

)H), 6.42 (1H, d, J 8.5, C(8)H), 7.09e7.15 (1H, m, Ph), 7.20

C(2⁰)); m/z (ESI^þ) 585 ([MþNa]^þ, 40%), 563 ([MþH]^þ, 100%); HRMS

þ

(2H, app t, J 7.6, Ph), 7.36 (2H, d, J 7.6, Ph), 8.36 (1H, d, J 1.9, C(11)H),

8.41 (1H, dd, J 8.5, 1.9, C(9)H); d_C(125 MHz, C₆D₆) 9.1 (C( )Me), 23.5

(C(3)), 25.8 (C(5)), 31.9 (C(4)), 39.4 (C(3a)), 41.7 (C(6)), 47.2 (C(2)),

51.1 (OMe), 52.5 (C( )), 58.7 (C(3b)), 60.4 (C(11b)), 110.2 (C(8)),

(ESI^þ) C₃₄H₄₇N₂O₅([MþH]^þ) requires 563.3479; found 563.3458.

a

4.39. (3aR,9bS,aR)-N(1)-(a

-Methyl-4⁰-methoxybenzyl)-

2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-2,4-dione

a

116.3, 119.3, 126.4 (Ar, Ph), 131.5 (C(9)), 133.9 (C(11)), 145.0, 148.2

49

(C(7a), Ar, Ph), 167.4 (CO₂Me); m/z (ESI^þ) 377 ([MþH]^þ, 100%);

þ

HRMS (ESI^þ) C₂₄H₂₉N₂O₂([MþH]^þ) requires 377.2224; found

Step 1: Pd(PPh₃)₄(112 mg, 98 mmol) was added to a stirred,

377.2210.

degassed solution of 47 (1.10 g, 1.95 mmol, >99:1 dr) and DMBA

(2.74 g, 17.6 mmol) in degassed CH₂Cl₂(30 mL) under argon and the

resultant mixture was stirred at 35 ^ꢁC for 16 h. Additional Pd(PPh₃)₄

4.37. tert-Butyl (3S,

ybenzyl)amino]-3-(2⁰-N,N-diallylaminophenyl)propanoate 46

aR)-3-[N-allyl-N-(a

-methyl-4⁰⁰-methox-

(112 mg, 98 mmol) was then added and the reaction mixture was

stirred at 35 ^ꢁC for 16 h. The reaction mixture was then concen-

trated in vacuo and the residue was dissolved in Et₂O (50 mL). The

resultant solution was washed with satd aq K₂CO₃solution

(2ꢂ20 mL) and the combined aqueous layers were extracted with

Et₂O (2ꢂ20 mL). The combined organic extracts were then washed

with 3.0 M aq HCl (3ꢂ20 mL). The combined aqueous layers were

basiﬁed with 2.0 M aq NaOH until pH>10 was achieved, then

extracted with CHCl₃/IPA (3:1, 3ꢂ20 mL). The combined organic

extracts were then dried and concentrated in vacuo to give 48 as a

yellow oil (755 mg, >99:1 dr); d_H(400 MHz, CDCl₃) [selected peaks]

2.19 (1H, dd, J 16.9, 4.6, C(1⁰)H_A), 2.43 (1H, dd, J 16.9, 4.4, C(1⁰)H_B),

3.40 (1H, app dt, J 9.7, 4.4, C(2)H), 6.51 (1H, dd, J 7.9, 1.0, Ar), 6.62

(1H, td, J 7.4, 1.0, Ar), 6.78 (2H, d, J 8.6, C(3⁰⁰⁰)H, C(5⁰⁰⁰)H), 6.90 (1H, dd,

J 7.5, 1.4, Ar), 7.03 (1H, td, J 7.6, 1.5, Ar), 7.11 (2H, d, J 8.6, C(2⁰⁰⁰)H,

C(6⁰⁰⁰)H).

Following general procedure 1, (R)-N-allyl-N-(a-methyl-p-

methoxybenzyl)amine³¹(4.86 g, 25.4 mmol, >99:1 er), BuLi (2.5 M

in hexanes, 10.2 mL, 25.4 mmol) and 12 (4.75 g, 15.9 mmol, >99:1

dr) were reacted in THF (150 mL) to give 46 in >99:1 dr. Puriﬁcation

via ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O,

83:17) gave 46 as a yellow oil (6.90 g, 89%, >99:1 dr); [

1.3, CHCl₃); n_max(ATR) 3074, 2977, 2932, 2834 (CeH), 1727 (C]O),

a

]

²⁰þ19.9 (c

D

1640, 1610 (C]C); d_H(400 MHz, CDCl₃) 1.19 (3H, d, J 6.8, C(a)Me),

1.34 (9H, s, CMe₃), 2.54 (1H, dd, J 15.4, 6.1, C(2)H_A), 2.88 (1H, dd, J

15.4, 8.2, C(2)H_B), 3.11e3.20 (1H, m, NCH_AH_BCH]CH₂), 3.29e3.37

(1H, m, NCH_AH_BCH]CH₂), 3.49e3.67 (4H, m, N(CH₂CH]CH₂)₂),

3.79 (3H, s, OMe), 3.90 (1H, q, J 6.8, C(a)H), 4.89e5.19 (7H, m, C(3)H,

NCH₂CH]CH₂, N(CH₂CH]CH₂)₂), 5.70e5.91 (3H, m, NCH₂CH]CH₂,

N(CH₂CH]CH₂)₂), 6.81 (2H, d, J 8.9, C(3⁰⁰), C(5⁰⁰)), 7.06e7.14 (2H, m,

Ar), 7.16e7.24 (1H, app t, J 7.6, Ar), 7.27 (2H, d, J 8.9, C(2⁰⁰), C(6⁰⁰)), 7.53

Step 2: Following general procedure 4, a solution of PhCO₂H

(47 mg, 0.39 mmol) and 48 (755 mg, >98:2 dr) in PhMe (10 mL) was

heated at reﬂux for 16 h. Puriﬁcation via ﬂash column chroma-

tography (eluent CH₂Cl₂/MeOH, 95:5) gave 49 as a pale yellow solid

(1H, dd, J 7.9,1.7, Ar); d_C(100 MHz, CDCl₃) 15.7 (C(

40.4 (C(2)), 49.0 (NCH₂CH]CH₂), 54.5 (C(3)), 55.2 (OMe), 55.7

(C(

)), 57.0 (N(CH₂CH]CH₂)₂), 80.0 (CMe₃), 113.1 (C(3⁰⁰), C(5⁰⁰)),

a)Me), 28.0 (CMe₃),

a

(341 mg, 52% from 47, >99:1 dr); mp 108e112 ^ꢁC; [

CHCl₃); n_max(ATR) 3216, 3063, 2933, 2922 (CeH), 1682 [C]O (g-

a

]

D

²⁰þ61.8 (c 1.1,

114.3 (NCH₂CH]CH₂), 117.6 (N(CH₂CH]CH₂)₂), 123.7, 124.1, 127.0

(Ar), 128.8 (C(2⁰⁰), C(6⁰⁰)), 128.9 (Ar), 135.0 (NCH₂CH]CH₂), 137.2,

139.9 (Ar), 140.1 (N(CH₂CH]CH₂)₂), 150.0 (Ar), 158.1 (C(4⁰⁰)),

171.7 (C(1)); m/z (ESI^þ) 513 ([MþNa]^þ, 55%), 491 ([MþH]^þ, 100%);

lactam)], 1615 [C]O (

7.3, C( )Me), 2.78 (1H, dd, J 16.4, 8.1, C(3)H_A), 3.05e3.13 (1H, m,

C(3a)H), 3.28 (1H, d, J 16.4, C(3)H_B), 3.81 (3H, s, OMe), 4.69 (1H, d, J

5.6, C(9b)H), 5.43 (1H, q, J 7.3, C( )H), 6.36 (1H, d, J 7.6, Ar),

6.83e7.04 (6H, m, C(2⁰)H, C(3⁰)H, C(5⁰)H, C(6⁰)H, Ar), 7.26e7.33 (1H,

m, Ar), 10.06 (1H, s, N(5)H); d_C(100 MHz, CDCl₃) 16.8 (C( )Me), 34.3

d-lactam)]; d_H(400 MHz, CDCl₃) 1.00 (3H, d, J

a

þ

HRMS (ESI^þ) C₃₁H₄₃N₂O₃([MþH]^þ) requires 491.3268; found

a

491.3253.

a

4.38. tert-Butyl (2R,3S,

a

R)-2-(2⁰-methoxy-2⁰-oxoethyl)-3-[N-

(C(3)), 38.5 (C(3a)), 48.5 (C(a

)), 55.3 (OMe), 57.6 (C(9b)), 113.8 (C(3⁰),

allyl-N-(

a

-methyl-4⁰⁰⁰-methoxybenzyl)amino]-3-(2⁰⁰-N,N-dia-

C(5⁰)), 116.0, 117.4, 122.6 (Ar), 128.7 (C(2⁰), C(6⁰)), 130.7, 131.0_þ, 131.6,

137.7 (Ar), 158.7 (C(4⁰)), 171.0, 173.6 (C(2), C(4)); m/z (ESI ) 695

llylaminophenyl)propanoate 47

([2MþNa]^þ, 100%), 359 ([MþNa]^þ, 20%); HRMS (ESI^þ)

þ

Following general procedure 2, ⁱPr₂NH (7.72 mL, 55.1 mmol), BuLi

(2.5 M in hexanes, 22.0 mL, 55.1 mmol), 46 (18.0 g, 36.7 mmol,

>99:1 dr) and methyl bromoacetate (10.4 mL, 110 mmol) were

reacted in THF (250 mL) to give 47 in >95:5 dr. Puriﬁcation via ﬂash

C

₂₀H₂₀N₂NaO₃([MþNa]^þ) requires 359.1366; found 359.1362.

4.40. (3aR,9bS,aR)-N(1)-(a-Methyl-4'-methoxybenzyl)-N(5)-

(tert-butoxycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo

[3,2-c]quinolin-2,4-dione 50

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 5:1) gave 47

20

as a yellow oil (8.63 g, 42%, >99:1 dr); [

a

]

þ12.3 (c 1.4, CHCl₃);

D

n_max(ATR) 3074, 2977, 2835 (CeH), 1728 (C]O), 1640, 1611 (C]C);

Method A: Boc₂O (243 mg, 1.12 mmol) was added to a solution of

49 (341 mg, 1.01 mmol, >99:1 dr), Et₃N (0.28 mL, 2.02 mmol) and

DMAP (12 mg, 0.10 mmol) in CH₂Cl₂(20 mL) and the resultant

mixture was heated at 35 ^ꢁC for 16 h. The reaction mixture was then

washed with 1.0 M aq HCl (10 mL) and the aqueous layer was

extracted with CH₂Cl₂(10 mL). The combined organic extracts were

washed sequentially with satd aq NaHCO₃(10 mL) and brine

(10 mL), then dried and concentrated in vacuo. Puriﬁcation via

recrystallisation (PhMe) gave 50 as a white solid (345 mg, 78%,

d_H(400 MHz, CDCl₃) 1.02 (3H, d, J 6.6, C(a)Me), 1.51 (9H, s, CMe₃),

2.20 (1H, dd, J 15.5, 3.2, C(1⁰)H_A), 2.50 (1H, dd, J 15.5, 11.5, C(1⁰)H_B),

3.10e3.26 (2H, m, NCH₂CH]CH₂), 3.48e3.58 (3H, m, C(2)H,

N(CH_AH_BCH]CH₂)₂), 3.60 (3H, s, CO₂Me), 3.58e3.68 (2H, m,

N(CH_AH_BCH]CH₂)₂), 3.78 (3H, s, ArOMe), 4.11 (1H, q, J 6.6, C(a)

H), 4.76e4.89 (2H, m, NCH₂CH]CH₂), 5.02 (1H, d, J 11.9, C(3)

H), 5.11e5.22 (4H, m, N(CH₂CH]CH₂)₂), 5.60e5.73 (1H, m,

NCH₂CH]CH₂), 5.81e5.95 (2H, m, N(CH₂CH]CH₂)₂), 6.66 (2H, d, J

8.8, C(3⁰⁰⁰)H, C(5⁰⁰⁰)H), 7.10e7.21 (4H, m, C(2⁰⁰⁰)H, C(6⁰⁰⁰)H, Ar),

7.24e7.30 (1H, m, Ar), 7.37 (1H, dd, J 7.8, 1.5, Ar); d_C(100 MHz,

>99:1 dr); C₂₅H₂₈N₂O₅requires C, 68.8; H, 6.5; N, 6.4%; found C,

20

68.8; H, 6.6; N, 6.5%; mp 162e167 ^ꢁC; [

a

]

þ49.0 (c 1.04, CHCl₃);

D

CDCl₃) 18.5 (C(

(NCH₂CH]CH₂), 51.6 (C(2)), 55.2 (OMe), 55.9 (C(

a

)Me), 28.1 (CMe₃), 35.9 (C(1⁰)), 46.6 (CO₂Me), 49.8

)), 57.3

n_max(ATR) 2980, 2936, 2837 (CeH), 1767 [C]O (carbamate)], 1691

(C]O [ lactam]); d_H(400 MHz, CDCl₃) 1.00 (3H, d, J 7.1, C( )Me),

a

g

a

(N(CH₂CH]CH₂)₂), 57.4 (C(3)), 80.7 (CMe₃), 112.9 (C(3⁰⁰), C(5⁰⁰)),

114.6 (NCH₂CH]CH₂), 118.4 (N(CH₂CH]CH₂)₂), 124.4, 124.5, 127.6

(Ar), 129.0 (C(2⁰⁰), C(6⁰⁰)), 134.3 (N(CH₂CH]CH₂)₂), 134.7, 137.4 (Ar),

138.9 (NCH₂CH]CH₂), 151.4 (Ar), 158.0 (C(4⁰⁰)), 172.1, 173.7 (C(1),

1.59 (9H, s, CMe₃), 2.69 (1H, dd, J 16.4, 7.5, C(3)H_A), 3.04e3.12 (1H,

app t, J 5.6, C(3a)H), 3.25 (1H, d, J 16.4, C(3)H_B), 3.81 (3H, s, OMe),

4.59 (1H, d, J 5.6, C(9b)H), 5.42 (1H, q, J 7.1, C(

a)H), 6.34 (1H, d, J 6.8,

Ar), 6.82e7.00 (6H, m, C(2⁰)H, C(3⁰)H, C(5⁰)H, C(6⁰)H, Ar), 7.33 (1H,

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9797

app td, J 7.8, 1.3, Ar); d_C(100 MHz, CDCl₃) 16.9 (C(

a

)Me), 27.6 (CMe₃),

found 517.2310. Further elution gave 52 as a colourless oil (1.03 g,

34.6 (C(3)), 39.5 (C(3a)), 48.4 (C(

a

)), 55.3 (OMe), 57.4 (C(9b)), 85.8

20%, >99:1 dr); [

a]

²⁰þ70.5 (c 1.45, CHCl₃); n_max(ATR) 2975, 2936,

D

(CMe₃), 113.8 (C(3⁰), C(5⁰)), 116.1, 118.7, 123.7 (Ar), 128.6 (C(2⁰), C(6⁰)),

130.5, 130.9, 132.0, 137.0 (Ar), 156.8 (NCO), 158.8 (C(4⁰)), 167.7, 173.2

(C(2), C(4)); m/z (ESI^þ) 895 ([2MþNa]^þ, 100%), 459 ([MþNa]^þ, 30%);

2838 (CeH), 1738 (C]O, [ester]), 1695 [C]O (g-lactam, carba-

mate)], 1609 [C]O (carbamate)]; d_H(400 MHz, C₆D₆) 1.02 (3H, d, J

7.3, C(a

)Me), 1.55 (9H, s, CMe₃), 1.89 (1H, dd, J 15.4, 7.3, C(1⁰)H_A), 1.97

þ

HRMS (ESI^þ) C₂₅H₂₈N₂NaO₅([MþNa]^þ) requires 459.1890; found

(1H, dd, J 15.4, 8.1, C(1⁰)H_B), 2.14e2.25 (1H, m, C(3a)H), 2.67 (1H, dd,

J 17.2, 9.6, C(3)H_A), 2.72e2.82 (1H, m, C(3)H_B), 3.38 (3H, s, CO₂Me),

3.52 (3H, s, ArOMe), 4.17 (1H, J 7.8, C(9b)H), 5.04 (1H, br s, C(4)H),

459.1885.

4.41. (3aR,4R,9bS,

a

R)- or (3aR,4S,9bS,

a

R)-N(1)-(

a

-Methyl-4⁰-

5.70 (1H, q, J 7.3, C(a)H), 6.50 (1H, dd, J 7.6, 1.3, C(9)H), 6.87 (1H, dd,

methoxybenzyl)-4-hydroxy-N(5)-(tert-butoxycarbonyl)-

2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-2-one 51

J 7.6, 1.0, C(8)H), 6.91 (2H, d, J 8.8, C(3⁰⁰)H, C(5⁰⁰)H), 7.05 (2H, d,

J 8.8, C(2⁰⁰)H, C(6⁰⁰)H), 7.19 (1H, app td, J 7.8,1.5, C(7)H), 7.53 (1H, br s,

C(6)H); d_C(100 MHz, C₆D₆) 17.0 (C(

a

)Me), 28.2 (CMe₃), 38.7 (C(3)),

LiAl(O^tBu)₃H (5.97 g, 23.4 mmol) was added to a stirred solution

of 50 (6.83 g, 15.6 mmol, >99:1 dr) in THF (150 mL) at 0 ^ꢁC and the

resultant mixture was stirred at 0 ^ꢁC for 1 h. H₂O (2.0 mL) was then

added, the reaction mixture was diluted with EtOAc (50 mL) and

stirred at rt for 30 min, then ﬁltered through Celite^Ò(eluent EtOAc/

39.2 (C(1⁰)), 40.3 (C(3a)), 49.4, 51.1 (OMe, C(

a

)), 53.5, 54.9, 56.6

(C(4), C(9b), OMe), 80.9 (CMe₃), 113.9 (C(3⁰⁰), C(5⁰⁰)), 124.3 (C(8)),

127.5 (C(6)), 129.0 (C(7)), 129.3 (C(2⁰⁰), C(6⁰⁰)), 130.2 (C(9)), 130.4,

131.7, 139.3, 152.9 (Ar, NCO), 159.2 (C(4⁰⁰)), 170.3, 173.1 (C(2), C(2⁰));

m/z (ESI^þ) 989 ([2MþH]^þ, 100%), 517 ([MþNa]^þ, 100%), 495

þ

Et₃N, 100:1, 300 mL), dried and concentrated in vacuo to give 51

([MþH]^þ, 35%); HRMS (ESI^þ) C₂₈H₃₄N₂NaO₆([MþNa]^þ) requires

20

as a colourless foam (6.86 g, quant, >99:1 dr);⁴⁶

[

a]

þ45.9 (c

517.2309; found 517.2307.

D

1.0, CHCl₃); n_max(ATR) 3299 (OeH), 2976, 2934, 2837 (CeH), 1695

[C]O ( -lactam, carbamate)]; d_H(500 MHz, CDCl₃) 0.93 (3H, d, J

7.3, C( )Me),1.51 (9H, s, CMe₃), 2.60 (1H, d, J 15.1, C(3)H_A), 2.82e2.94

(2H, m, C(3)H_B, C(3a)H), 3.84 (3H, s, OMe), 4.48 (1H, d, J 6.9, C(9b)H),

5.39 (1H, q, J 7.3, C( )H), 5.84 (1H, s, C(4)H), 6.47 (1H, d, J 7.3, Ar),

6.88 (2H, d, J 8.5, C(3⁰)H, C(5⁰)H), 6.96e7.02 (3H, m, C(2⁰)H, C(6⁰)H,

Ar), 7.29e7.69 (2H, m, Ar); d_C(125 MHz, CDCl₃) 16.8 (C( )Me), 28.4

)), 55.4 (OMe), 56.8

g

4.43. (3aR,4S,9bS)-4-(2⁰-Methoxy-2⁰-oxoethyl)-N(5)-(tert-bu-

toxycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]qui-

nolin-2-one 55

a

Following general procedure 5, reaction of CAN (1.55 g,

2.84 mmol) in H₂O (10 mL) and 52 (467 mg, 0.95 mmol, >99:1 dr)

in MeCN (10 mL) gave 55 in >99:1 dr. Puriﬁcation via ﬂash column

a

(CMe₃), 36.5 (C(3)), 42.4 (C(3a)), 49.3 (C(

a

(C(9b)), 82.1, 82.2 (C(4), CMe₃),113.6 (C(3⁰), C(5⁰)),124.3,125.9,128.3

(Ar), 129.0 (C(2⁰), C(6⁰)), 129.3, 130.6, 130.7, 137.3 (Ar), 152.8 (NCO),

chromatography

(eluent

CHCl₃/MeOH,

95:5)

gave

4-

methoxyacetophenone as a yellow oil (92 mg, 65%). Further elu-

158.8 (C(4⁰)), 173.4 (C(2)); m/z (ESI^þ) 461 ([MþH]^þ, 100%); HRMS

tion gave 55 as a yellow oil (195 mg, 57%, >99:1 dr); [

1.1, CHCl₃); n_max(ATR) 3227 (NeH), 2977 (CeH),1738 [C]O (ester)],

a

]

²⁰þ32.1 (c

D

þ

(ESI^þ) C₂₅H₃₀N₂NaO₅

461.2037.

([MþNa]^þ) requires 461.2047; found

1696 [C]O (g-lactam, carbamate)]; d_H(400 MHz, C₆D₆) 1.45 (9H,

s, CMe₃), 2.10 (1H, dd, J 15.2, 6.3, C(1⁰)H_A), 2.28 (1H, dd, J 15.2, 8.6,

C(1⁰)H_B), 2.41e2.57 (3H, m, C(3)H₂, C(3a)H), 3.40 (3H, s, OMe), 4.38

(1H, d, J 7.6, C(9b)H), 5.18 (1H, app br t, J 7.2, C(4)H), 6.94 (1H, app td,

J 7.6, 1.2, C(8)H), 7.10 (1H, app td, J 7.6, 1.2, C(7)H), 7.28 (1H, dd, J 7.6,

1.2, C(9)H), 7.74 (1H, br s, C(6)H), 8.73 (1H, s, N(1)H); d_C(100 MHz,

C₆D₆) 28.1 (CMe₃), 34.1 (C(3)), 36.8 (C(1⁰)), 38.8 (C(3a)), 51.3 (OMe),

52.1, 52.1 (C(4), C(9b)), 81.1 (CMe₃), 125.1 (C(8)), 126.2 (C(6)), 127.9

(C(7)), 129.4 (Ar), 129.6 _þ(C(9)), 135.5 (Ar), _þ153.7 (NCO), 170.6, 176_þ.7

4.42. (3aS,4S,9bS,aR)-N(1)-[a

-Methyl-4⁰⁰-methoxybenzyl]-4-

(2⁰-methoxy-2⁰-oxoethyl)-N(5)-(tert-butoxycarbonyl)-

2,3,3a,4,5,9b-hexahydropyrrolo[3,2-c]quinolin-2-one 52 and

(3aS,4R,9bS,aR)-N(1)-[a

-methyl-4⁰⁰-methoxybenzyl]-4-(2⁰-me-

thoxy-2⁰-oxoethyl)-N(5)-(tert-butoxycarbonyl)-2,3,3a,4,5,9b-

hexahydropyrrolo[3,2-c]quinolin-2-one 53

NaH (60% w/w in mineral oil, 636 mg, 15.9 mmol) was added to

a stirred solution of 54 (3.34 g, 15.9 mmol, >99:1 dr) in THF (50 mL)

at 0 ^ꢁC and the resultant mixture was stirred at 0 ^ꢁC for 10 min. A

solution of 51 (4.65 g, 10.6 mmol) in THF (50 mL) at 0 ^ꢁC was added

and the resultant mixture was stirred at 0 ^ꢁC for 2 h. H₂O (1 mL) was

then added, the reaction mixture was diluted with brine (50 mL),

and the aqueous layer was extracted with EtOAc (50 mL). The

combined organic extracts were dried and concentrated in vacuo to

give a 24:76 mixture of 52 and 53, respectively. Puriﬁcation via

(C(2), C(2⁰)); m/z (ESI ) 383 ([MþNa] , 100%); HRMS (ESI )

þ

C

₁₉H₂₄N₂NaO₅([MþNa]^þ) requires 383.1577; found 383.1574.

4.44. (3aR,4S,9bS)-4-(2⁰-Hydroxyethyl)-N(5)-(tert-butox-

ycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quino-

line borane complex 56

BH₃$THF (1.0 M in THF, 5.70 mL, 5.70 mmol) was added to

a solution of 55 (172 mg, 0.47 mmol, >99:1 dr) in THF (10 mL) at

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N,

50:50:1) gave 53 as a colourless oil (3.54 g, 67%, >99:1 dr); [

0

^ꢁC. The resultant mixture was heated at reﬂux for 4 h then

20

a

]

allowed to cool to rt before being cooled to 0 ^ꢁC. Satd aq K₂CO₃

(5 mL) was added and the resultant mixture was heated at 70 ^ꢁC for

1 h then allowed to cool to rt. The reaction mixture was washed

with brine (2ꢂ20 mL) and the combined aqueous washings were

extracted EtOAc (2ꢂ20 mL). The combined organic extracts were

then dried and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N, 50:50:1)

D

ꢀ38.5 (c 1.0, CHCl₃); n_max(ATR) 2979, 2935, 2838 (CeH), 1738 [C]O

(ester)], 1696 [C]O ( -lactam, carbamate)]; d_H(400 MHz, CDCl₃)

1.38 (3H, d, J 7.1, C( )Me), 1.47 (9H, s, CMe₃), 2.31 (2H, app d, J

g

a

8.6, C(3)H₂), 2.39 (1H, dd, J 15.2, 7.1, C(1⁰)H_A), 2.53e2.69 (1H, m,

C(1⁰)H_B), 3.04e3.16 (1H, m, C(3a)H), 3.65 (3H, s, CO₂Me), 3.82 (3H, s,

ArOMe), 4.36 (1H, d, J 7.8, C(9b)H), 4.60 (1H, br s, C(4)H), 5.54 (1H, q,

J 7.1, C(

a

)H), 6.88 (2H, d, J 8.6, C(3⁰⁰)H, C(5⁰⁰)H), 7.05 (1H, d, J 7.3, Ar),

gave 56 as a colourless foam (86 mg, 57%, >99:1 dr); [

a

]

²⁰þ55.2 (c

D

7.11 (1H, app td, J 7.3, 1.3, Ar), 7.17 (2H, d, J 8.6, C(2⁰⁰)H, C(6⁰⁰)H), 7.30

(1H, app td, J 7.6, 1.4, Ar), 7.37 (1H, d, J 7.8, Ar); d_C(100 MHz, CDCl₃)

1.4, CHCl₃); n_max(ATR) 3465 (NeH), 3193 (OeH), 2975, 2936, 2880

(CeH), 2361, 2270 (BeH), 1684 [C]O (carbamate)]; d_H(400 MHz,

CDCl₃) 1.30e1.42 (1H, m, C(1⁰)H_A), 1.52 (9H, s, CMe₃), 1.45e1.63

(1H, m, C(1⁰)H_B), 1.77 (1H, app tt, J 10.1, 2.8, C(3)H_A), 2.26e2.39 (1H,

m, C(3)H_B), 2.81 (1H, dd, J 17.8, 16.1, C(2)H_A), 2.86e2.95 (1H, m,

C(3a)H), 3.22e3.34 (1H, m, C(2)H_B), 3.36e3.51 (2H, m, C(2⁰)H₂),

4.04 (1H, br s, N(1)H), 4.25 (1H, dd, J 9.6, 5.8, C(9b)H), 4.63 (1H, dd,

J 11.7, 2.9, C(4)H), 7.13 (1H, app td, J 7.5, 0.9, C(8)H), 7.28 (1H, app td,

18.0 (C(

50.3 (C(

a

)Me), 28.2 (CMe₃), 32.5 (C(3)), 36.2 (C(1⁰)), 40.8 (C(3a)),

)), 51.9 (CO₂Me), 52.3 (C(4)), 55.2 (ArOMe), 56.5 (C(9b)),

81.4 (CMe₃), 113.9 (C(3⁰⁰), C(5⁰⁰)), 124.9, 126.3, 128.0, 128.1 (Ar), 128.4

(C(2⁰⁰), C(6⁰⁰)), 130.7, 132.5, 153.2 (Ar, NCO), 158.9 (C(4⁰⁰)), 171_þ.2, 174.5

(C(2), C(2⁰)); m/z (ESI^þ) 517 ([MþNa]^þ, 100%), 495 ([MþH] , 50%);

þ

HRMS (ESI^þ) C₂₈H₃₄N₂NaO₆

([MþNa]^þ) requires 517.2309;

9798

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

J 7.8, 1.2, C(7)H), 7.39 (1H, br s, C(6)H), 7.61 (1H, dd, J 7.7, 1.2, C(9)H);

d_C(100 MHz, CDCl₃) 28.2 (CMe₃), 30.4 (C(3)), 34.3 (C(1⁰)), 43.6

(C(3a)), 52.8 (C(4)), 54.0 (C(2)), 58.6 (C(2⁰)), 63.6 (C(9b)), 82.4

(CMe₃), 124.9, 125.0 (C(6), C(8)), 126.3 (Ar), 129.2 (C(7)), 130.4 (C(9)),

dried and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O/Et₃N, 80:20:1) gave

59 as a colourless oil (134 mg, 38% from 57, >99:1 dr); [

a]

D

²⁰ꢀ104 (c

1.0, CHCl₃); n_max(ATR) 2976, 2932 (CeH),1691 (C]O); d_H(400 MHz,

PhMe-d₈, 363 K) 1.33e1.55 (2H, C(1⁰)H₂), 1.47 (9H, s, CMe₃), 1.49

(9H, s, CMe₃), 1.58e1.74 (2H, m, C(3)H₂), 1.86e1.95 (1H, m, C(3a)H),

2.02 (3H, s, C(4⁰⁰)Me), 3.05e3.15 (1H, m, C(2)H_A), 3.23e3.41 (1H, m,

C(2)H_B), 3.82e3.91 (1H, m, C(2⁰)H_A), 3.92e4.03 (1H, m, C(2⁰)H_B),

4.57e4.64 (1H, m, C(4)H), 5.01 (1H, d, J 7.6, C(9b)H), 6.87 (2H, d, J 8.0,

C(3⁰⁰), C(5⁰⁰)), 6.94 (1H, app t, J 7.4, Ar), 6.97e7.06 (1H, m, Ar), 7.56

(1H, d, J 8.2, Ar), 7.69 (2H, d, J 8.0, C(2⁰⁰)H, C(6⁰⁰)H), 8.08 (1H, br s, Ar);

d_C(100 MHz, PhMe-d₈, 363 K) 21.0 (C(4⁰⁰)Me), 28.1 (C(3)), 28.3, 28.6

(2ꢂCMe₃), 32.2 (C(1⁰)), 42.7 (C(3a)), 45.6 (C(2)), 52.3 (C(4)), 54.6

(C(9b)), 67.2 (C(2⁰)), 79.2, 80.9 (2ꢂCMe₃), 124.5, 125.5, 127.4 (Ar),

128.1 (C(2⁰⁰), C(6⁰⁰)), 129.6 (C(3⁰⁰), C(5⁰⁰)), 130.1, 131.0, 135.2, 135.6,

143.9 (Ar), 154.2, 155.5 (2ꢂNCO); m/z (ESI^þ) 595 ([MþNa]^þ, 100%);

HRMS (ESI^þ) C₃₀H₄₀N₂NaO₇S^þ([MþNa]^þ) requires 595.2448;

found 595.2445.

135.8 (Ar) 155.0 (NCO); d_B

(

¹¹B, 160 MHz, CDCl₃) ꢀ14.9; m/z (ESI^þ)

687 ([2MþNa]^þ, 100%), 319 ([MꢀBH₂]^þ, 50%); HRMS (ESI^þ)

þ

C

₁₈H₂₉BN₂NaO₃([MþNa]^þ) requires 355.2163; found 355.2162.

4.45. (3aR,4S,9bS)-4-(2⁰-Hydroxyethyl)-N(5)-(tert-butox-

ycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quino-

line 57

Step 1: Following general procedure 5, reaction of CAN (2.22 g,

4.06 mmol) in H₂O (13 mL) and 52 (669 mg,1.35 mmol, >99:1 dr) in

MeCN (13 mL) gave 55 as a yellow oil (589 mg, >99:1 dr).

Step 2: BH₃$THF (1.0 M in THF, 16.0 mL, 16.0 mmol) was added to

a solution of 55 (589 mg, >99:1 dr) in THF (50 mL) at 0 ^ꢁC. The

resultant mixture was heated at reﬂux for 4 h then allowed to cool

to rt before being cooled to 0 ^ꢁC and satd aq K₂CO₃(5 mL) was

added. The resultant mixture was heated at 60 ^ꢁC for 1 h then

allowed to cool to rt and washed with satd aq K₂CO₃(2ꢂ10 mL). The

combined aqueous layers were extracted with EtOAc (20 mL) and

the combined organic extracts were dried and concentrated in

vacuo to give 56 (831 mg).

Step 3: Pd/C (10% w/w, 60 mg) was added to a solution of 56

(584 mg) in MeOH (15 mL) and the resultant mixture was stirred at

rt for 16 h. The reaction mixture was then ﬁltered through a pad of

Celite^Ò(eluent MeOH/Et₃N,100:1) and the ﬁltrate was concentrated

in vacuo. Puriﬁcation via ﬂash column chromatography (eluent

4.47. (S,S,S)-N(1),N(5)-(Bis-tert-butoxycarbonyl)-4-(2⁰-cya-

noethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

60

NaCN (12 mg, 0.23 mmol) was added to a stirred solution of 59

(85 mg, 0.15 mmol, >99:1 dr) in NMP (2 mL) and the resultant

mixture was heated at 60 ^ꢁC for 16 h. The reaction mixture was then

diluted with EtOAc (20 mL) and washed with H₂O (2ꢂ10 mL). The

combined aqueous layers were extracted with EtOAc (2ꢂ10 mL)

and the combined organic extracts were dried and concentrated in

vacuo. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢁC petrol/EtOAc/Et₃₂N₀, 66:34:1) gave 60 as a white foam

CH₂Cl₂/MeOH/Et₃N, 95:5:1) gave 57 as a colourless oil (197 mg, 57%

20

from 52, >99:1 dr); [

a

]

þ50.9 (c 1.0, CHCl₃); n_max(ATR) 3377

D

(OeH, NeH), 2974, 2934, 2878, 2730 (CeH), 1694 (C]O); d_H

(400 MHz, CDCl₃) 1.40e1.52 (1H, m, C(1⁰)H_A), 1.48 (9H, s, CMe₃)

1.54e1.63 (1H, m, C(1⁰)H_B), 1.66e1.79 (1H, m, C(3)H_A), 2.18e2.28

(1H, m, C(3)H_B), 2.68 (1H, app q, J 8.8, C(3a)H), 2.87e2.98 (1H, m,

C(2)H_A), 2.97e3.07 (1H, m, C(2)H_B), 3.40e3.50 (2H, m, C(2⁰)H₂), 4.57

(1H, d, J 9.4, C(9b)H), 4.66 (1H, dd, J 11.5, 3.4, C(4)H), 7.08 (1H, app t, J

7.4, C(8)H), 7.21 (1H, app td, J 7.4, 1.3, C(7)H), 7.38 (1H, br d, J 7.4, C(6)

H), 7.43 (1H, d, J 7.4, C(9)H); d_C(100 MHz, CDCl₃) 28.3 (CMe₃), 30.6

(C(3)), 34.6 (C(1⁰)), 43.2 (C(3a)), 44.9 (C(2)), 52.6 (C(4)), 55.9 (C(9b)),

58.7 (C(2⁰)), 82.1 (CMe₃), 125.0, 127.1, 128.5, 130.0, 136.1 (Ar) 155.0

(45 mg, 70%, >99:1 dr); [

a]

ꢀ127 (c 1.1, CHCl₃); n_max(ATR) 2976,

D

2933 (CeH), 2247 (C^N), 1691 (C]O); d_H(500 MHz, PhMe-d₈,

363 K) 1.02e1.13 (1H, m, C(1⁰)H_A), 1.23e1.38 (1H, m, C(1⁰)H_B), 1.47

(9H, s, CMe₃), 1.50 (9H, s, CMe₃), 1.61e1.90 (5H, m, C(3)H₂, C(3a)H,

C(2⁰)H₂), 3.05e3.15 (1H, m, C(2)H_A), 3.27e3.40 (1H, m, C(2)H_B), 4.42

(1H, app d, J 11.0, C(4)H), 4.99 (1H, d, J 7.3, C(9b)H), 6.95 (1H, app t, J

7.6, C(8)H), 7.05 (1H, app t, J 7.6, C(7)H), 7.59 (1H, d, J 8.2, C(6)H),

8.08 (1H, br s, C(9)H); d_C(125 MHz, PhMe-d₈, 363 K) 14.1 (C(2⁰)),

28.2, 28.3, 28.5, 28.6 (C(3), C(1⁰), 2ꢂCMe₃), 42.8 (C(3a)), 45.5 (C(2)),

54.6, 54.6 (C(4), C(9b)), 79.3, 81.2 (2ꢂCMe₃), 118.3 (C(3⁰)), 124.7

(C(8)), 125.6 (C(6)), 127.5 (C(7)), 129.9 (C(9)), 131.0, 135.2 (C(5a),

C(9a)), 154.3, 155.5 (2ꢂNCO); m/z (ESI^þ) 450 ([MþNa]^þ, 100%);

(NCO); m/z (ESI^þ) 341 ([MþNa]^þ, 95%), 319 ([MþH]^þ, 100%); HRMS

þ

(ESI^þ) C₁₈H₂₆N₂NaO₃

341.1837.

([MþNa]^þ) requires 341.1836; found

þ

HRMS (ESI^þ) C₂₄H₃₃N₃NaO₄([MþNa]^þ) requires 450.2363; found

450.2368.

4.46. (S,S,S)-N(1),N(5)-(Bis-tert-butoxycarbonyl)-4-[2⁰-(4⁰⁰-tol-

uenesulfonyloxy)ethyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo

[3,2-c]quinoline 59

4.48. (S,S,S)-N(1),N(5)-(Bis-tert-butoxycarbonyl)-4-[3⁰-(N-tert-

butoxycarbonylamino)propyl]-2,3,3a,4,5,9b-hexahydro-1H-

pyrrolo[3,2-c]quinoline 61

Step 1: Boc₂O (147 mg, 0.67 mmol), DMAP (8 mg, 61 mmol) and

Et₃N (0.26 mL, 1.83 mmol) were added sequentially to a stirred

solution of 57 (195 mg, 0.61 mmol, >99:1 dr) in CH₂Cl₂(10 mL) and

the resultant mixture was stirred at 35 ^ꢁC for 16 h. The reaction

mixture was then diluted with CH₂Cl₂(20 mL) and washed with

1.0 M aq HCl (10 mL). The aqueous layer was extracted with CHCl₃/

IPA (3:1, 2ꢂ20 mL) and the combined organic extracts were washed

sequentially with satd aq NaHCO₃(10 mL) and brine (10 mL), then

dried and concentrated in vacuo to give 58 (178 mg, >99:1 dr).

Boc₂O (45 mg, 0.21 mmol) was added to a stirred solution of

NiCl₂$6H₂O (5 mg, 21 mmol) and 60 (45 mg, 0.10 mmol, >99:1 dr) in

dry MeOH (3 mL) and the resultant mixture was stirred at 0 ^ꢁC for

5 min. NaBH₄(55 mg, 1.45 mmol) was then added, during which

time a ﬁne black precipitate formed and a gas was evolved. The

resultant mixture was allowed to warm to rt over 16 h then DETA

(11 mL, 0.10 mmol) was added and the reaction mixture was allowed

to stir for 30 min at rt before being concentrated in vacuo. The

residue was dissolved in EtOAc (10 mL) and the resultant solution

was washed with satd aq NaHCO₃(2ꢂ10 mL). The combined

aqueous layers were extracted with EtOAc (10 mL) and the com-

bined organic extracts were then dried and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC

petrol/Et₂O/Et₃N, 50:50:1) gave 61 as a colourless oil (40 mg, 71%,

Step 2: TsCl (140 mg, 0.73 mmol), DMAP (8 mg, 61 mmol) and

Et₃N (0.26 mL, 1.83 mmol) were added sequentially to a stirred

solution of 58 (178 mg, >99:1 dr) in CH₂Cl₂(10 mL) and the re-

sultant mixture was stirred at 35 ^ꢁC for 16 h. The reaction mixture

was then diluted with CH₂Cl₂(20 mL) and washed with 1.0 M aq

HCl (10 mL). The aqueous layer was extracted with CHCl₃/IPA (3:1,

2ꢂ20 mL) and the combined organic extracts were washed se-

quentially with satd aq NaHCO₃(10 mL) and brine (10 mL), then

>99:1 dr); [

a

]

²⁰ꢀ67.1 (c 1.0, CHCl₃); n_max(ATR) 3361 (NeH), 2976,

D

2932 (CeH), 1693 (C]O); d_H(500 MHz, PhMe-d₈, 363 K) 1.20e1.62

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9799

(4H, m, C(1⁰)H₂, C(2⁰)H₂), 1.63e1.84 (2H, m, C(3)H₂), 1.44 (9H,

4.51. (3aS,4R,9bS)-4-(2⁰-Hydroxyethyl)-N(5)-(tert-butox-

s, CMe₃), 1.46 (9H, s, CMe₃), 1.50 (9H, s, CMe₃), 1.99e2.09 (1H,

br m, C(3a)H), 2.99e3.22 (1H, br m, C(2)H_A), 3.26e3.45 (1H,

br m, C(2)H_B), 3.87e4.03 (1H, br m, C(3⁰)H_A), 4.12e4.22 (1H, br m,

C(3⁰)H_B), 4.37e4.77 (2H, br m, C(4)H, NH), 4.99e5.22 (1H, br m,

C(9b)H), 6.85e7.17 (2H, br m, Ar), 7.51e7.73 (1H, br m, Ar),

7.99e8.23 (1H, br m, Ar); d_C(125 MHz, PhMe-d₈, 363 K) 26.8, 31.6

(C(1⁰), C(2⁰)), 27.9, 28.1, 28.2 (3ꢂCMe₃), 45.2 (C(2)), 47.7 (C(4)), 52.1

(C(9b)), 64.4 (C(3⁰)), 78.2, 78.7, 80.2 (3ꢂCMe₃), 129.8, 130.1, 130.7

(Ar),153.8,155.4,155.7 (3ꢂNCO);⁴⁷m/z (ESI^þ) 554 ([MþNa]^þ,100%),

ycarbonyl)-8-bromo-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-

c]quinoline 74

Step 1: Following general procedure 5, reaction of CAN (6.05 g,

11.1 mmol) in H₂O (35 mL) and 72 (2.11 g, 3.68 mmol, >99:1 dr) in

MeCN (70 mL) gave 73 as a yellow oil (2.11 g, >99:1 dr); d_H

(400 MHz, CDCl₃) [selected peaks] 1.51 (9H, s, CMe₃), 2.20e2.31

(2H, m, C(2)H_A, C(2⁰)H_A), 3.05e3.15 (1H, m, C(3a)H), 4.72 (1H, d, J 7.1,

C(9b)H), 5.04e5.17 (1H, m, C(4)H), 6.86 (1H, br s, NH), 7.36e7.51

(3H, m, C(6)H, C(7)H, C(9)H).

Step 2: BH₃$THF (1.0 M in THF, 37.0 mL, 37.0 mmol) was added

dropwise to a solution of 73 (2.11 g, >99:1 dr) in THF (50 mL) at 0 ^ꢁC.

The resultant mixture was heated at reﬂux for 4 h then allowed to

cool to rt before being cooled further to 0 ^ꢁC. Satd aq K₂CO₃(30 mL)

and EtOAc (30 mL) were then carefully added and the resultant

mixture was heated at 60 ^ꢁC for 1 h. The reaction mixture was then

allowed to cool to rt and washed with satd aq K₂CO₃(2ꢂ30 mL). The

combined aqueous layers were extracted with EtOAc (50 mL) and

the combined organic extracts were dried and concentrated in

vacuo to give a mixture of 74 and 74 BH₃(831 mg).⁴⁹

þ

532 ([MþH]^þ, 40%); HRMS (ESI^þ) C₂₉H₄₅N₃NaO₆([MþNa]^þ) re-

quires 554.3206; found 554.3203.

4.49. (S,S,S)-4-(3⁰-Aminopropyl)-2,3,3a,4,5,9b-hexahydro-1H-

pyrrolo[3,2-c]quinoline$xHCl 62$xHCl

A solution of 61 (35 mg, 65 mmol, >99:1 dr) in HCl (1.25 M in

MeOH, 4 mL) was stirred at rt for 16 h then was concentrated in

vacuo. HCl (1.25 M in MeOH, 2 mL) was added and the resultant

mixture was concentrated in vacuo to give 62$xHCl as an amor-

20

phous white solid (19 mg, quant, >99:1 dr);⁴⁸

[a

]

ꢀ58.0 (c 0.2,

D

MeOH); n_max(ATR) 3376 (NeH), 2904, 2745 (CeH); d_H(500 MHz,

MeOH-d₄) 1.84e2.09 (4H, m, C(1⁰)H₂, C(2⁰)H₂), 2.15e2.25 (1H, m,

C(3)H_A), 2.51e2.62 (1H, m, C(3)H_B), 2.82e2.91 (1H, m, C(3a)H),

3.00e3.13 (2H, m, C(3⁰)H₂), 3.31e3.35 (1H, m, C(4)H), 3.40e3.57

(2H, m, C(2)H₂), 4.85 (1H, d, J 7.3, C(9b)H), 7.22e7.28 (1H, m, Ar),

7.32 (1H, d, J 7.9, Ar), 7.40e7.46 (1H, m, Ar), 7.57 (1H, d, J 6.3, Ar); d_C

(125 MHz, MeOH-d₄) 24.1 (C(1⁰)), 28.3 (C(3)), 29.6 (C(2⁰)), 39.5

(C(3a)), 40.6 (C(3⁰)), 44.7 (C(2)), 54.0 (C(4)), 58.4 (C(9b)), 120.6,

121.0, 125.6, 131.5, 131.8, 139.5 (Ar); m/z (ESI^þ) 232 ([MþH]^þ, 100%);

Step 3: The residue of 74 and 74 BH₃(831 mg) was dissolved in

MeOH (100 mL) and the resultant mixture was heated at reﬂux for

48 h, then was allowed to cool to rt and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent EtOAc/Et₃N,

100:1) gave 74 as a white foam (770 mg, 53% from 72, >99:1 dr);

[

a

]

²⁰ꢀ11.5 (c 1.0, CHCl₃); n_max(ATR) 3315 (OeH, NeH), 2975, 2931,

D

2879 (CeH),1692 (C]O); d_H(400 MHz, CDCl₃) 1.11 (1H, m, C(1⁰)H_A),

1.52 (9H, s, CMe₃), 1.64e1.82 (2H, m, C(3)H_A, C(1⁰)H_B), 2.02e2.15

(1H, m, C(3)H_B), 2.77e2.88 (1H, m, C(3a)H), 2.90e3.00 (1H, m, C(2)

H_A), 3.03e3.12 (1H, m, C(2)H_B), 3.40e3.54 (2H, m, C(2⁰)H₂), 3.97

(1H, d, J 8.1, C(9b)H), 4.68e4.82 (1H, m, C(4)H), 7.23e7.33 (2H, m,

C(6)H, C(7)H), 7.62 (1H, d, J 1.3, C(9)H); d_C(100 MHz, CDCl₃) 28.3

(CMe₃), 28.6 (C(3)), 29.9 (C(1⁰)), 41.2 (C(3a)), 45.7 (C(2)), 49.3 (C(4))

56.6 (C(9b)), 58.7 (C(2⁰)), 82.1 (CMe₃), 117.4 (Ar), 126.4, 129.9 (C(6),

C(7)), 131.4 (C(9)), 133.7, 133.8 (Ar);⁵⁰m/_þz (ESI^þ) 397 ([M(⁷⁹Br)þH]^þ,

100%); HRMS (ESI^þ) C₁₈H₂₆⁷⁹BrN₂O₃([M(⁷⁹Br)þH]^þ) requires

397.1121; found 397.1114.

HRMS (ESI^þ) C₁₄H₂₂N₃([MþH]^þ) requires 232.1808; found

þ

232.1815.

4.50. (3aS,4R,9bS,aR)-N(1)-(a

-Methyl-4⁰⁰-methoxybenzyl)-4-

(2⁰-methoxy-2⁰-oxoethyl)-N(5)-(tert-butoxycarbonyl)-8-

bromo-2,3,3a,4,5,9b-hexahydropyrrolo[3,2-c]quinolin-2-one

72

NaH (60% w/w in mineral oil, 236 mg, 5.90 mmol) was added

portionwise to a solution of 54 (1.24 g, 5.90 mmol) in THF (59 mL) at

4.52. (3aS,4R,9bS)-N(1),N(5)-(Bis-tert-butoxycarbonyl)-4-[2⁰-

(4⁰⁰-toluenesulfonyloxy)ethyl]-8-bromo-2,3,3a,4,5,9b-hexahy-

dro-1H-pyrrolo[3,2-c]quinoline 75

0

^ꢁC and the resultant mixture was stirred at 0 ^ꢁC for 5 min. A so-

lution of 71 (2.78 g, 5.36 mmol, >99:1 dr) in THF (59 mL) at 0 ^ꢁC was

then added dropwise. The resultant mixture was stirred at 0 ^ꢁC for

2 h, then H₂O (2 mL) was added. The reaction mixture was then

diluted with EtOAc (50 mL) and washed with brine (2ꢂ50 mL). The

combined aqueous layers were extracted with EtOAc (50 mL) and

the combined organic extracts were dried and concentrated in

vacuo to give a 50:50 mixture of 67 and 72. Puriﬁcation via ﬂash

Step 1: Boc₂O (447 mg, 2.05 mmol), DMAP (23 mg, 0.19 mmol)

and Et₃N (0.78 mL, 5.58 mmol) were added sequentially to a solu-

tion of 74 (739 mg, 1.86 mmol, >99:1 dr) in CH₂Cl₂(50 mL) and the

resultant mixture was stirred at 35 ^ꢁC for 16 h. The reaction mixture

was then diluted with CH₂Cl₂(20 mL) and washed with 1.0 M aq

HCl (10 mL). The aqueous layer was extracted with CH₂Cl₂(20 mL)

and the combined organic extracts were washed sequentially with

satd aq NaHCO₃(10 mL) and brine (10 mL), then dried and con-

centrated in vacuo.

column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N,

20

66:34:1) gave 72 as a colourless oil (1.09 g, 36%, >99:1 dr); [a]

D

ꢀ19.7 (c 1.0, CHCl₃); n_max(ATR) 2977, 2935, 2837 (CeH), 1738 (C]O,

[ester]), 1698 (C]O, [carbamate]); d_H(400 MHz, CDCl₃) 1.23 (3H, d,

J 7.1, C(

a

)Me), 1.38 (9H, s, CMe₃), 2.16e2.46 (3H, m, C(3)H_A, C(1⁰)H₂),

Step 2: The residue (900 mg, >99:1 dr) was dissolved in CH₂Cl₂

(20 mL) and TsCl (390 mg, 2.05 mmol), DMAP (23 mg, 0.19 mmol)

and Et₃N (0.78 mL, 5.58 mmol) were added sequentially. The re-

sultant mixture was stirred at 35 ^ꢁC for 16 h, then diluted with

CH₂Cl₂(20 mL) and washed with 1.0 M aq HCl (20 mL). The aqueous

layer was extracted with CH₂Cl₂(20 mL) and the combined organic

extracts were washed sequentially with satd aq NaHCO₃(10 mL)

and brine (10 mL), then dried and concentrated in vacuo. Puriﬁ-

cation via ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/

EtOAc/Et₃N, 66:34:1) gave 75 as a colourless foam (760 mg, 63%

2.49e2.70 (1H, br s, C(3)H_B), 2.91e3.06 (1H, m, C(3a)H), 3.56 (3H, s,

CO₂Me), 3.72 (3H, s, ArOMe), 4.26 (1H, d, J 8.1, C(9b)H), 4.39 (1H, br

s, C(4)H), 5.43 (1H, q, J 7.1, C(a

)H), 6.82 (2H, d, J 8.7, C(3⁰⁰)H, C(5⁰⁰)H),

6.93 (1H, br s, C(9)H), 7.07 (2H, d, J 8.7, C(2⁰⁰)H, C(6⁰⁰)H), 7.19 (1H, d, J

8.6, C(6)H), 7.32 (1H, dd, J 8.6, 2.2, C(7)H); d_C(100 MHz, CDCl₃) 18.0

(C(

a

)Me), 28.1 (CMe₃), 32.3 (C(1⁰)), 35.9 (C(3)), 40.1 (C(3a)), 50.3

)), 51.9 (CO₂Me), 53.0 (C(4)), 55.2 (ArOMe), 56.5 (C(9b)), 81.8

(CMe₃), 114.0 (C(3⁰⁰), C(5⁰⁰)), 117.8 (C(6)), 127.8 (Ar), 128.5 (C(2⁰⁰),

C(6⁰⁰)), 131.1 (C(7)), 131.4 (C(9)), 131.7, 132.5, 139._þ0 (Ar), 152.8, 158.9

(C(4⁰⁰), NCO), 171.0, 174.2 (C(2), C(2⁰)); m/z (ESI ) 595 ([M(⁷⁹Br)þ

from 74, >99:1 dr); [

a

]

²⁰ꢀ91.0 (c 1.0, CHCl₃); n_max(ATR) 2977, 2932

D

þ

Na]^þ, 100%); HRMS (ESI^þ) C₂₈H₃₃⁷⁹BrN₂NaO₆([M(⁷⁹Br)þNa]^þ)

(CeH), 1694, 1598 (C]O); d_H(400 MHz, C₆D₆) 0.57e0.92 (2H, br m,

C(3)H₂), 0.94e1.16 (2H, br m, C(1⁰)H₂), 1.38 (18H, s, 2ꢂCMe₃),

1.86 (3H, s, C(4⁰⁰)Me), 2.20e2.46 (1H, br s, C(3a)H), 2.83e3.34

requires 595.1414; found 595.1414. Further elution gave 67 as

a colourless oil (1.15 g, 38%, >99:1 dr).

9800

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

(2H, br m, C(2)H₂), 3.90e4.11 (2H, br m, C(2⁰)H₂), 4.37e4.55 (1H, br

m, C(9b)H), 4.62 (1H, td, J 10.7, 3.5, C(4)H), 6.76 (2H, d, J 8.2, C(3⁰⁰)H,

C(5⁰⁰)H), 6.91e7.12 (1H, br s, Ar), 7.18 (1H, br d, J 8.3, Ar), 7.65 (1H,

br s, Ar), 7.81 (2H, d, J 8.2, C(2⁰⁰)H, C(6⁰⁰)H); d_C(100 MHz, C₆D₆)

20.8 (C(4⁰⁰)Me), 27.8, 28.0 (2ꢂCMe₃), 30.4 (C(1⁰)), 45.8 (C(2)), 48.0

(C(4)), 55.7 (C(9b)), 67.3 (C(2⁰)) 79.4, 80.7 (2ꢂCMe₃), 118.5, 128.2,

129.3 (Ar), 129.6 (C(2⁰⁰), C(6⁰⁰)), 129.9, 133.9, 134.7, 135.5 (Ar),

144.1, 152.9 (2ꢂNCO);⁵¹m/z (ESI^þ) 675 ([M(⁸¹Br)þNa]^þ, 95%),

673 ([M(⁷⁹Br)þNa]^þ, 100%); HRMS (ESI^þ) C₃₀H₃₉⁷⁹BrN₂NaO₇S^þ

([M(⁷⁹Br)þNa]^þ) requires 673.1554; found 673.1562.

in dry MeOH (5 mL) and the resultant mixture was stirred at 0 ^ꢁC for

5 min. NaBH₄(237 mg, 6.26 mmol) was then added portionwise

over a period of 15 min, during which time a ﬁne black precipitate

formed and a gas was evolved. The reaction mixture was stirred at

0

^ꢁC for 1 h then DETA (48

mL, 0.45 mmol) was added and the re-

sultant mixture was allowed to stir for 30 min at 0 ^ꢁC before being

concentrated in vacuo. The residue was dissolved in EtOAc (20 mL)

and the resultant solution was washed with satd aq NaHCO₃

(2ꢂ10 mL). The combined aqueous layers were extracted with

EtOAc (10 mL) and the combined organic extracts were dried and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N, 66:34:1) gave 78 as

4.53. (3aS,4R,9bS)-N(1),N(5)-(Bis-tert-butoxycarbonyl)-4-(2⁰-

cyanoethyl)-8-bromo-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo

[3,2-c]-quinoline 76

a colourless oil (218 mg, 83%, >99:1 dr); [

a]

²⁰ꢀ151 (c 0.98, CHCl₃);

D

n_max(ATR) 3368 (NeH), 2977, 2933 (CeH), 1692, 1611 (C]O); d_H

(400 MHz, C₆D₆) 0.79e1.14 (4H, m, C(3)H₂, C(1⁰)H₂), 1.25e1.70 (2H,

br m, C(2⁰)H₂), 1.37 (9H, s, CMe₃), 1.43 (18H, s, 2ꢂCMe₃), 2.41e2.65

(1H, br s, C(3a)H), 2.83e3.43 (4H, br m, C(2)H₂, C(3⁰)H₂), 3.50 (3H, s,

OMe), 4.38 (1H, br m, NH), 4.49e4.89 (2H, br m, C(4)H, C(9b)H), 7.42

(1H, br s, C(6)H), 8.09 (1H, d, J 7.8, C(7)H), 8.35 (1H, s, C(9)H); d_C

(100 MHz, C₆D₆) 25.1 (C(3)), 26.7 (C(2⁰)), 27.9 (CMe₃), 28.0 (C(1⁰)),

28.1, 28.2 (2ꢂCMe₃), 39.9 (C(3⁰)), 46.0 (C(2)), 50.9, 51.2 (C(4), OMe),

55.8 (C(9b)), 78.1, 79.4, 80.5 (3ꢂCMe₃), 126.0 (C(6)), 126.6 (Ar),

128.1, 128.1 (C(7), C(9)), 133.3, 140.4 (Ar), 153.0, 154.7, 155.6

NaCN (72 mg, 1.47 mmol) was added to a solution of 75 (639 mg,

0.98 mmol, >99:1 dr) in NMP (4 mL) and the resultant mixture was

stirred at 60 ^ꢁC for 16 h. The reaction mixture was then diluted with

EtOAc (30 mL) and washed with H₂O (3ꢂ10 mL). The combined

aqueous layers were extracted with EtOAc (2ꢂ10 mL) and the

combined organic extracts were dried and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC

petrol/EtOAc/Et₃N, 66:34:1) gave 76 as a white foam (430 mg, 87%,

20

>99:1 dr); [

a

]

ꢀ119 (c 1.0, CHCl₃); n_max(ATR) 2977, 2932 (CeH),

(3ꢂNCO), 166.1 (CO₂Me);⁵²m/z (ESI^þ) 612 ([MþNa]^þ, 100%); HRMS

D

þ

2247 (C^N), 1693 (C]O); d_H(400 MHz, C₆D₆) 0.53e0.88 (4H, br m,

C(3)H₂, C(1⁰)H₂), 1.38 (18H, s, 2ꢂCMe₃), 1.61e1.74 (1H, m, C(2⁰)H_A),

1.74e1.89 (1H, m, C(2⁰)H_B), 2.16e2.42 (1H, br s, C(3a)H), 2.87e3.34

(2H, br m, C(2)H₂), 4.46 (1H, td, J 11.0, 3.4, C(4)H), 4.53e4.74 (1H, br

s, C(9b)H), 7.10e7.29 (2H, br m, Ar), 7.64 (1H, br s, Ar); d_C(100 MHz,

C₆D₆) 14.1 (C(2⁰)), 24.6, 26.7 (C(3), C(1⁰)), 27.8, 28.0 (2ꢂCMe₃), 43.9

(C(3a)), 45.7 (C(2)), 50.3 (C(4)), 55.7 (C(9b)), 79.5, 81.0 (2ꢂCMe₃),

118.7, 119.1 (C(3⁰), Ar), 128.4, 129.2, 130.0, 134.4, 135.4 (Ar), 153.2,

154.5 (2ꢂNCO); m/z (ESI^þ) 528 ([M(⁷⁹Br)þNa]^þ, 100%); HRMS

(ESI^þ) C₃₁H₄₇N₃NaO₈

612.3247.

([MþNa]^þ) requires 612.3255; found

4.56. (3aS,4R,9bS)-4-(3⁰-Aminoethyl)-8-(methoxycarbonyl)-

2,3,3a,4,5,9b-hexahydropyrrolo[3,2-c]-1H-quinoline hydro-

chloride 79$xHCl

A solution of 78 (158 mg, 0.27 mmol, >99:1 dr) in HCl (1.25 M in

MeOH, 4 mL) was stirred at rt for 6 h then concentrated in vacuo.

HCl (1.25 M in MeOH, 2 mL) was then added and the resultant

þ

(ESI^þ) C₂₄H₃₂⁷⁹BrN₃NaO₄([M(⁷⁹Br)þNa]^þ) requires 528.1468;

found 528.1469.

mixture was concentrated in vacuo to give 79$xHCl as an amor-

20

phous white solid (105 mg, quant, >99:1 dr); [

a

]

D

þ93.7 (c 0.35,

4.54. (3aS,4R,9bS)-N(1),N(5)-(Bis-tert-butoxycarbonyl)-4-(2⁰-

cyanoethyl)-8-(methoxycarbonyl)-2,3,3a,4,5,9b-hexahydro-

1H-pyrrolo[3,2-c]quinoline 77

MeOH) {lit.^9cfor enantiomer [

a]

D

²⁰ꢀ73.7 (c 0.34, MeOH)}; n_max(ATR)

3361, 2948 (NeH), 2361, 2342 (CeH), 1699 (C]O); d_H(400 MHz,

MeOH-d₄) 1.64e1.99 (4H, br m, C(1⁰)H₂, C(2⁰)H₂), 1.99e2.13 (1H, m,

C(3)H_A), 2.14e2.27 (1H, br m, C(3)H_B), 2.92e3.03 (1H, m, C(3a)H),

3.06 (2H, t, J 7.1, C(3⁰)H₂), 3.26e3.39 (2H, br m, C(2)H₂), 3.47e3.58

(1H, br m, C(4)H), 3.86 (3H, s, OMe), 5.07e5.16 (1H, C(9b)H),

6.90 (1H, d, J 8.6, C(6)H), 7.77 (1H, dd, J 8.6, 1.5, C(7)H), 8.01 (1H, d,

J 1.5, C(9)H); d_C(100 MHz, MeOH-d₄) 22.3 (C(3)), 23.4 (C(2⁰)), 29.4

(C(1⁰)), 39.2 (C(3⁰)), 40.9 (C(3a)), 44.1 (C(2)), 50.9, 50.9 (C(4), OMe),

57.4 (C(9b)), 115.1 (Ar), 115.2 (C(6)), 119.6 (Ar), 130.8 (C(7)), 131.4

(C(9)), 150.4 (Ar), 166.9 (CO₂Me); m/z (ESI^þ) 290 ([MþH]^þ, 100%);

Following general procedure 6, Pd(OAc)₂(16 mg, 73

mmol),

Xantphos (85 mg, 0.15 mmol), 76 (372 mg, 0.73 mmol, >99:1 dr)

and Et₃N (5 mL) were reacted in MeOH (1 mL). Resubjection of the

crude reaction mixture to the reaction conditions twice more gave

77 as the sole product. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30e40 ^ꢁC petrol/EtOAc/Et₃N, 75:25:1) gave 77 as

20

a colourless oil (263 mg, 74%, >99:1 dr); [

a]

ꢀ172 (c 1.0, CHCl₃);

D

þ

n_max(ATR) 2977, 2934 (CeH), 2247 (C^N), 1694, 1611 (C]O); d_H

(400 MHz, C₆D₆) 0.51e0.80 (4H, m, C(3)H₂, C(1⁰)H₂), 1.16 (9H, s,

CMe₃), 1.24 (9H, s, CMe₃), 1.52e1.74 (2H, m, C(2⁰)H₂), 2.23 (1H, br s,

C(3a)H), 2.71e3.16 (2H, br m, C(2)H₂), 3.29 (3H, s, OMe), 4.24e4.38

(1H, m, C(4)H), 4.36e4.56 (1H, br s, C(9b)H), 7.21 (1H, br s, C(6)H),

7.78 (1H, d, J 7.8, C(7)H), 7.99 (1H, s, C(9)H); d_C(100 MHz, C₆D₆) 14.1

(C(2⁰)), 25.0, 26.9 (C(3), C(1⁰)), 27.8, 28.0 (2ꢂCMe₃), 43.9 (C(3a)),

45.8 (C(2)), 50.6 (C(4)), 51.3 (OMe), 55.6 (C(9b)), 79.5, 81.2

(2ꢂCMe₃), 119.1 (C(3⁰)), 126.5 (C(6)), 127.0 (C(9)), 128.2 (C(7)), 133.0,

139.6 (Ar), 153.0, 154.6 (2ꢂNCO), 166.1 (CO₂Me); m/z (ESI^þ) 508

HRMS (ESI^þ) C₁₆H₂₄N₃O₂([MþH]^þ) requires 290.1863; found

290.1862.

4.57. (S,S,S)-N(1)-[N⁰⁰-Prenylcarbamimidoyl]-4-[3⁰-(N⁰⁰-pre-

nylguanidino)propyl]-8-carboxy-2,3,3a,4,5,9b-hexahydro-1H-

pyrrolo[3,2-c]quinoline$xTFA [(L)-martinellic acid] 1$xTFA

Method Adstep 1: A solution of 0.2 M aq NaOH (2 mL) was added

to a solution of 80¹⁵(39 mg, 55

mmol, >99:1 dr) in MeOH (6 mL) and

the resultant mixture was heated at reﬂux for 16 h. The reaction

mixture was then partially concentrated in vacuo to approximately

25% of its original volume and the residue was poured onto satd aq

NH₄Cl (25 mL). The aqueous layer was extracted with CH₂Cl₂

(3ꢂ10 mL) and the combined organic extracts were washed with

brine (10 mL), then dried and concentrated in vacuo.

þ

([MþNa]^þ, 100%); HRMS (ESI^þ) C₂₆H₃₅N₃NaO₆([MþNa]^þ) re-

quires 508.2418; found 508.2408.

4.55. (3aS,4R,9bS)-N(1),N(5)-(Di-tert-butoxycarbonyl)-4-[3⁰-

(N-tert-butoxycarbonylamino)propyl]-8-(methoxycarbonyl)-

2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline 78

Method Adstep 2: Anisole (60 mL, 0.55 mmol) and TFA (0.12 mL,

1.62 mmol) were added sequentially to a solution of the residue in

CH₂Cl₂(3.5 mL) and the resultant mixture was stirred at rt for 16 h.

The reaction mixture was then concentrated in vacuo and the

Boc₂O (195 mg, 0.89 mmol) was added to a solution of

NiCl₂$6H₂O (21 mg, 89 mmol) and 77 (217 mg, 0.45 mmol, >99:1 dr)

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9801

residue was puriﬁed by preparative HPLC^53e55to give 1$xTFA as

CHCl₃/MeOH, 97:3) gave 81 as a pale yellow oil, which crystallised

a pale yellow oil (13.3 mg, 34% from 80, >99:1 dr); [

a

]

²⁰ꢀ118 (c 0.3,

slowly on standing to a yellow solid (86 mg, 45%, >99:1 dr); mp

D

20

MeOH); {lit.¹for sample isolated from natural source [

a

]

ꢀ8.5 (c

130e136 ^ꢁC; [

a]

ꢀ52.0 (c 0.3, CHCl₃); n_max(ATR) 3271 (NeH),

D

0.01, MeOH); lit.³⁵

0.14, MeOH); lit.^7c

[

a

]

²⁰ꢀ122.7 (c 0.31, MeOH); lit.³⁷

[

a

]

²⁹ꢀ164.3 (c

2974, 2931 (CeH), 1715 [C]O (ester)],1639,1609 [C]O (carbamate),

C]N]; d_H(400 MHz, CDCl₃) 1.44e1.57 (2H, C(2⁰)H₂), 1.48 (9H, s,

CMe₃), 1.51 (9H, s, CMe₃), 1.57e1.66 (2H, m, C(1⁰)H₂), 1.66 (3H,

s, NCH₂CH]CMe_AMe_B), 1.69 (3H, s, NCH₂CH]CMe_AMe_B), 1.72 (3H, s,

NCH₂CH]CMe_AMe_B), 1.74 (3H, s, CH₂CH]CMe_AMe_B),1.85 (3H, app t,

J 9.7, C(3)H₂), 2.28e2.40 (1H, m, C(3a)H), 3.21e3.51 (5H, m, C(2)H₂,

C(4)H, C(3⁰)H₂), 3.71e3.91 (7H, m, OMe, 2ꢂNCH₂CH]CMe₂), 4.58

(1H br s, N(5)H), 5.19e5.27 (1H, m, NCH₂CH]CMe₂), 5.27e5.35

(1H, m, NCH₂CH]CMe₂), 5.85 (1H, d, J 6.9, C(9b)H), 6.52 (1H, d, J 8.4,

C(6)H), 7.65 (1H, dd, J 8.4, 1.8, C(7)H), 7.29e7.76 (3H, br m, 3ꢂNH),

7.87 (1H, br s, C(9)H); d_C(100 MHz, CDCl₃) 18.0, 18.0, 25.6,

25.7 (2ꢂNCH₂CH]CMe₂), 22.6 (C(3)), 28.5, 28.5 (2ꢂCMe₃), 31.0

(C(2⁰)), 39.0 (C(3a)), 39.5 (NCH₂CH]CMe₂), 40.8 (C(2)), 42.7

(NCH₂CH]CMe₂), 47.3 (C(3⁰)), 50.4 (C(4)), 51.5 (OMe), 56.0 (C(9b)),

77.9, 78.1 (2ꢂCMe₃), 113.6 (C(6)), 119.2, 119.6 (Ar), 119.8, 120.2

(2ꢂNCH₂CH]CMe₂), 129.8 (C(7)), 131.5 (C(9)), 136.9, 137.1

(2ꢂNCH₂CH]CMe₂), 147.7 (Ar), 160.1, 162.0, 162.8, 164.0 (2ꢂNCO,

2ꢂNCN), 167.3 (CO₂Me);⁵⁷m/z (ESI^þ) 710 ([MþH]^þ, 100%); HRMS

D

23

ꢀ164.8 (c 0.33, MeOH)}; n_max(ATR) 3338,

D

3207 (NeH, OeH) 2980, 2932 (CeH), 1673 (C]O), 1611, 1526, 1452;

d_H(500 MHz, DMSO-d₆) 1.35e1.52 (2H, m, C(1⁰)H₂), 1.51e1.76 (3H,

m, C(3)H_A, C(2⁰)H₂), 1.63 (3H, s, NCH₂CH]CMeMe), 1.68 (3H, s,

NCH₂CH]CMeMe), 1.69 (3H, s, NCH₂CH]CMeMe), 1.73 (3H, s,

NCH₂CH]CMeMe), 2.03e2.14 (1H, m, C(3)H_B), 2.37e2.48 (1H, m,

C(3a)H), 3.04e3.20 (2H, m, C(3⁰)H₂), 3.27 (1H, br s, C(4)H),

3.33e3.43 (2H, m, C(2)H₂), 3.66e3.77 (2H, m, NCH₂CH]CMe₂),

3.79e3.87 (1H, m, NCH_AH_BCH]CMe₂), 3.88e3.89 (1H, m,

NCH_AH_BCH]CMe₂), 5.13e5.20 (1H, m, NCH₂CH]CMe₂), 5.25 (1H,

d, J 6.4, C(9b)H), 5.27e5.34 (1H, m, NCH₂CH]CMe₂), 6.58 (1H, d, J

8.5, C(6)H), 7.07 (1H, br s, NH), 7.43 (2H, br s, 2ꢂNH), 7.51e7.62 (2H,

br m, 2ꢂNH), 7.54 (1H, dd, J 8.5, 1.5, C(7)H), 7.66 (1H, br s, C(9)H),

7.70 (1H, br s, NH), 7.78 (1H, br s, NH); d_C(125 MHz, DMSO-d₆) 17.8,

17.9, 25.2, 25.2 (2ꢂNCH₂CH]CMe₂), 25.3 (C(2⁰)), 26.3 (C(3)), 33.4

(C(1⁰)), 39.5, 39.8 (2ꢂNCH₂CH]CMe₂), 40.7 (C(3⁰)), 45.8 (C(2)), 49.2

(C(4)), 53.0 (C(9b)), 113.3 (C(6)), 115.7 (C(9a)), 116.6 (br q, J 299, CF₃),

117.1 (C(8)), 119.2, 119.6 (2ꢂNCH₂CH]CMe₂), 130.0 (C(7)), 130.5

(C(9)), 135.6, 136.0 (2ꢂNCH₂CH]CMe₂), 146.3 (C(5a)), 154.3, 155.5

(2ꢂNCN), 158.2 (q, J 33.4, CF₃CO^e₂), 167.2 (CO₂H);⁵⁶d_F(470 MHz,

DMSO-d₆) ꢀ73.7 (CF₃); m/z (ESI^þ) 496 ([MþH]^þ, 100%); HRMS

þ

(ESI^þ) C₃₈H₆₀N₇O₆([MþH]^þ) requires 710.4600; found 710.4594.

4.59. 2-[3⁰-(N⁰⁰-Prenylguanidino)propyl]-3-[2⁰⁰-(N⁰⁰-pre-

nylguanidino)ethyl]-6-carboxy-quinoline$xTFA 82$xTFA and

(3aS,4R,9bS)-N(1)-[N⁰⁰-prenylcarbamimidoyl]-4-{3⁰-[N⁰⁰-pre-

nylguanidino]propyl}-8-carboxy-2,3,3a,4,5,9b-hexahydro-1H-

pyrrolo[3,2-c]quinoline$xTFA [(L)-4-epi-martinellic acid]

83$xTFA

þ

(ESI^þ) C₂₇H₄₂N₇O₂([MþH]^þ) requires 496.3395; found 496.3377.

Method Bdstep 1: NaHCO₃(289 mg, 3.45 mmol) was added to

a stirred solution of BrCN (32 mg, 0.30 mmol) and 3$xHCl (40 mg,

0.14 mmol, >99:1 dr) in MeOH (1.5 mL) at 0 ^ꢁC and the resultant

mixture was stirred at 0 ^ꢁC for 1 h. H₂O (1 mL) was added and the

resultant mixture was stirred at rt for 15 min. The reaction mixture

was then diluted with CH₂Cl₂(10 mL) and washed with H₂O

(2ꢂ5 mL). The combined aqueous layers were extracted with

CH₂Cl₂(5 mL) and the combined organic extracts were dried and

concentrated in vacuo to give 85 as a yellow oil (15 mg, >99:1 dr);

d_H(400 MHz, CDCl₃) [selected peaks] 3.85 (3H, s, OMe) 4.25 (1H, t,

J 5.1, C(4)H), 4.45 (1H, d, J 5.1, C(9b)H), 4.76 (1H, br s, NH), 6.60

(1H, d, J 8.6, C(6)H), 7.78 (1H, dd, J 8.6, 2.0, C(7)H), 8.00 (1H, d, J 2.0,

C(9)H).^8a

Method Adstep 1: A solution of 0.2 M aq NaOH (2 mL) was added

to a solution of 81 (35 mg, 49 mmol, >99:1 dr) in MeOH (6 mL) and

the resultant mixture was heated at reﬂux for 16 h. The reaction

mixture was then allowed to cool to rt and partially concentrated in

vacuo to approximately 25% of its original volume. The residue was

poured onto satd aq NH₄Cl (25 mL), the aqueous layer was

extracted with CH₂Cl₂(3ꢂ10 mL) and the combined organic ex-

tracts were washed with brine (10 mL), then dried and concen-

trated in vacuo.

Method Bdstep 2: A solution of prenylamine (35 mg, 0.41 mmol)

and 85 (15 mg, >99:1 dr) in HFIP (1.5 mL) was heated in a sealed

vial at 110 ^ꢁC for 5 days, then concentrated in vacuo. The residue

was dissolved in MeOH (4 mL) and 0.15 M aq NaOH (1.0 mL) was

added. The resultant mixture was heated at reﬂux for 16 h, then

allowed to cool to rt. The reaction mixture was neutralised by ad-

dition of 1% TFA in MeOH, and the resultant mixture was concen-

trated in vacuo. Puriﬁcation via preparative HPLC⁴⁵gave

(ꢀ)-martinellic acid 1$xTFA as a yellow oil (6 mg, 6% from 3$xHCl,

>99:1 dr).

Method Adstep 2: Anisole (60 mL, 0.55 mmol) and TFA (0.12 mL,

1.62 mmol) were added sequentially to a solution of the residue in

CH₂Cl₂(3.5 mL) and the resultant mixture was stirred at rt for 16 h.

The reaction mixture was then concentrated in vacuo and the resi-

due was puriﬁed by preparative HPLC^53,58to give 83$xTFA as

a brown oil (0.8 mg, 2% from 81, >99:1 dr); [

a

]

²⁰ꢀ7.1 (c 0.31, MeOH);

D

n_max(ATR) 3304, 3177 (OeH, NeH), 2879, 2854 (CeH), 1695 (C]O);

d_H(500 MHz, DMSO-d₆) 1.40e1.78 (5H, m, C(3)H_A, C(1⁰)H₂, C(2⁰)H₂),

1.66 (3H, s, NCH₂CH]CMeMe), 1.70 (3H, s, NCH₂CH]CMeMe), 1.72

(3H, s, NCH₂CH]CMeMe), 1.74 (3H, s, NCH₂CH]CMeMe), 1.97e2.05

(1H, m, C(3)H_B), 2.54 (3H, obsc m, C(2)H₂, C(4)H), 3.14e3.24 (2H, m,

C(3⁰)H₂), 3.75 (2H, app t, J 5.5, NCH₂CH]CMe₂), 3.80e4.05 (2H, m,

NCH₂CH]CMe₂), 5.20 (1H, t, J 6.6, NCH₂CH]CMe₂), 5.31 (1H, d, J

6.3, C(9b)H), 5.25e5.40 (1H, m, NCH₂CH]CMe₂), 6.57 (1H, br s, N(5)

H), 6.64 (1H, d, J 8.5, C(6)H), 7.56 (1H, dd, J 8.5, 1.6, C(7)H), 7.67 (1H,

br s, C(9)H), 12.20 (1H, br s, CO₂H); d_C(125 MHz, DMSO-d₆) 17.8,17.9,

25.3, 25.4 (2ꢂNCH₂CH]CMe₂), 21.3 (C(3)), 24.6 (C(2⁰)), 30.1 (C(1⁰)),

40.9 (C(3⁰)), 49.1 (C(4)), 113.4 (C(6)), 116.9, 117.8 (Ar), 119.2, 119.6

(2ꢂNCH₂CH]CMe₂), 128.4 (Ar), 129.9 (C(7)), 130.5 (C(9)), 147.9 (Ar),

154.2, 155.5 (2ꢂNCN), 157.8 (q, J 32.0, CF₃CO^e₂), 147.9 (CO₂H);⁵⁹m/z

(ESI^þ) 496 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₄₂N₇O^þ₂([MþH]^þ)

requires 496.3395; found 496.3390. Further elution gave 82$xTFA as

a pale yellow oil (6 mg, 16% from 81, >99:1 dr); UV l_max(MeOH)

4.58. (3aS,4R,9bS)-N(1)-[N⁰-(tert-Butoxycarbonyl)-N⁰⁰-pre-

nylcarbamimidoyl]-4-{3⁰-[N⁰-(tert-butoxycarbonyl)-N⁰⁰-pre-

nylguanidino]propyl}-8-(methoxycarbonyl)-2,3,3a,4,5,9b-hex-

ahydro-1H-pyrrolo[3,2-c]quinoline 81

Et₃N (0.45 mL, 3.22 mmol) was added to a solution of 79$xHCl

(88 mg, 0.27 mmol, >99:1 dr) and 84 (346 mg, 1.34 mmol) in MeCN/

MeOH (2:1, 9 mL) at 40 ^ꢁC. A solution of AgNO₃(252 mg, 1.48 mmol)

in MeCN (2 mL) was added over a period of 30 min. The resultant

mixture was stirred at 40 ^ꢁC (in the dark) for 16 h. The reaction

mixture was then ﬁltered through a short pad of Celite^Ò(eluent

CHCl₃/Et₃N, 100:1) and concentrated in vacuo. The residue was dis-

solved in CHCl₃(30 mL) and the resultant solution was washed with

H₂O (30 mL). The aqueous layer was extracted with CHCl₃(10 mL)

and the combined organic extracts were dried and concentrated

in vacuo. Puriﬁcation via ﬂash column chromatography (eluent

243 nm ( 27,453); n_max(ATR) 3327, 3205 (NeH), 2979, 2922 (CeH),

3

1670, 1636 (C]O, C]N); d_H(500 MHz, DMSO-d₆) 1.60 (3H, s,

NCH₂CH]CMeMe), 1.65 (3H, s, NCH₂CH]CMeMe), 1.67 (3H,

s, NCH₂CH]CMeMe), 1.71 (3H, s, NCH₂CH]CMeMe), 2.04e2.13

9802

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

(2H, m, C(2⁰)H₂), 3.05 (4H, app q, J 7.4, C(1⁰)H₂, C(1⁰⁰)H₂), 3.31 (2H, app

q, J 6.6, C(3⁰)H₂), 3.57 (2H, app q, J 6.5, C(2⁰⁰)H₂), 3.69 (2H, app t, J 5.7,

NCH₂CH]CMe₂), 3.75 (2H, app t, J 5.7, NCH₂CH]CMe₂), 5.07e5.13

(1H, m, NCH₂CH]CMe₂), 5.16e5.23 (1H, m, NCH₂CH]CMe₂),

7.41e7.72 (8H, m, 8ꢂNH), 8.02 (1H, d, J 8.8, C(8)H), 8.17 (1H, dd, J 8.8,

1.9, C(7)H), 8.30 (1H, s, C(4)H), 8.56 (1H, d, J 1.9, C(5)H); d_C(125 MHz,

DMSO-d₆) 17.7, 17.8, 25.2, 25.3 (2ꢂNCH₂CH]CMe₂), 26.6 (C(2⁰)), 30.6

(C(1⁰⁰)), 31.3 (C(1⁰)), 40.5 (C(2⁰⁰)), 40.6 (C(3⁰)), 119.1, 119.2

(2ꢂNCH₂CH]CMe₂), 125.9 (C(8a)), 128.2 (C(8)), 128.4 (C(7)), 130.1

(C(5)), 131.3 (C(3)), 136.0, 136.0 (2ꢂNCH₂CH]CMe₂), 137.1 (C(4)),

147.3 (C(4a)), 155.5, 155.6 (2ꢂNCN), 158.3 (q, J 34.3, CF₃CO^e₂), 162.7

(C(2)), 167.0 (C(6)), 173.1 (CO₂H);⁶⁰d_F(470 MHz, DMSO-d₆) ꢀ74.2

57 , 5615; (c) Fadel, F.; Titouani, S. L.; Sou ﬁ aoui, M.; Ajamaya, H.; Mazzah, A.

Tetrahedron Lett. 2004 , 45 , 5905; (d) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis

2005 , 1431; (e) Stevenson, P. J.; Nieuwenhuyzen, M.; Osborne, D. ARKIVOC 200 7 ,

xi , 129; (f) Rahaman, H.; Shirai, A.; Miyata, O.; Naito, T. Tetrahedron Lett. 2008 ,

49 , 5789; (g) Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J.

E. Org. Lett. 2009 , 1 1 , 1959.

7. For asymmetric syntheses, see: (a) Ma, D.; Xia, C. F.; Jiang, J. Q.; Zhang, J. Org.

Lett. 2001 , 3 , 2189; (b) Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem. Commun. 200 7 ,

504; (c) Shirai, A.; Miyata, O.; Tohnai, N.; Miyata, M.; Procter, D. J.; Sucunza, D.;

Naito, T. J. Org. Chem. 2008 , 73 , 4464; (d) Naito, T. Pure Appl. Chem. 2008 , 80 , 717.

8. For racemic syntheses, see: (a) Snider, B. B.; Ahn, Y.; O ’Hare, S. M. Org. Lett. 2001 ,

3 , 4217; (b) Powell, D. A.; Batey, R. A. Org. Lett. 2002 , 4 , 2913; (c) Xia, C. F.; Heng,

L. S.; Ma, D. Tetrahedron Lett. 2002 , 43 , 9405.

9. For asymmetric syntheses, see: (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J.

Org. Chem. 2003 , 68 , 442; (b) Badarinarayana, V.; Lovely, C. J. Tetrahedron Lett.

200 7 , 48 , 2607; (c) Yoshitomi, Y.; Arai, H.; Makino, K.; Hamada, Y. Tetrahedron

2008 , 64 , 1 1568.

10. For racemic syntheses, see: (a) He, Y.; Moningka, R.; Lovely, C. J. Tetrahedron

Lett. 2005 , 46 , 1251; (b) He, Y.; Mahmud, H.; Moningka, R.; Lovely, C. J.; Dias, H.

V. R. Tetrahedron 2006 , 62 , 8755; (c) Miyata, O.; Shirai, A.; Yoshino, S.; Naka-

bayashi, T.; Takeda, Y.; Kiguchi, T.; Fukumoto, D.; Ueda, M.; Naito, T. Tetrahedron

200 7 , 63 , 10092; (d) Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.; Miyata, O. J. Org.

Chem. 2010 , 75 , 914; (e) Rong, Z.; Li, Q.; Lin, W.; Jia, Y. Tetrahedron Lett. 2013 , 54 ,

4432.

(CF₃CO^e₂); m/z (ESI^þ) 494 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₇H₄₀N₇O₂([MþH]^þ) requires 494.3238; found 494.3230.

Method Bdstep 1: NaHCO₃(71 mg, 0.84 mmol) was added to

a stirred solution of BrCN (8 mg, 74

mmol) and 79$xHCl (20 mg,

34

m

mol, 99:1 dr) in MeOH (1.5 mL) at 0 ^ꢁC and the resultant

mixture was stirred at 0 ^ꢁC for 1 h H₂O (1 mL) was added and the

reaction mixture was stirred at rt for 15 min, then diluted with

CH₂Cl₂(10 mL) and washed with H₂O (2ꢂ5 mL). The combined

aqueous layers were extracted with CH₂Cl₂(5 mL) and the com-

bined organic extracts were dried and concentrated in vacuo to give

87 as a yellow oil (9 mg, >99:1 dr); d_H(400 MHz, CDCl₃) [selected

peaks] 3.87 (3H, s, OMe), 4.82 (1H, d, J 7.8, C(9b)H), 6.55 (1H, d, J 8.6,

C(6)H), 7.76 (1H, dd, J 8.6, 1.9, C(7)H), 8.13 (1H, d, J 1.9, C(9)H).

11. For a review, see: Lovely, C. J.; Bararinarayana, V. Curr. Org. Chem. 2008 , 12 , 1431.

12. For reviews, see: (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asym-

metry 2005 , 16 , 2833; (b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson,

J. E. Tetrahedron: Asymmetry 2012 , 23 , 1 111.

13. For selected examples from this laboratory, see: (a) Davies, S. G.; Iwamoto, K.;

Smethurst, C. A. P.; Smith, A. D.; Rodríguez-Solla, H. Synlett 2002 , 1 146; (b)

Davies, S. G.; Kelly, R. J.; Price Mortimer, A. J. Chem. Commun. 2003 , 2132; (c)

Davies, S. G.; Burke, A. J.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A.

D.; Rodríguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004 , 2 , 1387; (d) Da-

vies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer, A.

J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004 , 2 , 2630; (e) Abraham, E.;

Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.;

Method Bdstep 2: A solution of prenylamine (5.7 mg, 67 mmol)

and 87 (9 mg, >99:1 dr) in HFIP (1.5 mL) was stirred in a sealed vial

at 110 ^ꢁC for 5 days, then concentrated in vacuo. The residue was

dissolved in MeOH (4 mL) and 0.15 M aq NaOH (1.0 mL) was added.

The resultant mixture was heated at reﬂux for 16 h, then allowed to

cool to rt. The reaction mixture was neutralised by addition of 1%

TFA in MeOH, and the resultant mixture was concentrated in vacuo.

ꢀ

Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron:

Asymmetry 200 7 , 18 , 2510; (f) Abraham, E.; Davies, S. G.; Millican, N. L.; Nich-

olson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008 , 6 , 1655; (g)

Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.;

ꢀ

Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez,

E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008 , 6 , 1665;

(h) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009 ,

65 , 10192; (i) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.

Org. Lett. 2011 , 13 , 2544; (j) Davies, S. G.; Ichihara, O.; Roberts, P. M.; Thomson, J.

E. Tetrahedron 2011 , 67 , 216; (k) Davies, S. G.; Fletcher, A. M.; Hughes, D. G.; Lee,

J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.;

Williams, O. M. H. Tetrahedron 2011 , 67 , 9975; (l) Davies, S. G.; Lee, J. A.; Roberts,

P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett. 2011 , 52 , 6477; (m) Bagal, S. K.;

Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E.

Tetrahedron Lett. 2011 , 52 , 2216; (n) Davies, S. G.; Lee, J. A.; Roberts, P. M.;

Stonehouse, J. P.; Thomson, J. E. Tetrahedron Lett. 2012 , 53 , 1 119; (o) Davies, S. G.;

Fletcher, A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E. Tetrahedron Lett. 2012 , 53 ,

3052; (p) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;

Taylor, R. J.; Thomson, A. D.; Thomson, J. E. Org. Lett. 2012 , 14 , 1672; (q) Davies,

S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron 2012 , 68 ,

4302; (r) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org.

Lett. 2012 , 14 , 4278; (s) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Stonehouse, J. P.;

Thomson, J. E. J. Org. Chem. 2012 , 77 , 7028; (t) Davies, S. G.; Lee, J. A.; Roberts, P.

M.; Stonehouse, J. P.; Thomson, J. E. J. Org. Chem. 2012 , 77 , 9724; (u) Brock, E. A.;

Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Biomol. Chem. 2013 , 1 1 ,

3187; (v) Davies, S. G.; Figuccia, A. L. A.; Fletcher, A. M.; Roberts, P. M.; Thomson,

J. E. Org. Lett. 2013 , 15 , 2042; (w) Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Lee,

J. A.; Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2013 , 78 , 2500; (x) Davies, S. G.;

Puriﬁcation via preparative HPLC⁵⁸gave 4-epi-martinellic acid

20

83$xTFA as a yellow oil (0.7 mg, 3% from 79$xHCl, >99:1 dr); [

a]

D

ꢀ12.6 (c 0.31, MeOH).

Supplementary data

Supplementary data related to this article can be found at http://

dx.doi.org/10.1016/j.tet.2013.09.013.

References and notes

1. Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.; Salvatore, M. J.;

Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc.

1995 , 1 17 , 6682.

2. Gentry, A.; Cook, K. J. Ethnopharmacol. 1984 , 1 1 , 337.

3. Boralkar, A.; Dindore, P.; Fule, R.; Bangde, B.; Albel, M.; Saoji, A. Indian J. Oph-

thalmol. 1989 , 37 , 94.

4. A manuscript by the botanist Alexander Anderson documenting the medicinal

properties of Martinella was sent to the eminent horticulturalist William For-

syth in 1791. Unfortunately, Forsyth died before the manuscript could be

published, delaying the widespread knowledge of the medicinal properties of

these plants for almost 200 years.

ꢀ

Fletcher, A. M.; Lebee, C.; Roberts, P. M.; Thomson, J. E.; Yin, J. Tetrahedron 2013 ,

69 , 1369.

14. Hart, B. P.; Rapoport, H. J. Org. Chem. 1999 , 64 , 2050.

15. Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J.

E. Org. Lett. 2013 , 15 , 2050.

16. Bis-N-allylation of an authentic sample of 11 was achieved by treatment with

allyl iodide and K₃PO₄in acetone at reﬂux for 48 h, which gave 12 in 73% yield

and >99:1 dr.

5. (a) Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999 , 40 , 2079; (b) Snider, B. B.;

Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999 , 40 , 3339; (c) Nyerges, M.; Fejes, I.;

}

Toke, L. Tetrahedron Lett. 2000 , 41 , 7951; (d) Hadden, M.; Nieuwenhuyzen, M.;

Osborne, D.; Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2001 , 42 , 6417; (e)

Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001 , 57 , 4095; (f) He, Y.;

Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2002 ,

17. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994 , 5 , 1999.

ꢀ

}

18. Conjugate addition of lithium (R)-N-benzyl-N-(

unsaturated ester 12 and in situ alkylation of the resultant lithium (Z)-

enolate was also investigated, although this approach was not as efﬁcacious as

the alkylation of -amino ester 13.

a

-methylbenzyl)amide to

a,b-

43 , 1 171; (g) Viranyi, A.; Nyerges, M.; Blasko, G.; Toke, L. Synthesis 2003 , 2655;

ꢀ

}

b-amino

(h) Nyerges, M.; Viranyi, A.; Toke, L. Heterocycl. Commun. 2003 , 9 , 239; (i) Yadav,

J. S.; Subba Reddy, B. V.; Sunitha, V.; Srinivasa Reddy, K.; Ramakrishna, K. V. S.

Tetrahedron Lett. 2004 , 45 , 7947; (j) Hadden, M.; Nieuwenhuyzen, M.; Osborne,

D.; Stevenson, P. J.; Thompson, N.; Walker, A. D. Tetrahedron 2006 , 62 , 3977; (k)

Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006 , 8 , 3999; (l) Miyata, O.; Shirai, A.;

Yoshino, S.; Takeda, Y.; Sugiura, M.; Naito, T. Synlett 2006 , 893; (m) Zhang, Z.;

Zhang, Q.; Yan, Z.; Liu, Q. J. Org. Chem. 200 7 , 72 , 9808; (n) Neuschl, M.; Bogdal,

D.; Potacek, M. Molecules 200 7 , 12 , 49; (o) Comesse, S.; Sanselme, M.; Daïch, A. J.

Org. Chem. 2008 , 73 , 5566.

b

19. Crystallographic data (excluding structure factors) for the structures of 19, 20,

24, 26, 33, 36 and 50 have been deposited with the Cambridge Crystallographic

Data Centre as supplementary publication numbers CCDC 951639e951645,

respectively.

20. (a) Davies, S. G.; Díez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price,

P. D.; Smith, A. D. Org. Biomol. Chem. 2005 , 3 , 1284; (b) Davies, S. G.; Foster, E.

M.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2013 , 69 , 8680.

21. Cho, C. S.; Kim, J. U. Tetrahedron Lett. 200 7 , 48 , 3775.

6. (a) Snider, B. B.; O ’Hare, S. M. Tetrahedron Lett. 2001 , 42 , 2455; (b) Hadden, M.;

Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.; Thompson, N. Tetrahedron 2001 ,

S.G. Davies et al. / Tetrahedron 69 (2013) 9779e9803

9803

22. Flack, H. D.; Bernardinelli, G. Acta. Crystallogr., Sect. A 1999 , 55 , 908.

23. (R)-N-Allyl-N-( -methylbenzyl)amine was prepared in 91% yield by treatment

of (R)-

-methylbenzylamine (>99:1 er) with BuLi at 0 ^ꢁC in THF, followed by

addition of allyl bromide. Subsequent deprotonation with BuLi in THF gener-

ated a solution of the lithium amide reagent.

24. In both 33 and 50, the N(5)-Boc group adopts a conformation in which it is

perpendicular to the ring system; in this conformation it is not able to become

conjugated with the N(5)-lone pair.

43. Similar fragmentation pathways have been observed in related hexahy-

dropyrroloquinoline systems; see: Ref. 6b.

a

44. The procedure reported by Snider, et al. reports heating 85 and prenylamine in

HFIP at 120 ^ꢁC in a sealed tube.

45. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.

Organometallics 1996 , 15 , 1518.

46. Compounds 34 and 51 were isolated as single diastereoisomers (>99:1 dr) of

unknown conﬁguration at C(4).

25. Ding, R.; He, Y.; Xu, J.; Chen, Y.; Feng, M.; Qi, C. Molecules 2011 , 16 , 5665.

26. The complicated nature of the ¹H NMR spectrum of the crude reaction mixture

prevented the determination of an accurate product distribution.

47. Peaks corresponding to C(3) and C(3a) were not observed in the ¹³C NMR

spectrum of 61; however, resonances corresponding to C(3) and C(3a) were

observed at 27.8 and 42.3 ppm, respectively, in the HSQC spectrum of 61.

48. For ¹H and ¹³C NMR data for (ꢃ)-62, see: Ref. 5b.

ꢀ

27. For example, see: Seo, J.; Martasek, P.; Roman, L. J.; Silverman, R. B. Bioorg. Med.

Chem. Lett. 200 7 , 15 , 1928.

49. The presence of 74 could be distinguished by TLC analysis and by the obser-

vation of characteristic BeH stretches in the IR spectrum of the crude reaction

mixture: n_max(ATR) 2368, 2273 (BeH).

28. Tetracyclic products arising from intramolecular displacement of a C(3⁰) sub-

stituent by the aniline have previously been observed in related systems; see:

Refs. 7a,5l

50. A peak corresponding to NCO was not observed in the ¹³C NMR spectrum of 74.

51. Peaks corresponding to C(3) and C(3a) were not observed in the ¹³C NMR

spectrum of 75; however, a resonance corresponding to C(3a) was observed at

43.4 ppm in the HSQC spectrum of 75.

29. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Shyam Prasad, R.; Smith,

A. D. J. Chem. Soc., Perkin Trans. 1 2000 , 3765.

30. Hungerhoff, B.; Samanta, S. S.; Roels, J.; Metz, P. Synlett 2000 , 7 7.

31. (R)-N-Allyl-N-(

a

-methyl-p-methoxybenzyl)amine was prepared in 90% yield by

a

52. A peak corresponding to C(3a) was not observed in the ¹³C NMR spectrum of

78; however, a resonance corresponding to C(3a) was observed at 43.8 ppm in

the HSQC spectrum of 78.

treatment of (R)-

-methylbenzylamine (>99:1 er) with BuLi at 0 ^ꢁC in THF,

followed by addition of allyl bromide. Subsequent deprotonation with BuLi in

THF generated a solution of the lithium amide reagent.

53. The authors would like to thank Veronique Gouverneur and Stefan Verhoog for

their assistance with the puriﬁcation of 1$xTFA, 82$xTFA and 83$xTFA

54. Puriﬁcation of 1$xTFA was conducted using a SunFireÔ preparative column

32. Repetition of the reaction for both 52 and 53 with excess NaH (3.0 equiv) re-

sulted in substantial decomposition to mixtures of unidentiﬁed products.

ꢀ

33. Couturier, M.;A ndresen, B .M .;T ucker, J .L .; Dube, P.;N egri, J. T. Org .L ett. 2001 , 3 , 465.

(C₁₈, 10

m

m, 10ꢂ250 mm) eluting with H₂O/MeOH/CF₃CO₂H (80:20:0.1/20:80:

34. For the use of this reaction as a hydrogen source, see: Couturier, M.; Andresen, B.

0.1, gradient elution) for 40 min with a ﬂow rate of 2.50 mL/min. The detector

was set to 330 nm and the major component had a retention time of 19.1 min.

55. Although several literature reports begin the solvent gradient in 80:20 H₂O/MeOH,

this is not a suitable solvent system to load the crude material. After optimisation,

ꢀ

M.; Tucker, J. L.; Dube, P.; Brenek, S. J.; Negri, J. T. Tetrahedron Lett. 2001 , 42 , 2763.

35. The corresponding chloride was not observed in this case.

36. Davies, S. G.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 1 1976 , 2279.

37. Caddick, S.; Judd, D. B.; Lewis, A. K.; Reich, M. T.; Williams, M. R. V. Tetrahedron

2003 , 59 , 5417.

38. The synthesis of a racemic sample of 62 has been reported previously, see: Ref. 5b.

39. 2-Iodo-4-bromoaniline 63 is commercially available, although it can be pro-

duced in quantitative yield at far less cost from 2-iodoaniline by treatment with

KBr, NaBO₃$4H₂O and ammonium molybdate in AcOH; see Roche, D.; Prasad,

K.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2000 , 41 , 2083.

it was found best to dissolve the crude sample in w500

puriﬁcation with several w125 L injections.

mL of MeOH and perform

m

56. The remaining peak in the ¹³C NMR spectrum, corresponding to C(3a) within

1$xTFA, was obscured by the resonances corresponding to PhMe-d₈.

57. A peak corresponding to C(1⁰) was not observed in the ¹³C NMR spectrum of 81;

however, a resonance corresponding to C(1⁰) was observed at 25.8 ppm in the

HSQC spectrum of 81.

40. The relative and absolute conﬁgurations within both 66 and 67 were un-

ambiguously established by single crystal X-ray diffraction analyses. Crystal-

lographic data (excluding structure factors) for the structures of 66 and the

N(5)-deprotected derivative of 67 have been deposited with the Cambridge

Crystallographic Data Centre as supplementary publication numbers CCDC

926034 and 926035, respectively; see Ref. 15.

41. Phosphorane 38 could not be used in this case as it was not possible to separate

the product 67 from the excess phosphorane 38 and the Ph₃PO residues.

42. For examples of the use of 2-pyridyl phosphoranes, see: (a) Ca ﬁ ci, L.; Pirali, T.;

Condorelli, F.; Del Grosso, E.; Massarotti, A.; Sorba, G.; Canonico, P. L.; Tron, G.

C.; Genazzani, A. A. J. Comb. Chem. 2008 , 10 , 732; (b) O ’Brien, M.; Denton, R.;

Ley, S. V. Synthesis 2011 , 1 157.

58. Puriﬁcation of 82$xTFA and 83$xTFA was conducted using a SunFireÔ pre-

parative column (C₁₈, 10

m

m, 10ꢂ250 mm) eluting with H₂O/MeOH/CF₃CO₂H

(80:20:0.1/20:80:0.1, gradient elution) for 40 min with a ﬂow rate of 2.50 mL/

min. The detector was set to 330 nm, and 82$xTFA and 83$xTFA had retention

times of 21.9 and 20.4 min, respectively.

59. Peaks corresponding to C(2), C(3a) C(9b), CF₃and both NCH₂CH]CMe₂groups

were not observed in the ¹³C NMR spectrum of 83$xTFA; however, a resonance

corresponding to C(9b) was observed at 56.1 ppm in the HSQC spectrum of

83$xTFA.

60. Peaks corresponding to CF₃and both NCH₂CH]CMe₂groups were not ob-

served in the ¹³C NMR spectrum of 82$xTFA.

Article Doi

A diastereodivergent strategy for the asymmetric syntheses of (-)-martinellic acid and (-)-4-epi-martinellic acid

DOI: 10.1016/j.tet.2013.09.013

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